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1.  The Effect of Universal Influenza Immunization on Mortality and Health Care Use 
PLoS Medicine  2008;5(10):e211.
Background
In 2000, Ontario, Canada, initiated a universal influenza immunization program (UIIP) to provide free influenza vaccines for the entire population aged 6 mo or older. Influenza immunization increased more rapidly in younger age groups in Ontario compared to other Canadian provinces, which all maintained targeted immunization programs. We evaluated the effect of Ontario's UIIP on influenza-associated mortality, hospitalizations, emergency department (ED) use, and visits to doctors' offices.
Methods and Findings
Mortality and hospitalization data from 1997 to 2004 for all ten Canadian provinces were obtained from national datasets. Physician billing claims for visits to EDs and doctors' offices were obtained from provincial administrative datasets for four provinces with comprehensive data. Since outcomes coded as influenza are known to underestimate the true burden of influenza, we studied more broadly defined conditions. Hospitalizations, ED use, doctors' office visits for pneumonia and influenza, and all-cause mortality from 1997 to 2004 were modelled using Poisson regression, controlling for age, sex, province, influenza surveillance data, and temporal trends, and used to estimate the expected baseline outcome rates in the absence of influenza activity. The primary outcome was then defined as influenza-associated events, or the difference between the observed events and the expected baseline events. Changes in influenza-associated outcome rates before and after UIIP introduction in Ontario were compared to the corresponding changes in other provinces. After UIIP introduction, influenza-associated mortality decreased more in Ontario (relative rate [RR] = 0.26) than in other provinces (RR = 0.43) (ratio of RRs = 0.61, p = 0.002). Similar differences between Ontario and other provinces were observed for influenza-associated hospitalizations (RR = 0.25 versus 0.44, ratio of RRs = 0.58, p < 0.001), ED use (RR = 0.31 versus 0.69, ratio of RRs = 0.45, p < 0.001), and doctors' office visits (RR = 0.21 versus 0.52, ratio of RRs = 0.41, p < 0.001). Sensitivity analyses were carried out to assess consistency, specificity, and the presence of a dose-response relationship. Limitations of this study include the ecological study design, the nonspecific outcomes, difficulty in modeling baseline events, data quality and availability, and the inability to control for potentially important confounders.
Conclusions
Compared to targeted programs in other provinces, introduction of universal vaccination in Ontario in 2000 was associated with relative reductions in influenza-associated mortality and health care use. The results of this large-scale natural experiment suggest that universal vaccination may be an effective public health measure for reducing the annual burden of influenza.
Comparing influenza-related mortality and health care use between Ontario and other Canadian provinces, Jeffrey Kwong and colleagues find evidence that Ontario's universal vaccination program has reduced the burden of influenza.
Editors' Summary
Background.
Seasonal outbreaks (epidemics) of influenza—a viral disease of the nose, throat, and airways—affect millions of people and kill about 500,000 individuals every year. These epidemics occur because of “antigenic drift”: small but frequent changes in the viral proteins to which the human immune system responds mean that an immune response produced one year by exposure to an influenza virus provides only partial protection against influenza the next year. Immunization can boost this natural immunity and reduce a person's chances of catching influenza. That is, an injection of killed influenza viruses can be used to prime the immune system so that it responds quickly and efficiently when exposed to live virus. However, because of antigenic drift, for influenza immunization to be effective, it has to be repeated annually with a vaccine that contains the major circulating strains of the influenza virus.
Why Was This Study Done?
Public-health organizations recommend targeted vaccination programs, so that elderly people, infants, and chronically ill individuals—the people most likely to die from pneumonia and other complications of influenza—receive annual influenza vaccination. Some experts argue, however, that universal vaccination might provide populations with better protection from influenza, both directly by increasing the number of vaccinated people and indirectly through “herd immunity,” which occurs when a high proportion of the population is immune to an infectious disease, so that even unvaccinated people are unlikely to become infected (because infected people rarely come into contact with susceptible people). In this study, the researchers compare the effects of the world's first free universal influenza immunization program (UIIP), which started in 2000 in the Canadian province of Ontario, on influenza-associated deaths and health care use with the effects of targeted vaccine programs on the same outcomes elsewhere in Canada.
What Did the Researchers Do and Find?
Using national records, the researchers collected data on influenza vaccination, on all deaths, and on hospitalizations for pneumonia and influenza in all Canadian provinces between 1997 and 2004. They also collected data on emergency department and doctors' office visits for pneumonia and influenza for Ontario, Quebec, Alberta, and Manitoba. They then used a mathematical model to estimate the baseline rates for these outcomes in the absence of influenza activity, and from these calculated weekly rates for deaths and health care use specifically resulting from influenza. In 1996–1997, 18% of the population was vaccinated against influenza in Ontario whereas in the other provinces combined the vaccination rate was 13%. On average, since 2000—the year in which UIIP was introduced in Ontario—vaccination rates have risen to 38% and 24% in Ontario and the other provinces, respectively. Since the introduction of UIIP, the researchers report, influenza-associated deaths have decreased by 74% in Ontario but by only 57% in the other provinces combined. Influenza-associated use of health care facilities has also decreased more in Ontario than in the other provinces over the same period.
What Do These Findings Mean?
These findings are limited by some aspects of the study design. For example, they depend on the accuracy of the assumptions made when calculating events due specifically to influenza, and on the availability and accuracy of vaccination and clinical outcome data. In addition, it is possible that influenza-associated deaths and health care use may have decreased more in Ontario than in the other Canadian provinces because of some unrecognized health care changes specific to Ontario but unrelated to the introduction of universal influenza vaccination. Nevertheless, these findings indicate that, compared to the targeted vaccination programs in the other Canadian provinces, the Ontarian UIIP is associated with reductions in influenza-associated deaths and health care use, particularly in people younger than 65 years old. This effect is seen at a level of vaccination unlikely to produce herd immunity so might be more marked if the uptake of vaccination could be further increased. Thus, although it is possible that Canada is a special case, these findings suggest that universal influenza vaccination might be an effective way to reduce the global burden of influenza.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0050211.
Read the related PLoSMedicine Perspective by Cécile Viboud and Mark Miller
A related PLoSMedicine Research Article by Carline van den Dool and colleagues is also available
The Ontario Ministry of Health provides information on its universal influenza immunization program (in English and French)
The World Health Organization provides information on influenza and on influenza vaccines (in several languages)
The US Centers for Disease Control and Prevention provide information for patients and professionals on all aspects of influenza (in English and Spanish)
MedlinePlus provides a list of links to other information about influenza (in English and Spanish)
The UK National Health Service provides information about the science of immunization, including a simple explanatory animation of immunity
doi:10.1371/journal.pmed.0050211
PMCID: PMC2573914  PMID: 18959473
2.  Assessing Optimal Target Populations for Influenza Vaccination Programmes: An Evidence Synthesis and Modelling Study 
PLoS Medicine  2013;10(10):e1001527.
Marc Baguelin and colleagues use virological, clinical, epidemiological, and behavioral data to estimate how policies for influenza vaccination programs may be optimized in England and Wales.
Please see later in the article for the Editors' Summary
Background
Influenza vaccine policies that maximise health benefit through efficient use of limited resources are needed. Generally, influenza vaccination programmes have targeted individuals 65 y and over and those at risk, according to World Health Organization recommendations. We developed methods to synthesise the multiplicity of surveillance datasets in order to evaluate how changing target populations in the seasonal vaccination programme would affect infection rate and mortality.
Methods and Findings
Using a contemporary evidence-synthesis approach, we use virological, clinical, epidemiological, and behavioural data to develop an age- and risk-stratified transmission model that reproduces the strain-specific behaviour of influenza over 14 seasons in England and Wales, having accounted for the vaccination uptake over this period. We estimate the reduction in infections and deaths achieved by the historical programme compared with no vaccination, and the reduction had different policies been in place over the period. We find that the current programme has averted 0.39 (95% credible interval 0.34–0.45) infections per dose of vaccine and 1.74 (1.16–3.02) deaths per 1,000 doses. Targeting transmitters by extending the current programme to 5–16-y-old children would increase the efficiency of the total programme, resulting in an overall reduction of 0.70 (0.52–0.81) infections per dose and 1.95 (1.28–3.39) deaths per 1,000 doses. In comparison, choosing the next group most at risk (50–64-y-olds) would prevent only 0.43 (0.35–0.52) infections per dose and 1.77 (1.15–3.14) deaths per 1,000 doses.
Conclusions
This study proposes a framework to integrate influenza surveillance data into transmission models. Application to data from England and Wales confirms the role of children as key infection spreaders. The most efficient use of vaccine to reduce overall influenza morbidity and mortality is thus to target children in addition to older adults.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Every winter, millions of people catch influenza, a viral infection of the airways. Most infected individuals recover quickly, but seasonal influenza outbreaks (epidemics) kill about half a million people annually. In countries with advanced health systems, these deaths occur mainly among elderly people and among individuals with long-term illnesses such as asthma and heart disease that increase the risk of complications occurring after influenza virus infection. Epidemics of influenza occur because small but frequent changes in the influenza virus mean that an immune response produced one year through infection provides only partial protection against influenza the following year. Annual immunization with a vaccine that contains killed influenza viruses of the major circulating strains can greatly reduce a person's risk of catching influenza by preparing the immune system to respond quickly when challenged by a live influenza virus. Consequently, many countries run seasonal influenza vaccination programs that, in line with World Health Organization recommendations, target individuals 65 years old and older and people in high-risk groups.
Why Was This Study Done?
Is this approach the best use of available resources? Might, for example, vaccination of children—the main transmitters of influenza—provide more benefit to the whole population than vaccination of elderly people? Vaccination of children would not directly prevent as many influenza-related deaths as vaccination of elderly people, but it might indirectly prevent deaths in elderly adults by inducing herd immunity—vaccination of a large part of a population can protect unvaccinated members of the population by reducing the chances of an infection spreading. Policy makers need to know whether a change to an influenza vaccination program is likely to provide additional population benefits before altering the program. In this evidence synthesis and modeling study, the researchers combine (synthesize) longitudinal influenza surveillance datasets (data collected over time) from England and Wales, develop a mathematical model for influenza transmission based on these data using a Bayesian statistical approach, and use the model to evaluate the impact on influenza infections and deaths of changes to the seasonal influenza vaccination program in England and Wales.
What Did the Researchers Do and Find?
The researchers developed an influenza transmission model using clinical data on influenza-like illness consultations collected in a primary care surveillance scheme for each week of 14 influenza seasons in England and Wales, virological information on respiratory viruses detected in a subset of patients presenting with clinically suspected influenza, and data on vaccination coverage in the whole population (epidemiological data). They also incorporated data on social contacts (behavioral data) and on immunity to influenza viruses in the population (seroepidemiological data) into their model. To estimate the impact of potential changes to the current vaccination strategy in England and Wales, the researchers used their model, which replicated the patterns of disease observed in the surveillance data, to run simulated epidemics for each influenza season and for three strains of influenza virus under various vaccination scenarios. Compared to no vaccination, the current program (vaccination of people 65 years old and older and people in high-risk groups) averted 0.39 infections per dose of vaccine and 1.74 deaths per 1,000 doses. Notably, the model predicted that extension of the program to target 5–16-year-old children would increase the efficiency of the program and would avert 0.70 infections per dose and 1.95 deaths per 1,000 doses.
What Do These Findings Mean?
The finding that the transmission model developed by the researchers closely fit the available surveillance data suggests that the model should be able to predict what would have happened in England and Wales over the study period if an alternative vaccination regimen had been in place. The accuracy of such predictions may be limited, however, because the vaccination model is based on a series of simplifying assumptions. Importantly, given that influenza vaccination for children is being rolled out in England and Wales from September 2013, the model confirms that children are key spreaders of influenza and suggests that a vaccination program targeting children will reduce influenza infections and potentially influenza deaths in the whole population. More generally, the findings of this study support wider adoption of national vaccination strategies designed to block influenza transmission and to target those individuals most at risk from the complications of influenza infection.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371.journal.pmed.1001527.
The UK National Health Service Choices website provides information for patients about seasonal influenza and about vaccination; Public Health England (formerly the Health Protection Agency) provides information on influenza surveillance in the UK, including information about the primary care surveillance database used in this study
The World Health Organization provides information on seasonal influenza (in several languages)
The European Influenzanet is a system to monitor the activity of influenza-like illness with the aid of volunteers via the Internet
The US Centers for Disease Control and Prevention also provides information for patients and health professionals on all aspects of seasonal influenza, including information about vaccination and about the US influenza surveillance system; its website contains a short video about personal experiences of influenza
Flu.gov, a US government website, provides access to information on seasonal influenza and vaccination
MedlinePlus has links to further information about influenza and about immunization (in English and Spanish)
doi:10.1371/journal.pmed.1001527
PMCID: PMC3793005  PMID: 24115913
3.  Economic Appraisal of Ontario's Universal Influenza Immunization Program: A Cost-Utility Analysis 
PLoS Medicine  2010;7(4):e1000256.
Beate Sander and colleagues assess the cost-effectiveness of the program that provides free seasonal influenza vaccines to the entire population of Ontario, Canada.
Background
In July 2000, the province of Ontario, Canada, initiated a universal influenza immunization program (UIIP) to provide free seasonal influenza vaccines for the entire population. This is the first large-scale program of its kind worldwide. The objective of this study was to conduct an economic appraisal of Ontario's UIIP compared to a targeted influenza immunization program (TIIP).
Methods and Findings
A cost-utility analysis using Ontario health administrative data was performed. The study was informed by a companion ecological study comparing physician visits, emergency department visits, hospitalizations, and deaths between 1997 and 2004 in Ontario and nine other Canadian provinces offering targeted immunization programs. The relative change estimates from pre-2000 to post-2000 as observed in other provinces were applied to pre-UIIP Ontario event rates to calculate the expected number of events had Ontario continued to offer targeted immunization. Main outcome measures were quality-adjusted life years (QALYs), costs in 2006 Canadian dollars, and incremental cost-utility ratios (incremental cost per QALY gained). Program and other costs were drawn from Ontario sources. Utility weights were obtained from the literature. The incremental cost of the program per QALY gained was calculated from the health care payer perspective. Ontario's UIIP costs approximately twice as much as a targeted program but reduces influenza cases by 61% and mortality by 28%, saving an estimated 1,134 QALYs per season overall. Reducing influenza cases decreases health care services cost by 52%. Most cost savings can be attributed to hospitalizations avoided. The incremental cost-effectiveness ratio is Can$10,797/QALY gained. Results are most sensitive to immunization cost and number of deaths averted.
Conclusions
Universal immunization against seasonal influenza was estimated to be an economically attractive intervention.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Annual outbreaks (epidemics) of influenza—a viral disease of the nose, throat, and airways—make millions of people ill and kill about 500,000 individuals every year. In doing so, they impose a considerable economic burden on society in terms of health care costs and lost productivity. Influenza epidemics occur because small but frequent changes in the viral proteins to which the immune system responds mean that an immune response produced one year by exposure to an influenza virus provides only partial protection against influenza the next year. Annual immunization with a vaccine that contains killed influenza viruses of the major circulating strains can boost this natural immunity and greatly reduce a person's chances of catching influenza. Consequently, many countries run seasonal influenza vaccine programs. These programs usually target people at high risk of complications from influenza and individuals likely to come into close contact with them, and people who provide essential community services. So, for example, in most Canadian provinces, targeted influenza immunization programs (TIIPs) offer free influenza vaccinations to people aged 65 years or older, to people with chronic medical conditions, and to health care workers.
Why Was This Study Done?
Some experts argue, however, that universal vaccination might provide populations with better protection from influenza. In 2000, the province of Ontario in Canada decided, therefore, to introduce a universal influenza immunization program (UIIP) to provide free influenza vaccination to everyone older than 6 months, the first large program of this kind in the world. A study published in 2008 showed that, following the introduction of the UIIP, vaccination rates in Ontario increased more than in other Canadian provinces. In addition, deaths from influenza and influenza-related use of health care facilities decreased more in Ontario than in provinces that continued to offer a TIIP. But is universal influenza vaccination good value for money? In this study, the researchers evaluate the cost-effectiveness of the Ontario UIIP by comparing the health outcomes and costs associated with its introduction with the health outcomes and costs associated with a hypothetical continuation of targeted influenza immunization.
What Did the Researchers Do and Find?
The researchers used data on TIIP and UIIP vaccine uptake, physician visits, emergency department visits, hospitalizations for influenza, and deaths from influenza between 1997 and 2004 in Ontario and in nine Canadian states offering TIIPs, and Ontario cost data, in their “cost-utility” analysis. This type of analysis estimates the additional cost required to generate a year of perfect health (a quality-adjusted life-year or QALY) through the introduction of an intervention. QALYs are calculated by multiplying the time spent in a certain health state by a measure of the quality of that health state. The researchers report that the cost of Ontario's UIIP was about twice as much as the cost of a TIIP for the province. However, the introduction of the UIIP reduced the number of influenza cases by nearly two-thirds and reduced deaths from influenza by more than a quarter compared with what would have been expected had the province continued to offer a TIIP, an overall saving of 1,134 QALYs. Furthermore, the reduction in influenza cases halved influenza-related health care costs, mainly because of reductions in hospitalization. Overall, this means that the additional cost to Ontario of saving one QALY through the introduction of the UIIP was Can$10,797, an “incremental cost-effectiveness ratio” of $10,797 per QALY gained.
What Do These Findings Mean?
In Canada, an intervention is considered cost-effective from the point of view of a health care purchaser if it costs less than Canadian $50,000 to gain one QALY. These findings indicate, therefore, that for Ontario the introduction of the UIIP is economically attractive. Indeed, the researchers calculate that even if the costs of the UIIP were to double, the additional cost of saving one QALY by introducing universal immunization would remain below $50,000. Other “sensitivity” analyses undertaken by the researchers also indicate that universal immunization is likely to be effective and cost-effective in Ontario if other key assumptions and/or data included in the calculations are varied within reasonable limits. Given these findings, the researchers suggest that a UIIP might be an appealing intervention in other Canadian provinces and in other high-income countries where influenza transmission and health-care costs are broadly similar to those in Ontario.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000256.
A PLoS Medicine Research Article by Kwong and colleagues describes how the introduction of universal influenza immunization in Ontario altered influenza-related health care use and deaths in the province
Wikipedia pages are available on QALYs and on cost-utility analysis (note that Wikipedia is a free online encyclopedia that anyone can edit; available in several languages)
Bandolier, an independent online journal about evidence-based health-care, provides information about QALYs and their use in cost-utility analysis
The UK National Institute for Health and Clinical Excellence has a webpage on Measuring effectiveness and cost-effectiveness: the QALY
doi:10.1371/journal.pmed.1000256
PMCID: PMC2850382  PMID: 20386727
4.  The Effects of Influenza Vaccination of Health Care Workers in Nursing Homes: Insights from a Mathematical Model 
PLoS Medicine  2008;5(10):e200.
Background
Annual influenza vaccination of institutional health care workers (HCWs) is advised in most Western countries, but adherence to this recommendation is generally low. Although protective effects of this intervention for nursing home patients have been demonstrated in some clinical trials, the exact relationship between increased vaccine uptake among HCWs and protection of patients remains unknown owing to variations between study designs, settings, intensity of influenza seasons, and failure to control all effect modifiers. Therefore, we use a mathematical model to estimate the effects of HCW vaccination in different scenarios and to identify a herd immunity threshold in a nursing home department.
Methods and Findings
We use a stochastic individual-based model with discrete time intervals to simulate influenza virus transmission in a 30-bed long-term care nursing home department. We simulate different levels of HCW vaccine uptake and study the effect on influenza virus attack rates among patients for different institutional and seasonal scenarios. Our model reveals a robust linear relationship between the number of HCWs vaccinated and the expected number of influenza virus infections among patients. In a realistic scenario, approximately 60% of influenza virus infections among patients can be prevented when the HCW vaccination rate increases from 0 to 1. A threshold for herd immunity is not detected. Due to stochastic variations, the differences in patient attack rates between departments are high and large outbreaks can occur for every level of HCW vaccine uptake.
Conclusions
The absence of herd immunity in nursing homes implies that vaccination of every additional HCW protects an additional fraction of patients. Because of large stochastic variations, results of small-sized clinical trials on the effects of HCW vaccination should be interpreted with great care. Moreover, the large variations in attack rates should be taken into account when designing future studies.
Using a mathematical model to simulate influenza transmission in nursing homes, Carline van den Dool and colleagues find that each additional staff member vaccinated further reduces the risk to patients.
Editors' Summary
Background.
Every winter, millions of people catch influenza, a contagious viral disease of the nose, throat, and airways. Most people recover completely from influenza within a week or two but some develop life-threatening complications such as bacterial pneumonia. As a result, influenza outbreaks kill about half a million people—mainly infants, elderly people, and chronically ill individuals—each year. To minimize influenza-related deaths, the World Health Organization recommends that vulnerable people be vaccinated against influenza every autumn. Annual vaccination is necessary because flu viruses continually make small changes to the viral proteins (antigens) that the immune system recognizes. This means that an immune response produced one year provides only partial protection against influenza the next year. To provide maximum protection against influenza, each year's vaccine contains disabled versions of the major circulating strains of influenza viruses.
Why Was This Study Done?
Most Western countries also recommend annual flu vaccination for health care workers (HCWs) in hospitals and other institutions to reduce the transmission of influenza to vulnerable patients. However, many HCWs don't get a regular flu shot, so should efforts be made to increase their rate of vaccine uptake? To answer this question, public-health experts need to know more about the relationship between vaccine uptake among HCWs and patient protection. In particular, they need to know whether a high rate of vaccine uptake by HCWs will provide “herd immunity.” Herd immunity occurs because, when a sufficient fraction of a population is immune to a disease that passes from person to person, infected people rarely come into contact with susceptible people, which means that both vaccinated and unvaccinated people are protected from the disease. In this study, the researchers develop a mathematical model to investigate the relationship between vaccine uptake among HCWs and patient protection in a nursing home department.
What Did the Researchers Do and Find?
To predict influenza virus attack rates (the number of patient infections divided by the number of patients in a nursing home department during an influenza season) at different levels of HCW vaccine uptake, the researchers develop a stochastic transmission model to simulate epidemics on a computer. This model predicts that as the HCW vaccination rate increases from 0 (no HCWs vaccinated) to 1 (all the HCWs vaccinated), the expected average influenza virus attack rate decreases at a constant rate. In the researchers' baseline scenario—a nursing home department with 30 beds where patients come into contact with other patients, HCWs, and visitors—the model predicts that about 60% of the patients who would have been infected if no HCWs had been vaccinated are protected when all the HCWs are vaccinated, and that seven HCWs would have to be vaccinated to protect one patient. This last figure does not change with increasing vaccine uptake, which indicates that there is no level of HCW vaccination that completely stops the spread of influenza among the patients; that is, there is no herd immunity. Finally, the researchers show that large influenza outbreaks can happen by chance at every level of HCW vaccine uptake.
What Do These Findings Mean?
As with all mathematical models, the accuracy of these predictions may depend on the specific assumptions built into the model. Therefore the researchers verified that their findings hold for a wide range of plausible assumptions. These findings have two important practical implications. First, the direct relationship between HCW vaccination and patient protection and the lack of any herd immunity suggest that any increase in HCW vaccine uptake will be beneficial to patients in nursing homes. That is, increasing the HCW vaccination rate from 80% to 90% is likely to be as important as increasing it from 10% to 20%. Second, even 100% HCW vaccination cannot guarantee that influenza outbreaks will not occasionally occur in nursing homes. Because of the large variation in attack rates, the results of small clinical trials on the effects of HCW vaccination may be inaccurate and future studies will need to be very large if they are to provide reliable estimates of the amount of protection that HCW vaccination provides to vulnerable patients.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0050200.
Read the related PLoSMedicine Perspective by Cécile Viboud and Mark Miller
A related PLoSMedicine Research Article by Jeffrey Kwong and colleagues is also available
The World Health Organization provides information on influenza and on influenza vaccines (in several languages)
The US Centers for Disease Control and Prevention provide information for patients and professionals on all aspects of influenza (in English and Spanish)
The UK Health Protection Agency also provides information on influenza
MedlinePlus provides a list of links to other information about influenza (in English and Spanish)
The UK National Health Service provides information about herd immunity, including a simple explanatory animation
The European Centre for Disease Prevention and Control provides an overview on the types of influenza
doi:10.1371/journal.pmed.0050200
PMCID: PMC2573905  PMID: 18959470
5.  Herpes Zoster Vaccine Effectiveness against Incident Herpes Zoster and Post-herpetic Neuralgia in an Older US Population: A Cohort Study 
PLoS Medicine  2013;10(4):e1001420.
Sinead Marie Langan and colleagues studied a cohort of more than 750,000 individuals over the age of 65 years to assess whether herpes zoster vaccine is effective against incident zoster and post-herpetic neuralgia in an older population.
Background
Herpes zoster is common and has serious consequences, notably post-herpetic neuralgia (PHN). Vaccine efficacy against incident zoster and PHN has been demonstrated in clinical trials, but effectiveness has not been studied in unselected general populations unrestricted by region, full health insurance coverage, or immune status. Our objective was to assess zoster vaccine effectiveness (VE) against incident zoster and PHN in a general population-based setting.
Methods and Findings
A cohort study of 766,330 fully eligible individuals aged ≥65 years was undertaken in a 5% random sample of Medicare who received and did not receive zoster vaccination between 1st January 2007 and 31st December 2009.
Incidence rates and hazard ratios for zoster and PHN were determined in vaccinated and unvaccinated individuals. Analyses were adjusted for age, gender, race, low income, immunosuppression, and important comorbidities associated with zoster, and then stratified by immunosuppression status. Adjusted hazard ratios were estimated using time-updated Cox proportional hazards models.
Vaccine uptake was low (3.9%) particularly among black people (0.3%) and those with evidence of low income (0.6%). 13,112 US Medicare beneficiaries developed incident zoster; the overall zoster incidence rate was 10.0 (9.8–10.2) per 1,000 person-years in the unvaccinated group and 5.4 (95% CI 4.6–6.4) per 1,000 person-years in vaccinees, giving an adjusted VE against incident zoster of 0.48 (95% CI 0.39–0.56). In immunosuppressed individuals, VE against zoster was 0.37 (95% CI 0.06–0.58). VE against PHN was 0.59 (95% CI 0.21–0.79).
Conclusions
Vaccine uptake was low with variation in specific patient groups. In a general population cohort of older individuals, zoster vaccination was associated with reduction in incident zoster, including among those with immunosuppression. Importantly, this study demonstrates that zoster vaccination is associated with a reduction in PHN.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Chickenpox is an extremely common childhood infectious disease that is caused by the herpes varicella-zoster virus. Children usually recover quickly from chickenpox, but dormant varicella-zoster virus persists throughout life inside the nervous system. The dormant virus causes no symptoms but if it becomes reactivated, it causes shingles (zoster), a painful skin rash. Anyone who has had chickenpox can develop shingles but shingles is most common and most severe in 60–80-year-old people. Indeed, about half of people who live to 85 will have an episode of shingles. Early signs of shingles include burning or shooting pain and tingling or itching. Blister-like sores, which last from 1–14 days, then develop in a region of one side of the body or on one side of the face. The pain of shingles can be debilitating and can continue after the rash disappears—“post-herpetic neuralgia,” which can last for months to years, greatly reduces the quality of life. There is no cure for shingles but early treatment with antivirals may help to prevent lingering pain by inhibiting viral replication.
Why Was This Study Done?
Shingles vaccination can prevent shingles or lessen its effects. In clinical trials, vaccination reduced the incidence of shingles (the proportion of a population who develop shingles in a year) and the incidence of post-herpetic neuralgia, and vaccination against shingles is now recommended in the US for everyone over the age of 60 except individuals with a weakened immune system (for example, people with HIV/AIDS). However, these clinical trials determined the vaccine's efficacy in selected populations under controlled conditions. How effective is the vaccine in unselected populations in routine clinical use? In this cohort study, the researchers assess zoster (shingles) vaccine effectiveness against incident shingles and post-herpetic neuralgia in an unselected population of older individuals in the US. A cohort study follows a group of individuals who differ with respect to specific factors (in this study, vaccination against shingles) to determine how these factors affect the rates of specific outcomes (shingles and post-herpetic neuralgia).
What Did the Researchers Do and Find?
The researchers undertook their cohort study in 766,330 randomly chosen Medicare beneficiaries aged 65 years or more. Medicare is a US government health insurance scheme that mainly helps to pay the health care costs of people aged 65 or older. The researchers used Medicare administrative data to identify which cohort members received zoster vaccination between January 2007 and December 2009 and which developed incident shingles (defined as a first diagnosis of shingles combined with the use of antivirals) or post-herpetic neuralgia (defined as a code for post-herpetic neuralgia, non-specific neuralgia, or a second diagnostic code for shingles 90 days after the first diagnosis combined with a prescription for pain relief, an anticonvulsant, or an antidepressant). Vaccine uptake was low in this unselected study population—only 3.9% of the participants were vaccinated. The vaccination rate was particularly low among black people (0.6% of person-time) and among people with a low income (0.3%). About 13,000 participants developed incident shingles. The shingles incidence rate was 10.0 per 1,000 person-years among unvaccinated participants and 5.4 per 1,000 person-years among vaccinated participants. Vaccine effectiveness against incident shingles was 48%. That is, vaccination reduced the incidence of shingles by 48% (in other words, approximately half as many vaccinated individuals developed shingles as those who were not vaccinated). Vaccine effectiveness against incident shingles among immunosuppressed individuals was lower (37%). Finally, vaccine effectiveness against post-herpetic neuralgia was 59%.
What Do These Findings Mean?
These findings show that shingles vaccine uptake is low among elderly people in the US and varies between different patient groups. They show that shingles vaccination is effective against incident shingles in a general population of older individuals, including those who are immunosuppressed, and suggest that shingles vaccination is effective against post-herpetic neuralgia. However, because these findings rely on administrative data, their accuracy may be affected by misclassification of vaccination and of outcomes. Moreover, because shingles vaccination was not randomized, the vaccinated individuals might have shared other characteristics that were actually responsible for their lower incidence of shingles and/or post-herpetic neuralgia compared to unvaccinated individuals. Despite these limitations, these findings provide useful information for policy makers in countries that are currently considering the introduction of shingles vaccination into routine practice. Moreover, they highlight the need to increase shingles vaccination among elderly individuals in the US, the section of the population at the highest risk of post-herpetic neuralgia.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/ 10.1371/journal.pmed.1001420.
The US Centers for Disease Control and Prevention have detailed information about all aspects of shingles (zoster), including information on vaccination for the public and for health care professionals, and a personal story about shingles
The NIH Senior Health website includes information on shingles and a video describing a personal experience of shingles
The UK National Health Service Choices also provides information about all aspects of shingles and a personal story
MedlinePlus provides links to other resources about shingles (in English and Spanish)
The British Association of Dermatologists website has an information leaflet on shingles
The New Zealand Dermatological Society website has a leaflet on shingles
doi:10.1371/journal.pmed.1001420
PMCID: PMC3621740  PMID: 23585738
6.  Decline in Diarrhea Mortality and Admissions after Routine Childhood Rotavirus Immunization in Brazil: A Time-Series Analysis 
PLoS Medicine  2011;8(4):e1001024.
A time series analysis by Manish Patel and colleagues shows that the introduction of rotavirus vaccination in Brazil is associated with reduced diarrhea-related deaths and hospital admissions in children under 5 years of age.
Background
In 2006, Brazil began routine immunization of infants <15 wk of age with a single-strain rotavirus vaccine. We evaluated whether the rotavirus vaccination program was associated with declines in childhood diarrhea deaths and hospital admissions by monitoring disease trends before and after vaccine introduction in all five regions of Brazil with varying disease burden and distinct socioeconomic and health indicators.
Methods and Findings
National data were analyzed with an interrupted time-series analysis that used diarrhea-related mortality or hospitalization rates as the main outcomes. Monthly mortality and admission rates estimated for the years after rotavirus vaccination (2007–2009) were compared with expected rates calculated from pre-vaccine years (2002–2005), adjusting for secular and seasonal trends. During the three years following rotavirus vaccination in Brazil, rates for diarrhea-related mortality and admissions among children <5 y of age were 22% (95% confidence interval 6%–44%) and 17% (95% confidence interval 5%–27%) lower than expected, respectively. A cumulative total of ∼1,500 fewer diarrhea deaths and 130,000 fewer admissions were observed among children <5 y during the three years after rotavirus vaccination. The largest reductions in deaths (22%–28%) and admissions (21%–25%) were among children younger than 2 y, who had the highest rates of vaccination. In contrast, lower reductions in deaths (4%) and admissions (7%) were noted among children two years of age and older, who were not age-eligible for vaccination during the study period.
Conclusions
After the introduction of rotavirus vaccination for infants, significant declines for three full years were observed in under-5-y diarrhea-related mortality and hospital admissions for diarrhea in Brazil. The largest reductions in diarrhea-related mortality and hospital admissions for diarrhea were among children younger than 2 y, who were eligible for vaccination as infants, which suggests that the reduced diarrhea burden in this age group was associated with introduction of the rotavirus vaccine. These real-world data are consistent with evidence obtained from clinical trials and strengthen the evidence base for the introduction of rotavirus vaccination as an effective measure for controlling severe and fatal childhood diarrhea.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Diarrheal disease, usually caused by infectious agents, is the second major cause of death in children aged under five years. As highlighted in a recent PLoS Medicine series, access to clean water and improved sanitation is the key to the primary prevention of diarrheal illnesses. Yet despite the targets of Millennium Development Goal 7 to half the number of people without access to clean water or improved sanitation by 2015, over one billion people worldwide do not currently have access to clean water and over two billion do not currently have access to improved sanitation.
Since enteric viruses are primarily transmitted directly from one person to another, they cannot be controlled completely by improvements in sanitation. Therefore, although not replacing the urgent need to provide access to clean water and improved sanitation for all, vaccination programs that protect young children against some infections that cause diarrhea, such as rotavirus, which accounts for one-third of all child deaths caused by diarrhea, are a pragmatic way forward. As large clinical trials have shown the safety and efficacy of rotavirus vaccines in population settings, in July 2009, the World Health Organization recommended including rotavirus vaccines into every country's national immunization programs.
Why Was This Study Done?
Although the protective effect of rotavirus vaccines has been assessed in various high-, middle-, and low-income settings, for reasons that remain unclear, the efficacy of live, oral rotavirus vaccines appears to be dependent on geographical location and correlated to the socioeconomic status of the population. Because of these concerns, evaluating the health impact of large-scale rotavirus vaccine programs and ensuring their equity in a real-world setting (rather than in clinical trial conditions) is important.
Therefore, the researchers addressed this issue by conducting this study to evaluate the effect of rotavirus vaccination on mortality and hospital admissions for diarrhea due to all causes among young children in the five regions of Brazil. The researchers chose to do this study in Brazil because of the high incidence of diarrhea-related deaths and hospital admissions and because five years ago, in July 2006, the Brazilian Ministry of Health introduced the single-strain rotavirus vaccine simultaneously in all 27 states through its national immunization program—allowing for “before” and “after” intervention analysis.
What Did the Researchers Do and Find?
The researchers obtained data on diarrheal deaths and hospital admissions in children aged under five years for the period 2002–2005 and 2007–2009 and data on rotavirus vaccination rates. The researchers got the data on diarrhea deaths from the Brazilian Mortality Information System—the national database of information collected from death certificates that covers 90% of all deaths in Brazil. The data on hospital admissions came from the electronic Hospital Information System of Brazil's Unified Health System (Sistema Unico de Saúde, SUS)—the publicly funded health-care system that covers roughly 70% of the hospitalizations and includes information on all admissions (from public hospitals and some private hospitals) authorized for payment by the Unified Health System. The researchers got regional rotavirus vaccination coverage estimates for 2007–2009 from the information department of the Ministry of Health, and estimated coverage of the two doses of oral rotavirus vaccine by taking the annual number of second doses administered divided by the number of infants in the region.
In 2007, an estimated 80% of infants received two doses of rotavirus vaccine, and by 2009, this proportion rose to 84% of children younger than one year of age. The researchers found that in the three years following the introduction of rotavirus vaccination, diarrhea-related mortality rates and admissions among children aged under five years were respectively 22% and 17% lower than expected, with a cumulative total of 1,500 fewer diarrhea deaths and 130,000 fewer admissions. Furthermore, the largest reductions in deaths and admissions were among children who had the highest rates of vaccination (less than two years of age), and the lowest reductions were among children who were not eligible for vaccination during the study period (aged 2–4 years).
What Do These Findings Mean?
These findings suggest that the introduction of rotavirus vaccination in all areas of Brazil is associated with reduced diarrhea-related deaths and hospital admissions in children aged under five years. These real-world impact data are consistent with the clinical trials and strengthen the evidence base for rotavirus vaccination as an effective measure for controlling severe and fatal childhood diarrhea.
These findings have important global policy implications. In middle-income countries, such as Brazil, that are not eligible for financial support from donors, the potential reductions in admissions and other health-care costs will be important for cost-effectiveness considerations to justify the purchase of these still relatively expensive vaccines.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001024
PLoS Medicine has published a series on water and sanitation
More information is available from the World Health Organization on diarrheal illness in children
More information is available about rotavirus vaccines from the World Health Organization, the US Centers for Disease Control and Prevention, and the Rotavirus Vaccine Program
doi:10.1371/journal.pmed.1001024
PMCID: PMC3079643  PMID: 21526228
7.  Association between the 2008–09 Seasonal Influenza Vaccine and Pandemic H1N1 Illness during Spring–Summer 2009: Four Observational Studies from Canada 
PLoS Medicine  2010;7(4):e1000258.
In three case-control studies and a household transmission cohort, Danuta Skowronski and colleagues find an association between prior seasonal flu vaccination and increased risk of 2009 pandemic H1N1 flu.
Background
In late spring 2009, concern was raised in Canada that prior vaccination with the 2008–09 trivalent inactivated influenza vaccine (TIV) was associated with increased risk of pandemic influenza A (H1N1) (pH1N1) illness. Several epidemiologic investigations were conducted through the summer to assess this putative association.
Methods and Findings
Studies included: (1) test-negative case-control design based on Canada's sentinel vaccine effectiveness monitoring system in British Columbia, Alberta, Ontario, and Quebec; (2) conventional case-control design using population controls in Quebec; (3) test-negative case-control design in Ontario; and (4) prospective household transmission (cohort) study in Quebec. Logistic regression was used to estimate odds ratios for TIV effect on community- or hospital-based laboratory-confirmed seasonal or pH1N1 influenza cases compared to controls with restriction, stratification, and adjustment for covariates including combinations of age, sex, comorbidity, timeliness of medical visit, prior physician visits, and/or health care worker (HCW) status. For the prospective study risk ratios were computed. Based on the sentinel study of 672 cases and 857 controls, 2008–09 TIV was associated with statistically significant protection against seasonal influenza (odds ratio 0.44, 95% CI 0.33–0.59). In contrast, estimates from the sentinel and three other observational studies, involving a total of 1,226 laboratory-confirmed pH1N1 cases and 1,505 controls, indicated that prior receipt of 2008–09 TIV was associated with increased risk of medically attended pH1N1 illness during the spring–summer 2009, with estimated risk or odds ratios ranging from 1.4 to 2.5. Risk of pH1N1 hospitalization was not further increased among vaccinated people when comparing hospitalized to community cases.
Conclusions
Prior receipt of 2008–09 TIV was associated with increased risk of medically attended pH1N1 illness during the spring–summer 2009 in Canada. The occurrence of bias (selection, information) or confounding cannot be ruled out. Further experimental and epidemiological assessment is warranted. Possible biological mechanisms and immunoepidemiologic implications are considered.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Every winter, millions of people catch influenza—a viral infection of the airways—and hundreds of thousands of people die as a result. These seasonal epidemics occur because small but frequent changes in the influenza virus mean that an immune response produced one year through infection or vaccination provides only partial protection against influenza the next year. Annual vaccination with killed influenza viruses of the major circulating strains can greatly reduce a person's risk of catching influenza. Consequently, many countries run seasonal influenza vaccination programs. In most of Canada, vaccination with a mixture of three inactivated viruses (a trivalent inactivated vaccine or TIV) is provided free to children aged 6–23 months, to elderly people, to people with long-term conditions that increase their risk of influenza-related complications, and those who provide care for them; in Ontario, free vaccination is offered to everyone older than 6 months.
In addition, influenza viruses occasionally emerge that are very different and to which human populations have virtually no immunity. These viruses can start global epidemics (pandemics) that can kill millions of people. Experts have been warning for some time that an influenza pandemic is long overdue and, in March 2009, the first cases of influenza caused by a new virus called pandemic A/H1N1 2009 (pH1N1; swine flu) occurred in Mexico. The virus spread rapidly and on 11 June 2009, the World Health Organization declared that a global pandemic of pH1N1 influenza was underway. By the end of February 2010, more than 16,000 people around the world had died from pH1N1.
Why Was This Study Done?
During an investigation of a school outbreak of pH1N1 in the late spring 2009 in Canada, investigators noted that people with illness characterized by fever and coughing had been vaccinated against seasonal influenza more often than individuals without such illness. To assess whether this association between prior vaccination with seasonal 2008–09 TIV and subsequent pH1N1 illness was evident in other settings, researchers in Canada therefore conducted additional studies using different methods. In this paper, the researchers report the results of four additional studies conducted in Canada during the summer of 2009 to assess this possible association.
What Did the Researchers Do and Find?
The researchers conducted four epidemiologic studies. Epidemiology is the study of the causes, distribution, and control of diseases in populations.
Three of the four studies were case-control studies in which the researchers assessed the frequency of prior vaccination with the 2008–09 TIV in people with pH1N1 influenza compared to the frequency among healthy members of the general population or among individuals who had an influenza-like illness but no sign of infection with an influenza virus. The researchers also did a household transmission study in which they collected information about vaccination with TIV among the additional cases of influenza that were identified in 47 households in which a case of laboratory-confirmed pH1N1 influenza had occurred. The first of the case-control studies, which was based on Canada's vaccine effectiveness monitoring system, showed that, as expected, the 2008–09 TIV provided protection against seasonal influenza. However, estimates from all four studies (which included about 1,200 laboratory-confirmed pH1N1 cases and 1,500 controls) showed that prior recipients of the 2008–09 TIV had approximately 1.4–2.5 times increased chances of developing pH1N1 illness that needed medical attention during the spring–summer of 2009 compared to people who had not received the TIV. Prior seasonal vaccination was not associated with an increase in the severity of pH1N1 illness, however. That is, it did not increase the risk of being hospitalized among those with pH1N1 illness.
What Do These Findings Mean?
Because all the investigations in this study are “observational,” the people who had been vaccinated might share another unknown characteristic that is actually responsible for increasing their risk of developing pH1N1 illness (“confounding”). Furthermore, the results reported in this study might have arisen by chance, although the consistency of results across the studies makes this unlikely. Thus, the finding of an association between prior receipt of 2008–09 TIV and an increased risk of pH1N1 illness is not conclusive and needs to be investigated further, particularly since some other observational studies conducted in other countries have reported that seasonal vaccination had no influence or may have been associated with reduced chances of pH1N1 illness. If the findings in the current study are real, however, they raise important questions about the biological interactions between seasonal and pandemic influenza strains and vaccines, and about the best way to prevent and control both types of influenza in future.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/ 10.1371/journal.pmed.1000258.
This article is further discussed in a PLoS Medicine Perspective by Cécile Viboud and Lone Simonsen
FightFlu.ca, a Canadian government Web site, provides access to information on pH1N1 influenza
The US Centers for Disease Control and Prevention provides information about influenza for patients and professionals, including specific information on H1N1 influenza
Flu.gov, a US government website, provides access to information on H1N1, avian and pandemic influenza
The World Health Organization provides information on seasonal influenza and has detailed information on pH1N1 influenza (in several languages)
The UK Health Protection Agency provides information on pandemic influenza and on pH1N1 influenza
doi:10.1371/journal.pmed.1000258
PMCID: PMC2850386  PMID: 20386731
8.  Characterization of Regional Influenza Seasonality Patterns in China and Implications for Vaccination Strategies: Spatio-Temporal Modeling of Surveillance Data 
PLoS Medicine  2013;10(11):e1001552.
Cécile Viboud and colleagues describe epidemiological patterns of influenza incidence across China to support the design of a national vaccination program.
Please see later in the article for the Editors' Summary
Background
The complexity of influenza seasonal patterns in the inter-tropical zone impedes the establishment of effective routine immunization programs. China is a climatologically and economically diverse country, which has yet to establish a national influenza vaccination program. Here we characterize the diversity of influenza seasonality in China and make recommendations to guide future vaccination programs.
Methods and Findings
We compiled weekly reports of laboratory-confirmed influenza A and B infections from sentinel hospitals in cities representing 30 Chinese provinces, 2005–2011, and data on population demographics, mobility patterns, socio-economic, and climate factors. We applied linear regression models with harmonic terms to estimate influenza seasonal characteristics, including the amplitude of annual and semi-annual periodicities, their ratio, and peak timing. Hierarchical Bayesian modeling and hierarchical clustering were used to identify predictors of influenza seasonal characteristics and define epidemiologically-relevant regions. The annual periodicity of influenza A epidemics increased with latitude (mean amplitude of annual cycle standardized by mean incidence, 140% [95% CI 128%–151%] in the north versus 37% [95% CI 27%–47%] in the south, p<0.0001). Epidemics peaked in January–February in Northern China (latitude ≥33°N) and April–June in southernmost regions (latitude <27°N). Provinces at intermediate latitudes experienced dominant semi-annual influenza A periodicity with peaks in January–February and June–August (periodicity ratio >0.6 in provinces located within 27.4°N–31.3°N, slope of latitudinal gradient with latitude −0.016 [95% CI −0.025 to −0.008], p<0.001). In contrast, influenza B activity predominated in colder months throughout most of China. Climate factors were the strongest predictors of influenza seasonality, including minimum temperature, hours of sunshine, and maximum rainfall. Our main study limitations include a short surveillance period and sparse influenza sampling in some of the southern provinces.
Conclusions
Regional-specific influenza vaccination strategies would be optimal in China; in particular, annual campaigns should be initiated 4–6 months apart in Northern and Southern China. Influenza surveillance should be strengthened in mid-latitude provinces, given the complexity of seasonal patterns in this region. More broadly, our findings are consistent with the role of climatic factors on influenza transmission dynamics.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Every year, millions of people worldwide catch influenza, a viral disease of the airways. Most infected individuals recover quickly but seasonal influenza outbreaks (epidemics) kill about half a million people annually. These epidemics occur because antigenic drift—frequent small changes in the viral proteins to which the immune system responds—means that an immune response produced one year provides only partial protection against influenza the next year. Annual vaccination with a mixture of killed influenza viruses of the major circulating strains boosts this natural immunity and greatly reduces the risk of catching influenza. Consequently, many countries run seasonal influenza vaccination programs. Because the immune response induced by vaccination decays within 4–8 months of vaccination and because of antigenic drift, it is important that these programs are initiated only a few weeks before the onset of local influenza activity. Thus, vaccination starts in early autumn in temperate zones (regions of the world that have a mild climate, part way between a tropical and a polar climate), because seasonal influenza outbreaks occur in the winter months when low humidity and low temperatures favor the transmission of the influenza virus.
Why Was This Study Done?
Unlike temperate regions, seasonal influenza patterns are very diverse in tropical countries, which lie between latitudes 23.5°N and 23.5°S, and in the subtropical countries slightly north and south of these latitudes. In some of these countries, there is year-round influenza activity, in others influenza epidemics occur annually or semi-annually (twice yearly). This complexity, which is perhaps driven by rainfall fluctuations, complicates the establishment of effective routine immunization programs in tropical and subtropical countries. Take China as an example. Before a national influenza vaccination program can be established in this large, climatologically diverse country, public-health experts need a clear picture of influenza seasonality across the country. Here, the researchers use spatio-temporal modeling of influenza surveillance data to characterize the seasonality of influenza A and B (the two types of influenza that usually cause epidemics) in China, to assess the role of putative drivers of seasonality, and to identify broad epidemiological regions (areas with specific patterns of disease) that could be used as a basis to optimize the timing of future Chinese vaccination programs.
What Did the Researchers Do and Find?
The researchers collected together the weekly reports of laboratory-confirmed influenza prepared by the Chinese national sentinel hospital-based surveillance network between 2005 and 2011, data on population size and density, mobility patterns, and socio-economic factors, and daily meteorological data for the cities participating in the surveillance network. They then used various statistical modeling approaches to estimate influenza seasonal characteristics, to assess predictors of influenza seasonal characteristics, and to identify epidemiologically relevant regions. These analyses indicate that, over the study period, northern provinces (latitudes greater than 33°N) experienced winter epidemics of influenza A in January–February, southern provinces (latitudes less than 27°N) experienced peak viral activity in the spring (April–June), and provinces at intermediate latitudes experienced semi-annual epidemic cycles with infection peaks in January–February and June–August. By contrast, influenza B activity predominated in the colder months throughout China. The researchers also report that minimum temperatures, hours of sunshine, and maximum rainfall were the strongest predictors of influenza seasonality.
What Do These Findings Mean?
These findings show that influenza seasonality in China varies between regions and between influenza virus types and suggest that, as in other settings, some of these variations might be associated with specific climatic factors. The accuracy of these findings is limited by the short surveillance period, by sparse surveillance data from some southern and mid-latitude provinces, and by some aspects of the modeling approach used in the study. Further surveillance studies need to be undertaken to confirm influenza seasonality patterns in China. Overall, these findings suggest that, to optimize routine influenza vaccination in China, it will be necessary to stagger the timing of vaccination over three broad geographical regions. More generally, given that there is growing interest in rolling out national influenza immunization programs in low- and middle-income countries, these findings highlight the importance of ensuring that vaccination strategies are optimized by taking into account local disease patterns.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/ 10.1371/journal.pmed.1001552.
This study is further discussed in a PLOS Medicine Perspective by Steven Riley
The UK National Health Service Choices website provides information for patients about seasonal influenza and about influenza vaccination
The World Health Organization provides information on seasonal influenza (in several languages) and on influenza surveillance and monitoring
The US Centers for Disease Control and Prevention also provides information for patients and health professionals on all aspects of seasonal influenza, including information about vaccination; its website contains a short video about personal experiences of influenza.
Flu.gov, a US government website, provides access to information on seasonal influenza and vaccination
Information about the Chinese National Influenza Center, which is part of the Chinese Center for Disease Control and Prevention: and which runs influenza surveillance in China, is available (in English and Chinese)
MedlinePlus has links to further information about influenza and about vaccination (in English and Spanish)
A recent PLOS Pathogens Research Article by James D. Tamerius et al. investigates environmental predictors of seasonal influenza epidemics across temperate and tropical climates
A study published in PLOS ONE by Wyller Alencar de Mello et al. indicates that Brazil, like China, requires staggered timing of vaccination from Northern to Southern states to account for different timings of influenza activity.
doi:10.1371/journal.pmed.1001552
PMCID: PMC3864611  PMID: 24348203
9.  Improving uptake of influenza vaccination among older people: a randomised controlled trial. 
BACKGROUND: The uptake of influenza vaccination among older people is suboptimal. Contact with a doctor or nurse is associated with older people deciding to accept influenza vaccination. AIM: To compare different forms of approach in improving uptake of influenza vaccination among patients aged 75 years and over in primary care. DESIGN OF STUDY: Randomised controlled trial. SETTING: One large rural general practice serving the town and surrounding area of Melton Mowbray, Leicestershire. METHOD: All 2,052 patients aged 75 years and over, registered with the practice and not living in nursing/residential homes or sheltered accommodation, were included in the study. One-third of patients were randomised to receive an offer of influenza vaccination as part of an over-75 health check administered by a practice nurse in the patient's home, and two-thirds of patients were randomised to receive a personal letter of invitation to attend an influenza vaccination clinic held at the surgery. The main outcome measure was uptake of influenza vaccination. RESULTS: Six hundred and eighty patients were randomised to the health check arm of the trial and 1,372 were randomised to receive a personal letter. Of those randomised to the health check arm, 468 received the health check from the nurse. Overall, the difference in influenza vaccination uptake was 6.4% (95% confidence interval [CI] = 2.2% to 10.4%) with 67.9% (n = 932) of those who were sent a personal letter actually receiving the vaccine, compared with 74.3% (n = 505) of those offered a combined health check and influenza vaccination (P = 0.003). CONCLUSION: Combining home-based over- 75 health checks with influenza vaccination can improve uptake among older patients. However this intervention is likely to be costly and its effect on influenza vaccination rates is modest. The difference in uptake is greater among those who do not routinely comeforwardfor vaccination and a more viable option may be to target these patients.
PMCID: PMC1314411  PMID: 12236274
10.  A Population-Based Evaluation of a Publicly Funded, School-Based HPV Vaccine Program in British Columbia, Canada: Parental Factors Associated with HPV Vaccine Receipt 
PLoS Medicine  2010;7(5):e1000270.
Analysis of a telephone survey by Gina Ogilvie and colleagues identifies the parental factors associated with HPV vaccine uptake in a school-based program in Canada.
Background
Information on factors that influence parental decisions for actual human papillomavirus (HPV) vaccine receipt in publicly funded, school-based HPV vaccine programs for girls is limited. We report on the level of uptake of the first dose of the HPV vaccine, and determine parental factors associated with receipt of the HPV vaccine, in a publicly funded school-based HPV vaccine program in British Columbia, Canada.
Methods and Findings
All parents of girls enrolled in grade 6 during the academic year of September 2008–June 2009 in the province of British Columbia were eligible to participate. Eligible households identified through the provincial public health information system were randomly selected and those who consented completed a validated survey exploring factors associated with HPV vaccine uptake. Bivariate and multivariate analyses were conducted to calculate adjusted odds ratios to identify the factors that were associated with parents' decision to vaccinate their daughter(s) against HPV. 2,025 parents agreed to complete the survey, and 65.1% (95% confidence interval [CI] 63.1–67.1) of parents in the survey reported that their daughters received the first dose of the HPV vaccine. In the same school-based vaccine program, 88.4% (95% CI 87.1–89.7) consented to the hepatitis B vaccine, and 86.5% (95% CI 85.1–87.9) consented to the meningococcal C vaccine. The main reasons for having a daughter receive the HPV vaccine were the effectiveness of the vaccine (47.9%), advice from a physician (8.7%), and concerns about daughter's health (8.4%). The main reasons for not having a daughter receive the HPV vaccine were concerns about HPV vaccine safety (29.2%), preference to wait until the daughter is older (15.6%), and not enough information to make an informed decision (12.6%). In multivariate analysis, overall attitudes to vaccines, the impact of the HPV vaccine on sexual practices, and childhood vaccine history were predictive of parents having a daughter receive the HPV vaccine in a publicly funded school-based HPV vaccine program. By contrast, having a family with two parents, having three or more children, and having more education was associated with a decreased likelihood of having a daughter receive the HPV vaccine.
Conclusions
This study is, to our knowledge, one of the first population-based assessments of factors associated with HPV vaccine uptake in a publicly funded school-based program worldwide. Policy makers need to consider that even with the removal of financial and health care barriers, parents, who are key decision makers in the uptake of this vaccine, are still hesitant to have their daughters receive the HPV vaccine, and strategies to ensure optimal HPV vaccine uptake need to be employed.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
About 10% of cancers in women occur in the cervix, the structure that connects the womb to the vagina. Every year, globally, more than a quarter of a million women die because of cervical cancer, which only occurs after the cervix has been infected with a human papillomavirus (HPV) through sexual intercourse. There are many types of HPV, a virus that infects the skin and the mucosa (the moist membranes that line various parts of the body, including the cervix). Although most people become infected with HPV at some time in their life, most never know they are infected. However, some HPV types cause harmless warts on the skin or around the genital area and several—in particular, HPV 16 and HPV 18, so-called high-risk HPVs—can cause cervical cancer. HPV infections are usually cleared by the immune system, but about 10% of women infected with a high-risk HPV develop a long-term infection that puts them at risk of developing cervical cancer.
Why Was This Study Done?
Screening programs have greatly reduced cervical cancer deaths in developed countries in recent decades by detecting the cancer early when it can be treated; but it would be better to prevent cervical cancer ever developing. Because HPV is necessary for the development of cervical cancer, vaccination of girls against HPV infection before the onset of sexual activity might be one way to do this. Scientists recently developed a vaccine that prevents infection with HPV 16 and HPV 18 (and with two HPVs that cause genital warts) and that should, therefore, reduce the incidence of cervical cancer. Publicly funded HPV vaccination programs are now planned or underway in several countries; but before girls can receive the HPV vaccine, parental consent is usually needed, so it is important to know what influences parental decisions about HPV vaccination. In this study, the researchers undertake a telephone survey to determine the uptake of the HPV vaccine by 11-year-old girls (grade 6) in British Columbia, Canada, and to determine the parental factors associated with vaccine uptake; British Columbia started a voluntary school-based HPV vaccine program in September 2008.
What Did the Researchers Do and Find?
In early 2009, the researchers contacted randomly selected parents of girls enrolled in grade 6 during the 2008–2009 academic year and asked them to complete a telephone survey that explored factors associated with HPV vaccine uptake. 65.1% of the 2,025 parents who completed the survey had consented to their daughter receiving the first dose of HPV vaccine. By contrast, more than 85% of the parents had consented to hepatitis B and meningitis C vaccination of their daughters. Nearly half of the parents surveyed said their main reason for consenting to HPV vaccination was the effectiveness of the vaccine. Conversely, nearly a third of the parents said concern about the vaccine's safety was their main reason for not consenting to vaccination and one in eight said they had been given insufficient information to make an informed decision. In a statistical analysis of the survey data, the researchers found that a positive parental attitude towards vaccination, a parental belief that HPV vaccination had limited impact on sexual practices, and completed childhood vaccination increased the likelihood of a daughter receiving the HPV vaccine. Having a family with two parents or three or more children and having well-educated parents decreased the likelihood of a daughter receiving the vaccine.
What Do These Findings Mean?
These findings provide one of the first population-based assessments of the factors that affect HPV vaccine uptake in a setting where there are no financial or health care barriers to vaccination. By identifying the factors associated with parental reluctance to agree to HPV vaccination for their daughters, these findings should help public-health officials design strategies to ensure optimal HPV vaccine uptake, although further studies are needed to discover why, for example, parents with more education are less likely to agree to vaccination than parents with less education. Importantly, the findings of this study, which are likely to be generalizable to other high-income countries, indicate that there is a continued need to ensure that the public receives credible, clear information about both the benefits and long-term safety of HPV vaccination.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000270.
The US National Cancer Institute provides information about cervical cancer for patients and for health professionals, including information on HPV vaccines (in English and Spanish)
The US Centers for Disease Control and Prevention also has information about cervical cancer and about HPV
The UK National Health Service Choices website has pages on cervical cancer and on HPV vaccination
More information about cervical cancer and HPV vaccination is available from the Macmillan cancer charity
ImmunizeBC provides general information about vaccination and information about HPV vaccination in British Columbia
MedlinePlus provides links to additional resources about cervical cancer (in English and Spanish)
doi:10.1371/journal.pmed.1000270
PMCID: PMC2864299  PMID: 20454567
11.  Cross-sectional survey of older peoples' views related to influenza vaccine uptake 
BMC Public Health  2006;6:249.
Background
The population's views concerning influenza vaccine are important in maintaining high uptake of a vaccine that is required yearly to be effective. Little is also known about the views of the more vulnerable older population over the age of 74 years.
Methods
A cross-sectional survey of community dwelling people aged 75 years and over wh, previous participant was conducted using a postal questionnaire. Responses were analysed by vaccine uptake records and by socio-demographic and medical factors.
Results
85% of men and 75% of women were vaccinated against influenza in the previous year. Over 80% reported being influenced by a recommendation by a health care worker. The most common reason reported for non uptake was good health (44%), or illness considered to be due to the vaccine (25%). An exploration of the crude associations with socio-economic status suggested there may be some differences in the population with these two main reasons. 81% of people reporting good health lived in owner occupied housing with central heating vs. 63% who did not state this as a reason (p = 0.04), whereas people reporting ill health due to the vaccine was associated with poorer social circumstances. 11% lived in the least deprived neighbourhood compared to 36% who did not state this as a reason (p = 0.05) and were less likely to be currently married than those who did not state this as a reason (25% vs 48% p = 0.05).
Conclusion
Vaccine uptake was high, but non uptake was still noted in 1 in 4 women and 1 in 7 men aged over 74 years. Around 70% reported they would not have the vaccine in the following year. The divergent reasons for non-uptake, and the positive influence from a health care worker, suggests further uptake will require education and encouragement from a health care worker tailored towards the different views for not having influenza vaccination. Non-uptake of influenza vaccine because people viewed themselves as in good health may explain the modest socio-economic differentials in influenza vaccine uptake in elderly people noted elsewhere. Reporting of ill-health due to the vaccine may be associated with a different, poorer background.
doi:10.1186/1471-2458-6-249
PMCID: PMC1621069  PMID: 17034625
12.  Predicting the Epidemic Sizes of Influenza A/H1N1, A/H3N2, and B: A Statistical Method 
PLoS Medicine  2011;8(7):e1001051.
Using weekly influenza surveillance data from the US CDC, Edward Goldstein and colleagues develop a statistical method to predict the sizes of epidemics caused by seasonal influenza strains. This method could inform decisions about the most appropriate vaccines or drugs needed early in the influenza season.
Background
The epidemic sizes of influenza A/H3N2, A/H1N1, and B infections vary from year to year in the United States. We use publicly available US Centers for Disease Control (CDC) influenza surveillance data between 1997 and 2009 to study the temporal dynamics of influenza over this period.
Methods and Findings
Regional outpatient surveillance data on influenza-like illness (ILI) and virologic surveillance data were combined to define a weekly proxy for the incidence of each strain in the United States. All strains exhibited a negative association between their cumulative incidence proxy (CIP) for the whole season (from calendar week 40 of each year to calendar week 20 of the next year) and the CIP of the other two strains (the complementary CIP) from the start of the season up to calendar week 2 (or 3, 4, or 5) of the next year. We introduce a method to predict a particular strain's CIP for the whole season by following the incidence of each strain from the start of the season until either the CIP of the chosen strain or its complementary CIP exceed certain thresholds. The method yielded accurate predictions, which generally occurred within a few weeks of the peak of incidence of the chosen strain, sometimes after that peak. For the largest seasons in the data, which were dominated by A/H3N2, prediction of A/H3N2 incidence always occurred at least several weeks in advance of the peak.
Conclusion
Early circulation of one influenza strain is associated with a reduced total incidence of the other strains, consistent with the presence of interference between subtypes. Routine ILI and virologic surveillance data can be combined using this new method to predict the relative size of each influenza strain's epidemic by following the change in incidence of a given strain in the context of the incidence of cocirculating strains.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Every winter in temperate countries, millions of people catch influenza, a viral infection of the nose, throat, and airways. Most infected individuals recover quickly but seasonal influenza outbreaks (epidemics) kill about half a million people annually. Epidemics of influenza occur because small but frequent changes in the viral proteins (antigens) to which the immune system responds mean that an immune response produced one year provides only partial protection against influenza the next year. Annual immunization with a vaccine that contains killed influenza viruses of the major circulating strains boosts this natural immunity and greatly reduces a person's chances of catching influenza. Influenza epidemics in temperate latitudes are usually caused by an influenza B virus or one of two influenza A subtypes called A/H3N2 and A/H1N1. The names of the influenza A viruses indicate the types of two major influenza antigens—hemagglutinin (H3 or H1) and neuraminidase (N2 or N1)—present in the viruses.
Why Was This Study Done?
At present, there is no way to predict whether influenza B or an influenza A subtype will be dominant (responsible for the majority of infections) in any given influenza season. There is also no way to predict the size of the epidemic that will be caused by each viral strain. Public health officials would like to be able to make predictions of this sort early in the winter to help them determine which measures to recommend to minimize the illness and death caused by influenza. In this study, the researchers use weekly influenza surveillance data collected by the US Centers for Disease Control and Prevention (CDC) to study the temporal dynamics of seasonal influenza in the United States between 1997 and 2009 and to develop a statistical method to predict the sizes of epidemics caused by influenza A/H1N1, A/H3N2, and B.
What Did the Researchers Do and Find?
The CDC influenza surveillance system collects information on the proportion of patients attending US outpatient facilities who have an influenza-like illness (fever and a cough and/or a sore throat in the absence of any known cause other than influenza) and on the proportion of respiratory viral isolates testing positive for specific influenza strains at US viral surveillance laboratories. The researchers combined these data to define a weekly “proxy” incidence of each influenza strain across the United States (an estimate of the number of new cases per week in the US population) and a cumulative incidence proxy (CIP) for each influenza season. For each strain, there was a negative association between its whole-season CIP and the early-season CIP of the other two strains (the complementary CIP). That is, high infection rates with one strain appeared to interfere with the transmission of other strains. Given this relationship, the researchers then developed a statistical algorithm (a step-by-step problem solving method) that accurately predicted the whole-season CIP for a particular strain by following the incidence of each strain from the start of the season until either its CIP or the complementary CIP had exceeded a specific threshold. So, for example, for influenza B, the algorithm provided an accurate prediction of the whole-season CIP before the peak of influenza B incidence for each season included in the study. Similarly, prediction of whole-season A/H3N2 incidence always occurred several weeks in advance of its weekly incidence peak.
What Do These Findings Mean?
These findings suggest that early circulation of one influenza strain is associated with a reduced total incidence of other strains, possibly because of cross-subtype immunity. Importantly, they also suggest that routine early-season surveillance data can be used to predict the relative size of the epidemics caused by each influenza strain in the United States and in other countries where sufficient surveillance data are available. Because the algorithm makes many assumptions and simplifies the behavior of influenza epidemics, its predictions may not always be accurate. Moreover, it needs to be tested with data collected over more influenza seasons. Nevertheless, the algorithm's ability to predict the relative epidemic size of A/H3N2, the influenza strain with the highest death rates, several weeks before its peak in seasons in which it was the dominant strain suggests that this predictive method could help public-health officials introduce relevant preventative and/or treatment measures early in each influenza season.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001051.
The US Centers for Disease Control and Prevention provides information for patients and health professionals on all aspects of seasonal influenza, including information about the US influenza surveillance system
The UK National Health Service Choices Web site also provides information for patients about seasonal influenza; the UK Health Protection Agency provides information on influenza surveillance in the UK
MedlinePlus has links to further information about influenza l (in English and Spanish)
doi:10.1371/journal.pmed.1001051
PMCID: PMC3130020  PMID: 21750666
13.  Modeling the Worldwide Spread of Pandemic Influenza: Baseline Case and Containment Interventions 
PLoS Medicine  2007;4(1):e13.
Background
The highly pathogenic H5N1 avian influenza virus, which is now widespread in Southeast Asia and which diffused recently in some areas of the Balkans region and Western Europe, has raised a public alert toward the potential occurrence of a new severe influenza pandemic. Here we study the worldwide spread of a pandemic and its possible containment at a global level taking into account all available information on air travel.
Methods and Findings
We studied a metapopulation stochastic epidemic model on a global scale that considers airline travel flow data among urban areas. We provided a temporal and spatial evolution of the pandemic with a sensitivity analysis of different levels of infectiousness of the virus and initial outbreak conditions (both geographical and seasonal). For each spreading scenario we provided the timeline and the geographical impact of the pandemic in 3,100 urban areas, located in 220 different countries. We compared the baseline cases with different containment strategies, including travel restrictions and the therapeutic use of antiviral (AV) drugs. We investigated the effect of the use of AV drugs in the event that therapeutic protocols can be carried out with maximal coverage for the populations in all countries. In view of the wide diversity of AV stockpiles in different regions of the world, we also studied scenarios in which only a limited number of countries are prepared (i.e., have considerable AV supplies). In particular, we compared different plans in which, on the one hand, only prepared and wealthy countries benefit from large AV resources, with, on the other hand, cooperative containment scenarios in which countries with large AV stockpiles make a small portion of their supplies available worldwide.
Conclusions
We show that the inclusion of air transportation is crucial in the assessment of the occurrence probability of global outbreaks. The large-scale therapeutic usage of AV drugs in all hit countries would be able to mitigate a pandemic effect with a reproductive rate as high as 1.9 during the first year; with AV supply use sufficient to treat approximately 2% to 6% of the population, in conjunction with efficient case detection and timely drug distribution. For highly contagious viruses (i.e., a reproductive rate as high as 2.3), even the unrealistic use of supplies corresponding to the treatment of approximately 20% of the population leaves 30%–50% of the population infected. In the case of limited AV supplies and pandemics with a reproductive rate as high as 1.9, we demonstrate that the more cooperative the strategy, the more effective are the containment results in all regions of the world, including those countries that made part of their resources available for global use.
A metapopulation stochastic epidemic model for influenza shows the need to include air transportation when assessing the occurrence probability of global outbreaks. The impact of the use of antiviral drugs is also measured.
Editors' Summary
Background.
Seasonal outbreaks (epidemics) of influenza—a viral infection of the nose, throat, and airways—affect millions of people and kill about 500,000 individuals every year. Regular epidemics occur because flu viruses frequently make small changes in the viral proteins (antigens) recognized by the human immune system. Consequently, a person's immune-system response that combats influenza one year provides incomplete protection the next year. Occasionally, a human influenza virus appears that contains large antigenic changes. People have little immunity to such viruses (which often originate in birds or animals), so they can start a global epidemic (pandemic) that kills millions of people. Experts fear that a human influenza pandemic could be triggered by the avian H5N1 influenza virus, which is present in bird flocks around the world. So far, fewer than 300 people have caught this virus but more than 150 people have died.
Why Was This Study Done?
Avian H5N1 influenza has not yet triggered a human pandemic, because it rarely passes between people. If it does acquire this ability, it would take 6–8 months to develop a vaccine to provide protection against this new, potentially pandemic virus. Public health officials therefore need other strategies to protect people during the first few months of a pandemic. These could include international travel restrictions and the use of antiviral drugs. However, to get the most benefit from these interventions, public-health officials need to understand how influenza pandemics spread, both over time and geographically. In this study, the researchers have used detailed information on air travel to model the global spread of an emerging influenza pandemic and its containment.
What Did the Researchers Do and Find?
The researchers incorporated data on worldwide air travel and census data from urban centers near airports into a mathematical model of the spread of an influenza pandemic. They then used this model to investigate how the spread and health effects of a pandemic flu virus depend on the season in which it emerges (influenza virus thrives best in winter), where it emerges, and how infectious it is. Their model predicts, for example, that a flu virus originating in Hanoi, Vietnam, with a reproductive number (R0) of 1.1 (a measure of how many people an infectious individual infects on average) poses a very mild global threat. However, epidemics initiated by a virus with an R0 of more than 1.5 would often infect half the population in more than 100 countries. Next, the researchers used their model to show that strict travel restrictions would have little effect on pandemic evolution. More encouragingly, their model predicts that antiviral drugs would mitigate pandemics of a virus with an R0 up to 1.9 if every country had an antiviral drug stockpile sufficient to treat 5% of its population; if the R0 was 2.3 or higher, the pandemic would not be contained even if 20% of the population could be treated. Finally, the researchers considered a realistic scenario in which only a few countries possess antiviral stockpiles. In these circumstances, compared with a “selfish” strategy in which countries only use their antiviral drugs within their borders, limited worldwide sharing of antiviral drugs would slow down the spread of a flu virus with an R0 of 1.9 by more than a year and would benefit both drug donors and recipients.
What Do These Findings Mean?
Like all mathematical models, this model for the global spread of an emerging pandemic influenza virus contains many assumptions (for example, about viral behavior) that might affect the accuracy of its predictions. The model also does not consider variations in travel frequency between individuals or viral spread in rural areas. Nevertheless, the model provides the most extensive global simulation of pandemic influenza spread to date. Reassuringly, it suggests that an emerging virus with a low R0 would not pose a major public-health threat, since its attack rate would be limited and would not peak for more than a year, by which time a vaccine could be developed. Most importantly, the model suggests that cooperative sharing of antiviral drugs, which could be organized by the World Health Organization, might be the best way to deal with an emerging influenza pandemic.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0040013.
The US Centers for Disease Control and Prevention has information about influenza for patients and professionals, including key facts about avian influenza and antiviral drugs
The US National Institute of Allergy and Infectious Disease features information on seasonal, avian, and pandemic flu
The US Department of Health and Human Services provides information on pandemic flu and avian flu, including advice to travelers
World Health Organization has fact sheets on influenza and avian influenza, including advice to travelers and current pandemic flu threat
The UK Health Protection Agency has information on seasonal, avian, and pandemic influenza
The UK Department of Health has a feature article on bird flu and pandemic influenza
doi:10.1371/journal.pmed.0040013
PMCID: PMC1779816  PMID: 17253899
14.  Influenza and Pneumococcal Vaccinations for Patients With Chronic Obstructive Pulmonary Disease (COPD) 
Executive Summary
In July 2010, the Medical Advisory Secretariat (MAS) began work on a Chronic Obstructive Pulmonary Disease (COPD) evidentiary framework, an evidence-based review of the literature surrounding treatment strategies for patients with COPD. This project emerged from a request by the Health System Strategy Division of the Ministry of Health and Long-Term Care that MAS provide them with an evidentiary platform on the effectiveness and cost-effectiveness of COPD interventions.
After an initial review of health technology assessments and systematic reviews of COPD literature, and consultation with experts, MAS identified the following topics for analysis: vaccinations (influenza and pneumococcal), smoking cessation, multidisciplinary care, pulmonary rehabilitation, long-term oxygen therapy, noninvasive positive pressure ventilation for acute and chronic respiratory failure, hospital-at-home for acute exacerbations of COPD, and telehealth (including telemonitoring and telephone support). Evidence-based analyses were prepared for each of these topics. For each technology, an economic analysis was also completed where appropriate. In addition, a review of the qualitative literature on patient, caregiver, and provider perspectives on living and dying with COPD was conducted, as were reviews of the qualitative literature on each of the technologies included in these analyses.
The Chronic Obstructive Pulmonary Disease Mega-Analysis series is made up of the following reports, which can be publicly accessed at the MAS website at: http://www.hqontario.ca/en/mas/mas_ohtas_mn.html.
Chronic Obstructive Pulmonary Disease (COPD) Evidentiary Framework
Influenza and Pneumococcal Vaccinations for Patients With Chronic Obstructive Pulmonary Disease (COPD): An Evidence-Based Analysis
Smoking Cessation for Patients With Chronic Obstructive Pulmonary Disease (COPD): An Evidence-Based Analysis
Community-Based Multidisciplinary Care for Patients With Stable Chronic Obstructive Pulmonary Disease (COPD): An Evidence-Based Analysis
Pulmonary Rehabilitation for Patients With Chronic Obstructive Pulmonary Disease (COPD): An Evidence-Based Analysis
Long-term Oxygen Therapy for Patients With Chronic Obstructive Pulmonary Disease (COPD): An Evidence-Based Analysis
Noninvasive Positive Pressure Ventilation for Acute Respiratory Failure Patients With Chronic Obstructive Pulmonary Disease (COPD): An Evidence-Based Analysis
Noninvasive Positive Pressure Ventilation for Chronic Respiratory Failure Patients With Stable Chronic Obstructive Pulmonary Disease (COPD): An Evidence-Based Analysis
Hospital-at-Home Programs for Patients with Acute Exacerbations of Chronic Obstructive Pulmonary Disease (COPD): An Evidence-Based Analysis
Home Telehealth for Patients With Chronic Obstructive Pulmonary Disease (COPD): An Evidence-Based Analysis
Cost-Effectiveness of Interventions for Chronic Obstructive Pulmonary Disease Using an Ontario Policy Model
Experiences of Living and Dying With COPD: A Systematic Review and Synthesis of the Qualitative Empirical Literature
For more information on the qualitative review, please contact Mita Giacomini at: http://fhs.mcmaster.ca/ceb/faculty_member_giacomini.htm.
For more information on the economic analysis, please visit the PATH website: http://www.path-hta.ca/About-Us/Contact-Us.aspx.
The Toronto Health Economics and Technology Assessment (THETA) collaborative has produced an associated report on patient preference for mechanical ventilation. For more information, please visit the THETA website: http://theta.utoronto.ca/static/contact.
Objective
The objective of this analysis was to determine the effectiveness of the influenza vaccination and the pneumococcal vaccination in patients with chronic obstructive pulmonary disease (COPD) in reducing the incidence of influenza-related illness or pneumococcal pneumonia.
Clinical Need: Condition and Target Population
Influenza Disease
Influenza is a global threat. It is believed that the risk of a pandemic of influenza still exists. Three pandemics occurred in the 20th century which resulted in millions of deaths worldwide. The fourth pandemic of H1N1 influenza occurred in 2009 and affected countries in all continents.
Rates of serious illness due to influenza viruses are high among older people and patients with chronic conditions such as COPD. The influenza viruses spread from person to person through sneezing and coughing. Infected persons can transfer the virus even a day before their symptoms start. The incubation period is 1 to 4 days with a mean of 2 days. Symptoms of influenza infection include fever, shivering, dry cough, headache, runny or stuffy nose, muscle ache, and sore throat. Other symptoms such as nausea, vomiting, and diarrhea can occur.
Complications of influenza infection include viral pneumonia, secondary bacterial pneumonia, and other secondary bacterial infections such as bronchitis, sinusitis, and otitis media. In viral pneumonia, patients develop acute fever and dyspnea, and may further show signs and symptoms of hypoxia. The organisms involved in bacterial pneumonia are commonly identified as Staphylococcus aureus and Hemophilus influenza. The incidence of secondary bacterial pneumonia is most common in the elderly and those with underlying conditions such as congestive heart disease and chronic bronchitis.
Healthy people usually recover within one week but in very young or very old people and those with underlying medical conditions such as COPD, heart disease, diabetes, and cancer, influenza is associated with higher risks and may lead to hospitalization and in some cases death. The cause of hospitalization or death in many cases is viral pneumonia or secondary bacterial pneumonia. Influenza infection can lead to the exacerbation of COPD or an underlying heart disease.
Streptococcal Pneumonia
Streptococcus pneumoniae, also known as pneumococcus, is an encapsulated Gram-positive bacterium that often colonizes in the nasopharynx of healthy children and adults. Pneumococcus can be transmitted from person to person during close contact. The bacteria can cause illnesses such as otitis media and sinusitis, and may become more aggressive and affect other areas of the body such as the lungs, brain, joints, and blood stream. More severe infections caused by pneumococcus are pneumonia, bacterial sepsis, meningitis, peritonitis, arthritis, osteomyelitis, and in rare cases, endocarditis and pericarditis.
People with impaired immune systems are susceptible to pneumococcal infection. Young children, elderly people, patients with underlying medical conditions including chronic lung or heart disease, human immunodeficiency virus (HIV) infection, sickle cell disease, and people who have undergone a splenectomy are at a higher risk for acquiring pneumococcal pneumonia.
Technology
Influenza and Pneumococcal Vaccines
Trivalent Influenza Vaccines in Canada
In Canada, 5 trivalent influenza vaccines are currently authorized for use by injection. Four of these are formulated for intramuscular use and the fifth product (Intanza®) is formulated for intradermal use.
The 4 vaccines for intramuscular use are:
Fluviral (GlaxoSmithKline), split virus, inactivated vaccine, for use in adults and children ≥ 6 months;
Vaxigrip (Sanofi Pasteur), split virus inactivated vaccine, for use in adults and children ≥ 6 months;
Agriflu (Novartis), surface antigen inactivated vaccine, for use in adults and children ≥ 6 months; and
Influvac (Abbott), surface antigen inactivated vaccine, for use in persons ≥ 18 years of age.
FluMist is a live attenuated virus in the form of an intranasal spray for persons aged 2 to 59 years. Immunization with current available influenza vaccines is not recommended for infants less than 6 months of age.
Pneumococcal Vaccine
Pneumococcal polysaccharide vaccines were developed more than 50 years ago and have progressed from 2-valent vaccines to the current 23-valent vaccines to prevent diseases caused by 23 of the most common serotypes of S pneumoniae. Canada-wide estimates suggest that approximately 90% of cases of pneumococcal bacteremia and meningitis are caused by these 23 serotypes. Health Canada has issued licenses for 2 types of 23-valent vaccines to be injected intramuscularly or subcutaneously:
Pneumovax 23® (Merck & Co Inc. Whitehouse Station, NJ, USA), and
Pneumo 23® (Sanofi Pasteur SA, Lion, France) for persons 2 years of age and older.
Other types of pneumococcal vaccines licensed in Canada are for pediatric use. Pneumococcal polysaccharide vaccine is injected only once. A second dose is applied only in some conditions.
Research Questions
What is the effectiveness of the influenza vaccination and the pneumococcal vaccination compared with no vaccination in COPD patients?
What is the safety of these 2 vaccines in COPD patients?
What is the budget impact and cost-effectiveness of these 2 vaccines in COPD patients?
Research Methods
Literature search
Search Strategy
A literature search was performed on July 5, 2010 using OVID MEDLINE, MEDLINE In-Process and Other Non-Indexed Citations, EMBASE, the Cumulative Index to Nursing & Allied Health Literature (CINAHL), the Cochrane Library, and the International Agency for Health Technology Assessment (INAHTA) for studies published from January 1, 2000 to July 5, 2010. The search was updated monthly through the AutoAlert function of the search up to January 31, 2011. Abstracts were reviewed by a single reviewer and, for those studies meeting the eligibility criteria, full-text articles were obtained. Articles with an unknown eligibility were reviewed with a second clinical epidemiologist and then a group of epidemiologists until consensus was established. Data extraction was carried out by the author.
Inclusion Criteria
studies comparing clinical efficacy of the influenza vaccine or the pneumococcal vaccine with no vaccine or placebo;
randomized controlled trials published between January 1, 2000 and January 31, 2011;
studies including patients with COPD only;
studies investigating the efficacy of types of vaccines approved by Health Canada;
English language studies.
Exclusion Criteria
non-randomized controlled trials;
studies investigating vaccines for other diseases;
studies comparing different variations of vaccines;
studies in which patients received 2 or more types of vaccines;
studies comparing different routes of administering vaccines;
studies not reporting clinical efficacy of the vaccine or reporting immune response only;
studies investigating the efficacy of vaccines not approved by Health Canada.
Outcomes of Interest
Primary Outcomes
Influenza vaccination: Episodes of acute respiratory illness due to the influenza virus.
Pneumococcal vaccination: Time to the first episode of community-acquired pneumonia either due to pneumococcus or of unknown etiology.
Secondary Outcomes
rate of hospitalization and mechanical ventilation
mortality rate
adverse events
Quality of Evidence
The quality of each included study was assessed taking into consideration allocation concealment, randomization, blinding, power/sample size, withdrawals/dropouts, and intention-to-treat analyses. The quality of the body of evidence was assessed as high, moderate, low, or very low according to the GRADE Working Group criteria. The following definitions of quality were used in grading the quality of the evidence:
Summary of Efficacy of the Influenza Vaccination in Immunocompetent Patients With COPD
Clinical Effectiveness
The influenza vaccination was associated with significantly fewer episodes of influenza-related acute respiratory illness (ARI). The incidence density of influenza-related ARI was:
All patients: vaccine group: (total of 4 cases) = 6.8 episodes per 100 person-years; placebo group: (total of 17 cases) = 28.1 episodes per 100 person-years, (relative risk [RR], 0.2; 95% confidence interval [CI], 0.06−0.70; P = 0.005).
Patients with severe airflow obstruction (forced expiratory volume in 1 second [FEV1] < 50% predicted): vaccine group: (total of 1 case) = 4.6 episodes per 100 person-years; placebo group: (total of 7 cases) = 31.2 episodes per 100 person-years, (RR, 0.1; 95% CI, 0.003−1.1; P = 0.04).
Patients with moderate airflow obstruction (FEV1 50%−69% predicted): vaccine group: (total of 2 cases) = 13.2 episodes per 100 person-years; placebo group: (total of 4 cases) = 23.8 episodes per 100 person-years, (RR, 0.5; 95% CI, 0.05−3.8; P = 0.5).
Patients with mild airflow obstruction (FEV1 ≥ 70% predicted): vaccine group: (total of 1 case) = 4.5 episodes per 100 person-years; placebo group: (total of 6 cases) = 28.2 episodes per 100 person-years, (RR, 0.2; 95% CI, 0.003−1.3; P = 0.06).
The Kaplan-Meier survival analysis showed a significant difference between the vaccinated group and the placebo group regarding the probability of not acquiring influenza-related ARI (log-rank test P value = 0.003). Overall, the vaccine effectiveness was 76%. For categories of mild, moderate, or severe COPD the vaccine effectiveness was 84%, 45%, and 85% respectively.
With respect to hospitalization, fewer patients in the vaccine group compared with the placebo group were hospitalized due to influenza-related ARIs, although these differences were not statistically significant. The incidence density of influenza-related ARIs that required hospitalization was 3.4 episodes per 100 person-years in the vaccine group and 8.3 episodes per 100 person-years in the placebo group (RR, 0.4; 95% CI, 0.04−2.5; P = 0.3; log-rank test P value = 0.2). Also, no statistically significant differences between the 2 groups were observed for the 3 categories of severity of COPD.
Fewer patients in the vaccine group compared with the placebo group required mechanical ventilation due to influenza-related ARIs. However, these differences were not statistically significant. The incidence density of influenza-related ARIs that required mechanical ventilation was 0 episodes per 100 person-years in the vaccine group and 5 episodes per 100 person-years in the placebo group (RR, 0.0; 95% CI, 0−2.5; P = 0.1; log-rank test P value = 0.4). In addition, no statistically significant differences between the 2 groups were observed for the 3 categories of severity of COPD. The effectiveness of the influenza vaccine in preventing influenza-related ARIs and influenza-related hospitalization was not related to age, sex, severity of COPD, smoking status, or comorbid diseases.
safety
Overall, significantly more patients in the vaccine group than the placebo group experienced local adverse reactions (vaccine: 17 [27%], placebo: 4 [6%]; P = 0.002). Significantly more patients in the vaccine group than the placebo group experienced swelling (vaccine 4, placebo 0; P = 0.04) and itching (vaccine 4, placebo 0; P = 0.04). Systemic reactions included headache, myalgia, fever, and skin rash and there were no significant differences between the 2 groups for these reactions (vaccine: 47 [76%], placebo: 51 [81%], P = 0.5).
With respect to lung function, dyspneic symptoms, and exercise capacity, there were no significant differences between the 2 groups at 1 week and at 4 weeks in: FEV1, maximum inspiratory pressure at residual volume, oxygen saturation level of arterial blood, visual analogue scale for dyspneic symptoms, and the 6 Minute Walking Test for exercise capacity.
There was no significant difference between the 2 groups with regard to the probability of not acquiring total ARIs (influenza-related and/or non-influenza-related); (log-rank test P value = 0.6).
Summary of Efficacy of the Pneumococcal Vaccination in Immunocompetent Patients With COPD
Clinical Effectiveness
The Kaplan-Meier survival analysis showed no significant differences between the group receiving the penumoccocal vaccination and the control group for time to the first episode of community-acquired pneumonia due to pneumococcus or of unknown etiology (log-rank test 1.15; P = 0.28). Overall, vaccine efficacy was 24% (95% CI, −24 to 54; P = 0.33).
With respect to the incidence of pneumococcal pneumonia, the Kaplan-Meier survival analysis showed a significant difference between the 2 groups (vaccine: 0/298; control: 5/298; log-rank test 5.03; P = 0.03).
Hospital admission rates and median length of hospital stays were lower in the vaccine group, but the difference was not statistically significant. The mortality rate was not different between the 2 groups.
Subgroup Analysis
The Kaplan-Meier survival analysis showed significant differences between the vaccine and control groups for pneumonia due to pneumococcus and pneumonia of unknown etiology, and when data were analyzed according to subgroups of patients (age < 65 years, and severe airflow obstruction FEV1 < 40% predicted). The accumulated percentage of patients without pneumonia (due to pneumococcus and of unknown etiology) across time was significantly lower in the vaccine group than in the control group in patients younger than 65 years of age (log-rank test 6.68; P = 0.0097) and patients with a FEV1 less than 40% predicted (log-rank test 3.85; P = 0.0498).
Vaccine effectiveness was 76% (95% CI, 20−93; P = 0.01) for patients who were less than 65 years of age and −14% (95% CI, −107 to 38; P = 0.8) for those who were 65 years of age or older. Vaccine effectiveness for patients with a FEV1 less than 40% predicted and FEV1 greater than or equal to 40% predicted was 48% (95% CI, −7 to 80; P = 0.08) and −11% (95% CI, −132 to 47; P = 0.95), respectively. For patients who were less than 65 years of age (FEV1 < 40% predicted), vaccine effectiveness was 91% (95% CI, 35−99; P = 0.002).
Cox modelling showed that the effectiveness of the vaccine was dependent on the age of the patient. The vaccine was not effective in patients 65 years of age or older (hazard ratio, 1.53; 95% CI, 0.61−a2.17; P = 0.66) but it reduced the risk of acquiring pneumonia by 80% in patients less than 65 years of age (hazard ratio, 0.19; 95% CI, 0.06−0.66; P = 0.01).
safety
No patients reported any local or systemic adverse reactions to the vaccine.
PMCID: PMC3384373  PMID: 23074431
15.  Analysing Recent Socioeconomic Trends in Coronary Heart Disease Mortality in England, 2000–2007: A Population Modelling Study 
PLoS Medicine  2012;9(6):e1001237.
A modeling study conducted by Madhavi Bajekal and colleagues estimates the extent to which specific risk factors and changes in uptake of treatment contributed to the declines in coronary heart disease mortality in England between 2000 and 2007, across and within socioeconomic groups.
Background
Coronary heart disease (CHD) mortality in England fell by approximately 6% every year between 2000 and 2007. However, rates fell differentially between social groups with inequalities actually widening. We sought to describe the extent to which this reduction in CHD mortality was attributable to changes in either levels of risk factors or treatment uptake, both across and within socioeconomic groups.
Methods and Findings
A widely used and replicated epidemiological model was used to synthesise estimates stratified by age, gender, and area deprivation quintiles for the English population aged 25 and older between 2000 and 2007. Mortality rates fell, with approximately 38,000 fewer CHD deaths in 2007. The model explained about 86% (95% uncertainty interval: 65%–107%) of this mortality fall. Decreases in major cardiovascular risk factors contributed approximately 34% (21%–47%) to the overall decline in CHD mortality: ranging from about 44% (31%–61%) in the most deprived to 29% (16%–42%) in the most affluent quintile. The biggest contribution came from a substantial fall in systolic blood pressure in the population not on hypertension medication (29%; 18%–40%); more so in deprived (37%) than in affluent (25%) areas. Other risk factor contributions were relatively modest across all social groups: total cholesterol (6%), smoking (3%), and physical activity (2%). Furthermore, these benefits were partly negated by mortality increases attributable to rises in body mass index and diabetes (−9%; −17% to −3%), particularly in more deprived quintiles. Treatments accounted for approximately 52% (40%–70%) of the mortality decline, equitably distributed across all social groups. Lipid reduction (14%), chronic angina treatment (13%), and secondary prevention (11%) made the largest medical contributions.
Conclusions
The model suggests that approximately half the recent CHD mortality fall in England was attributable to improved treatment uptake. This benefit occurred evenly across all social groups. However, opposing trends in major risk factors meant that their net contribution amounted to just over a third of the CHD deaths averted; these also varied substantially by socioeconomic group. Powerful and equitable evidence-based population-wide policy interventions exist; these should now be urgently implemented to effectively tackle persistent inequalities.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Coronary heart disease is a chronic medical condition in which the blood vessels supplying the heart muscle become narrowed or even blocked by fatty deposits on the inner linings of the blood vessels—a process known as arthrosclerosis; this restricts blood flow to the heart, and if the blood vessels completely occlude, it may cause a heart attack. Lifestyle behaviors, such as unhealthy diets high in saturated fat, smoking, and physical inactivity, are the main risk factors for coronary heart disease, so efforts to reduce this condition are directed towards these factors. Global rates of coronary heart disease are increasing and the World Health Organization estimates that by 2030, it will be the biggest cause of death worldwide. However, in high-income countries, such as England, deaths due to coronary heart disease have actually fallen substantially over the past few decades with an accelerated reduction in annual death rates since 2000.
Why Was This Study Done?
Socioeconomic factors play an important role in chronic diseases such as coronary heart disease, with mortality rates almost twice as high in deprived than affluent areas. However, the potential effect of population-wide interventions on reducing inequalities in deaths from coronary heart disease remains unclear. So in this study, the researchers investigated the role of behavioral (changing lifestyle) and medical (treatments) management of coronary heart disease that contributed to the decrease in deaths in England for the period 2000–2007, within and between socioeconomic groups.
What Did the Researchers Do and Find?
The researchers used a well-known, tried and tested epidemiological model (IMPACT) but adapted it to include socioeconomic inequalities to analyze the total population of England aged 25 and older in 2000 and in 2007. The researchers included all the major risk factors for coronary heart disease plus 45 current medical and surgical treatments in their model. They used the Index of Multiple Deprivation 2007 as a proxy indicator of socioeconomic circumstances of residents in neighborhoods. Using the postal code of residence, the researchers matched deaths from, and patients treated for, coronary heart disease to the corresponding deprivation category (quintile). Changes in risk factor levels in each quintile were also calculated using the Health Survey for England. Using their model, the researchers calculated the total number of deaths prevented or postponed for each deprivation quintile by measuring the difference between observed deaths in 2007 and expected deaths based on 2000 data, if age, sex, and deprivation quintile death rates had remained the same.
The researchers found that between 2000 and 2007, death rates from coronary heart disease fell from 229 to 147 deaths per 100,000—a decrease of 36%. Both death rates and the number of deaths were lowest in the most affluent quintile and the pace of fall was also faster, decreasing by 6.7% per year compared to just 4.9% in the most deprived quintile. Furthermore, the researchers found that overall, about half of the decrease in death rates was attributable to improvements in uptake of medical and surgical treatments. The contribution of medical treatments to the deaths averted was very similar across all quintiles, ranging from 50% in the most affluent quintile to 53% in the most deprived. Risk factor changes accounted for approximately a third fewer deaths in 2007 than occurred in 2000, but were responsible for a smaller proportion of deaths prevented in the most affluent quintile compared with the most deprived (approximately 29% versus 44%, respectively). However, the benefits of improvements in blood pressure, cholesterol, smoking, and physical activity were partly negated by rises in body mass index and diabetes, particularly in more deprived quintiles.
What Do These Findings Mean?
These findings suggest that approximately half the recent substantial fall in deaths from coronary heart disease in England was attributable to improved treatment uptake across all social groups; this is consistent with equitable service delivery across the UK's National Health Service. However, opposing trends in major risk factors, which varied substantially by socioeconomic group, meant that their net contribution accounted for just a third of deaths averted. Other countries have implemented effective, evidence-based interventions to tackle lifestyle risk factors; the most powerful measures involve legislation, regulation, taxation, or subsidies, all of which tend to be equitable. Such measures should be urgently implemented in England to effectively tackle persistent inequalities in deaths due to coronary heart disease.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001237.
The World Health Organization has information about the global statistics of coronary heart disease
The National Heart Lung and Blood Institute provides a patient-friendly description of coronary heart disease
The National Heart Forum is the leading UK organization facilitating the prevention of coronary heart disease and other chronic diseases
The British Heart Foundation supports research and promotes preventative activity
Heart of Mersey is the UK's largest regional organization promoting the prevention of coronary heart disease and other chronic diseases
More information about the social determinants of health is available from WHO
doi:10.1371/journal.pmed.1001237
PMCID: PMC3373639  PMID: 22719232
16.  Feasibility, Yield, and Cost of Active Tuberculosis Case Finding Linked to a Mobile HIV Service in Cape Town, South Africa: A Cross-sectional Study 
PLoS Medicine  2012;9(8):e1001281.
Katharina Kranzer and colleagues investigate the operational characteristics of an active tuberculosis case-finding service linked to a mobile HIV testing unit that operates in underserviced areas in Cape Town, South Africa.
Background
The World Health Organization is currently developing guidelines on screening for tuberculosis disease to inform national screening strategies. This process is complicated by significant gaps in knowledge regarding mass screening. This study aimed to assess feasibility, uptake, yield, treatment outcomes, and costs of adding an active tuberculosis case-finding program to an existing mobile HIV testing service.
Methods and Findings
The study was conducted at a mobile HIV testing service operating in deprived communities in Cape Town, South Africa. All HIV-negative individuals with symptoms suggestive of tuberculosis, and all HIV-positive individuals regardless of symptoms were eligible for participation and referred for sputum induction. Samples were examined by microscopy and culture. Active tuberculosis case finding was conducted on 181 days at 58 different sites. Of the 6,309 adults who accessed the mobile clinic, 1,385 were eligible and 1,130 (81.6%) were enrolled. The prevalence of smear-positive tuberculosis was 2.2% (95% CI 1.1–4.0), 3.3% (95% CI 1.4–6.4), and 0.4% (95% CI 1.4 015–6.4) in HIV-negative individuals, individuals newly diagnosed with HIV, and known HIV, respectively. The corresponding prevalence of culture-positive tuberculosis was 5.3% (95% CI 3.5–7.7), 7.4% (95% CI 4.5–11.5), 4.3% (95% CI 2.3–7.4), respectively. Of the 56 new tuberculosis cases detected, 42 started tuberculosis treatment and 34 (81.0%) completed treatment. The cost of the intervention was US$1,117 per tuberculosis case detected and US$2,458 per tuberculosis case cured. The generalisability of the study is limited to similar settings with comparable levels of deprivation and TB and HIV prevalence.
Conclusions
Mobile active tuberculosis case finding in deprived populations with a high burden of HIV and tuberculosis is feasible, has a high uptake, yield, and treatment success. Further work is now required to examine cost-effectiveness and affordability and whether and how the same results may be achieved at scale.
Editors' Summary
Background
In 2010, 8.8 million people developed active tuberculosis—a contagious bacterial infection—and 1.4 million people died from the disease. Most of these deaths were in low- and middle-income countries and a quarter were in HIV-positive individuals—people who are infected with HIV, the virus that causes AIDS, are particularly susceptible to tuberculosis because of their weakened immune system. Tuberculosis is caused by Mycobacterium tuberculosis, which is spread in airborne droplets when people with the disease cough or sneeze. Its characteristic symptoms are a persistent cough, unintentional weight loss, hemoptysis (coughing up blood from the lungs), fever, and night sweats. Diagnostic tests for tuberculosis include sputum smear microscopy (microscopic analysis of mucus brought up from the lungs by coughing) and culture (growth) of M. tuberculosis from sputum samples. Tuberculosis can be cured by taking several powerful antibiotics daily for at least 6 months.
Why Was This Study Done?
To improve tuberculosis control, active disease must be diagnosed quickly and treated immediately. Passive tuberculosis case finding, which relies on people seeking medical help because they feel unwell, delays the diagnosis and treatment of tuberculosis and increases M. tuberculosis transmission. By contrast, active tuberculosis case finding—where health workers seek out and diagnose individuals with TB who have not sought care on their own initiative—has the potential to reduce tuberculosis transmission by improving case detection. The World Health Organization (WHO), which already recommends active tuberculosis case finding in HIV-infected individuals as part of its HIV/TB “Three I's” strategy, is currently developing guidelines to inform the design of national tuberculosis screening strategies based on the local prevalence of HIV and TB and other context-specific factors that affect how many individuals need to be screened to identify each additional new tuberculosis case (the “yield” of active case finding). Large gaps in our knowledge about mass-screening strategies are complicating the development of these guidelines so, in this observational prospective study, the researchers assess the feasibility, uptake, yield, treatment outcomes, and costs of adding an active tuberculosis case-finding program to an existing mobile HIV testing service in South Africa.
What Did the Researchers Do and Find?
All HIVnegative adults with symptoms characteristic of tuberculosis and all HIV-positive adults regardless of symptoms who attended a mobile HIV testing service operating in deprived communities in ape Town, South Africa between May 2009 and February 2011 were eligible for inclusion in the study. Of the 6,309 adults who accessed the mobile clinic during this period, 1,385 met these eligibility criteria, and 1,130 were enrolled and referred for the collection of sputum samples, which were analyzed by microscopy and culture. The prevalence of smear-positive tuberculosis was 2.2%, 3.3%, and 0.4% among HIV-negative study participants, newly diagnosed HIV-positive participants, and people already known to have HIV, respectively. The corresponding prevalences for smear-negative/culture-positive tuberculosis were 5.3%, 7.4%, and 4.3%, respectively (culture detects more tuberculosis cases than microscopy but, whereas microscopy can provide a result within 1–2 days, culture can take several weeks). Fifty-six new tuberculosis cases were identified, 42 people started tuberculosis treatment, and 34 completed treatment (a treatment success rate of 81%). Finally, the incremental cost of the intervention was US$1,117 per tuberculosis case detected and US$2,458 per tuberculosis case cured.
What Do These Findings Mean?
These findings show that active case finding for tuberculosis delivered through a mobile HIV testing service is feasible and has a high uptake, yield and treatment success in deprived communities with a high prevalence of HIV and tuberculosis. The findings also highlight the challenges faced by mobile population-based services such as losses between tuberculosis diagnosis and treatment, which were greatest for smear-negative/culture-positive people who were more difficult to contact than smear-positive people because of the greater time lag between sputum collection and diagnosis. Because the study was done in a single city, these findings need to be confirmed in other settings—the yield of active tuberculosis case finding reported here, for example, is not likely to be generalizable to countries that rely on sputum smears for tuberculosis diagnosis. Finally, given that the incremental cost per case treated in this study is 3-fold higher than the incremental cost per case treated under passive case detection in South Africa, further studies are needed to determine the cost-effectiveness and affordability of population-based tuberculosis screening.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001281.
The World Health Organization provides information on all aspects of tuberculosis, including information on tuberculosis and HIV, and on the Three I?s for HIV/TB (some information is in several languages); details of a 2011 meeting on the development of guidelines on screening for active tuberculosis are available
The Stop TB partnership is working towards tuberculosis elimination; patient stories about tuberculosis/HIV coinfection are available
The US Centers for Disease Control and Prevention has information about tuberculosis, about tuberculosis and HIV co-infection, and about the diagnosis of tuberculosis disease
The US National Institute of Allergy and Infectious Diseases also has detailed information on all aspects of tuberculosis
MedlinePlus has links to further information about tuberculosis (in English and Spanish)
The Tuberculosis Survival Project, which aims to raise awareness of tuberculosis and provide support for people with tuberculosis, provides personal stories about treatment for tuberculosis; the Tuberculosis Vaccine Initiative also provides personal stories about dealing with tuberculosis
doi:10.1371/journal.pmed.1001281
PMCID: PMC3413719  PMID: 22879816
17.  Socioeconomic Inequalities in Lung Cancer Treatment: Systematic Review and Meta-Analysis 
PLoS Medicine  2013;10(2):e1001376.
In a systematic review and meta-analysis, Lynne Forrest and colleagues find that patients with lung cancer who are more socioeconomically deprived are less likely to receive surgical treatment, chemotherapy, or any type of treatment combined, compared with patients who are more socioeconomically well off, regardless of cancer stage or type of health care system.
Background
Intervention-generated inequalities are unintended variations in outcome that result from the organisation and delivery of health interventions. Socioeconomic inequalities in treatment may occur for some common cancers. Although the incidence and outcome of lung cancer varies with socioeconomic position (SEP), it is not known whether socioeconomic inequalities in treatment occur and how these might affect mortality. We conducted a systematic review and meta-analysis of existing research on socioeconomic inequalities in receipt of treatment for lung cancer.
Methods and Findings
MEDLINE, EMBASE, and Scopus were searched up to September 2012 for cohort studies of participants with a primary diagnosis of lung cancer (ICD10 C33 or C34), where the outcome was receipt of treatment (rates or odds of receiving treatment) and where the outcome was reported by a measure of SEP. Forty-six papers met the inclusion criteria, and 23 of these papers were included in meta-analysis. Socioeconomic inequalities in receipt of lung cancer treatment were observed. Lower SEP was associated with a reduced likelihood of receiving any treatment (odds ratio [OR] = 0.79 [95% CI 0.73 to 0.86], p<0.001), surgery (OR = 0.68 [CI 0.63 to 0.75], p<0.001) and chemotherapy (OR = 0.82 [95% CI 0.72 to 0.93], p = 0.003), but not radiotherapy (OR = 0.99 [95% CI 0.86 to 1.14], p = 0.89), for lung cancer. The association remained when stage was taken into account for receipt of surgery, and was found in both universal and non-universal health care systems.
Conclusions
Patients with lung cancer living in more socioeconomically deprived circumstances are less likely to receive any type of treatment, surgery, and chemotherapy. These inequalities cannot be accounted for by socioeconomic differences in stage at presentation or by differences in health care system. Further investigation is required to determine the patient, tumour, clinician, and system factors that may contribute to socioeconomic inequalities in receipt of lung cancer treatment.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Lung cancer is the most commonly occurring cancer worldwide and the commonest cause of cancer-related death. Like all cancers, lung cancer occurs when cells begin to grow uncontrollably because of changes in their genes. The most common trigger for these changes in lung cancer is exposure to cigarette smoke. Most cases of lung cancer are non-small cell lung cancer, the treatment for which depends on the “stage” of the disease when it is detected. Stage I tumors, which are confined to the lung, can be removed surgically. Stage II tumors, which have spread to nearby lymph nodes, are usually treated with surgery plus chemotherapy or radiotherapy. For more advanced tumors, which have spread throughout the chest (stage III) or throughout the body (stage IV), surgery generally does not help to slow tumor growth and the cancer is treated with chemotherapy and radiotherapy. Small cell lung cancer, the other main type of lung cancer, is nearly always treated with chemotherapy and radiotherapy but sometimes with surgery as well. Overall, because most lung cancers are not detected until they are quite advanced, less than 10% of people diagnosed with lung cancer survive for 5 years.
Why Was This Study Done?
As with many other cancers, socioeconomic inequalities have been reported for both the incidence of and the survival from lung cancer in several countries. It is thought that the incidence of lung cancer is higher among people of lower socioeconomic position than among wealthier people, in part because smoking rates are higher in poorer populations. Similarly, it has been suggested that survival is worse among poorer people because they tend to present with more advanced disease, which has a worse prognosis (predicted outcome) than early disease. But do socioeconomic inequalities in treatment exist for lung cancer and, if they do, could these inequalities contribute to the poor survival rates among populations of lower socioeconomic position? In this systematic review and meta-analysis, the researchers investigate the first of these questions. A systematic review uses predefined criteria to identify all the research on a given topic; a meta-analysis is a statistical approach that combines the results of several studies.
What Did the Researchers Do and Find?
The researchers identified 46 published papers that studied people with lung cancer in whom receipt of treatment was reported in terms of an indicator of socioeconomic position, such as a measure of income or deprivation. Twenty-three of these papers were suitable for inclusion in a meta-analysis. Lower socioeconomic position was associated with a reduced likelihood of receiving any treatment. Specifically, the odds ratio (chance) of people in the lowest socioeconomic group receiving any treatment was 0.79 compared to people in the highest socioeconomic group. Lower socioeconomic position was also associated with a reduced chance of receiving surgery (OR = 0.68) and chemotherapy (OR = 0.82), but not radiotherapy. The association between socioeconomic position and surgery remained after taking cancer stage into account. That is, when receipt of surgery was examined in early-stage patients only, low socioeconomic position remained associated with reduced likelihood of surgery. Notably, the association between socioeconomic position and receipt of treatment was similar in studies undertaken in countries where health care is free at the point of service for everyone (for example, the UK) and in countries with primarily private insurance health care systems (for example, the US).
What Do These Findings Mean?
These findings suggest that patients in more socioeconomically deprived circumstances are less likely to receive any type of treatment, surgery, and chemotherapy (but not radiotherapy) for lung cancer than people who are less socioeconomically deprived. Importantly, these inequalities cannot be explained by socioeconomic differences in stage at presentation or by differences in health care system. The accuracy of these findings may be affected by several factors. For example, it is possible that only studies that found an association between socioeconomic position and receipt of treatment have been published (publication bias). Moreover, the studies identified did not include information regarding patient preferences, which could help explain at least some of the differences. Nevertheless, these results do suggest that socioeconomic inequalities in receipt of treatment may exacerbate socioeconomic inequalities in the incidence of lung cancer and may contribute to the observed poorer outcomes in lower socioeconomic position groups. Further research is needed to determine the system and patient factors that contribute to socioeconomic inequalities in lung cancer treatment before clear recommendations for changes to policy and practice can be made.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001376.
The US National Cancer Institute provides information about all aspects of lung cancer for patients and health care professionals (in English and Spanish); a monograph entitled Area Socioeconomic Variations in U. S. Cancer Incidence, Mortality, Stage, Treatment, and Survival, 19751999 is available
Cancer Research UK also provides detailed information about lung cancer and links to other resources, such as a policy statement on socioeconomic inequalities in cancer and a monograph detailing cancer and health inequalities in the UK
The UK National Health Service Choices website has a page on lung cancer that includes personal stories about diagnosis and treatment
MedlinePlus provides links to other US sources of information about lung cancer (in English and Spanish)
doi:10.1371/journal.pmed.1001376
PMCID: PMC3564770  PMID: 23393428
18.  Prevalence of visual impairment in people aged 75 years and older in Britain: results from the MRC trial of assessment and management of older people in the community 
Aims: To measure the prevalence of visual impairment in a large representative sample of people aged 75 years and over participating in the MRC trial of assessment and management of older people in the community.
Methods: 53 practices in the MRC general practice research framework. Data were obtained from 14 600 participants aged 75 years and older. Prevalence of visual impairment overall (binocular visual acuity <6/18) which was categorised separately into low vision (binocular visual acuity <6/18–3/60) or blindness (binocular visual acuity of <3/60). The prevalence of binocular acuity <6/12 was presented for comparison with other studies. Visual acuity was measured using Glasgow acuity charts; glasses, if worn, were not removed.
Results: Visual acuity was available for 14 600 people out of 21 241 invited (69%). Among people with visual acuity data, 12.4% overall (1803) were visually impaired (95% confidence intervals 10.8% to 13.9%); 1501 (10.3%) were categorised as having low vision (8.7% to 11.8%), and 302 (2.1%) were blind (1.8% to 2.4%). At ages 75–79, 6.2% of the cohort were visually impaired (5.1% to 7.3%) with 36.9% at age 90+ (32.5% to 41.3%). At ages 75–79, 0.6% (0.4% to 0.8%) of the study population were blind, with 6.9% (4.8% to 9.0%) at age 90+. In multivariate regression, controlling for age, women had significant excess risk of visual impairment (odds ratio 1.43, 95% confidence interval 1.29 to 1.58). Overall, 19.9% of study participants had a binocular acuity of less than 6/12 (17.8% to 22.0%).
Conclusion: The results from this large study show that visual impairment is common in the older population and that this risk increases rapidly with advancing age, especially for women. A relatively conservative measure of visual impairment was used. If visual impairment had been defined as visual acuity of <6/12 (American definition of visual impairment), the age specific prevalence estimates would have increased by 60%.
PMCID: PMC1771210  PMID: 12084753
visual impairment; blindness; prevalence; elderly
19.  Efficacy of Neonatal HBV Vaccination on Liver Cancer and Other Liver Diseases over 30-Year Follow-up of the Qidong Hepatitis B Intervention Study: A Cluster Randomized Controlled Trial 
PLoS Medicine  2014;11(12):e1001774.
In a 30-year follow-up of the Qidong Hepatitis B Intervention Study, Yawei Zhang and colleagues examine the effects of neonatal vaccination on liver diseases.
Please see later in the article for the Editors' Summary
Background
Neonatal hepatitis B vaccination has been implemented worldwide to prevent hepatitis B virus (HBV) infections. Its long-term protective efficacy on primary liver cancer (PLC) and other liver diseases has not been fully examined.
Methods and Findings
The Qidong Hepatitis B Intervention Study, a population-based, cluster randomized, controlled trial between 1985 and 1990 in Qidong, China, included 39,292 newborns who were randomly assigned to the vaccination group in which 38,366 participants completed the HBV vaccination series and 34,441 newborns who were randomly assigned to the control group in which the participants received neither a vaccine nor a placebo. However, 23,368 (67.8%) participants in the control group received catch-up vaccination at age 10–14 years. By December 2013, a total of 3,895 (10.2%) in the vaccination group and 3,898 (11.3%) in the control group were lost to follow-up. Information on PLC incidence and liver disease mortality were collected through linkage of all remaining cohort members to a well-established population-based tumor registry until December 31, 2013. Two cross-sectional surveys on HBV surface antigen (HBsAg) seroprevalence were conducted in 1996–2000 and 2008–2012. The participation rates of the two surveys were 57.5% (21,770) and 50.7% (17,204) in the vaccination group and 36.3% (12,184) and 58.6% (17,395) in the control group, respectively. Using intention-to-treat analysis, we found that the incidence rate of PLC and the mortality rates of severe end-stage liver diseases and infant fulminant hepatitis were significantly lower in the vaccination group than the control group with efficacies of 84% (95% CI 23%–97%), 70% (95% CI 15%–89%), and 69% (95% CI 34%–85%), respectively. The estimated efficacy of catch-up vaccination on HBsAg seroprevalence in early adulthood was 21% (95% CI 10%–30%), substantially weaker than that of the neonatal vaccination (72%, 95% CI 68%–75%). Receiving a booster at age 10–14 years decreased HBsAg seroprevalence if participants were born to HBsAg-positive mothers (hazard ratio [HR] = 0.68, 95% CI 0.47–0.97). Limitations to consider in interpreting the study results include the small number of individuals with PLC, participants lost to follow-up, and the large proportion of participants who did not provide serum samples at follow-up.
Conclusions
Neonatal HBV vaccination was found to significantly decrease HBsAg seroprevalence in childhood through young adulthood and subsequently reduce the risk of PLC and other liver diseases in young adults in rural China. The findings underscore the importance of neonatal HBV vaccination. Our results also suggest that an adolescence booster should be considered in individuals born to HBsAg-positive mothers and who have completed the HBV neonatal vaccination series.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Hepatitis B is a life-threatening liver infection caused by the hepatitis B virus (HBV). HBV, which is transmitted through contact with the blood or other bodily fluids of an infected person, can cause both acute (short-term) and chronic (long-term) liver infections. Acute infections rarely cause any symptoms and more than 90% of adults who become infected with HBV (usually through sexual intercourse with an infected partner or through the use of contaminated needles) are virus-free within 6 months. However, in sub-Saharan Africa, East Asia, and other regions where HBV infection is common, HBV is usually transmitted from mother to child at birth or between individuals during early childhood and, unfortunately, most infants who are infected with HBV during the first year of life and many children who are infected before the age of 6 years develop a chronic HBV infection. Such infections can cause liver cancer, liver cirrhosis (scarring of the liver), and other fatal liver diseases. In addition, HBV infection around the time of birth can cause infant fulminant hepatitis, a rare but frequently fatal condition.
Why Was This Study Done?
HBV infections kill about 780,000 people worldwide annually but can be prevented by neonatal vaccination—immunization against HBV at birth. A vaccine against HBV became available in 1982 and many countries now include HBV vaccination at birth followed by additional vaccine doses during early childhood in their national vaccination programs. But, although HBV vaccination has greatly reduced the rate of chronic HBV infection, the protective efficacy of neonatal HBV vaccination against liver diseases has not been fully examined. Here, the researchers investigate how well neonatal HBV vaccination protects against primary liver cancer and other liver diseases by undertaking a 30-year follow-up of the Qidong Hepatitis B intervention Study (QHBIS). This cluster randomized controlled trial of neonatal HBV vaccination was conducted between 1983 and 1990 in Qidong County, a rural area in China with a high incidence of HBV-related primary liver cancer and other liver diseases. A cluster randomized controlled trial compares outcomes in groups of people (towns in this study) chosen at random to receive an intervention or a control treatment (here, vaccination or no vaccination; this study design was ethically acceptable during the 1980s when HBV vaccination was unavailable in rural China but would be unethical nowadays).
What Did the Researchers Do and Find?
The QHBIS assigned nearly 80,000 newborns to receive either a full course of HBV vaccinations (the vaccination group) or no vaccination (the control group); two-thirds of the control group participants received a catch-up vaccination at age 10–14 years. The researchers obtained data on how many trial participants developed primary liver cancer or died from a liver disease during the follow-up period from a population-based tumor registry. They also obtained information on HBsAg seroprevalence—the presence of HBsAg (an HBV surface protein) in the blood of the participants, an indicator of current HBV infection—from surveys undertaken in1996–2000 and 2008–2012. The researchers estimate that the protective efficacy of vaccination was 84% for primary liver cancer (vaccination reduced the incidence of liver cancer by 84%), 70% for death from liver diseases, and 69% for the incidence of infant fulminant hepatitis. Overall, the efficacy of catch-up vaccination on HBsAg seroprevalence in early adulthood was weak compared with neonatal vaccination (21% versus 72%). Notably, receiving a booster vaccination at age 10–14 years decreased HBsAg seroprevalence among participants who were born to HBsAg-positive mothers.
What Do These Findings Mean?
The small number of cases of primary liver cancer and other liver diseases observed during the 30-year follow-up, the length of follow-up, and the availability of incomplete data on seroprevalence all limit the accuracy of these findings. Nevertheless, these findings indicate that neonatal HBV vaccination greatly reduced HBsAg seroprevalence (an indicator of current HBV infection) in childhood and young adulthood and subsequently reduced the risk of liver cancer and other liver diseases in young adults. These findings therefore support the importance of neonatal HBV vaccination. In addition, they suggest that booster vaccination during adolescence might consolidate the efficacy of neonatal vaccination among individuals who were born to HBsAg-positive mothers, a suggestion that needs to be confirmed in randomized controlled trials before booster vaccines are introduced into vaccination programs.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001774.
The World Health Organization provides a fact sheet about hepatitis B (available in several languages) and information about hepatitis B vaccination
The World Hepatitis Alliance (an international not-for-profit, non-governmental organization) provides information about viral hepatitis, including some personal stories about hepatitis B from Bangladesh, Pakistan, the Philippines, and Malawi
The UK National Health Service Choices website provides information about hepatitis B
The not-for-profit British Liver Trust provides information about hepatitis B, including Hepatitis B: PATH B, an interactive educational resource designed to improve the lives of people living with chronic hepatitis B
MedlinePlus provides links to other resources about hepatitis B (in English and Spanish)
Information about the Qidong Hepatitis B intervention Study is available
Chinese Center for Disease Control and Prevention provides links about hepatitis B prevention in Chinese
doi:10.1371/journal.pmed.1001774
PMCID: PMC4280122  PMID: 25549238
20.  Frequency of Adverse Events after Vaccination with Different Vaccinia Strains 
PLoS Medicine  2006;3(8):e272.
Background
Large quantities of smallpox vaccine have been stockpiled to protect entire nations against a possible reintroduction of smallpox. Planning for an appropriate use of these stockpiled vaccines in response to a smallpox outbreak requires a rational assessment of the risks of vaccination-related adverse events, compared to the risk of contracting an infection. Although considerable effort has been made to understand the dynamics of smallpox transmission in modern societies, little attention has been paid to estimating the frequency of adverse events due to smallpox vaccination. Studies exploring the consequences of smallpox vaccination strategies have commonly used a frequency of approximately one death per million vaccinations, which is based on a study of vaccination with the New York City Board of Health (NYCBH) strain of vaccinia virus. However, a multitude of historical studies of smallpox vaccination with other vaccinia strains suggest that there are strain-related differences in the frequency of adverse events after vaccination. Because many countries have stockpiled vaccine based on the Lister strain of vaccinia virus, a quantitative evaluation of the adverse effects of such vaccines is essential for emergency response planning. We conducted a systematic review and statistical analysis of historical data concerning vaccination against smallpox with different strains of vaccinia virus.
Methods and Findings
We analyzed historical vaccination data extracted from the literature. We extracted data on the frequency of postvaccinal encephalitis and death with respect to vaccinia strain and age of vaccinees. Using a hierarchical Bayesian approach for meta-analysis, we estimated the expected frequencies of postvaccinal encephalitis and death with respect to age at vaccination for smallpox vaccines based on the NYCBH and Lister vaccinia strains. We found large heterogeneity between findings from different studies and a time-period effect that showed decreasing incidences of adverse events over several decades. To estimate death rates, we then restricted our analysis to more-recent studies. We estimated that vaccination with the NYCBH strain leads to an average of 1.4 deaths per million vaccinations (95% credible interval, 0–6) and that vaccination with Lister vaccine leads to an average of 8.4 deaths per million vaccinations (95% credible interval, 0–31). We combined age-dependent estimates of the frequency of death after vaccination and revaccination with demographic data to obtain estimates of the expected number of deaths in present societies due to vaccination with the NYCBH and Lister vaccinia strains.
Conclusions
Previous analyses of smallpox vaccination policies, which rely on the commonly assumed value of one death per million vaccinations, may give serious underestimates of the number of deaths resulting from vaccination. Moreover, because there are large, strain-dependent differences in the frequency of adverse events due to smallpox vaccination, it is difficult to extrapolate from predictions for the NYCBH-derived vaccines (stockpiled in countries such as the US) to predictions for the Lister-derived vaccines (stockpiled in countries such as Germany). In planning for an effective response to a possible smallpox outbreak, public-health decision makers should reconsider their strategies of when to opt for ring vaccination and when to opt for mass vaccination.
Analysis of historical data for adverse events suggests that the commonly assumed number of one death per million vaccinations is inaccurate. Large differences between different vaccinia strains used should be taken into account when mass vaccinations are considered.
Editors' Summary
Background.
For thousands of years, smallpox was one of the world's most-feared diseases. This contagious disease, caused by the variola virus, historically killed about 30 percent of the people it infected. Over the centuries, it probably killed more people than all other infectious diseases combined, but it was also the first disease to be prevented by vaccination. In 1796, the English physician Edward Jenner rubbed pus from the spots of a milkmaid with cowpox into scratches on a young boy's arm; according to folklore, people who caught cowpox, a related but mild disease of cows, were protected against smallpox. Six weeks later, after a mild bout of cowpox, when the boy was challenged with pus from a smallpox patient, he did not develop smallpox. This vaccination procedure was later refined so that people were inoculated with pure preparations of live vaccinia virus, which is closely related to the smallpox and cowpox viruses, and by 1979 a global vaccination campaign had totally eradicated the disease.
Why Was This Study Done?
Smallpox vaccination has some adverse effects. In particular, vaccinia virus occasionally infects the brain. This so-called post-vaccination encephalitis can cause permanent brain damage and, it has been estimated, kills one vaccinee in every million. Consequently, as smallpox became rarer, the dangers of vaccination began to outweigh its benefits. Routine smallpox vaccination stopped in the US in 1972, and in 1980 the World Health Organization recommended that all countries stop vaccination. Now, however, there are fears that smallpox may be used for bioterrorism. If this did happen, exposed individuals and their contacts, possibly even whole populations, would have to be vaccinated as quickly as possible (very few people now have strong immunity to smallpox). Many countries have stockpiles of smallpox vaccines for this eventuality, but these contain different vaccinia virus strains. In this study, the researchers examined historical data to discover whether these strains differ in their potential to cause encephalitis and death. This information should help public-health officials plan their vaccination strategies in response to a bioterrorism attack with smallpox.
What Did the Researchers Do and Find?
The researchers collected data from published studies on smallpox vaccination and adverse events from several countries from the late 1950s onwards. They then used these data to extrapolate how often the different vaccinia strains might cause encephalitis and death if they were used today in vaccination programs. They estimate that vaccinating with the New York City Board of Health (NYCBH) strain, which is stockpiled in the US, might cause 2.9 cases of post-vaccination encephalitis and 1.4 deaths per million vaccinated individuals. In contrast, the Lister strain, which is stockpiled in many European countries, might cause 26.2 cases of post-vaccination encephalitis and 2.5 deaths per million vaccinees. For both strains, vaccination of children younger than 1 year old would cause the highest death rate, and individuals being re-vaccinated would be less likely to die than those being vaccinated for the first time. Finally, the researchers use their figures to estimate that about ten people would die if mass vaccination with the NYCBH strain were used in the Netherlands (population 16 million), whereas 55 people would die if the Lister strain were used.
What Do These Findings Mean?
The data used in this study are of variable quality, so the figures calculated by the researchers are only estimates. For instance, given the scatter of the original data, mass vaccination in the Netherlands with the Lister strain might cause anywhere between seven and nearly 200 deaths. However, the study clearly suggests that more serious adverse events would occur after vaccination with the Lister strain than after vaccination with the NYCBH strain. It also indicates that even in the US, where the NYCBH vaccine strain is stockpiled, previous analyses of the effects of vaccination in response to a bioterrorist attack have probably underestimated how many people might die from post-vaccination encephalitis. Public-health decision makers should incorporate these new estimates into their planning for a smallpox outbreak. These increased estimates of adverse events after vaccination might, for example, make mass vaccination with the Lister strain of vaccinia virus less acceptable. Instead, public-health officials might decide to rely on vaccination of only the people directly exposed to released smallpox virus and their close contacts (ring vaccination) to contain a smallpox outbreak.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0030272.
World Health Organization, information on smallpox and preparedness in the event of a smallpox outbreak
MedlinePlus encyclopedia entry on smallpox
US National Institute of Allergy and Infectious Diseases, patient fact sheet on smallpox
US Centers for Disease Control and Prevention, information for patients and professionals on smallpox
Wikipedia page on smallpox (note that Wikipedia is a free online encyclopedia that anyone can edit)
Wellcome Library MedHist, links to information on the history of smallpox vaccination
doi:10.1371/journal.pmed.0030272
PMCID: PMC1551910  PMID: 16933957
21.  Safety and Allele-Specific Immunogenicity of a Malaria Vaccine in Malian Adults: Results of a Phase I Randomized Trial 
PLoS Clinical Trials  2006;1(7):e34.
Objectives:
The objectives were to evaluate the safety, reactogenicity, and allele-specific immunogenicity of the blood-stage malaria vaccine FMP1/AS02A in adults exposed to seasonal malaria and the impact of natural infection on vaccine-induced antibody levels.
Design:
We conducted a randomized, double-blind, controlled phase I clinical trial.
Setting:
Bandiagara, Mali, West Africa, is a rural town with intense seasonal transmission of Plasmodium falciparum malaria.
Participants:
Forty healthy, malaria-experienced Malian adults aged 18–55 y were enrolled.
Interventions:
The FMP1/AS02A malaria vaccine is a 42-kDa recombinant protein based on the carboxy-terminal end of merozoite surface protein-1 (MSP-142) from the 3D7 clone of P. falciparum, adjuvanted with AS02A. The control vaccine was a killed rabies virus vaccine (Imovax). Participants were randomized to receive either FMP1/AS02A or rabies vaccine at 0, 1, and 2 mo and were followed for 1 y.
Outcome Measures:
Solicited and unsolicited adverse events and allele-specific antibody responses to recombinant MSP-142 and its subunits derived from P. falciparum strains homologous and heterologous to the 3D7 vaccine strain were measured.
Results:
Transient local pain and swelling were more common in the malaria vaccine group than in the control group (11/20 versus 3/20 and 10/20 versus 6/20, respectively). MSP-142 antibody levels rose during the malaria transmission season in the control group, but were significantly higher in malaria vaccine recipients after the second immunization and remained higher after the third immunization relative both to baseline and to the control group. Immunization with the malaria vaccine was followed by significant increases in antibodies recognizing three diverse MSP-142 alleles and their subunits.
Conclusions:
FMP1/AS02A was well tolerated and highly immunogenic in adults exposed to intense seasonal malaria transmission and elicited immune responses to genetically diverse parasite clones. Anti-MSP-142 antibody levels followed a seasonal pattern that was significantly augmented and prolonged by the malaria vaccine.
Editorial Commentary
Background: In sub-Saharan Africa the burden of death and disease from malaria is particularly severe. Most affected are young children under the age of five, in whom natural immunity against the malaria parasite has not yet developed. There are not yet any approved vaccines that would reduce this burden, although many research groups are currently developing potential vaccines. One such candidate vaccine is FMP1/AS02A. This vaccine is designed to trigger an immune response against a protein (merozoite surface protein-1, or MSP-1) found on the surface of the infectious, blood-stage form of the malaria parasite. Early-stage clinical trials have already been performed in healthy people in the United States, who were not exposed to clinical malaria, and in Kenyan adults who are exposed to malaria throughout the year. These studies did not identify any safety concerns regarding the candidate vaccine, which meant that it could progress further in clinical testing. As part of this next stage, a group of researchers wanted to examine the safety and ability of the vaccine to boost immune responses in an area of sub-Saharan Africa where people are not exposed to malaria throughout the year, but rather only in the wet season. The trial reported here was carried out in northeast Mali, in which 40 adults received either the FMP1/AS02A vaccine or a rabies vaccine for comparison, just at the start of the malaria transmission season. The researchers primarily looked at safety outcomes, collecting data on certain specific signs or symptoms up to 8 d after immunization, other reported symptoms up to 31 d after immunization, and any serious adverse events during a follow-up period of 364 d after immunization. The researchers also examined antibody levels in the participants' blood against the MSP-1 protein.
What this trial shows: The researchers found that participants receiving the FMP1/AS02A vaccine had more immediate symptoms at the injection site (for example, pain or swelling) than the comparison group did. Other general symptoms, both solicited and unsolicited, such as headache, muscle aches, fever, and infections, were also more common in the malaria vaccine group than in the group receiving the rabies vaccine. There were two serious adverse events in the vaccine group, but these were not judged to be related to the vaccination. Antibody levels against the MSP-1 protein increased in both study groups through the course of the rainy season (when individuals would be likely exposed to bites from malaria-infected mosquitoes) and subsequently fell after the end of the malaria transmission season. However, participants receiving the vaccine had higher antibody responses at all timepoints measured; the differences were statistically significant at some timepoints, but not at others. Finally, the researchers looked at antibody reactions against three different variants of the MSP-1 protein in sera from participants receiving the candidate vaccine and found that the sera reacted similarly to all three variants.
Strengths and limitations: The study protocol followed established procedures for phase I clinical trials of this type, which allows the data to be compared across studies. Randomization procedures were appropriate, and steps were taken to blind participants in the trial, as well as those assessing outcomes, to the intervention participants received. A limitation of this study, which can apply to other phase I studies in general, is that small numbers of participants were recruited. Therefore, the trial was not powered to detect statistically significant differences between participant groups. It is also not clear whether the higher antibody levels seen in the participants receiving the FMP1/AS02A vaccine would be biologically significant (that is, act to prevent clinical malaria cases), a question that would need to be addressed in further trials.
Contribution to the evidence: The safety results from this study are similar to those from other trials and confirm that no safety concerns have thus far been identified regarding the FMP1/AS02A vaccine, which has now progressed to efficacy testing. This study was also conducted in a population exposed to seasonal malaria, whereas previous trials had been done among people exposed to malaria year-round. Finally, results from the trial also suggest that this vaccine induces antibodies that recognize genetically diverse forms of the vaccine antigen.
doi:10.1371/journal.pctr.0010034
PMCID: PMC1851722  PMID: 17124530
22.  Evaluation of Coseasonality of Influenza and Invasive Pneumococcal Disease: Results from Prospective Surveillance 
PLoS Medicine  2011;8(6):e1001042.
Using a combination of modeling and statistical analyses, David Fisman and colleagues show that influenza likely influences the incidence of invasive pneumococcal disease by enhancing risk of invasion in colonized individuals.
Background
The wintertime co-occurrence of peaks in influenza and invasive pneumococcal disease (IPD) is well documented, but how and whether wintertime peaks caused by these two pathogens are causally related is still uncertain. We aimed to investigate the relationship between influenza infection and IPD in Ontario, Canada, using several complementary methodological tools.
Methods and Findings
We evaluated a total number of 38,501 positive influenza tests in Central Ontario and 6,191 episodes of IPD in the Toronto/Peel area, Ontario, Canada, between 1 January 1995 and 3 October 2009, reported through population-based surveillance. We assessed the relationship between the seasonal wave forms for influenza and IPD using fast Fourier transforms in order to examine the relationship between these two pathogens over yearly timescales. We also used three complementary statistical methods (time-series methods, negative binomial regression, and case-crossover methods) to evaluate the short-term effect of influenza dynamics on pneumococcal risk. Annual periodicity with wintertime peaks could be demonstrated for IPD, whereas periodicity for influenza was less regular. As for long-term effects, phase and amplitude terms of pneumococcal and influenza seasonal sine waves were not correlated and meta-analysis confirmed significant heterogeneity of influenza, but not pneumococcal phase terms. In contrast, influenza was shown to Granger-cause pneumococcal disease. A short-term association between IPD and influenza could be demonstrated for 1-week lags in both case-crossover (odds ratio [95% confidence interval] for one case of IPD per 100 influenza cases  = 1.10 [1.02–1.18]) and negative binomial regression analysis (incidence rate ratio [95% confidence interval] for one case of IPD per 100 influenza cases  = 1.09 [1.05–1.14]).
Conclusions
Our data support the hypothesis that influenza influences bacterial disease incidence by enhancing short-term risk of invasion in colonized individuals. The absence of correlation between seasonal waveforms, on the other hand, suggests that bacterial disease transmission is affected to a lesser extent.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Although some pathogens (disease-causing organisms) cause illness all year round, others are responsible for seasonal peaks of illness. These peaks occur because of a complex interplay of factors such as the loss of immunity to the pathogen over time and seasonal changes in the pathogen's ability to infect new individuals. Thus, in temperate countries in the northern hemisphere, illness caused by influenza viruses (pathogens that infect the nose, throat, and airways) usually peaks between December and March, perhaps because weather conditions during these months favor the survival of influenza virus in the environment and thus increase its chances of being transferred among people. Another illness that peaks during the winter months in temperate regions is pneumonia, a severe lung infection that is often caused by Streptococcus pneumoniae. These bacteria can colonize the back of the throat without causing disease but occasionally spread into the lungs and other organs where they cause potentially fatal invasive pneumococcal disease (IPD).
Why Was This Study Done?
Although the co-occurrence of seasonal peaks of influenza and IPD is well documented, it is unclear whether (or how) these peaks are causally related. For example, do the peaks of influenza and IPD both occur in the winter because influenza enhances person-to-person transmission of S. pneumoniae (hypothesis 1)? Alternatively, do the diseases co-occur because influenza infection increases the risk of IPD in individuals who are already colonized with S. pneumoniae (hypothesis 2)? Healthcare professionals need to know whether there is a causal relationship between influenza and IPD so that they can target vaccination for both diseases to those individuals most at risk of developing the potentially serious complications of these diseases. In this study, the researchers use several mathematical and statistical methods and data on influenza and IPD collected in Ontario, Canada to investigate the relationship between these seasonal illnesses.
What Did the Researchers Do and Find?
Between January 1995 and October 2009, 38,501 positive influenza tests were recorded in Ontario by the Canadian national influenza surveillance network. Over the same time period, the Toronto Invasive Bacterial Diseases Network (a group of hospitals, laboratories, and doctors that undertakes population-based surveillance for serious bacterial infections in the Toronto and Peel Regions of Ontario) recorded 6,191 IPD episodes. The researchers used a mathematical method called fast Fourier transforms that compares the shape of wave forms to look for any relationship between infections with the two pathogens over yearly timescales (a test of hypothesis 1) and three statistical methods to evaluate the short-term effect of influenza dynamics on IPD risk (tests of hypothesis 2). Although they found wintertime peaks for infections with both pathogens, there was no correlation between the seasonal wave forms for influenza and IPD. That is, there was no relationship between the seasonal patterns of the two infections. By contrast, two of the statistical methods used to test hypothesis 2 revealed a short-term association between infections with influenza and with IPD. Moreover, the third statistical method (the Granger causality Wald test, a type of time-series analysis) provided evidence that data collected at intervals on influenza can be used to predict peaks in IPD infections.
What Do These Findings Mean?
These findings support (but do not prove) the hypothesis that influenza influences IPD incidence by enhancing the short-term risk of bacterial invasion in individuals already colonized with S. pneumoniae, possibly by increasing the permeability of the lining of the airways to bacteria. By contrast, the lack of correlation between the seasonal wave forms for the two diseases suggests that person-to-person transfer of S. pneumoniae is affected by influenza infections to a lesser extent. These findings have important implications for disease control policy. First, they suggest that the increased number of influenza infections in pandemic years may not necessarily be accompanied by a marked surge in IPD. Second, because the findings suggest that some cases of IPD may be influenza-attributable, the extension of influenza vaccination to school-age children and young adults (a group of people at particular risk of IPD who are not normally vaccinated against influenza) could reduce the incidence of IPD as well as the incidence of influenza.
Additional Information
Please access these Web sites via the online version of this summary at http://www.plosone.org/article/info:doi/10.1371/journal.pone.0015493
A related research article by the same authors evaluating links between respiratory viruses and invasive meningococcal disease can be found in PLoS One (e0015493)
The US Centers for Disease Control and Prevention provides information for patients and health professionals on all aspects of seasonal influenza and pneumococcal disease and pneumococcal vaccination
The UK National Health Service Choices website also provides information for patients about seasonal influenza and pneumococcal infection
MedlinePlus has links to further information about influenza and pneumococcal infections (in English and Spanish)
FluWatch is the Canadian national surveillance system for influenza
More information about the Toronto Invasive Bacterial Network is available
The International Association for Ecology and Health provides information on the physical environment and its influence on health
doi:10.1371/journal.pmed.1001042
PMCID: PMC3110256  PMID: 21687693
23.  Association of quality of life in old age in Britain with socioeconomic position: baseline data from a randomised controlled trial 
Study objective: To identify socioeconomic differentials in quality of life among older people and their explanatory factors.
Design: Baseline data from a cluster randomised controlled trial of the assessment and management of older people in primary care. Outcome measures were being in the worst quintile of scores for, respectively, the Philadelphia geriatric morale scale and four dimensions of functioning from the sickness impact profile (home management, mobility, self care, and social interaction).
Setting: 23 general practices in Britain.
Participants: People aged 75 years and over on GP registers at the time of recruitment, excluding those in nursing homes or terminally ill. Of 9547 people eligible, 90% provided full information on quality of life and 6298 also did a brief assessment.
Results: The excess risk of poor quality of life for independent people renting rather than owning their home ranged from 27% for morale (95% CI 9% to 48%) to 62% for self care (95% CI 35% to 94%). Self reported health problems plus smoking and alcohol consumption accounted for half or more of the excess, depending on the outcome. Having a low socioeconomic position in middle age as well as in old age exacerbated the risks of poor outcomes. Among people living with someone other than spouse the excess risk from renting ranged from 24% (95%CI –10% to 70%) for poor home management to 93% (95%CI 30% to 180%) for poor morale.
Conclusions: Older people retain the legacy of past socioeconomic position and are subject to current socioeconomic influences.
doi:10.1136/jech.2003.014035
PMCID: PMC1732854  PMID: 15252069
24.  Indigenous Health and Socioeconomic Status in India 
PLoS Medicine  2006;3(10):e421.
Background
Systematic evidence on the patterns of health deprivation among indigenous peoples remains scant in developing countries. We investigate the inequalities in mortality and substance use between indigenous and non-indigenous, and within indigenous, groups in India, with an aim to establishing the relative contribution of socioeconomic status in generating health inequalities.
Methods and Findings
Cross-sectional population-based data were obtained from the 1998–1999 Indian National Family Health Survey. Mortality, smoking, chewing tobacco use, and alcohol use were four separate binary outcomes in our analysis. Indigenous status in the context of India was operationalized through the Indian government category of scheduled tribes, or Adivasis, which refers to people living in tribal communities characterized by distinctive social, cultural, historical, and geographical circumstances.
Indigenous groups experience excess mortality compared to non-indigenous groups, even after adjusting for economic standard of living (odds ratio 1.22; 95% confidence interval 1.13–1.30). They are also more likely to smoke and (especially) drink alcohol, but the prevalence of chewing tobacco is not substantially different between indigenous and non-indigenous groups. There are substantial health variations within indigenous groups, such that indigenous peoples in the bottom quintile of the indigenous-peoples-specific standard of living index have an odds ratio for mortality of 1.61 (95% confidence interval 1.33–1.95) compared to indigenous peoples in the top fifth of the wealth distribution. Smoking, drinking alcohol, and chewing tobacco also show graded associations with socioeconomic status within indigenous groups.
Conclusions
Socioeconomic status differentials substantially account for the health inequalities between indigenous and non-indigenous groups in India. However, a strong socioeconomic gradient in health is also evident within indigenous populations, reiterating the overall importance of socioeconomic status for reducing population-level health disparities, regardless of indigeneity.
Indigenous groups in India were found to have excess mortality rates compared with non-indigenous groups. A socioeconomic gradient within indigenous populations was also found.
Editors' Summary
Background.
In many parts of the world the majority of the population are the descendants of immigrants who arrived there within the last few hundred years. Living alongside of them, and in a minority, are the so-called indigenous (or aboriginal) people who are the descendants of people who lived there in more ancient times. It is estimated that there are 300 million indigenous people worldwide. They are frequently marginalized from the rest of the population, their human rights are often abused, and there are serious concerns about their health and welfare. The state of health of the indigenous people of developed countries such as the US and Australia has often been studied, and we have a fairly clear idea of the kinds of problems these people face. Most indigenous people, however, live in developing countries, and less is known about their health.
India is the second-most populous country in the world, with an estimated 1.1 billion inhabitants. An estimated 90 million indigenous people live in India, where they are often referred to as “scheduled tribes” or Adivasis. They live in many parts of the country but are much more numerous in some Indian states than in others.
Why Was This Study Done?
It has often been said that indigenous people in India have worse health than other Indians, though no figures have been compiled to confirm these claims. The researchers wanted to establish whether it is simply an issue of indigenous people being poorer than other Indians—poverty being well known as a cause of disease—or whether being indigenous is, in itself, a health risk. The researchers also wanted to establish whether there are health inequalities within indigenous groups, and if these differences also followed a socioeconomic patterning.
What Did the Researchers Do and Find?
They used figures collected in the 1998–1999 Indian National Family Health Survey. When this survey was conducted, it was noted whether people were considered to be members of scheduled tribes. The researchers also knew, from the survey, about the income of the families, their death rates, and whether they drank alcohol or smoked or chewed tobacco. They found that indigenous people had higher death rates than other Indians. They made statistical calculations to account for differences in standard of living, and this substantially reduced the difference in death rate among indigenous groups, but an indigenous person was still 1.2 times more likely to die than a non-indigenous person with the same standard of living. Indigenous people were also more likely to drink alcohol and smoke tobacco, and here again, differences in standard of living accounted for a substantial portion of the differences. Importantly, the researchers' analysis showed a strong socioeconomic patterning of health inequalities within the indigenous population groups: the health differences between the poorest and richest indigenous groups were similar in scale to the differences between the poorest and richest non-indigenous groups.
What Do These Findings Mean?
The authors consider their finding that there is a socioeconomic gradient in mortality and health behaviors among indigenous people to be an important result from the study. The socioeconomic marginalization of indigenous people from the rest of Indian society does seem to increase their health risks, and so does their use of alcohol and tobacco. However, if their standard of living can be improved there would be major benefits for their health and welfare.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0030421.
A useful discussion of the term “indigenous people” (with links to documents about international agreements intended to improve their human rights) may be found on Wikipedia. (Wikipedia is an internet encyclopedia that anyone can edit.)
Survival International is a human rights organization that campaigns for the rights of indigenous peoples, helping them preserve their land and culture.
The charity Health Unlimited also works with indigenous people and its Web site includes links to recent studies and conferences.
A news item from the BBC describes a recent investigation into the health of indigenous people worldwide.
The World Health Organization has produced a number of reports on the health of indigenous people
doi:10.1371/journal.pmed.0030421
PMCID: PMC1621109  PMID: 17076556
25.  The Relationship between Anti-merozoite Antibodies and Incidence of Plasmodium falciparum Malaria: A Systematic Review and Meta-analysis 
PLoS Medicine  2010;7(1):e1000218.
A systematic review and meta-analysis examining the association between anti-merozoite antibody responses and incidence of Plasmodium falciparum malaria by Freya Fowkes and colleagues aids identification of antigens that confer protection from malaria.
Background
One of the criteria to objectively prioritize merozoite antigens for malaria vaccine development is the demonstration that naturally acquired antibodies are associated with protection from malaria. However, published evidence of the protective effect of these antibodies is conflicting.
Methods and Findings
We performed a systematic review with meta-analysis of prospective cohort studies examining the association between anti-merozoite immunoglobin (Ig) G responses and incidence of Plasmodium falciparum malaria. Two independent researchers searched six databases and identified 33 studies that met predefined inclusion and quality criteria, including a rigorous definition of symptomatic malaria. We found that only five studies were performed outside sub-Saharan Africa and that there was a deficiency in studies investigating antibodies to leading vaccine candidates merozoite surface protein (MSP)-142 and erythrocyte binding antigen (EBA)-175. Meta-analyses of most-studied antigens were conducted to obtain summary estimates of the association between antibodies and incidence of P. falciparum malaria. The largest effect was observed with IgG to MSP-3 C terminus and MSP-119 (responders versus nonresponders, 54%, 95% confidence interval [CI] [33%–68%] and 18% [4%–30%] relative reduction in risk, respectively) and there was evidence of a dose-response relationship. A tendency towards protective risk ratios (RR<1) was also observed for individual study estimates for apical membrane antigen (AMA)-1 and glutamate-rich protein (GLURP)-R0. Pooled estimates showed limited evidence of a protective effect for antibodies to MSP-1 N-terminal regions or MSP-1-EGF (epidermal growth factor-like modules). There was no significant evidence for the protective effect for MSP-2 (responders versus nonresponders pooled RR, MSP-2FC27 0.82, 95% CI 0.62–1.08, p = 0.16 and MSP-23D7 0.92, 95% CI 0.75–1.13, p = 0.43). Heterogeneity, in terms of clinical and methodological diversity between studies, was an important issue in the meta-analysis of IgG responses to merozoite antigens.
Conclusions
These findings are valuable for advancing vaccine development by providing evidence supporting merozoite antigens as targets of protective immunity in humans, and to help identify antigens that confer protection from malaria. Further prospective cohort studies that include a larger number of lead antigens and populations outside Africa are greatly needed to ensure generalizability of results. The reporting of results needs to be standardized to maximize comparability of studies. We therefore propose a set of guidelines to facilitate the uniform reporting of malaria immuno-epidemiology observational studies.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Plasmodium falciparum malaria, a mosquito-borne parasitic infection, kills about one million people every year. Around a week after an infected mosquito has bitten a person, “merozoites” (one of the life-stages of the parasite) infect the person's red blood cells where they replicate and then burst out and infect more red blood cells. Rapid replication of parasites can occur in the bloodstream, leading to massive numbers of parasites that can damage vital organs. Although individuals can lower their risk of becoming infected with malaria parasites by avoiding mosquito bites, a vaccine is urgently needed to reduce the global burden of malaria. When malaria parasites infect a person for the first time, the human immune system begins to produce antibodies, proteins that recognize molecules (antigens) on the parasite's surface and that act directly or cooperate with other parts of the immune system to kill malaria parasites. The production of these “naturally acquired” antibodies is initially slow so the individual can become ill when infected. However, because the immune system “remembers” how to make the antibodies, its response to subsequent infections is quicker. The levels of these antibodies also build up with each infection and become more effective at killing parasites. Vaccines, which contain malaria antigens, “prime” the immune system to respond rapidly to malaria infections and produce high concentrations of antibodies to prevent the infection from causing serious illness.
Why Was This Study Done?
A malaria vaccine that stimulates an efficient immune response against merozoites would limit the severity of malarial infections and prevent many deaths but no one knows which (if any) of the antigens on merozoites stimulate a protective immune response. Although many different types of antibodies are produced by the immune system, only some of these are effective in protecting against malaria. By investigating whether there is an association between naturally acquired antibodies, which recognize specific candidate antigens, and protection from malaria in populations living in areas where malaria is endemic (always present), vaccine developers can get an idea about which antigens to include in their vaccines. Although many of these “malaria immuno-epidemiological studies” have been undertaken, their results are somewhat conflicting. In this study, the researchers reanalyze these results by doing a systematic review (a study that uses predefined criteria to identify all the research on a specific topic) and a meta-analysis (a statistical method for combining the results of several studies). The researchers evaluated studies of the relationship between anti-merozoite antibodies and the incidence (the number of new cases of a disease in a population per year) of P. falciparum malaria in naturally exposed populations in different regions of the world.
What Did the Researchers Do and Find?
The researchers' search of the published literature yielded 33 studies in which the incidence of malaria had been recorded over time in groups of people in whom levels of antibodies to specific merozoite antigens had been measured. These studies measured antibodies at the start of the study and examined the subsequent risk of malaria over several months of follow-up (these are known as prospective cohort studies). All but five of the studies were performed in Africa, and very few merozoite antigens had been well-studied in different populations, or studied at all. Of note, very few studies had examined naturally acquired antibodies to some leading vaccine candidates (for example, only one study considered antibodies to MSP-142, a leading vaccine candidate). Conversely, the association between malaria incidence and antibodies to the antigen MSP-119, which has been included in only one candidate vaccine, was frequently studied. In their meta-analyses, the researchers found that among people with antibodies to the merozoite antigens MSP-3 (C-terminal region) and MSP-119, the risk of developing P. falciparum malaria was reduced by 54% and 18%, respectively, compared to people without antibodies to these antigens. There was also some evidence of a reduced risk of malaria for people with antibodies to AMA1 and GLURP. For other merozoite antigens, MSP1 (N-terminal region) and MSP2, there was either weak or no evidence for a protective effect of naturally acquired antibodies.
What Do These Findings Mean?
These findings suggest that merozoite antigens are important targets of protective immunity in people who are naturally exposed to malaria and also suggest which of these antigens might be included in vaccines. However, the findings are limited by the small number of studies identified by the researchers and additional prospective cohort studies are clearly needed to guide vaccine development. These studies will need to include a larger number of lead antigens and populations outside Africa to ensure their generalizability, note the researchers. Furthermore, efforts will need to be made to ensure greater consistency between studies to improve the ability to compare results between different studies, which was a challenge in performing this study. To this end, the researchers propose a set of guidelines that, if followed, should make it easier to compare the results of different malaria immune-epidemiology studies in the future and thus lead to better identification of candidate vaccine antigens.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000218.
Information is available from the World Health Organization on malaria (in several languages) and on the development of malaria vaccines
The US Centers for Disease Control and Prevention provides information on malaria (in English and Spanish)
Information is available from the Wellcome Trust on all aspects of malaria, including vaccine development
The Malaria Vaccine Initiative provides information on the development of malaria vaccines and on ongoing trials
MedlinePlus provides links to additional information on malaria (in English and Spanish)
doi:10.1371/journal.pmed.1000218
PMCID: PMC2808214  PMID: 20098724

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