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1.  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
2.  Screening and Rapid Molecular Diagnosis of Tuberculosis in Prisons in Russia and Eastern Europe: A Cost-Effectiveness Analysis 
PLoS Medicine  2012;9(11):e1001348.
Daniel Winetsky and colleagues investigate eight strategies for screening and diagnosis of tuberculosis within prisons of the former Soviet Union.
Background
Prisons of the former Soviet Union (FSU) have high rates of multidrug-resistant tuberculosis (MDR-TB) and are thought to drive general population tuberculosis (TB) epidemics. Effective prison case detection, though employing more expensive technologies, may reduce long-term treatment costs and slow MDR-TB transmission.
Methods and Findings
We developed a dynamic transmission model of TB and drug resistance matched to the epidemiology and costs in FSU prisons. We evaluated eight strategies for TB screening and diagnosis involving, alone or in combination, self-referral, symptom screening, mass miniature radiography (MMR), and sputum PCR with probes for rifampin resistance (Xpert MTB/RIF). Over a 10-y horizon, we projected costs, quality-adjusted life years (QALYs), and TB and MDR-TB prevalence. Using sputum PCR as an annual primary screening tool among the general prison population most effectively reduced overall TB prevalence (from 2.78% to 2.31%) and MDR-TB prevalence (from 0.74% to 0.63%), and cost US$543/QALY for additional QALYs gained compared to MMR screening with sputum PCR reserved for rapid detection of MDR-TB. Adding sputum PCR to the currently used strategy of annual MMR screening was cost-saving over 10 y compared to MMR screening alone, but produced only a modest reduction in MDR-TB prevalence (from 0.74% to 0.69%) and had minimal effect on overall TB prevalence (from 2.78% to 2.74%). Strategies based on symptom screening alone were less effective and more expensive than MMR-based strategies. Study limitations included scarce primary TB time-series data in FSU prisons and uncertainties regarding screening test characteristics.
Conclusions
In prisons of the FSU, annual screening of the general inmate population with sputum PCR most effectively reduces TB and MDR-TB prevalence, doing so cost-effectively. If this approach is not feasible, the current strategy of annual MMR is both more effective and less expensive than strategies using self-referral or symptom screening alone, and the addition of sputum PCR for rapid MDR-TB detection may be cost-saving over time.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Tuberculosis (TB)—a contagious bacterial disease—is a major public health problem, particularly in low- and middle-income countries. In 2010, about nine million people developed TB, and about 1.5 million people died from the disease. Mycobacterium tuberculosis, the bacterium that causes TB, is spread in airborne droplets when people with active disease cough or sneeze. The characteristic symptoms of TB include fever, a persistent cough, and night sweats. Diagnostic tests include sputum smear microscopy (examination of mucus from the lungs for M. tuberculosis bacilli), mycobacterial culture (growth of M. tuberculosis from sputum), and chest X-rays. TB can also be diagnosed by looking for fragments of the M. tuberculosis genetic blueprint in sputum samples (sputum PCR). Importantly, sputum PCR can detect the genetic changes that make M. tuberculosis resistant to rifampicin, a constituent of the cocktail of antibiotics that is used to cure TB. Rifampicin resistance is an indicator of multidrug-resistant TB (MDR-TB), the emergence of which is thwarting ongoing global efforts to control TB.
Why Was This Study Done?
Prisons present unique challenges for TB control. Overcrowding, poor ventilation, and inadequate medical care increase the spread of TB among prisoners, who often come from disadvantaged populations where the prevalence of TB (the proportion of the population with TB) is already high. Prisons also act as reservoirs for TB, recycling the disease back into the civilian population. The prisons of the former Soviet Union, for example, which have extremely high rates of MDR-TB, are thought to drive TB epidemics in the general population. Because effective identification of active TB among prison inmates has the potential to improve TB control outside prisons, the World Health Organization recommends active TB case finding among prisoners using self-referral, screening with symptom questionnaires, or screening with chest X-rays or mass miniature radiography (MMR). But which of these strategies will reduce the prevalence of TB in prisons most effectively, and which is most cost-effective? Here, the researchers evaluate the relative effectiveness and cost-effectiveness of alternative strategies for screening and diagnosis of TB in prisons by modeling TB and MDR-TB epidemics in prisons of the former Soviet Union.
What Did the Researchers Do and Find?
The researchers used a dynamic transmission model of TB that simulates the movement of individuals in prisons in the former Soviet Union through different stages of TB infection to estimate the costs, quality-adjusted life years (QALYs; a measure of disease burden that includes both the quantity and quality of life) saved, and TB and MDR-TB prevalence for eight TB screening/diagnostic strategies over a ten-year period. Compared to annual MMR alone (the current strategy), annual screening with sputum PCR produced the greatest reduction in the prevalence of TB and of MDR-TB among the prison population. Adding sputum PCR for detection of MDR-TB to annual MMR screening did not affect the overall TB prevalence but slightly reduced the MDR-TB prevalence and saved nearly US$2,000 over ten years per model prison of 1,000 inmates, compared to MMR screening alone. Annual sputum PCR was the most cost-effective strategy, costing US$543/QALY for additional QALYs gained compared to MMR screening plus sputum PCR for MDR-TB detection. Other strategies tested, including symptom screening alone or combined with sputum PCR, were either more expensive and less effective or less cost-effective than these two options.
What Do These Findings Mean?
These findings suggest that, in prisons in the former Soviet Union, annual screening with sputum PCR will most effectively reduce TB and MDR-TB prevalence and will be cost-effective. That is, the cost per QALY saved of this strategy is less than the per-capita gross domestic product of any of the former Soviet Union countries. The paucity of primary data on some facets of TB epidemiology in prisons in the former Soviet Union and the assumptions built into the mathematical model limit the accuracy of these findings. Moreover, because most of the benefits of sputum PCR screening come from treating the MDR-TB cases that are detected using this screening approach, these findings cannot be generalized to prison settings without a functioning MDR-TB treatment program or with a very low MDR-TB prevalence. Despite these and other limitations, these findings provide valuable information about the screening strategies that are most likely to interrupt the TB cycle in prisons, thereby saving resources and averting preventable deaths both inside and outside prisons.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001348.
The World Health Organization provides information (in several languages) on all aspects of tuberculosis, including general information on tuberculosis diagnostics and on tuberculosis in prisons; a report published in the Bulletin of the World Health Organization in 2006 describes tough measures taken in Russian prisons to slow the spread of TB
The Stop TB Partnership is working towards tuberculosis elimination; patient stories about tuberculosis are available (in English and Spanish)
The US Centers for Disease Control and Prevention has information about tuberculosis, about its diagnosis, and about tuberculosis in prisons (some information in English and Spanish)
A PLOS Medicine Research Article by Iacapo Baussano et al. describes a systematic review of tuberculosis incidence in prisons; a linked editorial entitled The Health Crisis of Tuberculosis in Prisons Extends beyond the Prison Walls is also available
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
MedlinePlus has links to further information about tuberculosis (in English and Spanish)
doi:10.1371/journal.pmed.1001348
PMCID: PMC3507963  PMID: 23209384
3.  Hepatitis B vaccination practices in state and federal prisons. 
Public Health Reports  2001;116(3):203-209.
OBJECTIVE: Incarcerated populations are a group at high risk for hepatitis B. About 30% of people experiencing acute hepatitis B virus infection (HBV) have a history of incarceration. Offering routine HBV vaccinations to incarcerated individuals could have a significant effect on public health. The objective of this study is to identify current vaccine practices and the perceived feasibility of routine vaccinations for hepatitis B within correctional settings. METHOD: The authors surveyed the medical directors of state correctional facilities in all 50 states and the federal prison system regarding current HBV vaccine practices. Surveys were faxed or mailed between July 1 and September 1, 2000. RESULTS: Thirty-five states and the federal system responded (response rate = 70.6%). These systems account for 77% of all inmates in federal or state prisons and jails. Two states give hepatitis B vaccine routinely, nine states offer no hepatitis B vaccine, and 26 states and the Federal Bureau of Prisons offer hepatitis vaccine to some inmates. Most states do not spend enough money to vaccinate even those prisoners at highest risk. Under the Vaccine for Children program, 19,520 youths could receive vaccine immediately. According to the respondents, if vaccine were available at no-cost, 25 states and the Federal Bureau of Prisons would routinely offer vaccination to all inmates. CONCLUSIONS: Most correctional systems do not routinely offer vaccine to their incarcerated populations, but would if funds were available. There exists now a unique public health opportunity to prevent a significant proportion of new hepatitis B infections.
PMCID: PMC1497321  PMID: 12034909
4.  Estimates of Pandemic Influenza Vaccine Effectiveness in Europe, 2009–2010: Results of Influenza Monitoring Vaccine Effectiveness in Europe (I-MOVE) Multicentre Case-Control Study 
PLoS Medicine  2011;8(1):e1000388.
Results from a European multicentre case-control study reported by Marta Valenciano and colleagues suggest good protection by the pandemic monovalent H1N1 vaccine against pH1N1 and no effect of the 2009–2010 seasonal influenza vaccine on H1N1.
Background
A multicentre case-control study based on sentinel practitioner surveillance networks from seven European countries was undertaken to estimate the effectiveness of 2009–2010 pandemic and seasonal influenza vaccines against medically attended influenza-like illness (ILI) laboratory-confirmed as pandemic influenza A (H1N1) (pH1N1).
Methods and Findings
Sentinel practitioners swabbed ILI patients using systematic sampling. We included in the study patients meeting the European ILI case definition with onset of symptoms >14 days after the start of national pandemic vaccination campaigns. We compared pH1N1 cases to influenza laboratory-negative controls. A valid vaccination corresponded to >14 days between receiving a dose of vaccine and symptom onset. We estimated pooled vaccine effectiveness (VE) as 1 minus the odds ratio with the study site as a fixed effect. Using logistic regression, we adjusted VE for potential confounding factors (age group, sex, month of onset, chronic diseases and related hospitalizations, smoking history, seasonal influenza vaccinations, practitioner visits in previous year). We conducted a complete case analysis excluding individuals with missing values and a multiple multivariate imputation to estimate missing values. The multivariate imputation (n = 2902) adjusted pandemic VE (PIVE) estimates were 71.9% (95% confidence interval [CI] 45.6–85.5) overall; 78.4% (95% CI 54.4–89.8) in patients <65 years; and 72.9% (95% CI 39.8–87.8) in individuals without chronic disease. The complete case (n = 1,502) adjusted PIVE were 66.0% (95% CI 23.9–84.8), 71.3% (95% CI 29.1–88.4), and 70.2% (95% CI 19.4–89.0), respectively. The adjusted PIVE was 66.0% (95% CI −69.9 to 93.2) if vaccinated 8–14 days before ILI onset. The adjusted 2009–2010 seasonal influenza VE was 9.9% (95% CI −65.2 to 50.9).
Conclusions
Our results suggest good protection of the pandemic monovalent vaccine against medically attended pH1N1 and no effect of the 2009–2010 seasonal influenza vaccine. However, the late availability of the pandemic vaccine and subsequent limited coverage with this vaccine hampered our ability to study vaccine benefits during the outbreak period. Future studies should include estimation of the effectiveness of the new trivalent vaccine in the upcoming 2010–2011 season, when vaccination will occur before the influenza season starts.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Following the World Health Organization's declaration of pandemic phase six in June 2009, manufacturers developed vaccines against pandemic influenza A 2009 (pH1N1). On the basis of the scientific opinion of the European Medicines Agency, the European Commission initially granted marketing authorization to three pandemic vaccines for use in European countries. During the autumn of 2009, most European countries included the 2009–2010 seasonal influenza vaccine and the pandemic vaccine in their influenza vaccination programs.
The Influenza Monitoring Vaccine Effectiveness in Europe network (established to monitor seasonal and pandemic influenza vaccine effectiveness) conducted seven case-control and three cohort studies in seven European countries in 2009–2010 to estimate the effectiveness of the pandemic and seasonal vaccines. Data from the seven pilot case-control studies were pooled to provide overall adjusted estimates of vaccine effectiveness.
Why Was This Study Done?
After seasonal and pandemic vaccines are made available to populations, it is necessary to estimate the effectiveness of the vaccines at the population level during every influenza season. Therefore, this study was conducted in European countries to estimate the pandemic influenza vaccine effectiveness and seasonal influenza vaccine effectiveness against people presenting to their doctor with influenza-like illness who were confirmed (by laboratory tests) to be infected with pH1N1.
What Did the Researchers Do and Find?
The researchers conducted a multicenter case-control study on the basis of practitioner surveillance networks from seven countries—France, Hungary, Ireland, Italy, Romania, Portugal, and Spain. Patients consulting a participating practitioner for influenza-like illness had a nasal or throat swab taken within 8 days of symptom onset. Cases were swabbed patients who tested positive for pH1N1. Patients presenting with influenza-like illness whose swab tested negative for any influenza virus were controls.
Individuals were considered vaccinated if they had received a dose of the vaccine more than 14 days before the date of onset of influenza-like illness and unvaccinated if they were not vaccinated at all, or if the vaccine was given less than 15 days before the onset of symptoms. The researchers analyzed pandemic influenza vaccination effectiveness in those vaccinated less than 8 days, those vaccinated between and including 8 and 14 days, and those vaccinated more than 14 days before onset of symptoms compared to those who had never been vaccinated.
The researchers used modeling (taking account of all potential confounding factors) to estimate adjusted vaccine effectiveness and stratified the adjusted pandemic influenza vaccine effectiveness and the adjusted seasonal influenza vaccine effectiveness in three age groups (<15, 15–64, and ≥65 years of age).
The adjusted results suggest that the 2009–2010 seasonal influenza vaccine did not protect against pH1N1 illness. However, one dose of the pandemic vaccines used in the participating countries conferred good protection (65.5%–100% according to various stratifications performed) against pH1N1 in people who attended their practitioner with influenza-like illness, especially in people aged <65 years and in those without any chronic disease. Furthermore, good pandemic influenza vaccine effectiveness was observed as early as 8 days after vaccination.
What Do These Findings Mean?
The results of this study provide early estimates of the pandemic influenza vaccine effectiveness suggesting that the monovalent pandemic vaccines have been effective. The findings also give an indication of the vaccine effectiveness for the Influenza A (H1N1) 2009 strain included in the 2010–2011 seasonal vaccines, although specific vaccine effectiveness studies will have to be conducted to verify if similar good effectiveness are observed with 2010–2011 trivalent vaccines. However, the results of this study should be interpreted with caution because of limitations in the pandemic context (late timing of the studies, low incidence, low vaccine coverage leading to imprecise estimates) and potential biases due the study design, confounding factors, and missing values. The researchers recommend that in future season studies, the sample size per country should be enlarged in order to allow for precise pooled and stratified analyses.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000388.
The World Health Organization has information on H1N1 vaccination
The US Centers for Disease Control and Prevention provides a fact sheet on the 2009 H1N1 influenza virus
The US Department of Health and Human services has a comprehensive website on flu
The European Centre for Disease Prevention and Control provides information on 2009 H1N1 pandemic
The European Centre for Disease Prevention and Control presents a summary of the 2009 H1N1 pandemic in Europe and elsewhere
doi:10.1371/journal.pmed.1000388
PMCID: PMC3019108  PMID: 21379316
5.  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
6.  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
7.  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
8.  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
9.  Dynamics of Polymorphism in a Malaria Vaccine Antigen at a Vaccine-Testing Site in Mali 
PLoS Medicine  2007;4(3):e93.
Background
Malaria vaccines based on the 19-kDa region of merozoite surface protein 1 (MSP-119) derived from the 3D7 strain of Plasmodium falciparum are being tested in clinical trials in Africa. Knowledge of the distribution and natural dynamics of vaccine antigen polymorphisms in populations in which malaria vaccines will be tested will guide vaccine design and permit distinction between natural fluctuations in genetic diversity and vaccine-induced selection.
Methods and Findings
Using pyrosequencing, six single-nucleotide polymorphisms in the nucleotide sequence encoding MSP-119 were genotyped from 1,363 malaria infections experienced by 100 children who participated in a prospective cohort study in Mali from 1999 to 2001. The frequencies of 14 MSP-119 haplotypes were compared over the course of the malaria transmission season for all three years, in three age groups, and in consecutive infections within individuals. While the frequency of individual MSP-119 haplotypes fluctuated, haplotypes corresponding to FVO and FUP strains of P. falciparum (MSP-119 haplotypes QKSNGL and EKSNGL, respectively) were most prevalent during three consecutive years and in all age groups with overall prevalences of 46% (95% confidence interval [CI] 44%–49%) and 36% (95% CI 34%–39%), respectively. The 3D7 haplotype had a lower overall prevalence of 16% (95% CI 14%–18%). Multiplicity of infection based on MSP-119 was higher at the beginning of the transmission season and in the oldest individuals (aged ≥11 y). Three MSP-119 haplotypes had a reduced frequency in symptomatic infections compared to asymptomatic infections. Analyses of the dynamics of MSP-119 polymorphisms in consecutive infections implicate three polymorphisms (at positions 1691, 1700, and 1701) as being particularly important in determining allele specificity of anti-MSP-119 immunity.
Conclusions
Parasites with MSP-119 haplotypes different from that of the leading vaccine strain were consistently the most prevalent at a vaccine trial site. If immunity elicited by an MSP-1-based vaccine is allele-specific, a vaccine based on either the FVO or FUP strain might have better initial efficacy at this site. This study, to our knowledge the largest of its kind to date, provides molecular information needed to interpret population responses to MSP-1-based vaccines and suggests that certain MSP-119 polymorphisms may be relevant to cross-protective immunity.
Christopher Plowe and colleagues surveyed local malaria parasites for genetic diversity in MSP-1, a candidate vaccine antigen. These data are needed to interpret population responses to MSP-1-based vaccines during trials planned at this site.
Editors' Summary
Background.
Malaria, a tropical parasitic disease, kills about one million people—mainly children—every year. Most of these deaths are caused by Plasmodium falciparum, which is transmitted to humans through the bites of infected mosquitoes. These insects inject a form of the parasite known as sporozoites into people that replicates inside liver cells without causing symptoms. Four to five days later, merozoites (another form of the parasite) are released from the liver cells and invade red blood cells. Here, they replicate 10-fold before bursting out and infecting other red blood cells. This massive increase in parasite burden causes malaria's flu-like symptoms. If untreated, it also causes anemia (a red blood cell deficit) and damages the brain and other organs where parasitized red blood cells sequester. Malaria can be treated with antimalarial drugs and partly prevented by reducing the chances of being bitten by an infected mosquito. In addition, researchers are developing vaccines designed to reduce the global burden of malaria. These contain individual malaria antigens (proteins from the parasite that stimulate an immune response) that should, when injected into people, prime the immune system so that it can rapidly control malaria infections.
Why Was This Study Done?
The development of an effective malaria vaccine is not easy, in part because people can be simultaneously infected with several parasite strains. These often carry different variants (alleles) of the genes encoding antigens, which means that the actual parasite proteins might differ from the ones used for vaccination. If this is the case, the immune response generated by the vaccine might be less effective or even ineffective. An ideal vaccine would therefore stimulate an immune response that recognizes all these strain-specific antigens. However, little is known about their distribution in parasite populations in malarial regions, or about how this distribution changes over time (its dynamics). This information is needed to aid vaccine design and development. In this study, the researchers have investigated the distribution and dynamics of genetic variants of a merozoite antigen called MSP-119, which is included in a vaccine currently being tested in Mali, West Africa. Although most of the MSP-119 sequence is conserved, it contains six strain-specific polymorphisms (genetic variations); the candidate vaccine contains MSP-119 from the 3D7 strain of P. falciparum.
What Did the Researchers Do and Find?
The researchers used rapid DNA sequencing (pyrosequencing) to examine the MSP-119 sequence in more than 1,300 malaria infections in 100 Malian children. They compared the frequencies of 14 MSP-119 haplotypes (sets of polymorphisms at the six variant sites) over three years, in three age groups, and in consecutive infections within individuals. They found that the frequency of individual MSP-119 haplotypes fluctuated in their study population but that those found in P. falciparum FVO and FUP strains were always the commonest, each being present in about 40% of the infections. By contrast, the P. falciparum 3D7 MSP-119 haplotype was present in only 16% of the infections. They also found that mixed infections were more common at the start of each malaria season and in older individuals. In addition, individuals who were infected repeatedly by parasites from different strains (with different MSP-119 variants) seemed to get sick with malaria more often than those infected multiple times by the same strain. The differences might, therefore, be important in determining the specificity of the immune response to MSP-119.
What Do These Findings Mean?
These findings indicate that most parasites that cause malaria at the Malian test site for the malaria vaccine that contains 3D7-specific MSP-119 have a different form of MSP-119. Although early results from field trials suggest that the 3D7-derived vaccine provides some protection against the more common FVO and FUP strains, the immunity stimulated by the vaccine might be mainly allele specific. If this turns out to be the case, these results suggest that a FVO- or FUP-derived vaccine might be more effective in Mali than the 3D7-derived vaccine, though not necessarily elsewhere. More generally, these results show the importance of determining the genetics of pathogen populations before starting vaccine trials. Without this information, a vaccine's ability to prevent infections with specific parasite strains cannot be determined accurately and potentially useful vaccines might be abandoned if they are tested in inappropriate populations. Importantly, baseline information of this sort will also allow vaccine developers to detect any vaccine-induced changes in the pathogen population that might affect the long-term efficacy of their vaccines.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0040093.
A related PLoS Medicine Perspective by Colin Sutherland discusses variation in malaria antigens as a challenge in vaccine development
The malaria program of the University of Maryland Center for Vaccine Development performs research on many aspects of malaria
Information on malaria and the development of vaccines is available from the Malaria Vaccine Initiative
The World Health Organization provides links to general information on malaria plus some specific information on malaria vaccine development
MedlinePlus encyclopedia has entries on malaria and on vaccination
US Centers for Disease Control and Prevention provides information for patients and professionals on malaria
US National Institute of Allergy and Infectious Diseases has information on malaria, including research into vaccines
doi:10.1371/journal.pmed.0040093
PMCID: PMC1820605  PMID: 17355170
10.  Removing the Age Restrictions for Rotavirus Vaccination: A Benefit-Risk Modeling Analysis 
PLoS Medicine  2012;9(10):e1001330.
A modeling analysis conducted by Manish Patel and colleagues predicts the possible number of rotavirus deaths prevented, and number of intussusception deaths caused, by use of an unrestricted rotavirus schedule in low- and middle-income countries.
Background
To minimize potential risk of intussusception, the World Health Organization (WHO) recommended in 2009 that rotavirus immunization should be initiated by age 15 weeks and completed before 32 weeks. These restrictions could adversely impact vaccination coverage and thereby its health impact, particularly in developing countries where delays in vaccination often occur.
Methods and Findings
We conducted a modeling study to estimate the number of rotavirus deaths prevented and the number of intussusception deaths caused by vaccination when administered on the restricted schedule versus an unrestricted schedule whereby rotavirus vaccine would be administered with DTP vaccine up to age 3 years. Countries were grouped on the basis of child mortality rates, using WHO data. Inputs were estimates of WHO rotavirus mortality by week of age from a recent study, intussusception mortality based on a literature review, predicted vaccination rates by week of age from USAID Demographic and Health Surveys, the United Nations Children's Fund (UNICEF) Multiple Indicator Cluster Surveys (MICS), and WHO-UNICEF 2010 country-specific coverage estimates, and published estimates of vaccine efficacy and vaccine-associated intussusception risk. On the basis of the error estimates and distributions for model inputs, we conducted 2,000 simulations to obtain median estimates of deaths averted and caused as well as the uncertainty ranges, defined as the 5th–95th percentile, to provide an indication of the uncertainty in the estimates.
We estimated that in low and low-middle income countries a restricted schedule would prevent 155,800 rotavirus deaths (5th–95th centiles, 83,300–217,700) while causing potentially 253 intussusception deaths (76–689). In contrast, vaccination without age restrictions would prevent 203,000 rotavirus deaths (102,000–281,500) while potentially causing 547 intussusception deaths (237–1,160). Thus, removing the age restrictions would avert an additional 47,200 rotavirus deaths (18,700–63,700) and cause an additional 294 (161–471) intussusception deaths, for an incremental benefit-risk ratio of 154 deaths averted for every death caused by vaccine. These extra deaths prevented under an unrestricted schedule reflect vaccination of an additional 21%–25% children, beyond the 63%–73% of the children who would be vaccinated under the restricted schedule. Importantly, these estimates err on the side of safety in that they assume high vaccine-associated risk of intussusception and do not account for potential herd immunity or non-fatal outcomes.
Conclusions
Our analysis suggests that in low- and middle-income countries the additional lives saved by removing age restrictions for rotavirus vaccination would far outnumber the potential excess vaccine-associated intussusception deaths.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Rotavirus causes severe diarrhea and vomiting. It is responsible for a large number of hospitalizations among young children in developed countries (an estimated 60,000 hospitalizations per year in the US in 2005, for example). In poor countries, rotavirus is a major cause of death in children under five. In 1998, the first rotavirus vaccine, called RotaShield, was approved in the US by the Food and Drug Administration. Shortly after the vaccine became widely used, doctors noticed a small increase in a problem called intussusception among the vaccinated infants. Intussusception is a rare type of bowel obstruction that occurs when the bowel telescopes in on itself. Prompt treatment of intussusception normally leads to full recovery, but some children with the condition need surgery, and when the disease is left untreated it can be fatal. Because intussusception is a serious condition and because very few children die from rotavirus infection in the United States, the US authorities stopped recommending vaccination with RotaShield in 1999. The manufacturer withdrew the vaccine from the market shortly thereafter.
Since then, two new vaccines (named Rotarix and RotaTeq) have been developed. Before they were approved in the US and elsewhere, they were extensively tested for any adverse side effects, especially intussusception. No increase in the risk for intussusception was found in these studies, and both are now approved and recommended for vaccination of infants around the world.
Why Was This Study Done?
Since 2006, hundreds of thousands of infants have been vaccinated with Rotarix or RotaTeq, with safety being closely monitored. Some countries have reported a small increase in intussusception (one to four additional cases per 100,000 vaccinated infants, compared with one per 2,000 of cases that occur in unvaccinated children). This increase is much lower than the one seen previously with RotaShield. In response to these findings, authorities in the US and other developed countries as well as the World Health Organization declared that the benefits of the vaccine outweigh the risks of the small number of additional intussusception cases in both developed and poor countries. However, because older infants have a higher risk of naturally occurring intussusception, they decided that the course of vaccination (three oral doses for Rotarix and two for RotaTeq) should be initiated before 15 weeks of age and completed before the age of 32 weeks. This is usually not a problem in countries with easy access to health facilities. However, in many poor countries where delays in infant vaccination are common, giving the vaccine only to very young children means that many others who could benefit from its protection will be excluded. In this study, the researchers examined the risks and benefits of rotavirus vaccination in poor countries where most of the rotavirus deaths occur. Specifically, they looked at the benefits and risks if the age restrictions were removed, with a particular emphasis on allowing infants to initiate rotavirus immunization even if they arrive after 15 weeks of age.
What Did the Researchers Do and Find?
The researchers used the most recent estimates for how well the vaccines protect children in Africa and Asia from becoming infected with rotavirus, how many deaths from rotavirus infection can be avoided by vaccination, how many additional cases of intussusception will likely occur in vaccinated children, and what proportion of children would be excluded from rotavirus vaccination because they are too old when they come to a health facility for their infant vaccination. They then estimated the number of rotavirus deaths prevented and the number of intussusception deaths caused by vaccination in two scenarios. The first one (the restricted scenario) corresponds to previous guidelines from WHO and others, in which rotavirus vaccination needs to be initiated before 15 weeks and the full series completed before 32 weeks. The second one (called the unrestricted scenario) allows rotavirus vaccination of children alongside current routinely administered vaccines up to three years of age, recognizing that most children receive their vaccination by 1 year of life.
The researchers estimated that removing the age restriction would prevent an additional 154 rotavirus deaths for each intussusception death caused by the vaccine. Under the unrestricted scenario, roughly a third more children would get vaccinated, which would prevent an additional approximately 47,000 death from rotavirus while causing approximately 300 additional intussusception deaths.
They also calculated some best- and worst-case scenarios. The worst-case scenario assumed a much higher risk of intussusception for children receiving their first dose after 15 weeks of life than what has been seen anywhere, and also that an additional 20% of children with intussusception would die from it than what was already assumed in their routine scenario (again, a higher number than seen in reality). In addition, it assumes a lower protection from rotavirus death for the vaccine than has been observed in children vaccinated so far. In this pessimistic case, the number of rotavirus deaths prevented was 24 for each intussusception death caused by the vaccine.
What Do These Findings Mean?
If one accepts that deaths caused by a vaccine are not fundamentally different from deaths caused by a failure to vaccinate, then these results show that the benefits of lifting the age restriction for rotavirus vaccine clearly outweigh the risks, at least when only examining mortality outcomes. The calculations are valid only for low-income countries in Africa and Asia where both vaccination delays and deaths from rotavirus are common. The risk-benefit ratio will be different elsewhere. There are also additional risks and benefits that are not included in the study's estimates. For example, early vaccination might be seen as less of an urgent priority when this vaccine can be had at a later date, leaving very young children more vulnerable. On the other hand, when many children in the community are vaccinated, even the unvaccinated children are less likely to get infected (what is known as “herd immunity”), something that has not been taken into account in the benefits here. The results of this study (and its limitations) were reviewed in April 2012 by WHO's Strategic Advisory Group of Experts. The group then recommended that, while early vaccination is still strongly encouraged, the age restriction on rotavirus vaccination should be removed in countries where delays in vaccination and rotavirus mortality are common so that more vulnerable children can be vaccinated and deaths from rotavirus averted.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001330.
The World Health Organization provides information on rotavirus
Wikipedia has information on rotavirus vaccine and intussusception (note that Wikipedia is a free online encyclopedia that anyone can edit; available in several languages)
The US Centers for Disease Control and Prevention rotavirus vaccination page includes a link to frequently asked questions
PATH Rotavirus Vaccine Access and Delivery has timely, useful updates on status of rotavirus vaccines globally
doi:10.1371/journal.pmed.1001330
PMCID: PMC3479108  PMID: 23109915
11.  Sex-Specific Immunization for Sexually Transmitted Infections Such as Human Papillomavirus: Insights from Mathematical Models 
PLoS Medicine  2011;8(12):e1001147.
Johannes Bogaards and colleagues use mathematical models to investigate whether vaccinating females only, males only, or both sexes is the best way to achieve the most effective reduction in the population prevalence of sexually-transmitted infections
Background
Sex-specific differences regarding the transmissibility and the course of infection are the rule rather than the exception in the epidemiology of sexually transmitted infections (STIs). Human papillomavirus (HPV) provides an example: disease outcomes differ between men and women, as does the potential for transmission to the opposite sex. HPV vaccination of preadolescent girls was recently introduced in many countries, and inclusion of boys in the vaccination programs is being discussed. Here, we address the question of whether vaccinating females only, males only, or both sexes is the most effective strategy to reduce the population prevalence of an STI like HPV.
Methods and Findings
We use a range of two-sex transmission models with varying detail to identify general criteria for allocating a prophylactic vaccine between both sexes. The most effective reduction in the population prevalence of infection is always achieved by single-sex vaccination; vaccinating the sex with the highest prevaccine prevalence is the preferred strategy in most circumstances. Exceptions arise only when the higher prevaccine prevalence is due to a substantially lower rate of natural immunity, or when natural immunity is lifelong, and a prolonged duration of infectiousness coincides with increased transmissibility. Predictions from simple models were confirmed in simulations based on an elaborate HPV transmission model. Our analysis suggests that relatively inefficient genital transmission from males to females might render male vaccination more effective in reducing overall infection levels. However, most existing HPV vaccination programs have achieved sufficient coverage to continue with female-only vaccination.
Conclusions
Increasing vaccine uptake among preadolescent girls is more effective in reducing HPV infection than including boys in existing vaccination programs. As a rule, directing prophylactic immunization at the sex with the highest prevaccine prevalence results in the largest reduction of the population prevalence.
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, more than a quarter of a million women (85% of them in developing countries) die because of cervical cancer, which only occurs after the cervix has been infected with a human papillomavirus (HPV) through sexual intercourse (HPV is one of more than thirty sexually transmissable organisms that, globally, cause many millions of sexually transmitted infections every year). 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). Most people become infected with HPV at some time during their life, but most never know they have been infected. Some HPV types cause harmless warts on the skin or around the genital area, and several—in particular HPV16 and HPV18, so-called high-risk HPVs—can cause cervical cancer (and some other cancers, including anal, penile, head, and neck cancers). 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 by detecting the cancer early, when it can be treated. However, it would be better to prevent cervical cancer ever developing. Moreover, most women in developing countries do not have access to screening. Because infection with specific HPV types can cause the development of some types of cervical cancer, vaccination of girls against HPV before the onset of sexual activity might be one way to prevent cervical cancer. Scientists recently developed a vaccine that prevents infection with HPV16 and HPV18, and HPV vaccination programs have been introduced in several countries. These programs are currently directed only at girls because HPV-related illness and death are higher among women than men, but should boys also be included in HPV vaccination programs? Men would benefit directly from immunization against HPV-related diseases, but, in addition, vaccination of boys might help to reduce the circulation of HPV in the population, thereby indirectly improving the protection of women through so-called “herd immunity.” In this study, the researchers used mathematical models to investigate whether vaccinating girls only, boys only, or both sexes is the most effective way to reduce the population prevalence of HPV infection (the proportion of the population infected with HPV).
What Did the Researchers Do and Find?
The researchers first used a range of standard two-sex mathematical models of infection and transmission in heterosexual populations to identify general criteria for allocating an HPV vaccine between the sexes. They found that the most effective reduction in the population prevalence of HPV infection was always achieved by single-sex vaccination and that, in most situations, the preferred strategy was to vaccinate the sex with the highest prevaccine prevalence of HPV infection. The researchers confirmed these predictions using a more elaborate HPV transmission model that incorporated differences among individuals in age and level of sexual activity. Importantly, this second analysis also suggested that for existing girl-only vaccination programs, increasing coverage of vaccination among girls would bolster herd immunity more effectively than switching to a policy of vaccinating both sexes.
What Do These Findings Mean?
The findings of this study suggest that increasing vaccine uptake among preadolescent girls is a more effective way to reduce HPV infection than including boys in existing vaccination programs. They also suggest that directing HPV vaccination at the sex with the highest prevaccine prevalence of infection will reduce the population prevalence of HPV most effectively. Although the accuracy of these findings is dependent on the assumptions included in the mathematical transmission models used by the researchers, these findings support a policy of increasing female HPV vaccine coverage as far as possible, within the limits set by vaccine acceptance and economic constraints. More generally, these findings suggest that single-sex preventative interventions might be the best way to reduce heterosexual transmission of other sexually transmitted infections and that targeting the sex with the highest prevalence of infection might achieve the most effective reduction in the population prevalence of these common diseases.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001147.
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 HPV
The UK National Health Service Choices website has pages on cervical cancer and HPV vaccination (available in several languages and including a short video of girls talking about HPV vaccination)
The PREHDICT project investigates health-economic modeling of prevention strategies for HPV-related diseases in European countries; information about this project is available from the European Cervical Cancer Association
More information about cervical cancer and HPV vaccination is available from Macmillan Cancer Support
Personal stories about cervical cancer are available through the charity Healthtalkonline
MedlinePlus provides links to additional resources about cervical cancer and other sexually transmitted infections (in English and Spanish)
doi:10.1371/journal.pmed.1001147
PMCID: PMC3243713  PMID: 22205887
12.  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
13.  Measuring the Performance of Vaccination Programs Using Cross-Sectional Surveys: A Likelihood Framework and Retrospective Analysis 
PLoS Medicine  2011;8(10):e1001110.
Justin Lessler and colleagues describe a method that estimates the fraction of a population accessible to vaccination activities, and they apply it to measles vaccination in three African countries: Ghana, Madagascar, and Sierra Leone.
Background
The performance of routine and supplemental immunization activities is usually measured by the administrative method: dividing the number of doses distributed by the size of the target population. This method leads to coverage estimates that are sometimes impossible (e.g., vaccination of 102% of the target population), and are generally inconsistent with the proportion found to be vaccinated in Demographic and Health Surveys (DHS). We describe a method that estimates the fraction of the population accessible to vaccination activities, as well as within-campaign inefficiencies, thus providing a consistent estimate of vaccination coverage.
Methods and Findings
We developed a likelihood framework for estimating the effective coverage of vaccination programs using cross-sectional surveys of vaccine coverage combined with administrative data. We applied our method to measles vaccination in three African countries: Ghana, Madagascar, and Sierra Leone, using data from each country's most recent DHS survey and administrative coverage data reported to the World Health Organization. We estimate that 93% (95% CI: 91, 94) of the population in Ghana was ever covered by any measles vaccination activity, 77% (95% CI: 78, 81) in Madagascar, and 69% (95% CI: 67, 70) in Sierra Leone. “Within-activity” inefficiencies were estimated to be low in Ghana, and higher in Sierra Leone and Madagascar. Our model successfully fits age-specific vaccination coverage levels seen in DHS data, which differ markedly from those predicted by naïve extrapolation from country-reported and World Health Organization–adjusted vaccination coverage.
Conclusions
Combining administrative data with survey data substantially improves estimates of vaccination coverage. Estimates of the inefficiency of past vaccination activities and the proportion not covered by any activity allow us to more accurately predict the results of future activities and provide insight into the ways in which vaccination programs are failing to meet their goals.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Immunization (vaccination) is a proven, cost-effective tool for controlling life-threatening infectious diseases. It provides protection against infectious diseases by priming the human immune system to respond quickly and efficiently to bacteria, viruses, and other disease-causing organisms (pathogens). Whenever the human body is exposed to a pathogen, the immune system—a network of cells, tissues, and organs—mounts an attack against the foreign invader. Importantly, the immune system “learns” from the encounter, and the next time the body is exposed to the same pathogen, the immune system responds much faster to the threat. Immunization exposes the body to a very small amount of a pathogen, thereby safely providing protection against subsequent infection. More than two billion deaths are averted every year through routine childhood immunization and supplemental immunization activities (mass vaccination campaigns designed to increase vaccination coverage where immunization goals have not been reached by routine vaccination). Indeed, these two types of vaccination activities have eliminated smallpox from the world and are close to doing the same for several other infectious diseases.
Why Was This Study Done?
To reduce deaths from infectious diseases even further, it is important to know the proportion of the population reached by vaccination activities. At present, countries report vaccination coverage to the World Health Organization (WHO) that is calculated by dividing the number of vaccine doses delivered during the activity by the size of the target population. However, estimates arrived at through this “administrative method” do not account for vaccine doses that were not actually delivered, and can only reflect a single vaccination activity, which prevents us from identifying populations that may be systematically missed by all vaccination activities (for example, children living in remote areas, or children whose parents refuse vaccination). Moreover, estimates of coverage obtained by the administrative method rarely agree with estimates obtained through cross-sectional surveys such as Demographic and Health Surveys (DHS), which are household surveys of family circumstances and health undertaken at a single time point. In this study, the researchers developed a method for measuring the performance of vaccination activities that estimates the fraction of the population accessible to these activities and within-activity inefficiencies. They then tested their method by applying it to measles vaccination in three African countries; before 1980, measles killed about 2.6 million children worldwide every year, but vaccination activities have reduced this death toll to about 164,000 per year.
What Did the Researchers Do and Find?
The researchers developed a set of formulae (a “likelihood framework”) to estimate the effective coverage of vaccination activities using data on vaccine coverage from cross-sectional surveys and administrative data. They then applied their method to measles vaccination in Ghana, Madagascar, and Sierra Leone using data obtained in each country's most recent DHS survey and administrative data reported to WHO. The researchers estimate that 93%, 77%, and 65% of the target populations in Ghana, Madagascar, and Sierra Leone, respectively, were ever covered by any vaccination activity, and that inefficiencies within vaccination activities were low for Ghana, but higher for Madagascar and Sierra Leone. Consequently, the researchers' estimates of vaccination activity coverage were substantially lower than the administrative estimates for Madagascar and Sierra Leone but only slightly lower than that for Ghana. Finally, the researchers' estimates of routine vaccination coverage were generally lower than WHO-adjusted estimates but broadly agreed with age-specific vaccination coverage levels from DHS surveys.
What Do These Findings Mean?
Although the accuracy of the estimates provided by this likelihood framework depends on the assumptions included in the framework and the quality of the data fed into it, these findings show that, by combining administrative data with survey data, estimates of vaccine coverage can be substantially improved. By providing estimates of both the inefficiency of past vaccination activities and the proportion of the target population inaccessible to any vaccination activity, this method should help public health experts predict the results of future activities and help them understand why some vaccination programs fail to meet their goals. Importantly, knowing both the size of the inaccessible population and the inefficiency level of past programs makes it possible to estimate the effect of providing additional doses of vaccine on vaccination coverage. Finally, the application of this new method might help individual countries understand how susceptibility to specific infectious diseases is building up in their population and enable them to avoid outbreaks similar to the measles outbreaks that have recently occurred in several African countries.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001080.
WHO provides information about immunization and details of its Expanded Program on Immunization and its Global Immunization Vision and Strategy; WHO Africa provides details about measles immunization in Africa; a photo story about mass measles vaccination in Côte d’Ivoire is available (some material in several languages)
The UK National Health Service Choices website provides information for members of the public about immunization
The Measles Initiative is a collaborative effort that aims to reduce global measles mortality through mass vaccination campaigns and by strengthening routine immunization; its website includes information on measles and measles vaccination, including photos and videos of vaccination activities
MedlinePlus provides links to additional resources about immunization and about measles (in English and Spanish)
The charity website Healthtalkonline has interviews with UK parents about their experience of immunizing their children
doi:10.1371/journal.pmed.1001110
PMCID: PMC3201935  PMID: 22039353
14.  Human papillomavirus (HPV) vaccination for the prevention of HPV 16/18 induced cervical cancer and its precursors 
Introduction
Essential precondition for the development of cervical cancer is a persistent human papillomavirus (HPV) infection. The majority - approximately 70% - of cervical carcinomas is caused by two high-risk HPV types (16 and 18). Recently, two vaccines have been approved to the German market with the potential to induce protection against HPV 16 and HPV 18 among additional low-risk virus types.
Objectives
To analyse whether HPV vaccination is effective with regard to the reduction of cervical cancer and precursors of cervical carcinoma (CIN), respectively? Does HPV vaccination represent a cost-effective alternative or supplement to present screening practice? Are there any differences concerning cost-effectiveness between the two available vaccines? Should HPV vaccination be recommended from a health economic point of view? If so, which recommendations can be conveyed with respect to a (re)organization of the German vaccination strategy? Which ethical, social and legal implications have to be considered?
Methods
Based on a systematic literature review, randomized controlled trials (RCT) looking at the effectiveness of HPV vaccination for the prevention of cervical carcinoma and its precursors - cervical intraepithelial neoplasia - have been identified. In addition, health economic models were identified to address the health economic research questions. Quality assessment of medical and economic literature was assured by application of general assessment standards for the systematic and critical appraisal of scientific studies.
Results
Vaccine efficacy in prevention of CIN 2 or higher lesions in HPV 16 or HPV 18 negative women, who received all vaccination doses, ranges between 98% and 100%. Side effects of the vaccination are mainly associated with injection site reactions (redness, turgor, pain). No significant differences concerning serious complications between the vaccination- and the placebo-groups were reported. Results of base case scenarios in the identified health economic modeling analyses range from approximately 3,000 Euro to 40,000 Euro per additional QALY (QALY = Quality-adjusted life year) and approximately 9,000 Euro to 65,000 Euro per additional life year (LYG), respectively.
Discussion
The included studies show that both available HPV vaccines are effective in preventing HPV 16 and HPV 18 infections and probable resulting premalignant lesions of the cervix. However, the duration of protection is currently unclear. With regard to side effects, the vaccination can be considered as secure. Nevertheless, the number of cases within the clinical studies is not sufficient to determine the occurrence of rarely occurring (severe) adverse events in a reliable way. A reduction in the incidence and induced mortality through cervical cancer in Germany is not only depending on the vaccine’s clinical efficacy. Effects of the new technology on the overall participation rate in screening programs and the resulting vaccination rate and immunization status are also important factors. The results of identified health economic models vary substantially due to the heterogeneity of methodological approaches as well as chosen input parameters. However, almost all model-based analyses reached the conclusion that the implementation of a vaccination with lifelong protection can be considered as cost-effective, if the present screening practice continues. A comparison of the two vaccines shows, that the cost effectiveness ratios are more favorable with the quadrivalent vaccine than with the bivalent alternative when considering QALY as primary outcome parameter. The reason for this finding might be that in the case of the quadrivalent vaccine the prevention of genital warts can also be incorporated into the analysis. Variations of the duration of protection as well as the discounting rate were identified as the primary influencing factors of cost-effectiveness results.
Conclusion
Implementation of HPV vaccination might lead to a reduction of cervical cancer in immunized women. However, uptake of immunization should be accompanied by further studies in order to assess long-term effectiveness and safety aiming at an optimization of possible implementation processes. High numbers of participants are of particular importance regarding immunization. This has to be backed up by programs to optimize early detection – as this affects even those women who already underwent immunization. Since cost-effectiveness evidence might be significantly affected by the unclear duration of protective benefits, a final verdict on the vaccination’s cost-effectiveness in the German setting is not possible. Hence, risk-sharing-agreements between third-party payers and manufacturers would pose an option to balance the consequences of uncertainty towards the duration of protection on cost-effectiveness.
doi:10.3205/hta000066
PMCID: PMC3011291  PMID: 21289891
15.  Efficacy of Pneumococcal Nontypable Haemophilus influenzae Protein D Conjugate Vaccine (PHiD-CV) in Young Latin American Children: A Double-Blind Randomized Controlled Trial 
PLoS Medicine  2014;11(6):e1001657.
In a double-blind randomized controlled trial, Xavier Saez-Llorens and colleagues examine the vaccine efficacy of PHiD-CV against community-acquired pneumonia in young children in Panama, Argentina, and Columbia.
Please see later in the article for the Editors' Summary
Background
The relationship between pneumococcal conjugate vaccine–induced antibody responses and protection against community-acquired pneumonia (CAP) and acute otitis media (AOM) is unclear. This study assessed the impact of the ten-valent pneumococcal nontypable Haemophilus influenzae protein D conjugate vaccine (PHiD-CV) on these end points. The primary objective was to demonstrate vaccine efficacy (VE) in a per-protocol analysis against likely bacterial CAP (B-CAP: radiologically confirmed CAP with alveolar consolidation/pleural effusion on chest X-ray, or non-alveolar infiltrates and C-reactive protein ≥ 40 µg/ml); other protocol-specified outcomes were also assessed.
Methods and Findings
This phase III double-blind randomized controlled study was conducted between 28 June 2007 and 28 July 2011 in Argentine, Panamanian, and Colombian populations with good access to health care. Approximately 24,000 infants received PHiD-CV or hepatitis control vaccine (hepatitis B for primary vaccination, hepatitis A at booster) at 2, 4, 6, and 15–18 mo of age. Interim analysis of the primary end point was planned when 535 first B-CAP episodes, occurring ≥2 wk after dose 3, were identified in the per-protocol cohort. After a mean follow-up of 23 mo (PHiD-CV, n = 10,295; control, n = 10,201), per-protocol VE was 22.0% (95% CI: 7.7, 34.2; one-sided p = 0.002) against B-CAP (conclusive for primary objective) and 25.7% (95% CI: 8.4%, 39.6%) against World Health Organization–defined consolidated CAP. Intent-to-treat VE was 18.2% (95% CI: 5.5%, 29.1%) against B-CAP and 23.4% (95% CI: 8.8%, 35.7%) against consolidated CAP. End-of-study per-protocol analyses were performed after a mean follow-up of 28–30 mo for CAP and invasive pneumococcal disease (IPD) (PHiD-CV, n = 10,211; control, n = 10,140) and AOM (n = 3,010 and 2,979, respectively). Per-protocol VE was 16.1% (95% CI: −1.1%, 30.4%; one-sided p = 0.032) against clinically confirmed AOM, 67.1% (95% CI: 17.0%, 86.9%) against vaccine serotype clinically confirmed AOM, 100% (95% CI: 74.3%, 100%) against vaccine serotype IPD, and 65.0% (95% CI: 11.1%, 86.2%) against any IPD. Results were consistent between intent-to-treat and per-protocol analyses. Serious adverse events were reported for 21.5% (95% CI: 20.7%, 22.2%) and 22.6% (95% CI: 21.9%, 23.4%) of PHiD-CV and control recipients, respectively. There were 19 deaths (n = 11,798; 0.16%) in the PHiD-CV group and 26 deaths (n = 11,799; 0.22%) in the control group. A significant study limitation was the lower than expected number of captured AOM cases.
Conclusions
Efficacy was demonstrated against a broad range of pneumococcal diseases commonly encountered in young children in clinical practice.
Trial registration
www.ClinicalTrials.gov NCT00466947
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Pneumococcal diseases are illnesses caused by Streptococcus pneumoniae bacteria, pathogens (disease-causing organisms) that are transmitted through contact with infected respiratory secretions. S. pneumoniae causes mucosal diseases–infections of the lining of the body cavities that are connected to the outside world–such as community-acquired pneumonia (CAP; lung infection) and acute otitis media (AOM; middle-ear infection). It also causes invasive pneumococcal diseases (IPDs) such as septicemia and meningitis (infections of the bloodstream and the covering of the brain, respectively). Although pneumococcal diseases can sometimes be treated with antibiotics, CAP and IPDs are leading global causes of childhood deaths, particularly in developing countries. It is best therefore to avoid S. pneumoniae infections through vaccination. Vaccination primes the immune system to recognize and attack pathogens rapidly and effectively by exposing it to weakened or dead pathogens or to pathogen molecules that it recognizes as foreign (antigens). Because there are more than 90 S. pneumoniae variants (“serotypes”), each characterized by a different antigenic polysaccharide (complex sugar) coat, S. pneumoniae vaccines have to include antigens from multiple serotypes. For example, the PHiD-CV vaccine contains polysaccharides from ten S. pneumoniae serotypes.
Why Was This Study Done?
Although in most countries PHiD-CV has been licensed for protection against IPD and pneumococcal AOM, at the time of study, it was not known how well it protected against CAP and overall AOM, which are important public health problems. In this double-blind randomized controlled trial (the Clinical Otitis Media and Pneumonia Study; COMPAS), the researchers investigate the efficacy of PHiD-CV against CAP and AOM and assess other clinical end points, such as IPD, in Latin American infants. Double-blind randomized controlled trials compare the effects of interventions by assigning study participants to different interventions randomly and measuring predefined outcomes without the study participants or researchers knowing who has received which intervention until the trial is completed. Vaccine efficacy is the reduction in the incidence of a disease (the number of new cases that occur in a population in a given time) among trial participants who receive the vaccine compared to the incidence among participants who do not receive the vaccine.
What Did the Researchers Do and Find?
The researchers enrolled around 24,000 infants living in urban areas of Argentina, Panama, and Colombia. Half the infants were given PHiD-CV at 2, 4, and 6 months of age and a booster dose at age 15–18 months. The remaining infants were given a hepatitis control vaccine at the same intervals. The trial's primary end point was likely bacterial CAP (B-CAP) –radiologically confirmed CAP, with the airspaces (alveoli) in the lungs filled with liquid instead of gas (alveolar consolidation) or with non-alveolar infiltrates and raised blood levels of C-reactive protein (a marker of inflammation). In a planned interim analysis, which was undertaken after an average follow-up of 23 months, the vaccine efficacy in the per-protocol cohort (the group of participants who actually received their assigned intervention) was 22% against B-CAP. Intent-to-treat vaccine efficacy in the interim analysis (which considered all the trial participants regardless of whether they received their assigned intervention) was 18.2%. At the end of the study (average follow up 30 months), the vaccine efficacy against B-CAP was 18.2% and 16.7% in the per-protocol and intent-to-treat cohorts, respectively. Per-protocol vaccine efficacies against clinically confirmed AOM and vaccine serotype AOM were 16.1% and 67.1%, respectively. Against any IPD and against vaccine serotype IPD, the respective vaccine efficacies were 65% and 100%. Finally, about one-fifth of children who received PHiD-CV and a similar proportion who received the control vaccine experienced a serious adverse event (for example, gastroenteritis); 19 children who received PHiD-CV died compared to 26 children who received the control vaccine.
What Do These Findings Mean?
These findings indicate that in Latin America, a region with an intermediate burden of pneumococcal disease, PHiD-CV is efficacious against a broad range of pneumococcal diseases that often affect young children. The accuracy of these findings may be limited by the withdrawal of 14% of participants from the trial because of adverse media coverage and by the low number of reported cases of AOM. Moreover, because most study participants lived in urban areas, these findings may not be generalizable to rural settings. Despite these and other study limitations, these findings provide new information about the magnitude of the effect of PHiD-CV vaccination against CAP and AOM, two mucosal pneumococcal diseases of global public health importance.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001657.
The US Centers for Disease Control and Prevention provides information for patients and health professionals on all aspects of pneumococcal disease and pneumococcal vaccination, including personal stories
Public Health England provides information on pneumococcal disease and on pneumococcal vaccines
The not-for-profit Immunization Action Coalition has information on pneumococcal disease, including personal stories
The GAVI Alliance provides information about pneumococcal disease and the importance of vaccination
MedlinePlus has links to further information about pneumococcal infections, including pneumonia and otitis media (in English and Spanish)
More information about COMPAS is available
The European Medicines Agency provides information about PHiD-CV (Synflorix)
doi:10.1371/journal.pmed.1001657
PMCID: PMC4043495  PMID: 24892763
16.  Ensemble Modeling of the Likely Public Health Impact of a Pre-Erythrocytic Malaria Vaccine 
PLoS Medicine  2012;9(1):e1001157.
Using an ensemble modeling approach, Thomas Smith and colleagues find that targeted mass vaccination with a pre-erythrocytic malaria vaccine RTS,S in low-transmission settings might have better health effects than vaccination through national EPI programs.
Background
The RTS,S malaria vaccine may soon be licensed. Models of impact of such vaccines have mainly considered deployment via the World Health Organization's Expanded Programme on Immunization (EPI) in areas of stable endemic transmission of Plasmodium falciparum, and have been calibrated for such settings. Their applicability to low transmission settings is unclear. Evaluations of the efficiency of different deployment strategies in diverse settings should consider uncertainties in model structure.
Methods and Findings
An ensemble of 14 individual-based stochastic simulation models of P. falciparum dynamics, with differing assumptions about immune decay, transmission heterogeneity, and treatment access, was constructed. After fitting to an extensive library of field data, each model was used to predict the likely health benefits of RTS,S deployment, via EPI (with or without catch-up vaccinations), supplementary vaccination of school-age children, or mass vaccination every 5 y. Settings with seasonally varying transmission, with overall pre-intervention entomological inoculation rates (EIRs) of two, 11, and 20 infectious bites per person per annum, were considered. Predicted benefits of EPI vaccination programs over the simulated 14-y time horizon were dependent on duration of protection. Nevertheless, EPI strategies (with an initial catch-up phase) averted the most deaths per dose at the higher EIRs, although model uncertainty increased with EIR. At two infectious bites per person per annum, mass vaccination strategies substantially reduced transmission, leading to much greater health effects per dose, even at modest coverage.
Conclusions
In higher transmission settings, EPI strategies will be most efficient, but vaccination additional to the EPI in targeted low transmission settings, even at modest coverage, might be more efficient than national-level vaccination of infants. The feasibility and economics of mass vaccination, and the circumstances under which vaccination will avert epidemics, remain unclear. The approach of using an ensemble of models provides more secure conclusions than a single-model approach, and suggests greater confidence in predictions of health effects for lower transmission settings than for higher ones.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
The World Health Organization estimates that there are over 200 million cases of malaria each year, and that more than three-quarters of a million people (mostly children living in sub-Saharan Africa) die as a result. Several Plasmodium parasites cause malaria, the most deadly being Plasmodium falciparum. Plasmodium parasites, which are transmitted to people through the bites of infected night-flying mosquitoes, cause recurring fever and can cause life-threatening organ damage. Malaria transmission can be prevented by using insecticides to control the mosquitoes that spread the parasite and by sleeping under insecticide-treated bed nets to avoid mosquito bites. Treatment with antimalarial drugs also reduces transmission. Together, these preventative measures have greatly reduced the global burden of malaria over recent years, but a malaria vaccine could be a valuable additional tool against the disease. At present there is no licensed malaria vaccine, but one promising vaccine—RTS,S—is currently undergoing phase III clinical trials (the last stage of testing before licensing) in infants and children in seven African countries.
Why Was This Study Done?
If the RTS,S vaccine fulfills its promise and is licensed, how should it be used to maximize its effect on the global malaria burden? Should it be given through the World Health Organization's Expanded Programme on Immunization (EPI), which aims to provide universal access to immunization against several infectious diseases during the first three months of life, for example, or through mass vaccination campaigns? Individual mathematical models have been used to investigate this type of question, but the predictions made by these models may be inaccurate because malaria immunity is poorly understood, because little is known about the levels of variability (heterogeneity) in host responses to malaria infection and in malaria transmission, and because it is unclear what the structure of models used to predict vaccine efficacy should be. In this study, the researchers use an “ensemble” approach to model the likely public health impact of the RTS,S malaria vaccine. That is, they simultaneously consider the effect of the vaccine in multiple models of P. falciparum dynamics. Ensemble modeling is widely used in weather forecasting and has been used to investigate several other infectious diseases.
What Did the Researchers Do and Find?
The researchers constructed an ensemble of 14 individual-based stochastic simulation models of P. falciparum dynamics that included different assumptions about immune decay, transmission heterogeneity, and access to treatment. Such models simulate the passage of thousands of hypothetical individuals through different stages of malaria infection; movement between stages occurs stochastically (by chance) at a probability based on field data. Each model was used to predict the health benefits over 14 years of RTS,S deployment through EPI (with and without catch-up vaccination for infants who were not immunized during their first three months of life), through EPI and supplementary vaccination of school children, and through mass vaccination campaigns every five years at malaria transmission levels of 2, 11, and 20 infectious bites per person per annum (low, medium, and high entomological inoculation rates [EIRs], respectively). The predicted benefits of EPI vaccination programs over the 14-year period were modest and similar over a wide range of settings. However, EPI with an initial catch-up phase averted the most deaths per vaccine dose at higher EIRs. At the lowest EIR, mass vaccination strategies substantially reduced transmission, leading to much greater health effects per dose than other strategies, even at modest coverage.
What Do These Findings Mean?
The ensemble approach taken here suggests that targeted mass vaccination with RTS,S in low transmission settings may have greater health benefits than vaccination through national EPI programs. Importantly, this computer-intensive approach, which used computers made available over the internet by volunteers, provides more secure predictions than can be obtained using single models. In addition, it suggests that predictions made about the health effects of RTS,S vaccination for low transmission settings are more likely to be accurate than those made for higher transmission settings. However, this study only reports the first stages of using ensemble modeling to predict the health effects of RTS,S vaccination. Future studies will need to combine the outputs of multiple models with economic analyses to provide a rational basis for the design of vaccine-containing malaria control and elimination programs.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001157.
Information is available from the World Health Organization on malaria and on malaria immunization; the 2010 World Malaria Report provides details on the current global malaria situation; WHO also provides information on its Expanded Programme on Immunization (EPI), and its Global Immunization Vision and Strategy (some information is available in several languages)
The US Centers for Disease Control and Prevention provide information on malaria (in English and Spanish), including a selection of personal stories about malaria
Information is available from the Roll Back Malaria Partnership on the global control of malaria and on malaria in Africa
The latest results from the phase III trial of RTS,S are available on the website of the PATH Malaria Vaccine Initiative, a global program of the international nonprofit organization PATH that aims to accelerate the development of malaria vaccines and ensure their availability and accessibility in the developing world
Wikipedia has a page on ensemble forecasting (note: Wikipedia is a free online encyclopedia that anyone can edit; available in several languages)
OpenMalaria is the open source simulator of malaria epidemiology and control used in this study; BOINC is the open source software for volunteer computing and grid computing that was used to run the simulations
MedlinePlus provides links to additional information on malaria and on immunization (in English and Spanish)
doi:10.1371/journal.pmed.1001157
PMCID: PMC3260300  PMID: 22272189
17.  Effects of Community-Wide Vaccination with PCV-7 on Pneumococcal Nasopharyngeal Carriage in The Gambia: A Cluster-Randomized Trial 
PLoS Medicine  2011;8(10):e1001107.
In a cluster-randomized trial conducted in Gambian villages, Anna Roca and colleagues find that vaccination of children with pneumococcal conjugate vaccines reduced vaccine-type pneumococcal carriage even among nonvaccinated older children and adults.
Background
Introduction of pneumococcal conjugate vaccines (PCVs) of limited valency is justified in Africa by the high burden of pneumococcal disease. Long-term beneficial effects of PCVs may be countered by serotype replacement. We aimed to determine the impact of PCV-7 vaccination on pneumococcal carriage in rural Gambia.
Methods and Findings
A cluster-randomized (by village) trial of the impact of PCV-7 on pneumococcal nasopharyngeal carriage was conducted in 21 Gambian villages between December 2003 to June 2008 (5,441 inhabitants in 2006). Analysis was complemented with data obtained before vaccination. Because efficacy of PCV-9 in young Gambian children had been shown, it was considered unethical not to give PCV-7 to young children in all of the study villages. PCV-7 was given to children below 30 mo of age and to those born during the trial in all study villages. Villages were randomized (older children and adults) to receive one dose of PCV-7 (11 vaccinated villages) or meningococcal serogroup C conjugate vaccine (10 control villages). Cross-sectional surveys (CSSs) to collect nasopharyngeal swabs were conducted before vaccination (2,094 samples in the baseline CSS), and 4–6, 12, and 22 mo after vaccination (1,168, 1,210, and 446 samples in CSS-1, -2, and -3, respectively).
A time trend analysis showed a marked fall in the prevalence of vaccine-type pneumococcal carriage in all age groups following vaccination (from 23.7% and 26.8% in the baseline CSS to 7.1% and 8.5% in CSS-1, in vaccinated and control villages, respectively). The prevalence of vaccine-type pneumococcal carriage was lower in vaccinated than in control villages among older children (5 y to <15 y of age) and adults (≥15 y of age) at CSS-2 (odds ratio [OR] = 0.15 [95% CI 0.04–0.57] and OR = 0.32 [95% CI 0.10–0.98], respectively) and at CSS-3 (OR = 0.37 [95% CI 0.15–0.90] for older children, and 0% versus 7.6% for adults in vaccinated and control villages, respectively). Differences in the prevalence of non-vaccine-type pneumococcal carriage between vaccinated and control villages were small.
Conclusions
Vaccination of Gambian children reduced vaccine-type pneumococcal carriage across all age groups, indicating a “herd effect” in non-vaccinated older children and adults. No significant serotype replacement was detected.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
The prevention of pneumococcal disease, especially in children in developing countries, is a major international public health priority. Despite all the international attention on the UN's Millennium Development Goal 4—to reduce deaths in children under five years by two-thirds between 1990 and 2015—pneumonia, sepsis, and meningitis together compose more than 25% of the 10 million deaths occurring in children less than five years of age. Streptococcus pneumoniae is a leading bacterial cause of these diseases, and the World Health Organization estimates that approximately 800,000 children die each year of invasive pneumococcal disease.
Pneumococcal conjugate vaccines are currently available and protect against the serotypes that most commonly cause invasive pneumococcal disease in young children in North America and Europe. Such vaccines have been highly successful in reducing the incidence of invasive pneumococcal disease in both vaccinated children and in the non-vaccinated older population by reducing nasopharyngeal carriage (presence of pneumococcal bacteria in the back of the nose) in vaccinated infants, resulting in decreased transmission to contacts—the so-called herd effect. However, few countries with the highest burden of invasive pneumococcal disease, especially those in sub-Saharan Africa, have introduced the vaccine into their national immunization programs.
Why Was This Study Done?
The features of pneumococcal nasopharyngeal carriage and invasive pneumococcal disease in sub-Saharan Africa are different than in other regions. Therefore, careful evaluation of the immune effects of vaccination requires long-term, longitudinal studies. As an alternative to such long-term observational studies, and to anticipate the potential long-term effects of the introduction of pneumococcal conjugate vaccination in sub-Saharan Africa, the researchers conducted a cluster-randomized (by village) trial in The Gambia in which the whole populations of some villages were immunized with the vaccine PCV-7, and other villages received a control.
What Did the Researchers Do and Find?
With full consent from communities, the researchers randomized 21 similar villages in a rural region of western Gambia to receive pneumococcal conjugate vaccine or a control—meningococcal serogroup C conjugated vaccine, which is unlikely to affect pneumococcal carriage rates. For ethical reasons, the researchers only randomized residents aged over 30 months—all young infants received PCV-7, as a similar vaccine had already been shown to be effective in young infants. Before immunization began, the researchers took nasopharyngeal swabs from a random selection of village residents to determine the baseline pneumococcal carriage rates of both the serotypes of pneumococci covered by the vaccine (vaccine types, VTs) and the serotypes of pneumococci not covered in the vaccine (non-vaccine types, NVTs). The researchers then took nasopharyngeal swabs from a random sample of 1,200 of village residents in both groups of villages in cross-sectional surveys at 4–6, 12, and 22 months after vaccination. Villagers and laboratory staff were unaware of which vaccine was which (that is, they were blinded).
Before immunization, the overall prevalence of pneumococcal carriage in both groups was high, at 71.1%, and decreased with age. After vaccination, the overall prevalence of pneumococcal carriage in all three surveys was similar between vaccinated and control villages, showing a marked fall. However, the prevalence of carriage of VT pneumococci was significantly lower in vaccinated than in control villages in all surveys for all age groups. The prevalence of carriage of NVT pneumococci was similar in vaccinated and in control villages, except for a slightly higher prevalence of NVT pneumococci among vaccinated communities in adults at 4–6 months after vaccination. The researchers also found that the overall prevalence of pneumococcal carriage fell markedly after vaccination and reached minimum levels at 12 months in both study arms and in all age groups.
What Do These Findings Mean?
These findings show that vaccination of young Gambian children reduced carriage of VT pneumococci in vaccinated children but also in vaccinated and non-vaccinated older children and adults, revealing a potential herd effect from vaccination of young children. Furthermore, the immunological pressure induced by vaccinating whole communities did not lead to a community-wide increase in carriage of NVT pneumococci during a two-year period after vaccination. The researchers plan to conduct more long-term follow-up studies to determine nasopharyngeal carriage in these communities.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001107.
The World Health Organization has information about pneumococcus
The US Centers for Disease Control and Prevention provides information about pneumococcal conjugate vaccination
doi:10.1371/journal.pmed.1001107
PMCID: PMC3196470  PMID: 22028630
18.  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
19.  Vaccination of children with a live-attenuated, intranasal influenza vaccine – analysis and evaluation through a Health Technology Assessment 
Background: Influenza is a worldwide prevalent infectious disease of the respiratory tract annually causing high morbidity and mortality in Germany. Influenza is preventable by vaccination and this vaccination is so far recommended by the The German Standing Committee on Vaccination (STIKO) as a standard vaccination for people from the age of 60 onwards. Up to date a parenterally administered trivalent inactivated vaccine (TIV) has been in use almost exclusively. Since 2011 however a live-attenuated vaccine (LAIV) has been approved additionally. Consecutively, since 2013 the STIKO recommends LAIV (besides TIV) for children from 2 to 17 years of age, within the scope of vaccination by specified indications. LAIV should be preferred administered in children from 2 to 6 of age. The objective of this Health Technology Assessment (HTA) is to address various research issues regarding the vaccination of children with LAIV. The analysis was performed from a medical, epidemiological and health economic perspective, as well as from an ethical, social and legal point of view.
Method: An extensive systematic database research was performed to obtain relevant information. In addition a supplementary research by hand was done. Identified literature was screened in two passes by two independent reviewers using predefined inclusion and exclusion criteria. Included literature was evaluated in full-text using acknowledged standards. Studies were graded with the highest level of evidence (1++), if they met the criteria of European Medicines Agency (EMA)-Guidance: Points to consider on applications with 1. meta-analyses; 2. one pivotal study.
Results: For the medical section, the age of the study participants ranges from 6 months to 17 years. Regarding study efficacy, in children aged 6 months to ≤7 years, LAIV is superior to placebo as well as to a vac-cination with TIV (Relative Risk Reduction – RRR – of laboratory confirmed influenza infection approx. 80% and 50%, respectively). In children aged >7 to 17 years (= 18th year of their lives), LAIV is superior to a vaccination with TIV (RRR 32%). For this age group, no studies that compared LAIV with placebo were identified. It can be concluded that there is high evidence for superior efficacy of LAIV (compared to placebo or TIV) among children aged 6 months to ≤7 years. For children from >7 to 17 years, there is moderate evidence for superiority of LAIV for children with asthma, while direct evidence for children from the general population is lacking for this age group. Due to the efficacy of LAIV in children aged 6 months to ≤7 years (high evidence) and the efficacy of LAIV in children with asthma aged >7 to 17 years (moderate evidence), LAIV is also very likely to be efficacious among children in the general population aged >7 to 17 years (indirect evidence). In the included studies with children aged 2 to 17 years, LAIV was safe and well-tolerated; while in younger children LAIV may increase the risk of obstruction of the airways (e.g. wheezing).
In the majority of the evaluated epidemiological studies, LAIV proved to be effective in the prevention of influenza among children aged 2–17 years under everyday conditions (effectiveness). The trend appears to indicate that LAIV is more effective than TIV, although this can only be based on limited evidence for methodological reasons (observational studies). In addition to a direct protective effect for vaccinated children themselves, indirect protective ("herd protection") effects were reported among non-vaccinated elderly population groups, even at relatively low vaccination coverage of children. With regard to safety, LAIV generally can be considered equivalent to TIV. This also applies to the use among children with mild chronically obstructive conditions, from whom LAIV therefore does not have to be withheld. In all included epidemiological studies, there was some risk of bias identified, e.g. due to residual confounding or other methodology-related sources of error.
In the evaluated studies, both the vaccination of children with previous illnesses and the routine vaccination of (healthy) children frequently involve cost savings. This is especially the case if one includes indirect costs from a societal perspective. From a payer perspective, a routine vaccination of children is often regarded as a highly cost-effective intervention. However, not all of the studies arrive at consistent results. In isolated cases, relatively high levels of cost-effectiveness are reported that make it difficult to perform a conclusive assessment from an economic perspective. Based on the included studies, it is not possible to make a clear statement about the budget impact of using LAIV. None of the evaluated studies provides results for the context of the German healthcare setting.
The efficacy of the vaccine, physicians' recommendations, and a potential reduction in influenza symptoms appear to play a role in the vaccination decision taken by parents/custodians on behalf of their children. Major barriers to the utilization of influenza vaccination services are a low level of perception and an underestimation of the disease risk, reservations concerning the safety and efficacy of the vaccine, and potential side effects of the vaccine. For some of the parents surveyed, the question as to whether the vaccine is administered as an injection or nasal spray might also be important.
Conclusion: In children aged 2 to 17 years, the use of LAIV can lead to a reduction of the number of influenza cases and the associated burden of disease. In addition, indirect preventive effects may be expected, especially among elderly age groups. Currently there are no data available for the German healthcare setting. Long-term direct and indirect effectiveness and safety should be supported by surveillance programs with a broader use of LAIV.
Since there is no general model available for the German healthcare setting, statements concerning the cost-effectiveness can be made only with precaution. Beside this there is a need to conduct health eco-nomic studies to show the impact of influenza vaccination for children in Germany. Such studies should be based on a dynamic transmission model. Only these models are able to include the indirect protective effects of vaccination correctly.
With regard to ethical, social and legal aspects, physicians should discuss with parents the motivations for vaccinating their children and upcoming barriers in order to achieve broader vaccination coverage.
The present HTA provides an extensive basis for further scientific approaches and pending decisions relating to health policy.
doi:10.3205/hta000119
PMCID: PMC4219018  PMID: 25371764
Health Technology Assessment; HTA; LAIV; live attenuated vaccine; TIV; trivalent inactivated vaccine
20.  Yellow Fever in Africa: Estimating the Burden of Disease and Impact of Mass Vaccination from Outbreak and Serological Data 
PLoS Medicine  2014;11(5):e1001638.
Neil Ferguson and colleagues estimate the disease burden of yellow fever in Africa, as well as the impact of mass vaccination campaigns.
Please see later in the article for the Editors' Summary
Background
Yellow fever is a vector-borne disease affecting humans and non-human primates in tropical areas of Africa and South America. While eradication is not feasible due to the wildlife reservoir, large scale vaccination activities in Africa during the 1940s to 1960s reduced yellow fever incidence for several decades. However, after a period of low vaccination coverage, yellow fever has resurged in the continent. Since 2006 there has been substantial funding for large preventive mass vaccination campaigns in the most affected countries in Africa to curb the rising burden of disease and control future outbreaks. Contemporary estimates of the yellow fever disease burden are lacking, and the present study aimed to update the previous estimates on the basis of more recent yellow fever occurrence data and improved estimation methods.
Methods and Findings
Generalised linear regression models were fitted to a dataset of the locations of yellow fever outbreaks within the last 25 years to estimate the probability of outbreak reports across the endemic zone. Environmental variables and indicators for the surveillance quality in the affected countries were used as covariates. By comparing probabilities of outbreak reports estimated in the regression with the force of infection estimated for a limited set of locations for which serological surveys were available, the detection probability per case and the force of infection were estimated across the endemic zone.
The yellow fever burden in Africa was estimated for the year 2013 as 130,000 (95% CI 51,000–380,000) cases with fever and jaundice or haemorrhage including 78,000 (95% CI 19,000–180,000) deaths, taking into account the current level of vaccination coverage. The impact of the recent mass vaccination campaigns was assessed by evaluating the difference between the estimates obtained for the current vaccination coverage and for a hypothetical scenario excluding these vaccination campaigns. Vaccination campaigns were estimated to have reduced the number of cases and deaths by 27% (95% CI 22%–31%) across the region, achieving up to an 82% reduction in countries targeted by these campaigns. A limitation of our study is the high level of uncertainty in our estimates arising from the sparseness of data available from both surveillance and serological surveys.
Conclusions
With the estimation method presented here, spatial estimates of transmission intensity can be combined with vaccination coverage levels to evaluate the impact of past or proposed vaccination campaigns, thereby helping to allocate resources efficiently for yellow fever control. This method has been used by the Global Alliance for Vaccines and Immunization (GAVI Alliance) to estimate the potential impact of future vaccination campaigns.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Yellow fever is a flavivirus infection that is transmitted to people and to non-human primates through the bites of infected mosquitoes. This serious viral disease affects people living in and visiting tropical regions of Africa and Central and South America. In rural areas next to forests, the virus typically causes sporadic cases or even small-scale epidemics (outbreaks) but, if it is introduced into urban areas, it can cause large explosive epidemics that are hard to control. Although many people who contract yellow fever do not develop any symptoms, some have mild flu-like symptoms, and others develop a high fever with jaundice (yellowing of the skin and eyes) or hemorrhaging (bleeding) from the mouth, nose, eyes, or stomach. Half of patients who develop these severe symptoms die. Because of this wide spectrum of symptoms, which overlap with those of other tropical diseases, it is hard to diagnose yellow fever from symptoms alone. However, serological tests that detect antibodies to the virus in the blood can help in diagnosis. There is no specific antiviral treatment for yellow fever but its symptoms can be treated.
Why Was This Study Done?
Eradication of yellow fever is not feasible because of the wildlife reservoir for the virus but there is a safe, affordable, and highly effective vaccine against the disease. Large-scale vaccination efforts during the 1940s, 1950s, and 1960s reduced the yellow fever burden for several decades but, after a period of low vaccination coverage, the number of cases rebounded. In 2005, the Yellow Fever Initiative—a collaboration between the World Health Organization (WHO) and the United Nations Children Fund supported by the Global Alliance for Vaccines and Immunization (GAVI Alliance)—was launched to create a vaccine stockpile for use in epidemics and to implement preventive mass vaccination campaigns in the 12 most affected countries in West Africa. Campaigns have now been implemented in all these countries except Nigeria. However, without an estimate of the current yellow fever burden, it is hard to determine the impact of these campaigns. Here, the researchers use recent yellow fever occurrence data, serological survey data, and improved estimation methods to update estimates of the yellow fever burden and to determine the impact of mass vaccination on this burden.
What Did the Researchers Do and Find?
The researchers developed a generalized linear statistical model and used data on the locations where yellow fever was reported between 1987 and 2011 in Africa, force of infection estimates for a limited set of locations where serological surveys were available (the force of infection is the rate at which susceptible individuals acquire a disease), data on vaccination coverage, and demographic and environmental data for their calculations. They estimate that about 130,000 yellow fever cases with fever and jaundice or hemorrhage occurred in Africa in 2013 and that about 78,000 people died from the disease. By evaluating the difference between this estimate, which takes into account the current vaccination coverage, and a hypothetical scenario that excluded the mass vaccination campaigns, the researchers estimate that these campaigns have reduced the burden of disease by 27% across Africa and by up to 82% in the countries targeted by the campaigns (an overall reduction of 57% in the 12 targeted countries).
What Do These Findings Mean?
These findings provide a contemporary estimate of the burden of yellow fever in Africa. This estimate is broadly similar to the historic estimate of 200,000 cases and 30,000 deaths annually, which was based on serological survey data obtained from children in Nigeria between 1945 and 1971. Notably, both disease burden estimates are several hundred-fold higher than the average number of yellow fever cases reported annually to WHO, which reflects the difficulties associated with the diagnosis of yellow fever. Importantly, these findings also provide an estimate of the impact of recent mass vaccination campaigns. All these findings have a high level of uncertainty, however, because of the lack of data from both surveillance and serological surveys. Other assumptions incorporated in the researchers' model may also affect the accuracy of these findings. Nevertheless, the framework for burden estimation developed here provides essential new information about the yellow fever burden and the impact of vaccination campaigns and should help the partners of the Yellow Fever Initiative estimate the potential impact of future vaccination campaigns and ensure the efficient allocation of resources for yellow fever control.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001638.
The World Health Organization provides detailed information about yellow fever (in several languages), including photo stories about vaccination campaigns in the Sudan and Mali; it also provides information about the Yellow Fever Initiative (in English and French)
The GAVI Alliance website includes detailed of its support for yellow fever vaccination
The US Centers for Disease Control and Prevention provides information about yellow fever for the public, travelers, and health care providers
The UK National Health Service Choices website also has information about yellow fever
Wikipedia has a page on yellow fever that includes information about the history of the disease (note that Wikipedia is a free online encyclopedia that anyone can edit; available in several languages)
doi:10.1371/journal.pmed.1001638
PMCID: PMC4011853  PMID: 24800812
21.  Costs and Cost-Effectiveness of 9-Valent Human Papillomavirus (HPV) Vaccination in Two East African Countries 
PLoS ONE  2014;9(9):e106836.
Background
Current prophylactic vaccines against human papillomavirus (HPV) target two of the most oncogenic types, HPV-16 and -18, which contribute to roughly 70% of cervical cancers worldwide. Second-generation HPV vaccines include a 9-valent vaccine, which targets five additional oncogenic HPV types (i.e., 31, 33, 45, 52, and 58) that contribute to another 15–30% of cervical cancer cases. The objective of this study was to determine a range of vaccine costs for which the 9-valent vaccine would be cost-effective in comparison to the current vaccines in two less developed countries (i.e., Kenya and Uganda).
Methods and Findings
The analysis was performed using a natural history disease simulation model of HPV and cervical cancer. The mathematical model simulates individual women from an early age and tracks health events and resource use as they transition through clinically-relevant health states over their lifetime. Epidemiological data on HPV prevalence and cancer incidence were used to adapt the model to Kenya and Uganda. Health benefit, or effectiveness, from HPV vaccination was measured in terms of life expectancy, and costs were measured in international dollars (I$). The incremental cost of the 9-valent vaccine included the added cost of the vaccine counterbalanced by costs averted from additional cancer cases prevented. All future costs and health benefits were discounted at an annual rate of 3% in the base case analysis. We conducted sensitivity analyses to investigate how infection with multiple HPV types, unidentifiable HPV types in cancer cases, and cross-protection against non-vaccine types could affect the potential cost range of the 9-valent vaccine. In the base case analysis in Kenya, we found that vaccination with the 9-valent vaccine was very cost-effective (i.e., had an incremental cost-effectiveness ratio below per-capita GDP), compared to the current vaccines provided the added cost of the 9-valent vaccine did not exceed I$9.7 per vaccinated girl. To be considered very cost-effective, the added cost per vaccinated girl could go up to I$5.2 and I$16.2 in the worst-case and best-case scenarios, respectively. At a willingness-to-pay threshold of three times per-capita GDP where the 9-valent vaccine would be considered cost-effective, the thresholds of added costs associated with the 9-valent vaccine were I$27.3, I$14.5 and I$45.3 per vaccinated girl for the base case, worst-case and best-case scenarios, respectively. In Uganda, vaccination with the 9-valent vaccine was very cost-effective when the added cost of the 9-valent vaccine did not exceed I$8.3 per vaccinated girl. To be considered very cost-effective, the added cost per vaccinated girl could go up to I$4.5 and I$13.7 in the worst-case and best-case scenarios, respectively. At a willingness-to-pay threshold of three times per-capita GDP, the thresholds of added costs associated with the 9-valent vaccine were I$23.4, I$12.6 and I$38.4 per vaccinated girl for the base case, worst-case and best-case scenarios, respectively.
Conclusions
This study provides a threshold range of incremental costs associated with the 9-valent HPV vaccine that would make it a cost-effective intervention in comparison to currently available HPV vaccines in Kenya and Uganda. These prices represent a 71% and 61% increase over the price offered to the GAVI Alliance ($5 per dose) for the currently available 2- and 4-valent vaccines in Kenya and Uganda, respectively. Despite evidence of cost-effectiveness, critical challenges around affordability and feasibility of HPV vaccination and other competing needs in low-resource settings such as Kenya and Uganda remain.
doi:10.1371/journal.pone.0106836
PMCID: PMC4157790  PMID: 25198104
22.  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
23.  Is a HIV vaccine a viable option and at what price? An economic evaluation of adding HIV vaccination into existing prevention programs in Thailand 
BMC Public Health  2011;11:534.
Background
This study aims to determine the maximum price at which HIV vaccination is cost-effective in the Thai healthcare setting. It also aims to identify the relative importance of vaccine characteristics and risk behavior changes among vaccine recipients to determine how they affect this cost-effectiveness.
Methods
A semi-Markov model was developed to estimate the costs and health outcomes of HIV prevention programs combined with HIV vaccination in comparison to the existing HIV prevention programs without vaccination. The estimation was based on a lifetime horizon period (99 years) and used the government perspective. The analysis focused on both the general population and specific high-risk population groups. The maximum price of cost-effective vaccination was defined by using threshold analysis; one-way and probabilistic sensitivity analyses were performed. The study employed an expected value of perfect information (EVPI) analysis to determine the relative importance of parameters and to prioritize future studies.
Results
The most expensive HIV vaccination which is cost-effective when given to the general population was 12,000 Thai baht (US$1 = 34 Thai baht in 2009). This vaccination came with 70% vaccine efficacy and lifetime protection as long as risk behavior was unchanged post-vaccination. The vaccine would be considered cost-ineffective at any price if it demonstrated low efficacy (30%) and if post-vaccination risk behavior increased by 10% or more, especially among the high-risk population groups. The incremental cost-effectiveness ratios were the most sensitive to change in post-vaccination risk behavior, followed by vaccine efficacy and duration of protection. The EVPI indicated the need to quantify vaccine efficacy, changed post-vaccination risk behavior, and the costs of vaccination programs.
Conclusions
The approach used in this study differentiated it from other economic evaluations and can be applied for the economic evaluation of other health interventions not available in healthcare systems. This study is important not only for researchers conducting future HIV vaccine research but also for policy decision makers who, in the future, will consider vaccine adoption.
doi:10.1186/1471-2458-11-534
PMCID: PMC3224093  PMID: 21729309
Vaccine; HIV; AIDS; Economic evaluation; Cost-utility analysis
24.  A cost-effectiveness analysis of hepatitis B vaccine in predialysis patients. 
Health Services Research  1993;28(1):97-121.
OBJECTIVE. Our objective was to assess the cost effectiveness of hepatitis B vaccine in predialysis patients. DATA SOURCES. Costs were calculated from estimated rates of health services use and unit costs of resource use. Efficacy data were based on probability estimates from the medical literature and included vaccination response rates, anticipated hepatitis B virus (HBV) infection rates, and outcomes from HBV. STUDY DESIGN. Costs and effectiveness of HBV vaccination was modeled with a decision tree constructed to analyze three vaccination strategies for patients with renal insufficiency: vaccine given prior to dialysis, vaccine given at time of dialysis, and no vaccine. Sensitivity analyses were performed to assess the effect of varying important clinical and cost variables. DATA COLLECTION/EXTRACTION METHODS. All analyses were based on efficacy and cost estimates derived from the medical literature. Analyses were conducted with the aid of SMLTREE software. PRINCIPAL FINDINGS. The number of patients requiring vaccination per case of HBV prevented was higher for dialysis patients (625 vaccinees/case prevented) than for predialysis patients (434 vaccinees/case prevented). The cost-effectiveness ratios were $25,313/case of HBV prevented for vaccination at the time of dialysis and $31,111 for the predialysis vaccine. When a higher HBV infection rate (based on clinical trial data) was substituted in the analysis, the cost effectiveness of a predialysis vaccination strategy improved to $856 per case prevented. Results were sensitive to the cost of the vaccine and the incidence of HBV infection in dialysis patients. For the predialysis strategy to become cost saving, the price of the vaccine would have to decrease from $114 to $1.50, or the incidence of infection would have to increase from 0.6 percent to 38 percent, holding all other variables constant. CONCLUSIONS. Additional HBV infection can be prevented by immunizing predialysis patients, but the cost is high. Decisions concerning vaccination policy should be influenced by local prevalence of HBV infection.
PMCID: PMC1069923  PMID: 8463111
25.  A model-based economic analysis of pre-pandemic influenza vaccination cost-effectiveness 
BMC Infectious Diseases  2014;14:266.
Background
A vaccine matched to a newly emerged pandemic influenza virus would require a production time of at least 6 months with current proven techniques, and so could only be used reactively after the peak of the pandemic. A pre-pandemic vaccine, although probably having lower efficacy, could be produced and used pre-emptively. While several previous studies have investigated the cost effectiveness of pre-emptive vaccination strategies, they have not been directly compared to realistic reactive vaccination strategies.
Methods
An individual-based simulation model of ~30,000 people was used to examine a pre-emptive vaccination strategy, assuming vaccination conducted prior to a pandemic using a low-efficacy vaccine. A reactive vaccination strategy, assuming a 6-month delay between pandemic emergence and availability of a high-efficacy vaccine, was also modelled. Social distancing and antiviral interventions were examined in combination with these alternative vaccination strategies. Moderate and severe pandemics were examined, based on estimates of transmissibility and clinical severity of the 1957 and 1918 pandemics respectively, and the cost effectiveness of each strategy was evaluated.
Results
Provided that a pre-pandemic vaccine achieved at least 30% efficacy, pre-emptive vaccination strategies were found to be more cost effective when compared to reactive vaccination strategies. Reactive vaccination coupled with sustained social distancing and antiviral interventions was found to be as effective at saving lives as pre-emptive vaccination coupled with limited duration social distancing and antiviral use, with both strategies saving approximately 420 life-years per 10,000 population for a moderate pandemic with a basic reproduction number of 1.9 and case fatality rate of 0.25%. Reactive vaccination was however more costly due to larger productivity losses incurred by sustained social distancing, costing $8 million per 10,000 population ($19,074/LYS) versus $6.8 million per 10,000 population ($15,897/LYS) for a pre-emptive vaccination strategy. Similar trends were observed for severe pandemics.
Conclusions
Compared to reactive vaccination, pre-emptive strategies would be more effective and more cost effective, conditional on the pre-pandemic vaccine being able to achieve a certain level of coverage and efficacy. Reactive vaccination strategies exist which are as effective at mortality reduction as pre-emptive strategies, though they are less cost effective.
doi:10.1186/1471-2334-14-266
PMCID: PMC4045999  PMID: 24884470
Pre-emptive vaccination; Reactive vaccination; Pandemic influenza; Cost effectiveness; Simulation model

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