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1.  Immunization with 1976 swine H1N1- or 2009 pandemic H1N1-inactivated vaccines protects mice from a lethal 1918 influenza infection 
Background
Zoonotic infections with H1N1 influenza viruses that evolved initially from the 1918 virus (1918) and adapted to swine threatened a pandemic in 1976 (1976 swH1N1) and a novel reassortant H1N1 virus caused a pandemic in 2009–2010 (2009 pH1N1). Epidemiological and laboratory animal studies show that protection from severe 2009 pH1N1 infection is conferred by vaccination or prior infection with 1976 swH1N1 or 1918.
Objectives
Our aim was to demonstrate cross-protection by immunization with 2009 pH1N1 or 1976 swH1N1 vaccines following a lethal challenge with 1918. Further, the mechanisms of cross-protective antibody responses were evaluated.
Methods
Mice were immunized with 1976 swH1N1, 2009 pH1N1, 2009 seasonal trivalent, or 1918 vaccines and challenged with 1918. Cross-reactive antibody responses were assessed and protection monitored by survival, weight loss, and pathology in mice.
Results and Conclusions
Vaccination with the 1976 swH1N1 or 2009 pH1N1 vaccines protected mice from a lethal challenge with 1918, and these mice lost no weight and had significantly reduced viral load and pathology in the lungs. Protection was likely due to cross-reactive antibodies detected by microneutralization assay. Our data suggest that the general population may be protected from a future 1918-like pandemic because of prior infection or immunization with 1976 swH1N1 or 2009 pH1N1. Also, influenza protection studies generally focus on cross-reactive hemagglutination-inhibiting antibodies; while hemagglutinin is the primary surface antigen, this fails to account for other influenza viral antigens. Neutralizing antibody may be a better correlate of human protection against pathogenic influenza strains and should be considered for vaccine efficacy.
doi:10.1111/j.1750-2659.2010.00191.x
PMCID: PMC3073596
1918 influenza; 1976 influenza; 2009 pandemic H1N1; cross-protection; microneutralization
2.  Evidence of Cross-Reactive Immunity to 2009 Pandemic Influenza A Virus in Workers Seropositive to Swine H1N1 Influenza Viruses Circulating in Italy 
PLoS ONE  2013;8(2):e57576.
Background
Pigs play a key epidemiologic role in the ecology of influenza A viruses (IAVs) emerging from animal hosts and transmitted to humans. Between 2008 and 2010, we investigated the health risk of occupational exposure to swine influenza viruses (SIVs) in Italy, during the emergence and spread of the 2009 H1N1 pandemic (H1N1pdm) virus.
Methodology/Principal Findings
Serum samples from 123 swine workers (SWs) and 379 control subjects (Cs), not exposed to pig herds, were tested by haemagglutination inhibition (HI) assay against selected SIVs belonging to H1N1 (swH1N1), H1N2 (swH1N2) and H3N2 (swH3N2) subtypes circulating in the study area. Potential cross-reactivity between swine and human IAVs was evaluated by testing sera against recent, pandemic and seasonal, human influenza viruses (H1N1 and H3N2 antigenic subtypes). Samples tested against swH1N1 and H1N1pdm viruses were categorized into sera collected before (n. 84 SWs; n. 234 Cs) and after (n. 39 SWs; n. 145 Cs) the pandemic peak. HI-antibody titers ≥10 were considered positive. In both pre-pandemic and post-pandemic peak subperiods, SWs showed significantly higher swH1N1 seroprevalences when compared with Cs (52.4% vs. 4.7% and 59% vs. 9.7%, respectively). Comparable HI results were obtained against H1N1pdm antigen (58.3% vs. 7.7% and 59% vs. 31.7%, respectively). No differences were found between HI seroreactivity detected in SWs and Cs against swH1N2 (33.3% vs. 40.4%) and swH3N2 (51.2 vs. 55.4%) viruses. These findings indicate the occurrence of swH1N1 transmission from pigs to Italian SWs.
Conclusion/Significance
A significant increase of H1N1pdm seroprevalences occurred in the post-pandemic peak subperiod in the Cs (p<0.001) whereas SWs showed no differences between the two subperiods, suggesting a possible occurrence of cross-protective immunity related to previous swH1N1 infections. These data underline the importance of risk assessment and occupational health surveillance activities aimed at early detection and control of SIVs with pandemic potential in humans.
doi:10.1371/journal.pone.0057576
PMCID: PMC3585202  PMID: 23469029
3.  Immune Protection Induced on Day 10 Following Administration of the 2009 A/H1N1 Pandemic Influenza Vaccine 
PLoS ONE  2010;5(12):e14270.
Background
The 2009 swine-origin influenza virus (S-OIV) H1N1 pandemic has caused more than 18,000 deaths worldwide. Vaccines against the 2009 A/H1N1 influenza virus are useful for preventing infection and controlling the pandemic. The kinetics of the immune response following vaccination with the 2009 A/H1N1 influenza vaccine need further investigation.
Methodology/Principal Findings
58 volunteers were vaccinated with a 2009 A/H1N1 pandemic influenza monovalent split-virus vaccine (15 µg, single-dose). The sera were collected before Day 0 (pre-vaccination) and on Days 3, 5, 10, 14, 21, 30, 45 and 60 post vaccination. Specific antibody responses induced by the vaccination were analyzed using hemagglutination inhibition (HI) assay and enzyme-linked immunosorbent assay (ELISA). After administration of the 2009 A/H1N1 influenza vaccine, specific and protective antibody response with a major subtype of IgG was sufficiently developed as early as Day 10 (seroprotection rate: 93%). This specific antibody response could maintain for at least 60 days without significant reduction. Antibody response induced by the 2009 A/H1N1 influenza vaccine could not render protection against seasonal H1N1 influenza (seroconversion rate: 3% on Day 21). However, volunteers with higher pre-existing seasonal influenza antibody levels (pre-vaccination HI titer ≥1∶40, Group 1) more easily developed a strong antibody protection effect against the 2009 A/H1N1 influenza vaccine as compared with those showing lower pre-existing seasonal influenza antibody levels (pre-vaccination HI titer <1∶40, Group 2). The titer of the specific antibody against the 2009 A/H1N1 influenza was much higher in Group 1 (geometric mean titer: 146 on Day 21) than that in Group 2 (geometric mean titer: 70 on Day 21).
Conclusions/Significance
Recipients could gain sufficient protection as early as 10 days after vaccine administration. The protection could last at least 60 days. Individuals with a stronger pre-existing seasonal influenza antibody response may have a relatively higher potential for developing a stronger humoral immune response after vaccination with the 2009 A/H1N1 pandemic influenza vaccine.
doi:10.1371/journal.pone.0014270
PMCID: PMC3000335  PMID: 21151563
4.  Association between the 2008–09 Seasonal Influenza Vaccine and Pandemic H1N1 Illness during Spring–Summer 2009: Four Observational Studies from Canada 
PLoS Medicine  2010;7(4):e1000258.
In three case-control studies and a household transmission cohort, Danuta Skowronski and colleagues find an association between prior seasonal flu vaccination and increased risk of 2009 pandemic H1N1 flu.
Background
In late spring 2009, concern was raised in Canada that prior vaccination with the 2008–09 trivalent inactivated influenza vaccine (TIV) was associated with increased risk of pandemic influenza A (H1N1) (pH1N1) illness. Several epidemiologic investigations were conducted through the summer to assess this putative association.
Methods and Findings
Studies included: (1) test-negative case-control design based on Canada's sentinel vaccine effectiveness monitoring system in British Columbia, Alberta, Ontario, and Quebec; (2) conventional case-control design using population controls in Quebec; (3) test-negative case-control design in Ontario; and (4) prospective household transmission (cohort) study in Quebec. Logistic regression was used to estimate odds ratios for TIV effect on community- or hospital-based laboratory-confirmed seasonal or pH1N1 influenza cases compared to controls with restriction, stratification, and adjustment for covariates including combinations of age, sex, comorbidity, timeliness of medical visit, prior physician visits, and/or health care worker (HCW) status. For the prospective study risk ratios were computed. Based on the sentinel study of 672 cases and 857 controls, 2008–09 TIV was associated with statistically significant protection against seasonal influenza (odds ratio 0.44, 95% CI 0.33–0.59). In contrast, estimates from the sentinel and three other observational studies, involving a total of 1,226 laboratory-confirmed pH1N1 cases and 1,505 controls, indicated that prior receipt of 2008–09 TIV was associated with increased risk of medically attended pH1N1 illness during the spring–summer 2009, with estimated risk or odds ratios ranging from 1.4 to 2.5. Risk of pH1N1 hospitalization was not further increased among vaccinated people when comparing hospitalized to community cases.
Conclusions
Prior receipt of 2008–09 TIV was associated with increased risk of medically attended pH1N1 illness during the spring–summer 2009 in Canada. The occurrence of bias (selection, information) or confounding cannot be ruled out. Further experimental and epidemiological assessment is warranted. Possible biological mechanisms and immunoepidemiologic implications are considered.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Every winter, millions of people catch influenza—a viral infection of the airways—and hundreds of thousands of people die as a result. These seasonal epidemics occur because small but frequent changes in the influenza virus mean that an immune response produced one year through infection or vaccination provides only partial protection against influenza the next year. Annual vaccination with killed influenza viruses of the major circulating strains can greatly reduce a person's risk of catching influenza. Consequently, many countries run seasonal influenza vaccination programs. In most of Canada, vaccination with a mixture of three inactivated viruses (a trivalent inactivated vaccine or TIV) is provided free to children aged 6–23 months, to elderly people, to people with long-term conditions that increase their risk of influenza-related complications, and those who provide care for them; in Ontario, free vaccination is offered to everyone older than 6 months.
In addition, influenza viruses occasionally emerge that are very different and to which human populations have virtually no immunity. These viruses can start global epidemics (pandemics) that can kill millions of people. Experts have been warning for some time that an influenza pandemic is long overdue and, in March 2009, the first cases of influenza caused by a new virus called pandemic A/H1N1 2009 (pH1N1; swine flu) occurred in Mexico. The virus spread rapidly and on 11 June 2009, the World Health Organization declared that a global pandemic of pH1N1 influenza was underway. By the end of February 2010, more than 16,000 people around the world had died from pH1N1.
Why Was This Study Done?
During an investigation of a school outbreak of pH1N1 in the late spring 2009 in Canada, investigators noted that people with illness characterized by fever and coughing had been vaccinated against seasonal influenza more often than individuals without such illness. To assess whether this association between prior vaccination with seasonal 2008–09 TIV and subsequent pH1N1 illness was evident in other settings, researchers in Canada therefore conducted additional studies using different methods. In this paper, the researchers report the results of four additional studies conducted in Canada during the summer of 2009 to assess this possible association.
What Did the Researchers Do and Find?
The researchers conducted four epidemiologic studies. Epidemiology is the study of the causes, distribution, and control of diseases in populations.
Three of the four studies were case-control studies in which the researchers assessed the frequency of prior vaccination with the 2008–09 TIV in people with pH1N1 influenza compared to the frequency among healthy members of the general population or among individuals who had an influenza-like illness but no sign of infection with an influenza virus. The researchers also did a household transmission study in which they collected information about vaccination with TIV among the additional cases of influenza that were identified in 47 households in which a case of laboratory-confirmed pH1N1 influenza had occurred. The first of the case-control studies, which was based on Canada's vaccine effectiveness monitoring system, showed that, as expected, the 2008–09 TIV provided protection against seasonal influenza. However, estimates from all four studies (which included about 1,200 laboratory-confirmed pH1N1 cases and 1,500 controls) showed that prior recipients of the 2008–09 TIV had approximately 1.4–2.5 times increased chances of developing pH1N1 illness that needed medical attention during the spring–summer of 2009 compared to people who had not received the TIV. Prior seasonal vaccination was not associated with an increase in the severity of pH1N1 illness, however. That is, it did not increase the risk of being hospitalized among those with pH1N1 illness.
What Do These Findings Mean?
Because all the investigations in this study are “observational,” the people who had been vaccinated might share another unknown characteristic that is actually responsible for increasing their risk of developing pH1N1 illness (“confounding”). Furthermore, the results reported in this study might have arisen by chance, although the consistency of results across the studies makes this unlikely. Thus, the finding of an association between prior receipt of 2008–09 TIV and an increased risk of pH1N1 illness is not conclusive and needs to be investigated further, particularly since some other observational studies conducted in other countries have reported that seasonal vaccination had no influence or may have been associated with reduced chances of pH1N1 illness. If the findings in the current study are real, however, they raise important questions about the biological interactions between seasonal and pandemic influenza strains and vaccines, and about the best way to prevent and control both types of influenza in future.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/ 10.1371/journal.pmed.1000258.
This article is further discussed in a PLoS Medicine Perspective by Cécile Viboud and Lone Simonsen
FightFlu.ca, a Canadian government Web site, provides access to information on pH1N1 influenza
The US Centers for Disease Control and Prevention provides information about influenza for patients and professionals, including specific information on H1N1 influenza
Flu.gov, a US government website, provides access to information on H1N1, avian and pandemic influenza
The World Health Organization provides information on seasonal influenza and has detailed information on pH1N1 influenza (in several languages)
The UK Health Protection Agency provides information on pandemic influenza and on pH1N1 influenza
doi:10.1371/journal.pmed.1000258
PMCID: PMC2850386  PMID: 20386731
5.  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
6.  Conserved Synthetic Peptides from the Hemagglutinin of Influenza Viruses Induce Broad Humoral and T-Cell Responses in a Pig Model 
PLoS ONE  2012;7(7):e40524.
Outbreaks involving either H5N1 or H1N1 influenza viruses (IV) have recently become an increasing threat to cause potential pandemics. Pigs have an important role in this aspect. As reflected in the 2009 human H1N1 pandemia, they may act as a vehicle for mixing and generating new assortments of viruses potentially pathogenic to animals and humans. Lack of universal vaccines against the highly variable influenza virus forces scientists to continuously design vaccines à la carte, which is an expensive and risky practice overall when dealing with virulent strains. Therefore, we focused our efforts on developing a broadly protective influenza vaccine based on the Informational Spectrum Method (ISM). This theoretical prediction allows the selection of highly conserved peptide sequences from within the hemagglutinin subunit 1 protein (HA1) from either H5 or H1 viruses which are located in the flanking region of the HA binding site and with the potential to elicit broader immune responses than conventional vaccines. Confirming the theoretical predictions, immunization of conventional farm pigs with the synthetic peptides induced humoral responses in every single pig. The fact that the induced antibodies were able to recognize in vitro heterologous influenza viruses such as the pandemic H1N1 virus (pH1N1), two swine influenza field isolates (SwH1N1 and SwH3N2) and a H5N1 highly pathogenic avian virus, confirm the broad recognition of the antibodies induced. Unexpectedly, all pigs also showed T-cell responses that not only recognized the specific peptides, but also the pH1N1 virus. Finally, a partial effect on the kinetics of virus clearance was observed after the intranasal infection with the pH1N1 virus, setting forth the groundwork for the design of peptide-based vaccines against influenza viruses. Further insights into the understanding of the mechanisms involved in the protection afforded will be necessary to optimize future vaccine formulations.
doi:10.1371/journal.pone.0040524
PMCID: PMC3398042  PMID: 22815759
7.  Cross-Reactive Neuraminidase Antibodies Afford Partial Protection against H5N1 in Mice and Are Present in Unexposed Humans 
PLoS Medicine  2007;4(2):e59.
Background
A pandemic H5N1 influenza outbreak would be facilitated by an absence of immunity to the avian-derived virus in the human population. Although this condition is likely in regard to hemagglutinin-mediated immunity, the neuraminidase (NA) of H5N1 viruses (avN1) and of endemic human H1N1 viruses (huN1) are classified in the same serotype. We hypothesized that an immune response to huN1 could mediate cross-protection against H5N1 influenza virus infection.
Methods and Findings
Mice were immunized against the NA of a contemporary human H1N1 strain by DNA vaccination. They were challenged with recombinant A/Puerto Rico/8/34 (PR8) viruses bearing huN1 (PR8-huN1) or avN1 (PR8-avN1) or with H5N1 virus A/Vietnam/1203/04. Additional naïve mice were injected with sera from vaccinated mice prior to H5N1 challenge. Also, serum specimens from humans were analyzed for reactivity with avN1. Immunization elicited a serum IgG response to huN1 and robust protection against the homologous challenge virus. Immunized mice were partially protected from lethal challenge with H5N1 virus or recombinant PR8-avN1. Sera transferred from immunized mice to naïve animals conferred similar protection against H5N1 mortality. Analysis of human sera showed that antibodies able to inhibit the sialidase activity of avN1 exist in some individuals.
Conclusions
These data reveal that humoral immunity elicited by huN1 can partially protect against H5N1 infection in a mammalian host. Our results suggest that a portion of the human population could have some degree of resistance to H5N1 influenza, with the possibility that this could be induced or enhanced through immunization with seasonal influenza vaccines.
Humoral immunity against endemic human H1N1 influenza viruses can partially protect mice against H5N1 challenge, raising the possibility that a portion of the human population could have some degree of resistance against avian flu.
Editors' Summary
Background.
Every winter, millions of people catch influenza—a viral infection of the airways. Most recover quickly but influenza can kill infants, elderly people, and chronically ill individuals. To minimize these deaths, the World Health Organization recommends that vulnerable people be vaccinated against influenza every autumn. Annual vaccination is necessary because flu viruses continually make small changes to the viral proteins (antigens) that the immune system recognizes. Each year's vaccine contains disabled versions of the circulating strains of influenza A type H1N1 and H3N2 viruses, and of influenza B virus. The H and N refer to the major influenza A antigens (hemagglutinin and neuraminidase), and the numbers refer to the type of each antigen; different H1N1 and H3N2 virus strains contain small variations in their respective hemagglutinin and neuraminidase type. Vaccines provide protection against seasonal influenza outbreaks, but sometimes flu viruses emerge that contain major antigenic changes, such as a different hemagglutinin type. These viruses can start pandemics (global outbreaks) because populations have little immunity to them. Many scientists believe that avian (bird) H5N1 influenza virus (which has caused about 250 confirmed cases of human flu and 150 deaths) could trigger the next human pandemic.
Why Was This Study Done?
Avian influenza H5N1 virus has not started a human pandemic yet because it cannot move easily between people. If it acquires this property, it could kill millions before an effective vaccine could be developed, so researchers are looking for other ways to provide protection against avian H5N1. One possibility is that an immune response to the human type 1 neuraminidase (huN1) in circulating H1N1 influenza virus strains and vaccines could provide some protection against avian H5N1 influenza virus, which contains the closely related avian type 1 neuraminidase (avN1). In this study, the researchers have investigated this possibility in mice and in a small human study.
What Did the Researchers Do and Find?
The researchers immunized mice with DNA encoding the huN1 present in a circulating H1N1 virus. They then examined the immune response of the mice to this huN1 and to avN1 from an avian H5N1 virus isolated from a human patient (A/Vietnam/1203/04). Most of the mice made antibodies (proteins that recognize antigens) against huN1; a few also made detectable levels of antibodies against avN1. All the vaccinated mice survived infection with a man-made flu virus containing huN1, and half also survived infection with low doses of a man-made virus containing avN1 or A/Vietnam/1203/04. To test whether the antibodies made by the vaccinated mice were responsible for this partial protection, the researchers collected serum (the liquid part of blood that contains the antibodies) from them and injected it into unvaccinated mice. Again, about half of the mice survived infection with the H5N1 virus, which indicates that the huN1-induced immunity against H5N1 is largely mediated by antibodies. Finally, the researchers tested serum samples from 38 human volunteers for their ability to inhibit neuraminidase from an H1N1 virus and two H5N1 viruses (antibodies to neuraminidase reduce viral replication and disease severity by inhibiting neuraminidase activity). Most of the sera inhibited the enzyme from the H1N1 virus; and seven also inhibited the enzyme from both H5N1 viruses.
What Do These Findings Mean?
These findings indicate that a vaccine containing huN1 induces the production of antibodies in mice that partly protect them against H5N1 infection. In addition, the human study suggests that some people may have some degree of resistance to H5N1 influenza because of exposure to H1N1 viruses or routine influenza vaccination. These results, while intriguing, don't show that there is actual protection, but it seems well worth doing additional work to address this question. The researchers also suggest that many more people might have been infected already with H5N1 but their strong H1N1 immunity meant they had only mild symptoms, and this hypothesis also deserves further investigation. Overall, these findings raise the possibility that seasonal influenza vaccination may provide some protection against pandemic H5N1. It is worth discussing whether, even while further studies are underway, seasonal vaccination should be increased, especially in areas where H5N1 is present in birds.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0040059.
A related PLoS Medicine Perspective article by Laura Gillim-Ross and Kanta Subbarao is available
US Centers for Disease Control and Prevention provides information about influenza for patients and professionals, including key facts about avian influenza and vaccination
US National Institute of Allergy and Infectious Disease has a feature on seasonal, avian and pandemic flu
World Health Organization has fact sheets on influenza and influenza vaccines, and information on avian influenza
UK Health Protection Agency provides information on seasonal, avian, and pandemic influenza
doi:10.1371/journal.pmed.0040059
PMCID: PMC1796909  PMID: 17298168
8.  Hedging against Antiviral Resistance during the Next Influenza Pandemic Using Small Stockpiles of an Alternative Chemotherapy 
PLoS Medicine  2009;6(5):e1000085.
Mathematically simulating an influenza pandemic, Joseph Wu and colleagues predict that using a secondary antiviral drug early in local epidemics would reduce global emergence of resistance to the primary stockpiled drug.
Background
The effectiveness of single-drug antiviral interventions to reduce morbidity and mortality during the next influenza pandemic will be substantially weakened if transmissible strains emerge which are resistant to the stockpiled antiviral drugs. We developed a mathematical model to test the hypothesis that a small stockpile of a secondary antiviral drug could be used to mitigate the adverse consequences of the emergence of resistant strains.
Methods and Findings
We used a multistrain stochastic transmission model of influenza to show that the spread of antiviral resistance can be significantly reduced by deploying a small stockpile (1% population coverage) of a secondary drug during the early phase of local epidemics. We considered two strategies for the use of the secondary stockpile: early combination chemotherapy (ECC; individuals are treated with both drugs in combination while both are available); and sequential multidrug chemotherapy (SMC; individuals are treated only with the secondary drug until it is exhausted, then treated with the primary drug). We investigated all potentially important regions of unknown parameter space and found that both ECC and SMC reduced the cumulative attack rate (AR) and the resistant attack rate (RAR) unless the probability of emergence of resistance to the primary drug pA was so low (less than 1 in 10,000) that resistance was unlikely to be a problem or so high (more than 1 in 20) that resistance emerged as soon as primary drug monotherapy began. For example, when the basic reproductive number was 1.8 and 40% of symptomatic individuals were treated with antivirals, AR and RAR were 67% and 38% under monotherapy if pA = 0.01. If the probability of resistance emergence for the secondary drug was also 0.01, then SMC reduced AR and RAR to 57% and 2%. The effectiveness of ECC was similar if combination chemotherapy reduced the probabilities of resistance emergence by at least ten times. We extended our model using travel data between 105 large cities to investigate the robustness of these resistance-limiting strategies at a global scale. We found that as long as populations that were the main source of resistant strains employed these strategies (SMC or ECC), then those same strategies were also effective for populations far from the source even when some intermediate populations failed to control resistance. In essence, through the existence of many wild-type epidemics, the interconnectedness of the global network dampened the international spread of resistant strains.
Conclusions
Our results indicate that the augmentation of existing stockpiles of a single anti-influenza drug with smaller stockpiles of a second drug could be an effective and inexpensive epidemiological hedge against antiviral resistance if either SMC or ECC were used. Choosing between these strategies will require additional empirical studies. Specifically, the choice will depend on the safety of combination therapy and the synergistic effect of one antiviral in suppressing the emergence of resistance to the other antiviral when both are taken in combination.
Editors' Summary
Background
Every winter, millions of people catch influenza—a viral infection of the airways—and about half a million people die as a result. These seasonal “epidemics” occur because small but frequent changes in the viral proteins (antigens) to which the human immune system responds mean that an immune response produced one year provides only partial protection against influenza the next year. Influenza viruses also occasionally appear that contain major antigenic changes. Human populations have little or no immunity to such viruses so they can start deadly pandemics (global epidemics). The 1918–19 influenza pandemic, for example, killed 40–50 million people. The last influenza pandemic was in 1968 and many experts fear the next pandemic might strike soon. To prepare for such an eventuality, scientists are trying to develop vaccines that might work against an emerging pandemic influenza virus. In addition, many governments are stockpiling antiviral drugs for the large-scale treatment of influenza and for targeted prophylaxis (prevention). Antiviral drugs prevent the replication of the influenza virus, thereby shortening the length of time that an infected person is ill and protecting uninfected people against infection. Their widespread use should, therefore, slow the spread of pandemic influenza.
Why Was This Study Done?
Although some countries are stockpiling more than one antiviral drug in preparation for an influenza pandemic, many countries are investing in large stockpiles of a single drug, oseltamivir (Tamiflu). But influenza viruses can become resistant to antiviral drugs and the widespread use of a single drug (the primary antiviral) is likely to increase the risk that a resistant strain will emerge. If this did happen, the ability of antiviral drugs to slow the spread of a pandemic would be greatly reduced. In this study, the researchers use a mathematical model of influenza transmission to investigate whether a small stockpile of a secondary antiviral drug could be used to prevent the adverse consequences of the emergence of antiviral-resistant pandemic influenza viruses.
What Did the Researchers Do and Find?
The researchers used their model of influenza transmission to predict how two strategies for the use of a small stockpile of a secondary antiviral might affect the cumulative attack rate (AR; the final proportion of the population infected) and the resistant attack rate (RAR; the proportion of the population infected with an influenza virus strain resistant to the primary drug, a measure that may reflect the impact of antiviral resistance on death rates during a pandemic). In a large, closed population, the model predicted that both “early combination chemotherapy” (treatment with both drugs together while both are available) and “sequential multi-drug chemotherapy” (treatment with the secondary drug until it is exhausted, then treatment with the primary drug) would reduce the AR and the RAR compared with monotherapy unless the probability of emergence of resistance to the primary drug was very low (resistance rarely occurred) or very high (resistance emerged as soon as the primary drug was used). The researchers then introduced international travel data into their model to investigate whether these two strategies could limit the development of antiviral resistance at a global scale. This analysis predicted that, provided the population that was the main source of resistant strains used one of the strategies, both strategies in distant, subsequently affected populations would be able to reduce the AR and RAR even if some intermediate populations failed to control resistance.
What Do These Findings Mean?
As with all mathematical models, the accuracy of these predictions depends on the assumptions used to build the model and the data fed into it. Nevertheless, these findings suggest that both of the proposed strategies for the use of small stockpiles of secondary antiviral drugs should limit the spread of drug-resistant influenza virus more effectively than monotherapy with the primary antiviral drug. Thus, small stockpiles of secondary antivirals could provide a hedge against the development of antiviral resistance during the early phases of an influenza pandemic and are predicted to be a worthwhile public-health investment. However, note the researchers, experimental studies—including determinations of which drugs are safe to use together, and how effectively a given combination prevents resistance compared with each drug used alone—are now needed to decide which of the strategies to recommend in real-life situations. In the context of the 2009 global spread of swine flu, these findings suggest that public health officials might consider zanamivir (Relenza) as the secondary antiviral drug for resistance-limiting strategies in countries that have stockpiled oseltamivir.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000085.
The US Centers for Disease Control and Prevention provides information about influenza for patients and professionals, including specific information on pandemic influenza and on influenza antiviral drugs
The World Health Organization provides information on influenza (in several languages) and has detailed guidelines on the use of vaccines and antivirals during influenza pandemics
The UK Health Protection Agency provides information on pandemic influenza
MedlinePlus provides a list of links to other information about influenza (in English and Spanish)
doi:10.1371/journal.pmed.1000085
PMCID: PMC2680070  PMID: 19440354
9.  Optimizing the Dose of Pre-Pandemic Influenza Vaccines to Reduce the Infection Attack Rate 
PLoS Medicine  2007;4(6):e218.
Background
The recent spread of avian influenza in wild birds and poultry may be a precursor to the emergence of a 1918-like human pandemic. Therefore, stockpiles of human pre-pandemic vaccine (targeted at avian strains) are being considered. For many countries, the principal constraint for these vaccine stockpiles will be the total mass of antigen maintained. We tested the hypothesis that lower individual doses (i.e., less than the recommended dose for maximum protection) may provide substantial extra community-level benefits because they would permit wider vaccine coverage for a given total size of antigen stockpile.
Methods and Findings
We used a mathematical model to predict infection attack rates under different policies. The model incorporated both an individual's response to vaccination at different doses and the process of person-to-person transmission of pandemic influenza. We found that substantial reductions in the attack rate are likely if vaccines are given to more people at lower doses. These results are applicable to all three vaccine candidates for which data are available. As a guide to the magnitude of the effect, we simulated epidemics based on historical studies of immunogenicity. For example, for one of the vaccines for which data are available, the attack rate would drop from 67.6% to 58.7% if 160 out of the total US population of 300 million were given an optimal dose rather than 20 out of 300 million given the maximally protective dose (as promulgated in the US National Pandemic Preparedness Plan). Our results are conservative with respect to a number of alternative assumptions about the precise nature of vaccine protection. We also considered a model variant that includes a single high-risk subgroup representing children. For smaller stockpile sizes that allow vaccine to be offered only to the high-risk group at the optimal dose, the predicted benefits of using the homogenous model formed a lower bound in the presence of a risk group, even when the high-risk group was twice as infective and twice as susceptible.
Conclusions
In addition to individual-level protection (i.e., vaccine efficacy), the population-level implications of pre-pandemic vaccine programs should be considered when deciding on stockpile size and dose. Our results suggest that a lower vaccine dose may be justified in order to increase population coverage, thereby reducing the infection attack rate overall.
Steven Riley and colleagues examine the potential benefits of "stretching" a limited supply of vaccine and suggest that substantial reductions in the attack rate are possible if vaccines are given to more people at lower doses.
Editors' Summary
Background.
Every winter, millions of people catch influenza, a viral infection of the nose, throat, and airways. Most recover quickly, but the disease can be deadly. In the US, seasonal influenza outbreaks (epidemics) cause 36,000 excess deaths annually. And now there are fears that an avian (bird) influenza virus might trigger a human influenza pandemic—a global epidemic that could kill millions. Seasonal epidemics occur because flu viruses continually make small changes to their hemagglutinin and neuraminidase molecules, the viral proteins (antigens) that the immune system recognizes. Because of this “antigenic drift,” an immune system response (which can be induced by catching flu or by vaccination with disabled circulating influenza strains) that combats flu one year may provide only partial protection the next year. “Antigenic shift” (large changes in flu antigens) can cause pandemics because communities have no immunity to the changed virus.
Why Was This Study Done?
Although avian influenza virus, which contains a hemagglutinin type that differs from currently circulating human flu viruses, has caused a few cases of human influenza, it has not started a human pandemic yet because it cannot move easily between people. If it acquires this property, which will probably involve further small antigenic changes, it could kill millions of people before scientists can develop an effective vaccine against it. To provide some interim protection, many countries are preparing stockpiles of “pre-pandemic” vaccines targeted against the avian virus. The US, for example, plans to store enough pre-pandemic vaccine to provide maximum protection to 20 million people (including key health workers) out of its population of 300 million. But, given a limited stockpile of pre-pandemic vaccine, might giving more people a lower dose of vaccine, which might reduce the number of people susceptible to infection and induce herd immunity by preventing efficient transmission of the flu virus, be a better way to limit the spread of pandemic influenza? In this study, the researchers have used mathematical modeling to investigate this question.
What Did the Researchers Do and Find?
To predict the infection rates associated with different vaccination policies, the researchers developed a mathematical model that incorporates data on human immune responses induced with three experimental vaccines against the avian virus and historical data on the person–person transmission of previous pandemic influenza viruses. For all the vaccines, the model predicts that giving more people a low dose of the vaccine would limit the spread of influenza better than giving fewer people the high dose needed for full individual protection. For example, the researchers estimate that dividing the planned US stockpile of one experimental vaccine equally between 160 million people instead of giving it at the fully protective dose to 20 million people might avert about 27 million influenza cases in less than year. However, giving the maximally protective dose to the 9 million US health-care workers and using the remaining vaccine at a lower dose to optimize protection within the general population might avert only 14 million infections.
What Do These Findings Mean?
These findings suggest that, given a limited stockpile of pre-pandemic vaccine, increasing the population coverage of vaccination by using low doses of vaccine might reduce the overall influenza infection rate more effectively than vaccinating fewer people with fully protective doses of vaccine. However, because the researchers' model includes many assumptions, it can only give an indication of how different strategies might perform, not firm numbers for how many influenza cases each strategy is likely to avert. Before public-health officials use this or a similar model to help them decide the best way to use pre-pandemic vaccines to control a human influenza pandemic, they will need more information about the efficacy of these vaccines and about transmission rates of currently circulating viruses. They will also need to know whether pre-pandemic vaccines actually provide good protection against the pandemic virus, as assumed in this study, before they can recommend mass immunization with low doses of pre-pandemic vaccine, selective vaccination with high doses, or a mixed strategy.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0040218.
US Centers for Disease Control and Prevention provide information on influenza and influenza vaccination for patients and health professionals (in English, Spanish, Filipino, Chinese, and Vietnamese)
The World Health Organization has a fact sheet on influenza and on the global response to avian influenza (in English, Spanish, French, Russian, Arabic, and Chinese)
The MedlinePlus online encyclopedia devotes a page to flu (in English and Spanish)
The UK Health Protection Agency information on avian, pandemic, and seasonal influenza
The US National Institute of Allergy and Infectious Diseases has a comprehensive feature called “focus on the flu”
doi:10.1371/journal.pmed.0040218
PMCID: PMC1892041  PMID: 17579511
10.  Comparative study of pandemic (H1N1) 2009, swine H1N1, and avian H3N2 influenza viral infections in quails 
Journal of Veterinary Science  2012;13(4):395-403.
Quail has been proposed to be an intermediate host of influenza A viruses. However, information on the susceptibility and pathogenicity of pandemic H1N1 2009 (pH1N1) and swine influenza viruses in quails is limited. In this study, the pathogenicity, virus shedding, and transmission characteristics of pH1N1, swine H1N1 (swH1N1), and avian H3N2 (dkH3N2) influenza viruses in quails was examined. Three groups of 15 quails were inoculated with each virus and evaluated for clinical signs, virus shedding and transmission, pathological changes, and serological responses. None of the 75 inoculated (n = 45), contact exposed (n = 15), or negative control (n = 15) quails developed any clinical signs. In contrast to the low virus shedding titers observed from the swH1N1-inoculated quails, birds inoculated with dkH3N2 and pH1N1 shed relatively high titers of virus predominantly from the respiratory tract until 5 and 7 DPI, respectively, that were rarely transmitted to the contact quails. Gross and histopathological lesions were observed in the respiratory and intestinal tracts of quail inoculated with either pH1N1 or dkH3N2, indicating that these viruses were more pathogenic than swH1N1. Sero-conversions were detected 7 DPI in two out of five pH1N1-inoculated quails, three out of five quails inoculated with swH1N1, and four out of five swH1N1-infected contact birds. Taken together, this study demonstrated that quails were more susceptible to infection with pH1N1 and dkH3N2 than swH1N1.
doi:10.4142/jvs.2012.13.4.395
PMCID: PMC3539125  PMID: 23271181
avian H3N2 virus; infection; pandemic H1N1 2009 virus; quail; swine H1N1 virus
11.  Cross-Neutralizing Antibodies to Pandemic 2009 H1N1 and Recent Seasonal H1N1 Influenza A Strains Influenced by a Mutation in Hemagglutinin Subunit 2 
PLoS Pathogens  2011;7(6):e1002081.
Pandemic 2009 H1N1 influenza A virus (2009 H1N1) differs from H1N1 strains that circulated in the past 50 years, but resembles the A/New Jersey/1976 H1N1 strain used in the 1976 swine influenza vaccine. We investigated whether sera from persons immunized with the 1976 swine influenza or recent seasonal influenza vaccines, or both, neutralize 2009 H1N1. Using retroviral pseudovirions bearing hemagglutinins on their surface (HA-pseudotypes), we found that 77% of the sera collected in 1976 after immunization with the A/New Jersey/1976 H1N1 swine influenza vaccine neutralized 2009 H1N1. Forty five percent also neutralized A/New Caledonia/20/1999 H1N1, a strain used in seasonal influenza vaccines during the 2000/01–2006/07 seasons. Among adults aged 48–64 who received the swine influenza vaccine in 1976 and recent seasonal influenza vaccines during the 2004/05–2008/09 seasons, 83% had sera that neutralized 2009 H1N1. However, 68% of age-matched subjects who received the same seasonal influenza vaccines, but did not receive the 1976 swine influenza vaccine, also had sera that neutralized 2009 H1N1. Sera from both 1976 and contemporary cohorts frequently had cross-neutralizing antibodies to 2009 H1N1 and A/New Caledonia/20/1999 that mapped to hemagglutinin subunit 2 (HA2). A conservative mutation in HA2 corresponding to a residue in the A/Solomon Islands/3/2006 and A/Brisbane/59/2007 H1N1 strains that circulated in the 2006/07 and 2007/08 influenza seasons, respectively, abrogated this neutralization. These findings highlight a cross-neutralization determinant influenced by a point mutation in HA2 and suggest that HA2 may be evolving under direct or indirect immune pressure.
Author Summary
Influenza A viruses mutate to escape neutralization by antibodies. These mutations predominantly occur in the globular head of the hemagglutinin protein, while the stalk is more conserved. Pandemic 2009 H1N1 influenza virus differs from seasonal H1N1 strains that circulated in the past 50 years and resembles a strain that did not circulate but was used in the 1976 swine influenza vaccine. We investigated whether persons immunized with either the 1976 swine influenza or recent seasonal influenza vaccines, or both, have antibodies that cross-neutralize pandemic 2009 H1N1. Sera from 1976 swine influenza vaccine trials cross-neutralized pandemic 2009 H1N1 and to a lesser extent the A/New Caledonia/20/1999 H1N1 strain that was used in vaccines during the 2000/01–2006/07 influenza seasons. Sera from persons who received several seasonal influenza vaccines containing A/New Caledonia/20/1999 H1N1 cross-neutralized pandemic 2009 H1N1, regardless of whether they received the 1976 swine influenza vaccine. We found that cross-neutralization between 2009 H1N1 and A/New Caledonia/20/1999 frequently mapped to the hemagglutinin stalk. A mutation in the stalk of strains circulating during the 2007/08–2008/09 seasons abrogates this neutralization. These findings highlight a cross-neutralization determinant influenced by a point mutation in the hemagglutinin stalk and suggest that the stalk may be evolving under direct or indirect immune pressure.
doi:10.1371/journal.ppat.1002081
PMCID: PMC3111540  PMID: 21695241
12.  Evaluation of Coseasonality of Influenza and Invasive Pneumococcal Disease: Results from Prospective Surveillance 
PLoS Medicine  2011;8(6):e1001042.
Using a combination of modeling and statistical analyses, David Fisman and colleagues show that influenza likely influences the incidence of invasive pneumococcal disease by enhancing risk of invasion in colonized individuals.
Background
The wintertime co-occurrence of peaks in influenza and invasive pneumococcal disease (IPD) is well documented, but how and whether wintertime peaks caused by these two pathogens are causally related is still uncertain. We aimed to investigate the relationship between influenza infection and IPD in Ontario, Canada, using several complementary methodological tools.
Methods and Findings
We evaluated a total number of 38,501 positive influenza tests in Central Ontario and 6,191 episodes of IPD in the Toronto/Peel area, Ontario, Canada, between 1 January 1995 and 3 October 2009, reported through population-based surveillance. We assessed the relationship between the seasonal wave forms for influenza and IPD using fast Fourier transforms in order to examine the relationship between these two pathogens over yearly timescales. We also used three complementary statistical methods (time-series methods, negative binomial regression, and case-crossover methods) to evaluate the short-term effect of influenza dynamics on pneumococcal risk. Annual periodicity with wintertime peaks could be demonstrated for IPD, whereas periodicity for influenza was less regular. As for long-term effects, phase and amplitude terms of pneumococcal and influenza seasonal sine waves were not correlated and meta-analysis confirmed significant heterogeneity of influenza, but not pneumococcal phase terms. In contrast, influenza was shown to Granger-cause pneumococcal disease. A short-term association between IPD and influenza could be demonstrated for 1-week lags in both case-crossover (odds ratio [95% confidence interval] for one case of IPD per 100 influenza cases  = 1.10 [1.02–1.18]) and negative binomial regression analysis (incidence rate ratio [95% confidence interval] for one case of IPD per 100 influenza cases  = 1.09 [1.05–1.14]).
Conclusions
Our data support the hypothesis that influenza influences bacterial disease incidence by enhancing short-term risk of invasion in colonized individuals. The absence of correlation between seasonal waveforms, on the other hand, suggests that bacterial disease transmission is affected to a lesser extent.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Although some pathogens (disease-causing organisms) cause illness all year round, others are responsible for seasonal peaks of illness. These peaks occur because of a complex interplay of factors such as the loss of immunity to the pathogen over time and seasonal changes in the pathogen's ability to infect new individuals. Thus, in temperate countries in the northern hemisphere, illness caused by influenza viruses (pathogens that infect the nose, throat, and airways) usually peaks between December and March, perhaps because weather conditions during these months favor the survival of influenza virus in the environment and thus increase its chances of being transferred among people. Another illness that peaks during the winter months in temperate regions is pneumonia, a severe lung infection that is often caused by Streptococcus pneumoniae. These bacteria can colonize the back of the throat without causing disease but occasionally spread into the lungs and other organs where they cause potentially fatal invasive pneumococcal disease (IPD).
Why Was This Study Done?
Although the co-occurrence of seasonal peaks of influenza and IPD is well documented, it is unclear whether (or how) these peaks are causally related. For example, do the peaks of influenza and IPD both occur in the winter because influenza enhances person-to-person transmission of S. pneumoniae (hypothesis 1)? Alternatively, do the diseases co-occur because influenza infection increases the risk of IPD in individuals who are already colonized with S. pneumoniae (hypothesis 2)? Healthcare professionals need to know whether there is a causal relationship between influenza and IPD so that they can target vaccination for both diseases to those individuals most at risk of developing the potentially serious complications of these diseases. In this study, the researchers use several mathematical and statistical methods and data on influenza and IPD collected in Ontario, Canada to investigate the relationship between these seasonal illnesses.
What Did the Researchers Do and Find?
Between January 1995 and October 2009, 38,501 positive influenza tests were recorded in Ontario by the Canadian national influenza surveillance network. Over the same time period, the Toronto Invasive Bacterial Diseases Network (a group of hospitals, laboratories, and doctors that undertakes population-based surveillance for serious bacterial infections in the Toronto and Peel Regions of Ontario) recorded 6,191 IPD episodes. The researchers used a mathematical method called fast Fourier transforms that compares the shape of wave forms to look for any relationship between infections with the two pathogens over yearly timescales (a test of hypothesis 1) and three statistical methods to evaluate the short-term effect of influenza dynamics on IPD risk (tests of hypothesis 2). Although they found wintertime peaks for infections with both pathogens, there was no correlation between the seasonal wave forms for influenza and IPD. That is, there was no relationship between the seasonal patterns of the two infections. By contrast, two of the statistical methods used to test hypothesis 2 revealed a short-term association between infections with influenza and with IPD. Moreover, the third statistical method (the Granger causality Wald test, a type of time-series analysis) provided evidence that data collected at intervals on influenza can be used to predict peaks in IPD infections.
What Do These Findings Mean?
These findings support (but do not prove) the hypothesis that influenza influences IPD incidence by enhancing the short-term risk of bacterial invasion in individuals already colonized with S. pneumoniae, possibly by increasing the permeability of the lining of the airways to bacteria. By contrast, the lack of correlation between the seasonal wave forms for the two diseases suggests that person-to-person transfer of S. pneumoniae is affected by influenza infections to a lesser extent. These findings have important implications for disease control policy. First, they suggest that the increased number of influenza infections in pandemic years may not necessarily be accompanied by a marked surge in IPD. Second, because the findings suggest that some cases of IPD may be influenza-attributable, the extension of influenza vaccination to school-age children and young adults (a group of people at particular risk of IPD who are not normally vaccinated against influenza) could reduce the incidence of IPD as well as the incidence of influenza.
Additional Information
Please access these Web sites via the online version of this summary at http://www.plosone.org/article/info:doi/10.1371/journal.pone.0015493
A related research article by the same authors evaluating links between respiratory viruses and invasive meningococcal disease can be found in PLoS One (e0015493)
The US Centers for Disease Control and Prevention provides information for patients and health professionals on all aspects of seasonal influenza and pneumococcal disease and pneumococcal vaccination
The UK National Health Service Choices website also provides information for patients about seasonal influenza and pneumococcal infection
MedlinePlus has links to further information about influenza and pneumococcal infections (in English and Spanish)
FluWatch is the Canadian national surveillance system for influenza
More information about the Toronto Invasive Bacterial Network is available
The International Association for Ecology and Health provides information on the physical environment and its influence on health
doi:10.1371/journal.pmed.1001042
PMCID: PMC3110256  PMID: 21687693
13.  Assessing Optimal Target Populations for Influenza Vaccination Programmes: An Evidence Synthesis and Modelling Study 
PLoS Medicine  2013;10(10):e1001527.
Marc Baguelin and colleagues use virological, clinical, epidemiological, and behavioral data to estimate how policies for influenza vaccination programs may be optimized in England and Wales.
Please see later in the article for the Editors' Summary
Background
Influenza vaccine policies that maximise health benefit through efficient use of limited resources are needed. Generally, influenza vaccination programmes have targeted individuals 65 y and over and those at risk, according to World Health Organization recommendations. We developed methods to synthesise the multiplicity of surveillance datasets in order to evaluate how changing target populations in the seasonal vaccination programme would affect infection rate and mortality.
Methods and Findings
Using a contemporary evidence-synthesis approach, we use virological, clinical, epidemiological, and behavioural data to develop an age- and risk-stratified transmission model that reproduces the strain-specific behaviour of influenza over 14 seasons in England and Wales, having accounted for the vaccination uptake over this period. We estimate the reduction in infections and deaths achieved by the historical programme compared with no vaccination, and the reduction had different policies been in place over the period. We find that the current programme has averted 0.39 (95% credible interval 0.34–0.45) infections per dose of vaccine and 1.74 (1.16–3.02) deaths per 1,000 doses. Targeting transmitters by extending the current programme to 5–16-y-old children would increase the efficiency of the total programme, resulting in an overall reduction of 0.70 (0.52–0.81) infections per dose and 1.95 (1.28–3.39) deaths per 1,000 doses. In comparison, choosing the next group most at risk (50–64-y-olds) would prevent only 0.43 (0.35–0.52) infections per dose and 1.77 (1.15–3.14) deaths per 1,000 doses.
Conclusions
This study proposes a framework to integrate influenza surveillance data into transmission models. Application to data from England and Wales confirms the role of children as key infection spreaders. The most efficient use of vaccine to reduce overall influenza morbidity and mortality is thus to target children in addition to older adults.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Every winter, millions of people catch influenza, a viral infection of the airways. Most infected individuals recover quickly, but seasonal influenza outbreaks (epidemics) kill about half a million people annually. In countries with advanced health systems, these deaths occur mainly among elderly people and among individuals with long-term illnesses such as asthma and heart disease that increase the risk of complications occurring after influenza virus infection. Epidemics of influenza occur because small but frequent changes in the influenza virus mean that an immune response produced one year through infection provides only partial protection against influenza the following year. Annual immunization with a vaccine that contains killed influenza viruses of the major circulating strains can greatly reduce a person's risk of catching influenza by preparing the immune system to respond quickly when challenged by a live influenza virus. Consequently, many countries run seasonal influenza vaccination programs that, in line with World Health Organization recommendations, target individuals 65 years old and older and people in high-risk groups.
Why Was This Study Done?
Is this approach the best use of available resources? Might, for example, vaccination of children—the main transmitters of influenza—provide more benefit to the whole population than vaccination of elderly people? Vaccination of children would not directly prevent as many influenza-related deaths as vaccination of elderly people, but it might indirectly prevent deaths in elderly adults by inducing herd immunity—vaccination of a large part of a population can protect unvaccinated members of the population by reducing the chances of an infection spreading. Policy makers need to know whether a change to an influenza vaccination program is likely to provide additional population benefits before altering the program. In this evidence synthesis and modeling study, the researchers combine (synthesize) longitudinal influenza surveillance datasets (data collected over time) from England and Wales, develop a mathematical model for influenza transmission based on these data using a Bayesian statistical approach, and use the model to evaluate the impact on influenza infections and deaths of changes to the seasonal influenza vaccination program in England and Wales.
What Did the Researchers Do and Find?
The researchers developed an influenza transmission model using clinical data on influenza-like illness consultations collected in a primary care surveillance scheme for each week of 14 influenza seasons in England and Wales, virological information on respiratory viruses detected in a subset of patients presenting with clinically suspected influenza, and data on vaccination coverage in the whole population (epidemiological data). They also incorporated data on social contacts (behavioral data) and on immunity to influenza viruses in the population (seroepidemiological data) into their model. To estimate the impact of potential changes to the current vaccination strategy in England and Wales, the researchers used their model, which replicated the patterns of disease observed in the surveillance data, to run simulated epidemics for each influenza season and for three strains of influenza virus under various vaccination scenarios. Compared to no vaccination, the current program (vaccination of people 65 years old and older and people in high-risk groups) averted 0.39 infections per dose of vaccine and 1.74 deaths per 1,000 doses. Notably, the model predicted that extension of the program to target 5–16-year-old children would increase the efficiency of the program and would avert 0.70 infections per dose and 1.95 deaths per 1,000 doses.
What Do These Findings Mean?
The finding that the transmission model developed by the researchers closely fit the available surveillance data suggests that the model should be able to predict what would have happened in England and Wales over the study period if an alternative vaccination regimen had been in place. The accuracy of such predictions may be limited, however, because the vaccination model is based on a series of simplifying assumptions. Importantly, given that influenza vaccination for children is being rolled out in England and Wales from September 2013, the model confirms that children are key spreaders of influenza and suggests that a vaccination program targeting children will reduce influenza infections and potentially influenza deaths in the whole population. More generally, the findings of this study support wider adoption of national vaccination strategies designed to block influenza transmission and to target those individuals most at risk from the complications of influenza infection.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371.journal.pmed.1001527.
The UK National Health Service Choices website provides information for patients about seasonal influenza and about vaccination; Public Health England (formerly the Health Protection Agency) provides information on influenza surveillance in the UK, including information about the primary care surveillance database used in this study
The World Health Organization provides information on seasonal influenza (in several languages)
The European Influenzanet is a system to monitor the activity of influenza-like illness with the aid of volunteers via the Internet
The US Centers for Disease Control and Prevention also provides information for patients and health professionals on all aspects of seasonal influenza, including information about vaccination and about the US influenza surveillance system; its website contains a short video about personal experiences of influenza
Flu.gov, a US government website, provides access to information on seasonal influenza and vaccination
MedlinePlus has links to further information about influenza and about immunization (in English and Spanish)
doi:10.1371/journal.pmed.1001527
PMCID: PMC3793005  PMID: 24115913
14.  Antigenic Fingerprinting of H5N1 Avian Influenza Using Convalescent Sera and Monoclonal Antibodies Reveals Potential Vaccine and Diagnostic Targets 
PLoS Medicine  2009;6(4):e1000049.
Using whole-genome-fragment phage display libraries, Hana Golding and colleagues identify the viral epitopes recognized by serum antibodies in humans who have recovered from infection with H5N1 avian influenza.
Background
Transmission of highly pathogenic avian H5N1 viruses from poultry to humans have raised fears of an impending influenza pandemic. Concerted efforts are underway to prepare effective vaccines and therapies including polyclonal or monoclonal antibodies against H5N1. Current efforts are hampered by the paucity of information on protective immune responses against avian influenza. Characterizing the B cell responses in convalescent individuals could help in the design of future vaccines and therapeutics.
Methods and Findings
To address this need, we generated whole-genome–fragment phage display libraries (GFPDL) expressing fragments of 15–350 amino acids covering all the proteins of A/Vietnam/1203/2004 (H5N1). These GFPDL were used to analyze neutralizing human monoclonal antibodies and sera of five individuals who had recovered from H5N1 infection. This approach led to the mapping of two broadly neutralizing human monoclonal antibodies with conformation-dependent epitopes. In H5N1 convalescent sera, we have identified several potentially protective H5N1-specific human antibody epitopes in H5 HA[(-10)-223], neuraminidase catalytic site, and M2 ectodomain. In addition, for the first time to our knowledge in humans, we identified strong reactivity against PB1-F2, a putative virulence factor, following H5N1 infection. Importantly, novel epitopes were identified, which were recognized by H5N1-convalescent sera but did not react with sera from control individuals (H5N1 naïve, H1N1 or H3N2 seropositive).
Conclusion
This is the first study, to our knowledge, describing the complete antibody repertoire following H5N1 infection. Collectively, these data will contribute to rational vaccine design and new H5N1-specific serodiagnostic surveillance tools.
Editors' Summary
Background
Every winter, millions of people catch influenza, a viral infection of the airways. Most recover quickly but seasonal influenza outbreaks (epidemics) kill about half a million people annually. These epidemics occur because small but frequent changes in the viral proteins (antigens) to which the human immune system responds mean that an immune response produced one year by infection or through vaccination provides only partial protection against influenza the next year. Influenza viruses also occasionally appear that contain major antigenic changes. Human populations have little or no immunity to such viruses (which often originate in animals or birds), so they can start deadly global epidemics (pandemics ). Worryingly, the last influenza pandemic occurred in 1968 and many experts fear that another pandemic is now overdue. The trigger for such a pandemic, they think, could be the avian (bird) H5N1 influenza virus, which first appeared in 1996 in a goose in China. The name indicates the types of two major influenza antigens present in the virus: H5N1 carries type 5 hemagglutinin and type 1 neuraminidase.
Why Was This Study Done?
H5N1 has caused about 400 confirmed cases of human influenza and more than 250 deaths in the past decade but it has not started a human pandemic because it cannot pass easily between people. However, it could possibly acquire this ability at any time, so it is a priority to develop both vaccines that will provide protection against a pandemic H5N1 viral strain, as well as antibody-based antiviral therapies for people not protected by vaccination (antibodies are proteins produced by the immune system that help to fight infections; people can sometimes be protected from infection by injecting them with pre-prepared antibodies). To do this, scientists need to know how the human immune system responds to the H5N1 virus. In particular, they need to know which parts of the virus the immune system can detect and make antibodies against. In this study, therefore, the researchers characterize the specific antibody responses found in people recovering from infection with H5N1.
What Did the Researchers Do and Find?
The researchers made several “genome-fragment phage display libraries”, collections of bacterial viruses (phages) engineered so that each phage makes one of many possible short pieces (polypeptides) of a nonphage protein. Such “libraries” can be used to investigate which fragments are recognized by antibodies from a given source. In this case, several libraries were made that contained fragments of the genome of the H5N1 strain responsible for an outbreak of human influenza in Vietnam in 2004–2005 (A/Vietnam/1203/2004). The researchers used these libraries to analyze the antibodies made by five Vietnamese people recovering from infection with A/Vietnam/1203/2004. H5N1 convalescent blood samples, the researchers report, contained antibodies that recognized small regions (“epitopes”) in several viral proteins, including hemagglutinin, neuraminidase, a structural protein called M2, and a viral protein called PB1-F2 that is partly responsible for the severity of H5N1 infections. Several of the novel epitopes identified were not recognized by antibodies in blood taken from people recovering from infection with other influenza viruses. The researchers also used their phage display libraries to analyze two neutralizing human monoclonal antibodies generated from patients infected with A/Vietnam/1203/2004 (neutralizing antibodies protect mice against normally lethal challenge with H5N1; monoclonal antibodies are generated in the laboratory by creating continuously growing cell lines that produce a single type of antibody). Importantly, both of the neutralizing monoclonal antibodies recognized “noncontinuous conformation-dependent epitopes”—protein sequences that are not adjacent to one another in the polypeptide sequence of the protein, but that lie close together in space because of the way the protein is folded up.
What Do These Findings Mean?
Although some aspects of the antibody repertoire produced in people exposed to the H5N1 influenza virus may have been missed in this analysis, these findings provide important and detailed new information about how the human immune system responds to infection with this virus. In particular, they show that people recovering from H5N1 infection make a diverse range of antibodies against several viral proteins for at least six months and identify specific parts of H5N1 that may be particularly good at stimulating a protective immune response. This information can now be used to help design vaccines against H5N1 and antibody-based therapies for the treatment of H5N1 infections, and to develop new tools for monitoring outbreaks of avian influenza in human populations.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000049.
This study is further discussed in a PLoS Medicine Perspective by Malik Peiris
The US Centers for Disease Control and Prevention provides information for about influenza for patients and professionals, including specific information on avian and pandemic influenza (in several languages)
The World Health Organization provides information on influenza (in several languages) and on H5N1 avian influenza (in several languages), and a global timeline about H5N1 avian influenza infection in birds and people
The UK Health Protection Agency provides information on avian, pandemic, and epidemic (seasonal) influenza
MedlinePlus provides a list of links to other information about influenza and bird flu (in English and Spanish)
doi:10.1371/journal.pmed.1000049
PMCID: PMC2661249  PMID: 19381279
15.  Protection of Mice against Lethal Challenge with 2009 H1N1 Influenza A Virus by 1918-Like and Classical Swine H1N1 Based Vaccines 
PLoS Pathogens  2010;6(1):e1000745.
The recent 2009 pandemic H1N1 virus infection in humans has resulted in nearly 5,000 deaths worldwide. Early epidemiological findings indicated a low level of infection in the older population (>65 years) with the pandemic virus, and a greater susceptibility in people younger than 35 years of age, a phenomenon correlated with the presence of cross-reactive immunity in the older population. It is unclear what virus(es) might be responsible for this apparent cross-protection against the 2009 pandemic H1N1 virus. We describe a mouse lethal challenge model for the 2009 pandemic H1N1 strain, used together with a panel of inactivated H1N1 virus vaccines and hemagglutinin (HA) monoclonal antibodies to dissect the possible humoral antigenic determinants of pre-existing immunity against this virus in the human population. By hemagglutinination inhibition (HI) assays and vaccination/challenge studies, we demonstrate that the 2009 pandemic H1N1 virus is antigenically similar to human H1N1 viruses that circulated from 1918–1943 and to classical swine H1N1 viruses. Antibodies elicited against 1918-like or classical swine H1N1 vaccines completely protect C57B/6 mice from lethal challenge with the influenza A/Netherlands/602/2009 virus isolate. In contrast, contemporary H1N1 vaccines afforded only partial protection. Passive immunization with cross-reactive monoclonal antibodies (mAbs) raised against either 1918 or A/California/04/2009 HA proteins offered full protection from death. Analysis of mAb antibody escape mutants, generated by selection of 2009 H1N1 virus with these mAbs, indicate that antigenic site Sa is one of the conserved cross-protective epitopes. Our findings in mice agree with serological data showing high prevalence of 2009 H1N1 cross-reactive antibodies only in the older population, indicating that prior infection with 1918-like viruses or vaccination against the 1976 swine H1N1 virus in the USA are likely to provide protection against the 2009 pandemic H1N1 virus. This data provides a mechanistic basis for the protection seen in the older population, and emphasizes a rationale for including vaccination of the younger, naïve population. Our results also support the notion that pigs can act as an animal reservoir where influenza virus HAs become antigenically frozen for long periods of time, facilitating the generation of human pandemic viruses.
Author Summary
Influenza A viruses generally infect individuals of all ages and cause severe respiratory disease in very young children and elderly people (>65 years). However, the 2009 pandemic H1N1 virus infection is predominantly seen in children and adults (<35 years of age), but rarely in people older than 65 years of age. Recent serological studies indicate that older people carry antibodies that recognize the 2009 H1N1 virus. This suggests that they may have been exposed to or vaccinated with an influenza virus similar to 2009 H1N1 virus. In this study, we wanted to identify the older H1N1 virus(es) that may confer protection to the elderly population. Using 11 different inactivated influenza A viruses that have circulated between 1918 to 2007, we immunized mice and challenged them with a lethal dose of the 2009 novel H1N1 virus. We find that mice vaccinated with human H1N1 viruses that circulated in 1918 and in 1943 were protected from the 2009 H1N1 virus. Also, the 1976 swine origin H1N1 virus, against which nearly 40 million people were immunized in 1976 in the United States, protects mice from death by the 2009 H1N1 virus. This indicates that people carrying antibodies against H1N1 viruses that circulated between 1918–1943 and to the 1976 swine origin H1N1 virus are likely to be protected against the 2009 pandemic H1N1. Importantly, our data underscores the significance of vaccinating people under 35 year of age, since the majority of them do not have protective antibodies against the 2009 H1N1, and provide a possible mechanism by which pandemic viruses could arise from antigenically frozen influenza viruses harbored in the swine population.
doi:10.1371/journal.ppat.1000745
PMCID: PMC2813279  PMID: 20126449
16.  A Comparative Analysis of Influenza Vaccination Programs 
PLoS Medicine  2006;3(10):e387.
Background
The threat of avian influenza and the 2004–2005 influenza vaccine supply shortage in the United States have sparked a debate about optimal vaccination strategies to reduce the burden of morbidity and mortality caused by the influenza virus.
Methods and Findings
We present a comparative analysis of two classes of suggested vaccination strategies: mortality-based strategies that target high-risk populations and morbidity-based strategies that target high-prevalence populations. Applying the methods of contact network epidemiology to a model of disease transmission in a large urban population, we assume that vaccine supplies are limited and then evaluate the efficacy of these strategies across a wide range of viral transmission rates and for two different age-specific mortality distributions.
We find that the optimal strategy depends critically on the viral transmission level (reproductive rate) of the virus: morbidity-based strategies outperform mortality-based strategies for moderately transmissible strains, while the reverse is true for highly transmissible strains. These results hold for a range of mortality rates reported for prior influenza epidemics and pandemics. Furthermore, we show that vaccination delays and multiple introductions of disease into the community have a more detrimental impact on morbidity-based strategies than mortality-based strategies.
Conclusions
If public health officials have reasonable estimates of the viral transmission rate and the frequency of new introductions into the community prior to an outbreak, then these methods can guide the design of optimal vaccination priorities. When such information is unreliable or not available, as is often the case, this study recommends mortality-based vaccination priorities.
A comparative analysis of two classes of suggested vaccination strategies, mortality-based strategies that target high-risk populations and morbidity-based strategies that target high-prevalence populations.
Editors' Summary
Background.
Influenza—a viral infection of the nose, throat, and airways that is transmitted in airborne droplets released by coughing or sneezing—is a serious public health threat. Most people recover quickly from influenza, but some individuals, especially infants, old people, and individuals with chronic health problems, can develop pneumonia and die. In the US, seasonal outbreaks (epidemics) of flu cause an estimated 36,000 excess deaths annually. And now there are fears that avian influenza might start a human pandemic—a global epidemic that could kill millions. Seasonal outbreaks of influenza occur because flu viruses continually change the viral proteins (antigens) to which the immune system responds. “Antigenic drift”—small changes in these proteins—means that an immune system response that combats flu one year may not provide complete protection the next winter. “Antigenic shift”—large antigen changes—can cause pandemics because communities have no immunity to the changed virus. Annual vaccination with vaccines based on the currently circulating viruses controls seasonal flu epidemics; to control a pandemic, vaccines based on the antigenically altered virus would have to be quickly developed.
Why Was This Study Done?
Most countries target vaccination efforts towards the people most at risk of dying from influenza, and to health-care workers who are likely come into contact with flu patients. But is this the best way to reduce the burden of illness (morbidity) and death (mortality) caused by influenza, particularly at the start of a pandemic, when vaccine would be limited? Old people and infants are much less likely to catch and spread influenza than school children, students, and employed adults, so could vaccination of these sections of the population—instead of those most at risk of death—be the best way to contain influenza outbreaks? In this study, the researchers used an analytical method called “contact network epidemiology” to compare two types of vaccination strategies: the currently favored mortality-based strategy, which targets high-risk individuals, and a morbidity-based strategy, which targets those segments of the community in which most influenza cases occur.
What Did the Researchers Do and Find?
Most models of disease transmission assume that each member of a community is equally likely to infect every other member. But a baby is unlikely to transmit flu to, for example, an unrelated, housebound elderly person. Contact network epidemiology takes the likely relationships between people into account when modeling disease transmission. Using information from Vancouver, British Columbia, Canada, on household size, age distribution, and occupations, and other factors such as school sizes, the researchers built a model population of a quarter of a million interconnected people. They then investigated how different vaccination strategies controlled the spread of influenza in this population. The optimal strategy depended on the level of viral transmissibility—the likelihood that an infectious person transmits influenza to a susceptible individual with whom he or she has contact. For moderately transmissible flu viruses, a morbidity-based vaccination strategy, in which the people most likely to catch the flu are vaccinated, was more effective at containing seasonal and pandemic outbreaks than a mortality-based strategy, in which the people most likely to die if they caught the flu are vaccinated. For highly transmissible strains, this situation was reversed. The level of transmissibility at which this reversal occurred depended on several factors, including whether vaccination was delayed and how many times influenza was introduced into the community.
What Do These Findings Mean?
The researchers tested their models by checking that they could replicate real influenza epidemics and pandemics, but, as with all mathematical models, they included many assumptions about influenza in their calculations, which may affect their results. Also, because the contact network used data from Vancouver, their results might not be applicable to other cities, or to nonurban areas. Nevertheless, their findings have important public health implications. When there are reasonable estimates of the viral transmission rate, and it is known how often influenza is being introduced into a community, contact network models could help public health officials choose between morbidity- and mortality-based vaccination strategies. When the viral transmission rate is unreliable or unavailable (for example, at the start of a pandemic), the best policy would be the currently preferred strategy of mortality-based vaccination. More generally, the use of contact network models should improve estimates of how infectious diseases spread through populations and indicate the best ways to control human epidemics and pandemics.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0030387.
US Centers for Disease Control and Prevention information about influenza for patients and professionals, including key facts on vaccination
US National Institute of Allergy and Infectious Diseases feature on seasonal, avian, and pandemic influenza
World Health Organization fact sheet on influenza, with links to information on vaccination
UK Health Protection Agency information on seasonal, avian, and pandemic influenza
MedlinePlus entry on influenza
doi:10.1371/journal.pmed.0030387
PMCID: PMC1584413  PMID: 17020406
17.  Experimental infection with H1N1 European swine influenza virus protects pigs from an infection with the 2009 pandemic H1N1 human influenza virus 
Veterinary Research  2010;41(5):74.
The recent pandemic caused by human influenza virus A(H1N1) 2009 contains ancestral gene segments from North American and Eurasian swine lineages as well as from avian and human influenza lineages. The emergence of this A(H1N1) 2009 poses a potential global threat for human health and the fact that it can infect other species, like pigs, favours a possible encounter with other influenza viruses circulating in swine herds. In Europe, H1N1, H1N2 and H3N2 subtypes of swine influenza virus currently have a high prevalence in commercial farms. To better assess the risk posed by the A(H1N1) 2009 in the actual situation of swine farms, we sought to analyze whether a previous infection with a circulating European avian-like swine A/Swine/Spain/53207/2004 (H1N1) influenza virus (hereafter referred to as SwH1N1) generated or not cross-protective immunity against a subsequent infection with the new human pandemic A/Catalonia/63/2009 (H1N1) influenza virus (hereafter referred to as pH1N1) 21 days apart. Pigs infected only with pH1N1 had mild to moderate pathological findings, consisting on broncho-interstitial pneumonia. However, pigs inoculated with SwH1N1 virus and subsequently infected with pH1N1 had very mild lung lesions, apparently attributed to the remaining lesions caused by SwH1N1 infection. These later pigs also exhibited boosted levels of specific antibodies. Finally, animals firstly infected with SwH1N1 virus and latter infected with pH1N1 exhibited undetectable viral RNA load in nasal swabs and lungs after challenge with pH1N1, indicating a cross-protective effect between both strains.
doi:10.1051/vetres/2010046
PMCID: PMC2939699  PMID: 20663475
influenza virus; swine H1N1; human A(H1N1) 2009; cross-protection
18.  B Cell Response and Hemagglutinin Stalk-Reactive Antibody Production in Different Age Cohorts following 2009 H1N1 Influenza Virus Vaccination 
The 2009 pandemic H1N1 (pH1N1) influenza virus carried a swine-origin hemagglutinin (HA) that was closely related to the HAs of pre-1947 H1N1 viruses but highly divergent from the HAs of recently circulating H1N1 strains. Consequently, prior exposure to pH1N1-like viruses was mostly limited to individuals over the age of about 60 years. We related age and associated differences in immune history to the B cell response to an inactivated monovalent pH1N1 vaccine given intramuscularly to subjects in three age cohorts: 18 to 32 years, 60 to 69 years, and ≥70 years. The day 0 pH1N1-specific hemagglutination inhibition (HAI) and microneutralization (MN) titers were generally higher in the older cohorts, consistent with greater prevaccination exposure to pH1N1-like viruses. Most subjects in each cohort responded well to vaccination, with early formation of circulating virus-specific antibody (Ab)-secreting cells and ≥4-fold increases in HAI and MN titers. However, the response was strongest in the 18- to 32-year cohort. Circulating levels of HA stalk-reactive Abs were increased after vaccination, especially in the 18- to 32-year cohort, raising the possibility of elevated levels of cross-reactive neutralizing Abs. In the young cohort, an increase in MN activity against the seasonal influenza virus A/Brisbane/59/07 after vaccination was generally associated with an increase in the anti-Brisbane/59/07 HAI titer, suggesting an effect mediated primarily by HA head-reactive rather than stalk-reactive Abs. Our findings support recent proposals that immunization with a relatively novel HA favors the induction of Abs against conserved epitopes. They also emphasize the need to clarify how the level of circulating stalk-reactive Abs relates to resistance to influenza.
doi:10.1128/CVI.00735-12
PMCID: PMC3675965  PMID: 23576673
19.  Baseline Levels of Influenza-Specific CD4 Memory T-Cells Affect T-Cell Responses to Influenza Vaccines 
PLoS ONE  2008;3(7):e2574.
Background
Factors affecting immune responses to influenza vaccines have not been studied systematically. We hypothesized that T-cell and antibody responses to the vaccines are functions of pre-existing host immunity against influenza antigens.
Methodology/Principal Findings
During the 2004 and 2005 influenza seasons, we have collected data on cellular and humoral immune reactivity to influenza virus in blood samples collected before and after immunization with inactivated or live attenuated influenza vaccines in healthy children and adults. We first used cross-validated lasso regression on the 2004 dataset to identify a group of candidate baseline correlates with T-cell and antibody responses to vaccines, defined as fold-increase in influenza-specific T-cells and serum HAI titer after vaccination. The following baseline parameters were examined: percentages of influenza-reactive IFN-γ+ cells in T and NK cell subsets, percentages of influenza-specific memory B-cells, HAI titer, age, and type of vaccine. The candidate baseline correlates were then tested with the independent 2005 dataset. Baseline percentage of influenza-specific IFN-γ+ CD4 T-cells was identified as a significant correlate of CD4 and CD8 T-cell responses, with lower baseline levels associated with larger T-cell responses. Baseline HAI titer and vaccine type were identified as significant correlates for HAI response, with lower baseline levels and the inactivated vaccine associated with larger HAI responses. Previously we reported that baseline levels of CD56dim NK reactivity against influenza virus inversely correlated with the immediate T-cell response to vaccination, and that NK reactivity induced by influenza virus depended on IL-2 produced by influenza-specific memory T-cells. Taken together these results suggest a novel mechanism for the homeostasis of virus-specific T-cells, which involves interaction between memory helper T-cells, CD56dim NK and DC.
Significance
These results demonstrate that assessment of baseline biomarkers may predict immunologic outcome of influenza vaccination and may reveal some of the mechanisms responsible for variable immune responses following vaccination and natural infection.
doi:10.1371/journal.pone.0002574
PMCID: PMC2440350  PMID: 18596908
20.  A Trivalent Virus-Like Particle Vaccine Elicits Protective Immune Responses against Seasonal Influenza Strains in Mice and Ferrets 
PLoS ONE  2009;4(6):e6032.
There is need for improved human influenza vaccines, particularly for older adults who are at greatest risk for severe disease, as well as to address the continuous antigenic drift within circulating human subtypes of influenza virus. We have engineered an influenza virus-like particle (VLP) as a new generation vaccine candidate purified from the supernatants of Sf9 insect cells following infection by recombinant baculoviruses to express three influenza virus proteins, hemagglutinin (HA), neuraminidase (NA), and matrix 1 (M1). In this study, a seasonal trivalent VLP vaccine (TVV) formulation, composed of influenza A H1N1 and H3N2 and influenza B VLPs, was evaluated in mice and ferrets for the ability to elicit antigen-specific immune responses. Animals vaccinated with the TVV formulation had hemagglutination-inhibition (HAI) antibody titers against all three homologous influenza virus strains, as well as HAI antibodies against a panel of heterologous influenza viruses. HAI titers elicited by the TVV were statistically similar to HAI titers elicited in animals vaccinated with the corresponding monovalent VLP. Mice vaccinated with the TVV had higher level of influenza specific CD8+ T cell responses than a commercial trivalent inactivated vaccine (TIV). Ferrets vaccinated with the highest dose of the VLP vaccine and then challenged with the homologous H3N2 virus had the lowest titers of replicating virus in nasal washes and showed no signs of disease. Overall, a trivalent VLP vaccine elicits a broad array of immunity and can protect against influenza virus challenge.
doi:10.1371/journal.pone.0006032
PMCID: PMC2698286  PMID: 19554101
21.  Maternal Influenza Immunization and Reduced Likelihood of Prematurity and Small for Gestational Age Births: A Retrospective Cohort Study 
PLoS Medicine  2011;8(5):e1000441.
In an analysis of surveillance data from the state of Georgia (US), Saad Omer and colleagues show an association between receipt of influenza vaccination among pregnant women and reduced risk of premature births.
Background
Infections during pregnancy have the potential to adversely impact birth outcomes. We evaluated the association between receipt of inactivated influenza vaccine during pregnancy and prematurity and small for gestational age (SGA) births.
Methods and Findings
We conducted a cohort analysis of surveillance data from the Georgia (United States) Pregnancy Risk Assessment Monitoring System. Among 4,326 live births between 1 June 2004 and 30 September 2006, maternal influenza vaccine information was available for 4,168 (96.3%). The primary intervention evaluated in this study was receipt of influenza vaccine during any trimester of pregnancy. The main outcome measures were prematurity (gestational age at birth <37 wk) and SGA (birth weight <10th percentile for gestational age). Infants who were born during the putative influenza season (1 October–31 May) and whose mothers were vaccinated against influenza during pregnancy were less likely to be premature compared to infants of unvaccinated mothers born in the same period (adjusted odds ratio [OR] = 0.60; 95% CI, 0.38–0.94). The magnitude of association between maternal influenza vaccine receipt and reduced likelihood of prematurity increased during the period of at least local influenza activity (adjusted OR = 0.44; 95% CI, 0.26–0.73) and was greatest during the widespread influenza activity period (adjusted OR = 0.28; 95% CI, 0.11–0.74). Compared with newborns of unvaccinated women, newborns of vaccinated mothers had 69% lower odds of being SGA (adjusted OR = 0.31; 95% CI, 0.13–0.75) during the period of widespread influenza activity. The adjusted and unadjusted ORs were not significant for the pre-influenza activity period.
Conclusions
This study demonstrates an association between immunization with the inactivated influenza vaccine during pregnancy and reduced likelihood of prematurity during local, regional, and widespread influenza activity periods. However, no associations were found for the pre-influenza activity period. Moreover, during the period of widespread influenza activity there was an association between maternal receipt of influenza vaccine and reduced likelihood of SGA birth.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Maternal infections during pregnancy can have harmful effects on both mother and baby. For example, influenza is associated with increased morbidity and mortality among pregnant women compared to women who are not pregnant or who acquire influenza infection after delivery. And some respiratory infections, especially those that can cause maternal pneumonia such as influenza virus, are known to be associated with the baby being small—below the 10th percentile—for gestational age and with an increased risk of preterm birth—birth before 37 weeks of gestation. Previous studies have shown that inactivated influenza vaccination during pregnancy provides protection against influenza virus for both mother and baby. As there has been an increase in the rate of preterm birth the United States from 9.5% in 1981 to 12.8% in 2006, the impact of maternal influenza immunization on birth outcomes has important public health implications and is of particular interest during influenza pandemics.
Why Was This Study Done?
Given that maternal vaccination can protect babies from influenza virus, it is plausible that influenza vaccination in pregnancy could mitigate adverse birth outcomes such as prematurity and the baby being small for gestational age. The researchers of this study set out to evaluate this hypothesis by investigating whether there was an association between women receiving inactivated influenza vaccine during pregnancy and positive birth outcomes for their babies in the population of the state of Georgia, in the United States.
What Did the Researchers Do and Find?
The researchers conducted a retrospective cohort analysis of a large surveillance dataset (the Georgia Pregnancy Risk Assessment Monitoring System) to analyze the relationship between receipt of inactivated influenza vaccine during any trimester of pregnancy by mothers of infants born between June 1, 2004, and September 30, 2006, and their baby being premature or small for gestational age. The study period encompassed the 2004–2005 and 2005–2006 influenza seasons—the two most recent seasons for which the data were available. The researchers did a stratified analysis for the overall study period, and various periods during it, and also weighted their analysis to adjust for possible oversampling. They used logistic regression to evaluate the association of maternal influenza vaccine and (a) prematurity and (b) small for gestational age, and also used linear regression to evaluate the statistical significance of differences between vaccinated and unvaccinated women for mean gestational age at first antenatal visit and mean birth weight.
During the study period, 4,168 mother–baby pairs were included in the analysis. Local influenza activity was detected during 27 weeks (22.1%), and 578 women (14.9% [weighted]) had received the influenza vaccine during pregnancy, giving a vaccination coverage of 19.2% (weighted) among mothers of infants born during the assumed influenza season. In the study sample, 1,547 babies (10.6% [weighted]) were born premature, and 1,186 babies (11.2% [weighted]) were small for gestational age. Infants who were born during the assumed influenza season (October–May) and whose mothers were vaccinated against influenza during pregnancy were less likely to be premature than infants of unvaccinated mothers born in the same period, with an adjusted odds ratio of 0.60. The effect of maternal influenza vaccine on reducing prematurity was the highest for infants born during the period of widespread influenza activity, with 72% lower odds of prematurity in infants of vaccinated mothers than infants of unvaccinated mothers. Compared with newborns of unvaccinated women, babies of vaccinated mothers also had 69% lower odds of being small for gestational age during the period of widespread influenza activity, but the adjusted and unadjusted odd ratios were not significant for the pre-influenza activity period.
What Do These Findings Mean?
These results show that there was an association between maternal immunization with the inactivated influenza vaccine during pregnancy and reduced likelihood of prematurity during local, regional, and widespread influenza activity periods. In addition, during the period of widespread influenza activity there was an negative association between maternal receipt of influenza vaccine and small for gestational age birth.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000441.
More information about influenza vaccination during pregnancy is available from the World Health Organization and the UK National Health Service
More information about the Georgia Pregnancy Risk Assessment Monitoring System is also available
doi:10.1371/journal.pmed.1000441
PMCID: PMC3104979  PMID: 21655318
22.  Predicting the Epidemic Sizes of Influenza A/H1N1, A/H3N2, and B: A Statistical Method 
PLoS Medicine  2011;8(7):e1001051.
Using weekly influenza surveillance data from the US CDC, Edward Goldstein and colleagues develop a statistical method to predict the sizes of epidemics caused by seasonal influenza strains. This method could inform decisions about the most appropriate vaccines or drugs needed early in the influenza season.
Background
The epidemic sizes of influenza A/H3N2, A/H1N1, and B infections vary from year to year in the United States. We use publicly available US Centers for Disease Control (CDC) influenza surveillance data between 1997 and 2009 to study the temporal dynamics of influenza over this period.
Methods and Findings
Regional outpatient surveillance data on influenza-like illness (ILI) and virologic surveillance data were combined to define a weekly proxy for the incidence of each strain in the United States. All strains exhibited a negative association between their cumulative incidence proxy (CIP) for the whole season (from calendar week 40 of each year to calendar week 20 of the next year) and the CIP of the other two strains (the complementary CIP) from the start of the season up to calendar week 2 (or 3, 4, or 5) of the next year. We introduce a method to predict a particular strain's CIP for the whole season by following the incidence of each strain from the start of the season until either the CIP of the chosen strain or its complementary CIP exceed certain thresholds. The method yielded accurate predictions, which generally occurred within a few weeks of the peak of incidence of the chosen strain, sometimes after that peak. For the largest seasons in the data, which were dominated by A/H3N2, prediction of A/H3N2 incidence always occurred at least several weeks in advance of the peak.
Conclusion
Early circulation of one influenza strain is associated with a reduced total incidence of the other strains, consistent with the presence of interference between subtypes. Routine ILI and virologic surveillance data can be combined using this new method to predict the relative size of each influenza strain's epidemic by following the change in incidence of a given strain in the context of the incidence of cocirculating strains.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Every winter in temperate countries, millions of people catch influenza, a viral infection of the nose, throat, and airways. Most infected individuals recover quickly but seasonal influenza outbreaks (epidemics) kill about half a million people annually. Epidemics of influenza occur because small but frequent changes in the viral proteins (antigens) to which the immune system responds mean that an immune response produced one year provides only partial protection against influenza the next year. Annual immunization with a vaccine that contains killed influenza viruses of the major circulating strains boosts this natural immunity and greatly reduces a person's chances of catching influenza. Influenza epidemics in temperate latitudes are usually caused by an influenza B virus or one of two influenza A subtypes called A/H3N2 and A/H1N1. The names of the influenza A viruses indicate the types of two major influenza antigens—hemagglutinin (H3 or H1) and neuraminidase (N2 or N1)—present in the viruses.
Why Was This Study Done?
At present, there is no way to predict whether influenza B or an influenza A subtype will be dominant (responsible for the majority of infections) in any given influenza season. There is also no way to predict the size of the epidemic that will be caused by each viral strain. Public health officials would like to be able to make predictions of this sort early in the winter to help them determine which measures to recommend to minimize the illness and death caused by influenza. In this study, the researchers use weekly influenza surveillance data collected by the US Centers for Disease Control and Prevention (CDC) to study the temporal dynamics of seasonal influenza in the United States between 1997 and 2009 and to develop a statistical method to predict the sizes of epidemics caused by influenza A/H1N1, A/H3N2, and B.
What Did the Researchers Do and Find?
The CDC influenza surveillance system collects information on the proportion of patients attending US outpatient facilities who have an influenza-like illness (fever and a cough and/or a sore throat in the absence of any known cause other than influenza) and on the proportion of respiratory viral isolates testing positive for specific influenza strains at US viral surveillance laboratories. The researchers combined these data to define a weekly “proxy” incidence of each influenza strain across the United States (an estimate of the number of new cases per week in the US population) and a cumulative incidence proxy (CIP) for each influenza season. For each strain, there was a negative association between its whole-season CIP and the early-season CIP of the other two strains (the complementary CIP). That is, high infection rates with one strain appeared to interfere with the transmission of other strains. Given this relationship, the researchers then developed a statistical algorithm (a step-by-step problem solving method) that accurately predicted the whole-season CIP for a particular strain by following the incidence of each strain from the start of the season until either its CIP or the complementary CIP had exceeded a specific threshold. So, for example, for influenza B, the algorithm provided an accurate prediction of the whole-season CIP before the peak of influenza B incidence for each season included in the study. Similarly, prediction of whole-season A/H3N2 incidence always occurred several weeks in advance of its weekly incidence peak.
What Do These Findings Mean?
These findings suggest that early circulation of one influenza strain is associated with a reduced total incidence of other strains, possibly because of cross-subtype immunity. Importantly, they also suggest that routine early-season surveillance data can be used to predict the relative size of the epidemics caused by each influenza strain in the United States and in other countries where sufficient surveillance data are available. Because the algorithm makes many assumptions and simplifies the behavior of influenza epidemics, its predictions may not always be accurate. Moreover, it needs to be tested with data collected over more influenza seasons. Nevertheless, the algorithm's ability to predict the relative epidemic size of A/H3N2, the influenza strain with the highest death rates, several weeks before its peak in seasons in which it was the dominant strain suggests that this predictive method could help public-health officials introduce relevant preventative and/or treatment measures early in each influenza season.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001051.
The US Centers for Disease Control and Prevention provides information for patients and health professionals on all aspects of seasonal influenza, including information about the US influenza surveillance system
The UK National Health Service Choices Web site also provides information for patients about seasonal influenza; the UK Health Protection Agency provides information on influenza surveillance in the UK
MedlinePlus has links to further information about influenza l (in English and Spanish)
doi:10.1371/journal.pmed.1001051
PMCID: PMC3130020  PMID: 21750666
23.  Humoral and cellular responses to a non-adjuvanted monovalent H1N1 pandemic influenza vaccine in hospital employees 
BMC Infectious Diseases  2013;13:544.
Background
The efficacy of the H1N1 influenza vaccine relies on the induction of both humoral and cellular responses. This study evaluated the humoral and cellular responses to a monovalent non-adjuvanted pandemic influenza A/H1N1 vaccine in occupationally exposed subjects who were previously vaccinated with a seasonal vaccine.
Methods
Sixty healthy workers from a respiratory disease hospital were recruited. Sera and peripheral blood mononuclear cells (PBMCs) were obtained prior to and 1 month after vaccination with a non-adjuvanted monovalent 2009 H1N1 vaccine (Influenza A (H1N1) 2009 Monovalent Vaccine Panenza, Sanofi Pasteur). Antibody titers against the pandemic A/H1N1 influenza virus were measured via hemagglutination inhibition (HI) and microneutralization assays. Antibodies against the seasonal HA1 were assessed by ELISA. The frequency of IFN-γ-producing cells as well as CD4+ and CD8+ T cell proliferation specific to the pandemic virus A/H1N peptides, seasonal H1N1 peptides and seasonal H3N2 peptides were assessed using ELISPOT and flow cytometry.
Results
At baseline, 6.7% of the subjects had seroprotective antibody titers. The seroconversion rate was 48.3%, and the seroprotection rate was 66.7%. The geometric mean titers (GMTs) were significantly increased (from 6.8 to 64.9, p < 0.05). Forty-nine percent of the subjects had basal levels of specific IFN-γ-producing T cells to the pandemic A/H1N1 peptides that were unchanged post-vaccination. CD4+ T cell proliferation in response to specific pandemic A/H1N1 virus peptides was also unchanged; in contrast, the antigen-specific proliferation of CD8+ T cells significantly increased post-vaccination.
Conclusion
Our results indicate that a cellular immune response that is cross-reactive to pandemic influenza antigens may be present in populations exposed to the circulating seasonal influenza virus prior to pandemic or seasonal vaccination. Additionally, we found that the pandemic vaccine induced a significant increase in CD8+ T cell proliferation.
doi:10.1186/1471-2334-13-544
PMCID: PMC3835617  PMID: 24238117
Pandemic influenza; H1N1; Vaccine; Cellular response; Proliferation; Humoral response
24.  Characterization of Regional Influenza Seasonality Patterns in China and Implications for Vaccination Strategies: Spatio-Temporal Modeling of Surveillance Data 
PLoS Medicine  2013;10(11):e1001552.
Cécile Viboud and colleagues describe epidemiological patterns of influenza incidence across China to support the design of a national vaccination program.
Please see later in the article for the Editors' Summary
Background
The complexity of influenza seasonal patterns in the inter-tropical zone impedes the establishment of effective routine immunization programs. China is a climatologically and economically diverse country, which has yet to establish a national influenza vaccination program. Here we characterize the diversity of influenza seasonality in China and make recommendations to guide future vaccination programs.
Methods and Findings
We compiled weekly reports of laboratory-confirmed influenza A and B infections from sentinel hospitals in cities representing 30 Chinese provinces, 2005–2011, and data on population demographics, mobility patterns, socio-economic, and climate factors. We applied linear regression models with harmonic terms to estimate influenza seasonal characteristics, including the amplitude of annual and semi-annual periodicities, their ratio, and peak timing. Hierarchical Bayesian modeling and hierarchical clustering were used to identify predictors of influenza seasonal characteristics and define epidemiologically-relevant regions. The annual periodicity of influenza A epidemics increased with latitude (mean amplitude of annual cycle standardized by mean incidence, 140% [95% CI 128%–151%] in the north versus 37% [95% CI 27%–47%] in the south, p<0.0001). Epidemics peaked in January–February in Northern China (latitude ≥33°N) and April–June in southernmost regions (latitude <27°N). Provinces at intermediate latitudes experienced dominant semi-annual influenza A periodicity with peaks in January–February and June–August (periodicity ratio >0.6 in provinces located within 27.4°N–31.3°N, slope of latitudinal gradient with latitude −0.016 [95% CI −0.025 to −0.008], p<0.001). In contrast, influenza B activity predominated in colder months throughout most of China. Climate factors were the strongest predictors of influenza seasonality, including minimum temperature, hours of sunshine, and maximum rainfall. Our main study limitations include a short surveillance period and sparse influenza sampling in some of the southern provinces.
Conclusions
Regional-specific influenza vaccination strategies would be optimal in China; in particular, annual campaigns should be initiated 4–6 months apart in Northern and Southern China. Influenza surveillance should be strengthened in mid-latitude provinces, given the complexity of seasonal patterns in this region. More broadly, our findings are consistent with the role of climatic factors on influenza transmission dynamics.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Every year, millions of people worldwide catch influenza, a viral disease of the airways. Most infected individuals recover quickly but seasonal influenza outbreaks (epidemics) kill about half a million people annually. These epidemics occur because antigenic drift—frequent small changes in the viral proteins to which the immune system responds—means that an immune response produced one year provides only partial protection against influenza the next year. Annual vaccination with a mixture of killed influenza viruses of the major circulating strains boosts this natural immunity and greatly reduces the risk of catching influenza. Consequently, many countries run seasonal influenza vaccination programs. Because the immune response induced by vaccination decays within 4–8 months of vaccination and because of antigenic drift, it is important that these programs are initiated only a few weeks before the onset of local influenza activity. Thus, vaccination starts in early autumn in temperate zones (regions of the world that have a mild climate, part way between a tropical and a polar climate), because seasonal influenza outbreaks occur in the winter months when low humidity and low temperatures favor the transmission of the influenza virus.
Why Was This Study Done?
Unlike temperate regions, seasonal influenza patterns are very diverse in tropical countries, which lie between latitudes 23.5°N and 23.5°S, and in the subtropical countries slightly north and south of these latitudes. In some of these countries, there is year-round influenza activity, in others influenza epidemics occur annually or semi-annually (twice yearly). This complexity, which is perhaps driven by rainfall fluctuations, complicates the establishment of effective routine immunization programs in tropical and subtropical countries. Take China as an example. Before a national influenza vaccination program can be established in this large, climatologically diverse country, public-health experts need a clear picture of influenza seasonality across the country. Here, the researchers use spatio-temporal modeling of influenza surveillance data to characterize the seasonality of influenza A and B (the two types of influenza that usually cause epidemics) in China, to assess the role of putative drivers of seasonality, and to identify broad epidemiological regions (areas with specific patterns of disease) that could be used as a basis to optimize the timing of future Chinese vaccination programs.
What Did the Researchers Do and Find?
The researchers collected together the weekly reports of laboratory-confirmed influenza prepared by the Chinese national sentinel hospital-based surveillance network between 2005 and 2011, data on population size and density, mobility patterns, and socio-economic factors, and daily meteorological data for the cities participating in the surveillance network. They then used various statistical modeling approaches to estimate influenza seasonal characteristics, to assess predictors of influenza seasonal characteristics, and to identify epidemiologically relevant regions. These analyses indicate that, over the study period, northern provinces (latitudes greater than 33°N) experienced winter epidemics of influenza A in January–February, southern provinces (latitudes less than 27°N) experienced peak viral activity in the spring (April–June), and provinces at intermediate latitudes experienced semi-annual epidemic cycles with infection peaks in January–February and June–August. By contrast, influenza B activity predominated in the colder months throughout China. The researchers also report that minimum temperatures, hours of sunshine, and maximum rainfall were the strongest predictors of influenza seasonality.
What Do These Findings Mean?
These findings show that influenza seasonality in China varies between regions and between influenza virus types and suggest that, as in other settings, some of these variations might be associated with specific climatic factors. The accuracy of these findings is limited by the short surveillance period, by sparse surveillance data from some southern and mid-latitude provinces, and by some aspects of the modeling approach used in the study. Further surveillance studies need to be undertaken to confirm influenza seasonality patterns in China. Overall, these findings suggest that, to optimize routine influenza vaccination in China, it will be necessary to stagger the timing of vaccination over three broad geographical regions. More generally, given that there is growing interest in rolling out national influenza immunization programs in low- and middle-income countries, these findings highlight the importance of ensuring that vaccination strategies are optimized by taking into account local disease patterns.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/ 10.1371/journal.pmed.1001552.
This study is further discussed in a PLOS Medicine Perspective by Steven Riley
The UK National Health Service Choices website provides information for patients about seasonal influenza and about influenza vaccination
The World Health Organization provides information on seasonal influenza (in several languages) and on influenza surveillance and monitoring
The US Centers for Disease Control and Prevention also provides information for patients and health professionals on all aspects of seasonal influenza, including information about vaccination; its website contains a short video about personal experiences of influenza.
Flu.gov, a US government website, provides access to information on seasonal influenza and vaccination
Information about the Chinese National Influenza Center, which is part of the Chinese Center for Disease Control and Prevention: and which runs influenza surveillance in China, is available (in English and Chinese)
MedlinePlus has links to further information about influenza and about vaccination (in English and Spanish)
A recent PLOS Pathogens Research Article by James D. Tamerius et al. investigates environmental predictors of seasonal influenza epidemics across temperate and tropical climates
A study published in PLOS ONE by Wyller Alencar de Mello et al. indicates that Brazil, like China, requires staggered timing of vaccination from Northern to Southern states to account for different timings of influenza activity.
doi:10.1371/journal.pmed.1001552
PMCID: PMC3864611  PMID: 24348203
25.  Estimating Infection Attack Rates and Severity in Real Time during an Influenza Pandemic: Analysis of Serial Cross-Sectional Serologic Surveillance Data 
PLoS Medicine  2011;8(10):e1001103.
This study reports that using serological data coupled with clinical surveillance data can provide real-time estimates of the infection attack rates and severity in an emerging influenza pandemic.
Background
In an emerging influenza pandemic, estimating severity (the probability of a severe outcome, such as hospitalization, if infected) is a public health priority. As many influenza infections are subclinical, sero-surveillance is needed to allow reliable real-time estimates of infection attack rate (IAR) and severity.
Methods and Findings
We tested 14,766 sera collected during the first wave of the 2009 pandemic in Hong Kong using viral microneutralization. We estimated IAR and infection-hospitalization probability (IHP) from the serial cross-sectional serologic data and hospitalization data. Had our serologic data been available weekly in real time, we would have obtained reliable IHP estimates 1 wk after, 1–2 wk before, and 3 wk after epidemic peak for individuals aged 5–14 y, 15–29 y, and 30–59 y. The ratio of IAR to pre-existing seroprevalence, which decreased with age, was a major determinant for the timeliness of reliable estimates. If we began sero-surveillance 3 wk after community transmission was confirmed, with 150, 350, and 500 specimens per week for individuals aged 5–14 y, 15–19 y, and 20–29 y, respectively, we would have obtained reliable IHP estimates for these age groups 4 wk before the peak. For 30–59 y olds, even 800 specimens per week would not have generated reliable estimates until the peak because the ratio of IAR to pre-existing seroprevalence for this age group was low. The performance of serial cross-sectional sero-surveillance substantially deteriorates if test specificity is not near 100% or pre-existing seroprevalence is not near zero. These potential limitations could be mitigated by choosing a higher titer cutoff for seropositivity. If the epidemic doubling time is longer than 6 d, then serial cross-sectional sero-surveillance with 300 specimens per week would yield reliable estimates when IAR reaches around 6%–10%.
Conclusions
Serial cross-sectional serologic data together with clinical surveillance data can allow reliable real-time estimates of IAR and severity in an emerging pandemic. Sero-surveillance for pandemics should be considered.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Every winter, millions of people catch influenza—a viral infection of the airways—and about half a million die as a result. These seasonal epidemics occur because small but frequent changes in the influenza virus mean that the immune response produced by infection with one year's virus provides only partial protection against the next year's virus. Occasionally, however, a very different influenza virus emerges to which people have virtually no immunity. Such viruses can start global epidemics (pandemics) and kill millions of people. The most recent influenza pandemic began in March 2009 in Mexico, when the first case of influenza caused by a new virus called pandemic A/H1N1 2009 (pdmH1N1) occurred. The virus spread rapidly despite strenuous efforts by national and international public health agencies to contain it, and on 11 June 2009, the World Health Organization (WHO) declared that an influenza pandemic was underway. By the time WHO announced that the pandemic was over (10 August 2010), pdmH1N1 had killed more than 18,000 people.
Why Was This Study Done?
Early in the 2009 influenza pandemic, as in any emerging pandemic, reliable estimates of pdmH1N1's transmissibility (how easily it spreads between people) and severity (the proportion of infected people who needed hospital treatment) were urgently needed to help public health officials plan their response to the pandemic and advise the public about the threat to their health. Because infection with an influenza virus does not always make people ill, the only way to determine the true size and severity of an influenza outbreak is to monitor the occurrence of antibodies (proteins made by the immune system in response to infections) to the influenza virus in the population—so-called serologic surveillance. In this study, the researchers developed a method that uses serologic data to provide real-time estimates of the infection attack rate (IAR; the cumulative occurrence of new infections in a population) and the infection-hospitalization probability (IHP; the proportion of affected individuals that needs to be hospitalized) during an influenza pandemic.
What Did the Researchers Do and Find?
The researchers tested nearly 15,000 serum samples collected in Hong Kong during the first wave of the 2009 pandemic for antibodies to pdmH1N1 and then used a mathematical approach called convolution to estimate IAR and IHP from these serologic data and hospitalization data. They report that if the serological data had been available weekly in real time, they would have been able to obtain reliable estimates of IAR and IHP by one week after, one to two weeks before, and three weeks after the pandemic peak for 5–14 year olds, 15–29 year olds, and 30–59 year olds, respectively. If serologic surveillance had begun three weeks after confirmation of community transmission of pdmH1N1, sample sizes of 150, 350, and 500 specimens per week from 5–14 year olds, 15–19 year olds, and 20–29 year olds, respectively, would have been sufficient to obtain reliable IAR and IHP estimates four weeks before the pandemic peak. However, for 30–59 year olds, even 800 specimens per week would not have generated reliable estimates because of pre-existing antibodies to an H1N1 virus in this age group. Finally, computer simulations of future pandemics indicate that serologic surveillance with 300 serum specimens per week would yield reliable estimates of IAR and IHP as soon as the true IAR reached about 6%.
What Do These Findings Mean?
These findings suggest that serologic data together with clinical surveillance data could be used to provide reliable real-time estimates of IARs and severity in an emerging influenza pandemic. Although the number of samples needed to provide accurate estimates of IAR and IHP in real life may vary somewhat from those reported here because of limitations in the design of this study, these findings nevertheless suggest that the level of testing capacity needed to provide real-time estimates of IAR and IHP during an emerging influenza pandemic should be logistically feasible for most developed countries. Moreover, collection of serologic surveillance data from any major city affected early in an epidemic could potentially provide information of global relevance for public health. Thus, the researchers conclude, serologic monitoring should be included in future plans for influenza pandemic preparedness and response and in planning for other pandemics.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001103.
A recent PLoS Medicine Research Article by Riley et al. provides further information on patterns of infection with the pdmH1N1 virus
The Hong Kong Centre for Health Protection provides information on pandemic H1N1 influenza
The US Centers for Disease Control and Prevention provides information about influenza for patients and professionals, including specific information on H1N1 influenza
Flu.gov, a US government website, provides access to information on seasonal, pandemic, and H1N1 influenza
WHO provides information on seasonal influenza and has information on the global response to H1N1 influenza (in several languages)
The UK Health Protection Agency provides information on pandemic influenza and on H1N1 influenza
More information for patients about H1N1 influenza is available through Choices, an information resource provided by the UK National Health Service
doi:10.1371/journal.pmed.1001103
PMCID: PMC3186812  PMID: 21990967

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