A Large Proportion of the Mexican Population Remained Susceptible to A(H1N1)pdm09 Infection One Year after the Emergence of 2009 Influenza Pandemic

Background

The 2009 H1N1 influenza pandemic initially affected Mexico from April 2009 to July 2010. By August 2010, a fourth of the population had received the monovalent vaccine against the pandemic virus (A(H1N1)pdm09). To assess the proportion of the Mexican population who remained potentially susceptible to infection throughout the summer of 2010, we estimated the population seroprevalence to A(H1N1)pdm09 in a serosurvey of blood donors.

Methods

We evaluated baseline cross-reactivity to the pandemic strain and set the threshold for seropositivity using pre-pandemic (2005–2008) stored serum samples and sera from confirmed A(H1N1)pdm09 infected individuals. Between June and September 2010, a convenience sample serosurvey of adult blood donors, children, and adolescents was conducted in six states of Mexico. Sera were tested by the microneutralization (MN) and hemagglutination inhibition (HI) assays, and regarded seropositive if antibody titers were equal or exceeded 1:40 for MN and 1:20 for HI. Age-standardized seroprevalence were calculated using the 2010 National Census population.

Results

Sera from 1,484 individuals were analyzed; 1,363 (92%) were blood donors, and 121 (8%) children or adolescents aged ≤19 years. Mean age (standard deviation) was 31.4 (11.5) years, and 276 (19%) were women. A total of 516 (35%) participants declared history of influenza vaccination after April 2009. The age-standardized seroprevalence to A(H1N1)pdm09 was 48% by the MN and 41% by the HI assays, respectively. The youngest quintile, aged 1 to 22 years, had the highest the seroprevalence; 61% (95% confidence interval [CI]: 56, 66%) for MN, and 56% (95% CI: 51, 62%) for HI.

Conclusions

Despite high transmission of A(H1N1)pdm09 observed immediately after its emergence and extensive vaccination, over a half of the Mexican population remained potentially susceptible to A(H1N1)pdm09 infection. Subsequent influenza seasons with high transmission of A(H1N1)pdm09, as 2011–2012 and 2013–2014, are compatible with these findings.     

Detection of Extensive Cross-Neutralization between Pandemic and Seasonal A/H1N1 Influenza Viruses Using a Pseudotype Neutralization Assay

Background

Cross-immunity between seasonal and pandemic A/H1N1 influenza viruses remains uncertain. In particular, the extent that previous infection or vaccination by seasonal A/H1N1 viruses can elicit protective immunity against pandemic A/H1N1 is unclear.

Methodology/Principal Findings

Neutralizing titers against seasonal A/H1N1 (A/Brisbane/59/2007) and against pandemic A/H1N1 (A/California/04/2009) were measured using an HIV-1-based pseudovirus neutralization assay. Using this highly sensitive assay, we found that a large fraction of subjects who had never been exposed to pandemic A/H1N1 express high levels of pandemic A/H1N1 neutralizing titers. A significant correlation was seen between neutralization of pandemic A/H1N1 and neutralization of a standard seasonal A/H1N1 strain. Significantly higher pandemic A/H1N1 neutralizing titers were measured in subjects who had received vaccination against seasonal influenza in 2008–2009. Higher pandemic neutralizing titers were also measured in subjects over 60 years of age.

Conclusions/Significance

Our findings reveal that the extent of protective cross-immunity between seasonal and pandemic A/H1N1 influenza viruses may be more important than previously estimated. This cross-immunity could provide a possible explanation of the relatively mild profile of the recent influenza pandemic.     

Immunogenicity and Acceptance of Influenza A (H1N1) Vaccine in a Cohort of Chronic Hepatitis C Patients Receiving Pegylated-Interferon Treatment

Background & Aims

Individuals at risk of (H1N1) influenza A infection are recommended to receive vaccination. Chronic hepatitis C (CHC) patients receiving treatment might be at a higher risk of respiratory bacterial infections after influenza infection. However, there are no observational studies evaluating the immunogenicity, tolerance and acceptance of 2009 influenza A vaccine in CHC patients.

Methods

We evaluated the immunogenicity of influenza A vaccine (Pandemrix®) by using the hemagglutination inhibition (HI) titers method in a well defined cohort of CHC patients receiving or not receiving pegylated-interferon and ribavirin, and compared it with healthy subjects (controls). A group of patients with inflammatory bowel disease (IBD) under immunosuppression, thought to have a lower immune response to seasonal influenza vaccine, were also included as a negative control group. In addition, tolerance to injection site reactions and acceptance was assessed by a validated questionnaire (Vaccinees'' perception of injection-VAPI-questionnaire).

Results

Of 114 subjects invited to participate, 68% accepted and, after exclusions, 72 were included. Post-vaccination geometric mean titers and seroprotection/seroconversion rates were optimal in CHC patients with ongoing treatment (n = 15; 232, CI95% 46–1166; 93%; 93%), without treatment (n = 10; 226, CI95% 69–743: 100%; 100%) and controls (n = 15;168, CI95% 42–680; 93%; 86%) with no differences between groups (P = 0.8). In contrast, IBD patients had a significantly lower immunogenic response (n = 27; 60, CI95% 42–680;66%;66%; P = 0.006). All the groups showed a satisfactory tolerance although CHC patients with ongoing treatment showed more local discomfort after vaccine injection.

Conclusion

There appeared to be no differences between CHC patients and healthy controls in serological response and acceptance of (H1N1) influenza vaccination.     

Profiling of Humoral Response to Influenza A(H1N1)pdm09 Infection and Vaccination Measured by a Protein Microarray in Persons with and without History of Seasonal Vaccination

Background

The influence of prior seasonal influenza vaccination on the antibody response produced by natural infection or vaccination is not well understood.

Methods

We compared the profiles of antibody responses of 32 naturally infected subjects and 98 subjects vaccinated with a 2009 influenza A(H1N1) monovalent MF59-adjuvanted vaccine (Focetria®, Novartis), with and without a history of seasonal influenza vaccination. Antibodies were measured by hemagglutination inhibition (HI) assay for influenza A(H1N1)pdm09 and by protein microarray (PA) using the HA1 subunit for seven recent and historic H1, H2 and H3 influenza viruses, and three avian influenza viruses. Serum samples for the infection group were taken at the moment of collection of the diagnostic sample, 10 days and 30 days after onset of influenza symptoms. For the vaccination group, samples were drawn at baseline, 3 weeks after the first vaccination and 5 weeks after the second vaccination.

Results

We showed that subjects with a history of seasonal vaccination generally exhibited higher baseline titers for the various HA1 antigens than subjects without a seasonal vaccination history. Infection and pandemic influenza vaccination responses in persons with a history of seasonal vaccination were skewed towards historic antigens.

Conclusions

Seasonal vaccination is of significant influence on the antibody response to subsequent infection and vaccination, and further research is needed to understand the effect of annual vaccination on protective immunity.     

Effectiveness of A(H1N1)pdm09 Influenza Vaccine in Adults Recommended for Annual Influenza Vaccination

Introduction

Because of variability in published A(H1N1)pdm09 influenza vaccine effectiveness estimates, we conducted a study in the adults belonging to the risk groups to assess the A(H1N1)pdm09 MF59-adjuvanted influenza vaccine effectiveness.

Methods

VE against influenza and/or pneumonia was assessed in the cohort study (n>25000), and vaccine effectiveness against laboratory-confirmed A(H1N1)pdm09 influenza was assessed in a matched case-control study (16 pairs). Odds ratios (OR) and their 95% confidence intervals (95% CI) were calculated by using multivariate logistic regression; vaccine effectiveness was estimated as (1-odds ratio)*100%.

Results

Vaccine effectiveness against laboratory-confirmed A(H1N1)pdm09 influenza and influenza and/or pneumonia was 98% (84–100%) and 33% (2–54%) respectively. The vaccine did not prevent influenza and/or pneumonia in 18–59 years old subjects, and was 49% (16–69%) effective in 60 years and older subjects.

Conclusions

Even though we cannot entirely rule out that selection bias, residual confounding and/or cross-protection has played a role, the present results indicate that the MF59-adjuvanted A(H1N1)pdm09 influenza vaccine has been effective in preventing laboratory-confirmed A(H1N1)pdm09 influenza and influenza and/or pneumonia, the latter notably in 60 years and older subjects.     

Household Transmission of Influenza A(H1N1)pdm09 in the Pandemic and Post-Pandemic Seasons

Background

The transmission of influenza viruses occurs person to person and is facilitated by contacts within enclosed environments such as households. The aim of this study was to evaluate secondary attack rates and factors associated with household transmission of laboratory-confirmed influenza A(H1N1)pdm09 in the pandemic and post-pandemic seasons.

Methods

During the 2009–2010 and 2010–2011 influenza seasons, 76 sentinel physicians in Navarra, Spain, took nasopharyngeal and pharyngeal swabs from patients diagnosed with influenza-like illness. A trained nurse telephoned households of those patients who were laboratory-confirmed for influenza A(H1N1)pdm09 to ask about the symptoms, risk factors and vaccination status of each household member.

Results

In the 405 households with a patient laboratory-confirmed for influenza A(H1N1)pdm09, 977 susceptible contacts were identified; 16% of them (95% CI 14–19%) presented influenza-like illness and were considered as secondary cases. The secondary attack rate was 14% in 2009–2010 and 19% in the 2010–2011 season (p = 0.049), an increase that mainly affected persons with major chronic conditions. In the multivariate logistic regression analysis, the risk of being a secondary case was higher in the 2010–2011 season than in the 2009–2010 season (adjusted odds ratio: 1.72; 95% CI 1.17–2.54), and in children under 5 years, with a decreasing risk in older contacts. Influenza vaccination was associated with lesser incidence of influenza-like illness near to statistical significance (adjusted odds ratio: 0.29; 95% CI 0.08–1.03).

Conclusion

The secondary attack rate in households was higher in the second season than in the first pandemic season. Children had a greater risk of infection. Preventive measures should be maintained in the second pandemic season, especially in high-risk persons.     

Reconstruction of the Evolutionary Dynamics of A(H3N2) Influenza Viruses Circulating in Italy from 2004 to 2012

Background

Influenza A viruses are characterised by their rapid evolution, and the appearance of point mutations in the viral hemagglutinin (HA) domain causes seasonal epidemics. The A(H3N2) virus has higher mutation rate than the A(H1N1) virus. The aim of this study was to reconstruct the evolutionary dynamics of the A(H3N2) viruses circulating in Italy between 2004 and 2012 in the light of the forces driving viral evolution.

Methods

Phylodinamic analyses were made using a Bayesian method, and codon-specific positive selection acting on the HA coding sequence was evaluated.

Results

Global and local phylogenetic analyses showed that the Italian strains collected between 2004 and 2012 grouped into five significant Italian clades that included viral sequences circulating in different epidemic seasons. The time of the most recent common ancestor (tMRCA) of the tree root was between May and December 2003. The tMRCA estimates of the major clades suggest that the origin of a new viral strain precedes the effective circulation of the strain in the Italian population by 6–31 months, thus supporting a central role of global migration in seeding the epidemics in Italy. The study of selection pressure showed that four codons were under positive selection, three of which were located in antigenic sites. Analysis of population dynamics showed the alternation of periods of exponential growth followed by a decrease in the effective number of infections corresponding to epidemic and inter-epidemic seasons.

Conclusions

Our analyses suggest that a complex interaction between the immune status of the population, migrations, and a few selective sweeps drive the influenza A(H3N2) virus evolution. Our findings suggest the possibility of the year-round survival of local strains even in temperate zones, a hypothesis that warrants further investigation.     

Low Rate of Pandemic A/H1N1 2009 Influenza Infection and Lack of Severe Complication of Vaccination in Pregnant Women: A Prospective Cohort Study

Background

In 2009, pregnant women were specifically targeted by a national vaccination campaign against pandemic A/H1N1 influenza virus. The objectives of the COFLUPREG study, initially set up to assess the incidence of serious forms of A/H1N1 influenza, were to assess the consequences of maternal vaccination on pregnancy outcomes and maternal seroprotection at delivery.

Methods

Pregnant women, between 12 and 35 weeks of gestation, non vaccinated against A/H1N1 2009 influenza were randomly selected to be included in a prospective cohort study conducted in three maternity centers in Paris (France) during pandemic period. Blood samples were planned to assess hemagglutination inhibition (HI) antibody against A/H1N1 2009 influenza at inclusion and at delivery.

Results

Among the 877 pregnant women included in the study, 678 (77.3%) had serum samples both at inclusion and delivery, and 320 (36.5%) received pandemic A/H1N1 2009 influenza vaccine with a median interval between vaccination and delivery of 92 days (95% CI 48–134). At delivery, the proportion of women with seroprotection (HI antibodies titers against A/H1N1 2009 influenza of 1∶40 or greater) was 69.9% in vaccinated women. Of the 422 non-vaccinated women with serological data, 11 (2.6%; 95%CI: 1.3–4.6) had laboratory documented A/H1N1 2009 influenza (1 with positive PCR and 10 with serological seroconversion). None of the 877 study’s women was hospitalized for flu. No difference on pregnancy outcomes was evidenced between vaccinated women, non-vaccinated women without seroconversion and non-vaccinated women with flu.

Conclusion

Despite low vaccine coverage, incidence of pandemic flu was low in this cohort of pregnant women.No effect on pregnancy and delivery outcomes was evidenced after vaccination.     

Impact of the 2009 H1N1 Pandemic on Age-Specific Epidemic Curves of Other Respiratory Viruses: A Comparison of Pre-Pandemic,Pandemic and Post-Pandemic Periods in a Subtropical City

Background

The 2009 H1N1 influenza pandemic caused offseason peaks in temperate regions but coincided with the summer epidemic of seasonal influenza and other common respiratory viruses in subtropical Hong Kong. This study was aimed to investigate the impact of the pandemic on age-specific epidemic curves of other respiratory viruses.

Methods

Weekly laboratory-confirmed cases of influenza A (subtypes seasonal A(H1N1), A(H3N2), pandemic virus A(H1N1)pdm09), influenza B, respiratory syncytial virus (RSV), adenovirus and parainfluenza were obtained from 2004 to 2013. Age-specific epidemic curves of viruses other than A(H1N1)pdm09 were compared between the pre-pandemic (May 2004 – April 2009), pandemic (May 2009 – April 2010) and post-pandemic periods (May 2010 – April 2013).

Results

There were two peaks of A(H1N1)pdm09 in Hong Kong, the first in September 2009 and the second in February 2011. The infection rate was found highest in young children in both waves, but markedly fewer cases in school children were recorded in the second wave than in the first wave. Positive proportions of viruses other than A(H1N1)pdm09 markedly decreased in all age groups during the first pandemic wave. After the first wave of the pandemic, the positive proportion of A(H3N2) increased, but those of B and RSV remained slightly lower than their pre-pandemic proportions. Changes in seasonal pattern and epidemic peak time were also observed, but inconsistent across virus-age groups.

Conclusion

Our findings provide some evidence that age distribution, seasonal pattern and peak time of other respiratory viruses have changed since the pandemic. These changes could be the result of immune interference and changing health seeking behavior, but the mechanism behind still needs further investigations.     

Heterosubtype Neutralizing Responses to Influenza A (H5N1) Viruses Are Mediated by Antibodies to Virus Haemagglutinin

Background

It is increasingly clear that influenza A infection induces cross-subtype neutralizing antibodies that may potentially confer protection against zoonotic infections. It is unclear whether this is mediated by antibodies to the neuraminidase (NA) or haemagglutinin (HA). We use pseudoviral particles (H5pp) coated with H5 haemagglutinin but not N1 neuraminidase to address this question. In this study, we investigate whether cross-neutralizing antibodies in persons unexposed to H5N1 is reactive to the H5 haemagglutinin.

Methodology/Principal Findings

We measured H5-neutralization antibody titers pre- and post-vaccination using the H5N1 micro-neutralization test (MN) and H5pp tests in subjects given seasonal vaccines and in selected sera from European elderly volunteers in a H5N1 vaccine trial who had detectable pre-vaccination H5N1 MN antibody titers. We found detectable (titer ≥20) H5N1 neutralizing antibodies in a minority of pre-seasonal vaccine sera and evidence of a serological response to H5N1 in others after seasonal influenza vaccination. There was excellent correlation in the antibody titers between the H5N1 MN and H5pp tests. Similar correlations were found between MN and H5pp in the pre-vaccine sera from the cohort of H5N1 vaccine trial recipients.

Conclusions/Significance

Heterosubtype neutralizing antibody to H5N1 in healthy volunteers unexposed to H5N1 is mediated by cross-reaction to the H5 haemagglutinin.     

The Impact of Immunosenescence on Humoral Immune Response Variation after Influenza A/H1N1 Vaccination in Older Subjects

Background

Although influenza causes significant morbidity and mortality in the elderly, the factors underlying the reduced vaccine immunogenicity and efficacy in this age group are not completely understood. Age and immunosenescence factors, and their impact on humoral immunity after influenza vaccination, are of growing interest for the development of better vaccines for the elderly.

Methods

We assessed associations between age and immunosenescence markers (T cell receptor rearrangement excision circles – TREC content, peripheral white blood cell telomerase – TERT expression and CD28 expression on T cells) and influenza A/H1N1 vaccine-induced measures of humoral immunity in 106 older subjects at baseline and three timepoints post-vaccination.

Results

TERT activity (TERT mRNA expression) was significantly positively correlated with the observed increase in the influenza-specific memory B cell ELISPOT response at Day 28 compared to baseline (p-value=0.025). TREC levels were positively correlated with the baseline and early (Day 3) influenza A/H1N1-specific memory B cell ELISPOT response (p-value=0.042 and p-value=0.035, respectively). The expression and/or expression change of CD28 on CD4+ and/or CD8+ T cells at baseline and Day 3 was positively correlated with the influenza A/H1N1-specific memory B cell ELISPOT response at baseline, Day 28 and Day 75 post-vaccination. In a multivariable analysis, the peak antibody response (HAI and/or VNA at Day 28) was negatively associated with age, the percentage of CD8+CD28low T cells, IgD+CD27- naïve B cells, and percentage overall CD20- B cells and plasmablasts, measured at Day 3 post-vaccination. The early change in influenza-specific memory B cell ELISPOT response was positively correlated with the observed increase in influenza A/H1N1-specific HAI antibodies at Day 28 and Day 75 relative to baseline (p-value=0.007 and p-value=0.005, respectively).

Conclusion

Our data suggest that influenza-specific humoral immunity is significantly influenced by age, and that specific markers of immunosenescence (e.g., the baseline/early expression of CD28 on CD4+ and/or CD8+ T cells and T cell immune abnormalities) are correlated with different humoral immune response outcomes observed after vaccination in older individuals, and thus can be potentially used to predict vaccine immunogenicity.     

Intent to Receive Pandemic Influenza A (H1N1) Vaccine,Compliance with Social Distancing and Sources of Information in NC, 2009

Background

Public adherence to influenza vaccination recommendations has been low, particularly among younger adults and children under 2, despite the availability of safe and effective seasonal vaccine. Intention to receive 2009 pandemic influenza A (H1N1) vaccine has been estimated to be 50% in select populations. This report measures knowledge of and intention to receive pandemic vaccine in a population-based setting, including target groups for seasonal and H1N1 influenza.

Methodology and Principal Findings

On August 28–29, 2009, we conducted a population-based survey in 2 counties in North Carolina. The survey used the 30×7 two-stage cluster sampling methodology to identify 210 target households. Prevalence ratios (PR) and 95% confidence intervals (CI) were estimated. Knowledge of pandemic influenza A (H1N1) vaccine was high, with 165 (80%) aware that a vaccine was being prepared. A total of 133 (64%) respondents intended to receive pandemic vaccine, 134 (64%) intended to receive seasonal vaccine, and 109 (53%) intended to receive both. Reporting great concern about H1N1 infection (PR 1.55; 95%CI: 1.30, 1.85), receiving seasonal influenza vaccine in 2008–09 (PR 1.47; 95%CI: 1.18, 1.82), and intending to receive seasonal influenza vaccine in 2009–10 (PR 1.27; 95%CI: 1.14, 1.42) were associated with intention to receive pandemic vaccine. Not associated were knowledge of vaccine, employment, having children under age 18, gender, race/ethnicity and age. Reasons cited for not intending to get vaccinated include not being at risk for infection, concerns about vaccine side effects and belief that illness caused by pandemic H1N1 would be mild. Forty-five percent of households with children under 18 and 65% of working adults reported ability to comply with self-isolation at home for 7–10 days if recommended by authorities.

Conclusions and Significance

This is the first report of a population based rapid assessment used to assess knowledge and intent to receive pandemic vaccine in a community sample. Intention to receive pandemic and seasonal vaccines was higher than previously published reports. To reach persons not intending to receive pandemic vaccine, public health communications should focus on the perceived risk of infection and concerns about vaccine safety.     

Immunogenicity and Safety of Influenza Vaccination in Systemic Lupus Erythematosus Patients Compared with Healthy Controls: A Meta-Analysis

Objective

To assess the immunogenicity and safety of influenza vaccine in patients with systemic lupus erythematosus (SLE).

Methods

Relevant articles were retrieved from electronic databases. Seroprotection rate, seroconversion rate and factors that increase antibody geometric mean titer (GMT) were used as indices to measure the immunogenicity. The safety of vaccine was assessed through monitoring adverse events, which included side effects and SLE exacerbations. We performed a meta-analysis of influenza vaccine seroprotection, seroconversion and adverse effects. SLE exacerbation after vaccination was comprehensively described. We used the Committee for Proprietary Medicinal Products (CPMP) guidelines to determine whether influenza can induce adequate immunogenicity in patients with SLE.

Results

Eighteen studies with 1966 subjects met the inclusion criteria. At least 565 of the subjects were patients with low-to-moderate SLE Disease Activity Index (SLEDAI) score or stable SLE disease. Compared with the general population, seroprotection rate in SLE patients was significantly decreased in patients with H1N1 [odds ratio (OR) = 0.36, 95% confidence interval (CI): 0.27–0.50] and H3N2 vaccination (OR = 0.48, 95% CI: 0.24–0.93), but not influenza B vaccination (OR = 0.55, 95% CI: 0.24–1.25). Seroconversion rate also significantly decreased in patients with H1N1 (OR = 0.39, 95% CI: 0.27–0.57) and influenza B (OR = 0.47, 95% CI: 0.29–0.76) vaccination, but not H3N2 vaccination (OR = 0.62, 95% CI: 0.21–1.79). However, the immunogenicity of influenza vaccine in SLE patients almost reached that of the CPMP guidelines. The OR for side effects (patients versus healthy controls) was 3.24 (95% CI: 0.62–16.76). Among 1966 patients with SLE, 32 experienced mild exacerbation of SLE and five had serious side effects for other reasons.

Conclusion

Influenza vaccine has moderate effect on protecting patients with SLE. The side effects of influenza vaccine are not serious and are manageable. With consideration of a higher risk of SLE exacerbation and a more severe course of infection among SLE patients, influenza vaccination should be promoted among SLE patients with a low-to-moderate SLEDAI score or stable disease.     

Clinical Characteristics Are Similar across Type A and B Influenza Virus Infections

Background

Studies that aimed at comparing the clinical presentation of influenza patients across virus types and subtypes/lineages found divergent results, but this was never investigated using data collected over several years in a countrywide, primary care practitioners-based influenza surveillance system.

Methods

The IBVD (Influenza B in Vircases Database) study collected information on signs and symptoms at disease onset from laboratory-confirmed influenza patients of any age who consulted a sentinel practitioner in France. We compared the clinical presentation of influenza patients across age groups (0–4, 5–14, 15–64 and 65+ years), virus types (A, B) and subtypes/lineages (A(H3N2), pandemic A(H1N1), B Victoria, B Yamagata).

Results

Overall, 14,423 influenza cases (23.9% of which were influenza B) were included between 2003–2004 and 2012–2013. Influenza A and B accounted for over 50% of total influenza cases during eight and two seasons, respectively. There were minor differences in the distribution of signs and symptoms across influenza virus types and subtypes/lineages. Compared to patients aged 0–4 years, those aged 5–14 years were more likely to have been infected with type B viruses (OR 2.15, 95% CI 1.87–2.47) while those aged 15–64 years were less likely (OR 0.83, 95% CI 0.73–0.96). Males and influenza patients diagnosed during the epidemic period were less likely to be infected with type B viruses.

Conclusions

Despite differences in age distribution, the clinical illness produced by the different influenza virus types and subtypes is indistinguishable among patients that consult a general practitioner for acute respiratory infections.     

Mortality Burden of the 2009 A/H1N1 Influenza Pandemic in France: Comparison to Seasonal Influenza and the A/H3N2 Pandemic

Background

The mortality burden of the 2009 A/H1N1 pandemic remains unclear in many countries due to delays in reporting of death statistics. We estimate the age- and cause-specific excess mortality impact of the pandemic in France, relative to that of other countries and past epidemic and pandemic seasons.

Methods

We applied Serfling and Poisson excess mortality approaches to model weekly age- and cause-specific mortality rates from June 1969 through May 2010 in France. Indicators of influenza activity, time trends, and seasonal terms were included in the models. We also reviewed the literature for country-specific estimates of 2009 pandemic excess mortality rates to characterize geographical differences in the burden of this pandemic.

Results

The 2009 A/H1N1 pandemic was associated with 1.0 (95% Confidence Intervals (CI) 0.2–1.9) excess respiratory deaths per 100,000 population in France, compared to rates per 100,000 of 44 (95% CI 43–45) for the A/H3N2 pandemic and 2.9 (95% CI 2.3–3.7) for average inter-pandemic seasons. The 2009 A/H1N1 pandemic had a 10.6-fold higher impact than inter-pandemic seasons in people aged 5–24 years and 3.8-fold lower impact among people over 65 years.

Conclusions

The 2009 pandemic in France had low mortality impact in most age groups, relative to past influenza seasons, except in school-age children and young adults. The historical A/H3N2 pandemic was associated with much larger mortality impact than the 2009 pandemic, across all age groups and outcomes. Our 2009 pandemic excess mortality estimates for France fall within the range of previous estimates for high-income regions. Based on the analysis of several mortality outcomes and comparison with laboratory-confirmed 2009/H1N1 deaths, we conclude that cardio-respiratory and all-cause mortality lack precision to accurately measure the impact of this pandemic in high-income settings and that use of more specific mortality outcomes is important to obtain reliable age-specific estimates.     

Serological Response of Patients with Influenza A (H1N1) pdm09-Associated Pneumonia: An Observational Study

Background

Little is known about the dynamics or magnitude of antibody response in patients with influenza A (H1N1) pdm09-associated pneumonia. We described and compared the antibody response to influenza A (H1N1) pdm09 in patients with and without pneumonia.

Methods

We collected serum samples and determined antibody titers by the hemagglutination inhibition (HI) and microneutralization (mNT) assays from patients with RT-PCR confirmed influenza A (H1N1) pdm09 virus at baseline, 1, 2 and 6 months after onset of illness.

Results

Fifty-nine patients were enrolled, 45 (76.3%) were between 15 and 60 years of age, 49 (83.1%) were hospitalized and 25 (42.4%) had complications with pneumonia. Ninety-four percent of patients had HI titers ≥ 1: 40 and 90% had mNT titers ≥ 1: 160 at 2 months after illness. Geometric mean titers (GMT) of HI and mNT increased significantly (p<0.001) between baseline and months 1 or 2, then declined significantly (p<0.001) at month 6 by the HI assay, but dropped to an insignificant level (p=0.24) by the mNT assay. The mNT-GMT was at least twice as high as corresponding HI antibodies over a 6 month period. The GMT of HI and mNT in those with pneumonia (1 mo) peaked earlier than that of those without pneumonia (2 mo). When adjusted by age and gender, those with pneumonia had a higher HI-GMT than those without pneumonia at 1 month (264 vs. 117, p=0.007), 2 months (212 vs. 159, p=0.013), and 6 months (160 vs. 82, p=0.018).

Conclusions

The patients recovered from influenza A (H1N1) pdm09-associated pneumonia, clearly developed an earlier and more robust antibody response until 6 months after onset of illness. The results in our study are useful to determine an appropriate donor and timing to obtain convalescent plasma for adjunctive treatment of seriously ill patients with pandemic H1N1 influenza.     

Association between the Severity of Influenza A(H7N9) Virus Infections and Length of the Incubation Period

Background

In early 2013, a novel avian-origin influenza A(H7N9) virus emerged in China, and has caused sporadic human infections. The incubation period is the delay from infection until onset of symptoms, and varies from person to person. Few previous studies have examined whether the duration of the incubation period correlates with subsequent disease severity.

Methods and Findings

We analyzed data of period of exposure on 395 human cases of laboratory-confirmed influenza A(H7N9) virus infection in China in a Bayesian framework using a Weibull distribution. We found a longer incubation period for the 173 fatal cases with a mean of 3.7 days (95% credibility interval, CrI: 3.4–4.1), compared to a mean of 3.3 days (95% CrI: 2.9–3.6) for the 222 non-fatal cases, and the difference in means was marginally significant at 0.47 days (95% CrI: -0.04, 0.99). There was a statistically significant correlation between a longer incubation period and an increased risk of death after adjustment for age, sex, geographical location and underlying medical conditions (adjusted odds ratio 1.70 per day increase in incubation period; 95% credibility interval 1.47–1.97).

Conclusions

We found a significant association between a longer incubation period and a greater risk of death among human H7N9 cases. The underlying biological mechanisms leading to this association deserve further exploration.     

French Experience of 2009 A/H1N1v Influenza in Pregnant Women

Background

The first reports on the pandemic influenza 2009 A/H1N1v from the USA, Mexico, and Australia indicated that this disease was associated with a high mortality in pregnant women. The aim of this study was to describe and compare the characteristics of severe critically ill and non-severe pregnant women with 2009 A/H1N1v-related illness in France.

Methodology/Principal Findings

A national registry was created to screen pregnant women with laboratory-confirmed 2009 A/H1N1v influenza. Three hundred and fifteen patients from 46 French hospitals were included: 40 patients were admitted to intensive care units (severe outcomes), 111 were hospitalized in obstetric or medical wards (moderate outcomes), and 164 were outpatients (mild outcomes). The 2009 A/H1N1v influenza illness occurred during all pregnancy trimesters, but most women (54%), notably the severe patients (70%), were in the third trimester. Among the severe patients, twenty (50%) underwent mechanical ventilation, and eleven (28%) were treated with extracorporeal membrane oxygenation. Three women died from A/H1N1v influenza. We found a strong association between the development of a severe outcome and both co-existing illnesses (adjusted odds ratio [OR], 5.1; 95% confidence interval [CI], 2.2–11.8) and a delay in oseltamivir treatment after the onset of symptoms (>3 or 5 days) (adjusted OR, 4.8; 95% CI, 1.9–12.1 and 61.2, 95% CI; 14.4–261.3, respectively). Among the 140 deliveries after 22 weeks of gestation known to date, 19 neonates (14%) were admitted to a neonatal intensive care unit, mainly for preterm delivery, and two neonates died. None of these neonates developed 2009 A/H1N1v infection.

Conclusions

This series confirms the high incidence of complications in pregnant women infected with pandemic A/H1N1v observed in other countries but depicts a lower overall maternal and neonatal mortality and morbidity than indicated in the USA or Australia. Moreover, our data demonstrate the benefit of early oseltamivir treatment in this specific population.     

Characterization of cross protection of Swine-Origin Influenza Virus (S-OIV) H1N1 and reassortant H5N1 influenza vaccine in BALB/c mice given a single-dose vaccination

Background

Influenza virus has antigen drift and antigen shift effect, vaccination with some influenza vaccine might not induce sufficient immunity for host to the threat of other influenza virus strains. S-OIV H1N1 and H5N1 influenza vaccines in single-dose immunization were evaluated in mice for cross protection to the challenge of A/California/7/2009 H1N1 or NIBRG-14 H5N1 virus.

Results

Both H1N1 and H5N1 induced significant homologous IgG, HAI, and microneutralization antibody responses in the mice, while only vaccines plus adjuvant produced significant heterogeneous IgG and HAI antibody responses. Both alum and MPLA adjuvants significantly reduced the S-OIV H1N1 vaccine dose required to elicit protective HAI antibody titers from 0.05 μg to 0.001 μg. Vaccines alone did not protect mice from challenge with heterogeneous influenza virus, while H5N1 vaccine plus alum and MPLA adjuvants did. Mouse body weight loss was also less significant in the presence of adjuvant than in the vaccine without adjuvant. Furthermore, both H1N1 and H5N1 lung viral titers of immunized mice were significantly reduced post challenge with homologous viruses.

Conclusion

Only in the presence of MPLA adjuvant could the H5N1 vaccine significantly reduce mouse lung viral titers post H1N1 virus challenge, and not vice versa. MPLA adjuvant induced cross protection with a single dose vaccination to the challenge of heterogeneous influenza virus in mice. Lung viral titer seemed to be a better indicator compared to IgG, neutralization antibody, and HAI titer to predict survival of mice infected with influenza virus.