Genetic diversity of the 2009 pandemic influenza A(H1N1) viruses in Finland

Background

In Finland, the first infections caused by the 2009 pandemic influenza A(H1N1) virus were identified on May 10. During the next three months almost all infections were found from patients who had recently traveled abroad. In September 2009 the pandemic virus started to spread in the general population, leading to localized outbreaks and peak epidemic activity was reached during weeks 43–48.

Methods/Results

The nucleotide sequences of the hemagglutinin (HA) and neuraminidase (NA) genes from viruses collected from 138 patients were determined. The analyzed viruses represented mild and severe infections and different geographic regions and time periods. Based on HA and NA gene sequences, the Finnish pandemic viruses clustered in four groups. Finnish epidemic viruses and A/California/07/2009 vaccine virus strain varied from 2–8 and 0–5 amino acids in HA and NA molecules, respectively, giving a respective maximal evolution speed of 1.4% and 1.1%. Most amino acid changes in HA and NA molecules accumulated on the surface of the molecule and were partly located in antigenic sites. Three severe infections were detected with a mutation at HA residue 222, in two viruses with a change D222G, and in one virus D222Y. Also viruses with change D222E were identified. All Finnish pandemic viruses were sensitive to oseltamivir having the amino acid histidine at residue 275 of the neuraminidase molecule.

Conclusions

The Finnish pandemic viruses were quite closely related to A/California/07/2009 vaccine virus. Neither in the HA nor in the NA were changes identified that may lead to the selection of a virus with increased epidemic potential or exceptionally high virulence. Continued laboratory-based surveillance of the 2009 pandemic influenza A(H1N1) is important in order to rapidly identify drug resistant viruses and/or virus variants with potential ability to cause severe forms of infection and an ability to circumvent vaccine-induced immunity.     

Effectiveness of pandemic H1N1-2009 vaccination in reducing laboratory confirmed influenza infections among military recruits in tropical Singapore

Background

Limited information is available about pandemic H1N1-2009 influenza vaccine effectiveness in tropical communities. We studied the effectiveness of a pandemic H1N1 vaccination program in reducing influenza cases in Singapore.

Methods

A surveillance study was conducted among military personnel presenting with febrile respiratory illness from mid-2009 to mid-2010. Consenting individuals underwent nasal washes, which were tested with RT-PCR and subtyped. A vaccination program (inactivated monovalent Panvax H1N1-2009 vaccine) was carried out among recruits. A Bayesian hierarchical model was used to quantify relative risks in the pre- and post-vaccination periods. An autoregressive generalised linear model (GLM) was developed to minimise confounding.

Results

Of 2858 participants, 437(15.3%), 60(2.1%), and 273(9.6%) had pandemic H1N1, H3N2, and influenza B. The ratio of relative risks for pandemic H1N1 infection before and after vaccination for the recruit camp relative to other camps was 0.14(0.016,0.49); for H3N2, 0.44(0.035,1.8); and for influenza B, 18(0.77,89). Using the GLM for the recruit camp, post-vaccination weekly cases decreased by 54%(37%,67%, p<0.001) from that expected without vaccination; influenza B increased by 66 times(9–479 times, p<0.001); with no statistical difference for H3N2 (p = 0.54).

Conclusions

Pandemic vaccination reduced H1N1-2009 disease burden among military recruits. Routine seasonal influenza vaccination should be considered.     

Identification of a highly conserved H1 subtype-specific epitope with diagnostic potential in the hemagglutinin protein of influenza A virus

Subtype specificity of influenza A virus (IAV) is determined by its two surface glycoproteins, hemagglutinin (HA) and neuraminidase (NA). For HA, 16 distinct subtypes (H1–H16) exist, while nine exist for NA. The epidemic strains of H1N1 IAV change frequently and cause annual seasonal epidemics as well as occasional pandemics, such as the notorious 1918 influenza pandemic. The recent introduction of pandemic A/H1N1 IAV (H1N1pdm virus) into humans re-emphasizes the public health concern about H1N1 IAV. Several studies have identified conserved epitopes within specific HA subtypes that can be used for diagnostics. However, immune specific epitopes in H1N1 IAV have not been completely assessed. In this study, linear epitopes on the H1N1pdm viral HA protein were identified by peptide scanning using libraries of overlapping peptides against convalescent sera from H1N1pdm patients. One epitope, P5 (aa 58–72) was found to be immunodominant in patients and to evoke high titer antibodies in mice. Multiple sequence alignments and in silico coverage analysis showed that this epitope is highly conserved in influenza H1 HA [with a coverage of 91.6% (9,860/10,767)] and almost completely absent in other subtypes [with a coverage of 3.3% (792/23,895)]. This previously unidentified linear epitope is located outside the five well-recognized antigenic sites in HA. A peptide ELISA method based on this epitope was developed and showed high correlation (χ² = 51.81, P<0.01, Pearson correlation coefficient R = 0.741) with a hemagglutination inhibition test. The highly conserved H1 subtype-specific immunodominant epitope may form the basis for developing novel assays for sero-diagnosis and active surveillance against H1N1 IAVs.     

Incidence of H1N1 2009 virus infection through the analysis of paired plasma specimens among blood donors, France

Background

Knowledge of the age-specific prevalence of seroprotection and incidence of seroconversion infection is necessary to complement clinical surveillance data and statistical models. It provides the basis for estimating the future impact of influenza A (H1N1pdm09) and implementing appropriate prevention and response strategies.

Methods

Using a cross-sectional design, two-stage stratified sampling and paired plasma samples, we estimated the age-specific prevalence of a protective level of H1N1pdm09 antibodies in the French adult population before and after the 2009/10 pandemic, and the proportion of those susceptible that seroconverted due to infection, from a single sample of 1,936 blood donors aged 20–70 years in mainland France in June 2010. Samples with a haemagglutination inhibition (HI) titre ≥1∶40 were considered seropositive, and seroconversion due to infection was defined as a 4-fold increase in titre in the absence of H1N1pdm09 vaccination or pre-pandemic seropositivity.

Results

Out of the 1,936 donors, 1,708 were included in the analysis. Seroprevalence before the pandemic was 6.7% (95% CI 5.0, 8.9) with no significant differences by age-group (p = 0.3). Seroprevalence afterwards was 23.0% (95% CI 17.7, 29.3) with 20–29 year olds having a higher level than older groups (p<0.001). Seroconversion due to infection was 12.2% (95% CI 6.9, 20.5). Younger age-group, vaccination against H1N1 and being seropositive before the pandemic were strongly associated with post-pandemic seropositivity.

Conclusions

Before the 2009/2010 winter influenza season, only 6.7% of the French mainland population aged 20–70 had a level of antibodies usually considered protective. During the first pandemic wave, 12.2% of the population seroconverted due to infection and the seroprevalence after the wave rose to 23%, either due to prepandemic seropositivity, infection or vaccination. This relatively low latter figure contributed to an extension of target groups for influenza vaccination for the 2010/2011 season.     

Effect of the H1N1 influenza pandemic on the incidence of epidemic keratoconjunctivitis and on hygiene behavior: a cross-sectional study

Background

EKC is transmitted chiefly by direct hand contact. It is suspected that the 2009/2010 influenza pandemic influenced hand washing. This study aims to examine the relationship between the 2009/2010 H1N1 influenza pandemic and hygiene behavior.

Methods

We compared the EKC prevalence trends before, during and after the 2009/2010 influenza pandemic by using a t-test comparison of EKC sentinel surveillance.

Results

During the pre-pandemic period, the incidence of EKC increased from the 21st to the 44th week each year. However, during the pandemic period in 2009, there was no epidemic peak. In the post-pandemic period, the epidemic curve was similar to that in the pre-pandemic period. Compared to the pre-pandemic period, the total number of EKC patients during the pandemic period showed a decrease of 44.9% (t value = −7.23, p = 0.002). Comparing the pre-pandemic and pandemic periods by age group, we found there to be a significant decrease in the number of EKC patients for all age groups (−4.12≤t value≤−7.23, all P<0.05). This finding was most evident in the teenage group (62%) compared to the other age groups (decreases of 29 to 44%).

Conclusions

A continuing effort should be made to educate the public on basic infection prevention behaviors in the aftermath of the pandemic, particularly to teenagers.     

A comparison of clinical and epidemiological characteristics of fatal human infections with H5N1 and human influenza viruses in Thailand, 2004-2006

Background

The National Avian Influenza Surveillance (NAIS) system detected human H5N1 cases in Thailand from 2004–2006. Using NAIS data, we identified risk factors for death among H5N1 cases and described differences between H5N1 and human (seasonal) influenza cases.

Methods and Findings

NAIS identified 11,641 suspect H5N1 cases (e.g. persons with fever and respiratory symptoms or pneumonia, and exposure to sick or dead poultry). All suspect H5N1 cases were tested with polymerase chain reaction (PCR) assays for influenza A(H5N1) and human influenza viruses. NAIS detected 25 H5N1 and 2074 human influenza cases; 17 (68%) and 22 (1%) were fatal, respectively. We collected detailed information from medical records on all H5N1 cases, all fatal human influenza cases, and a sampled subset of 230 hospitalized non-fatal human influenza cases drawn from provinces with ≥1 H5N1 case or human influenza fatality.Fatal versus non-fatal H5N1 cases were more likely to present with low white blood cell (p = 0.05), lymphocyte (p<0.02), and platelet counts (p<0.01); have elevated liver enzymes (p = 0.05); and progress to circulatory (p<0.001) and respiratory failure (p<0.001). There were no differences in age, medical conditions, or antiviral treatment between fatal and non-fatal H5N1 cases. Compared to a sample of human influenza cases, all H5N1 cases had direct exposure to sick or dead birds (60% vs. 100%, p<0.05). Fatal H5N1 and fatal human influenza cases were similar clinically except that fatal H5N1 cases more commonly: had fever (p<0.001), vomiting (p<0.01), low white blood cell counts (p<0.01), received oseltamivir (71% vs. 23%, p<.001), but less often had ≥1 chronic medical conditions (p<0.001).

Conclusions

In the absence of diagnostic testing during an influenza A(H5N1) epizootic, a few epidemiologic, clinical, and laboratory findings might provide clues to help target H5N1 control efforts. Severe human influenza and H5N1 cases were clinically similar, and both would benefit from early antiviral treatment.     

An analysis of 332 fatalities infected with pandemic 2009 influenza A (H1N1) in Argentina

Background

The apparent high number of deaths in Argentina during the 2009 pandemic led to concern that the influenza A H1N1pdm disease was different there. We report the characteristics and risk factors for influenza A H1N1pdm fatalities.

Methods

We identified laboratory-confirmed influenza A H1N1pdm fatalities occurring during June-July 2009. Physicians abstracted data on age, sex, time of onset of illness, medical history, clinical presentation at admission, laboratory, treatment, and outcomes using standardize questionnaires. We explored the characteristics of fatalities according to their age and risk group.

Results

Of 332 influenza A H1N1pdm fatalities, 226 (68%) were among persons aged <50 years. Acute respiratory failure was the leading cause of death. Of all cases, 249 (75%) had at least one comorbidity as defined by Advisory Committee on Immunization Practices. Obesity was reported in 32% with data and chronic pulmonary disease in 28%. Among the 40 deaths in children aged <5 years, chronic pulmonary disease (42%) and neonatal pathologies (35%) were the most common co-morbidities. Twenty (6%) fatalities were among pregnant or postpartum women of which only 47% had diagnosed co-morbidities. Only 13% of patients received antiviral treatment within 48 hours of symptom onset. None of children aged <5 years or the pregnant women received antivirals within 48 h of symptom onset. As the pandemic progressed, the time from symptom-onset to medical care and to antiviral treatment decreased significantly among case-patients who subsequently died (p<0.001).

Conclusion

Persons with co-morbidities, pregnant and who received antivirals late were over-represented among influenza A H1N1pdm deaths in Argentina, though timeliness of antiviral treatment improved during the pandemic.     

Severe pandemic H1N1 2009 infection is associated with transient NK and T deficiency and aberrant CD8 responses

Background

It is unclear why the severity of influenza varies in healthy adults or why the burden of severe influenza shifts to young adults when pandemic strains emerge. One possibility is that cross-protective T cell responses wane in this age group in the absence of recent infection. We therefore compared the acute cellular immune response in previously healthy adults with severe versus mild pandemic H1N1 infection.

Methods and Principal Findings

49 previously healthy adults admitted to the National Hospital of Tropical Diseases, Viet Nam with RT-PCR-confirmed 2009 H1N1 infection were prospectively enrolled. 39 recovered quickly whereas 10 developed severe symptoms requiring supplemental oxygen and prolonged hospitalization. Peripheral blood lymphocyte subset counts and activation (HLADR, CD38) and differentiation (CD27, CD28) marker expression were determined on days 0, 2, 5, 10, 14 and 28 by flow cytometry. NK, CD4 and CD8 lymphopenia developed in 100%, 90% and 60% of severe cases versus 13% (p<0.001), 28%, (p = 0.001) and 18% (p = 0.014) of mild cases. CD4 and NK counts normalized following recovery. B cell counts were not significantly associated with severity. CD8 activation peaked 6–8 days after mild influenza onset, when 13% (6–22%) were HLADR+CD38+, and was accompanied by a significant loss of resting/CD27+CD28+ cells without accumulation of CD27+CD28− or CD27−CD28− cells. In severe influenza CD8 activation peaked more than 9 days post-onset, and/or was excessive (30–90% HLADR+CD38+) in association with accumulation of CD27+CD28− cells and maintenance of CD8 counts.

Conclusion

Severe influenza is associated with transient T and NK cell deficiency. CD8 phenotype changes during mild influenza are consistent with a rapidly resolving memory response whereas in severe influenza activation is either delayed or excessive, and partially differentiated cells accumulate within blood indicating that recruitment of effector cells to the lung could be impaired.     

Distinguishing characteristics between pandemic 2009-2010 influenza A (H1N1) and other viruses in patients hospitalized with respiratory illness

Background

Differences in clinical presentation and outcomes among patients infected with pandemic 2009 influenza A H1N1 (pH1N1) compared to other respiratory viruses have not been fully elucidated.

Methodology/Principal Findings

A retrospective study was performed of all hospitalized patients at the peak of the pH1N1 season in whom a single respiratory virus was detected by a molecular assay targeting 18 viruses/subtypes (RVP, Luminex xTAG). Fifty-two percent (615/1192) of patients from October, 2009 to December, 2009 had a single respiratory virus (291 pH1N1; 207 rhinovirus; 45 RSV A/B; 37 parainfluenza; 27 adenovirus; 6 coronavirus; and 2 metapneumovirus). No seasonal influenza A or B was detected. Individuals with pH1N1, compared to other viruses, were more likely to present with fever (92% & 70%), cough (92% & 86%), sore throat (32% & 16%), nausea (31% & 8%), vomiting (39% & 30%), abdominal pain (14% & 7%), and a lower white blood count (8,500/L & 13,600/L, all p-values<0.05). In patients with cough and gastrointestinal complaints, the presence of subjective fever/chills independently raised the likelihood of pH1N1 (OR 10). Fifty-five percent (336/615) of our cohort received antibacterial agents, 63% (385/615) received oseltamivir, and 41% (252/615) received steroids. The mortality rate of our cohort was 1% (7/615) and was higher in individuals with pH1N1 compared to other viruses (2.1% & 0.3%, respectively; p = 0.04).

Conclusions/Significance

During the peak pandemic 2009–2010 influenza season in Rhode Island, nearly half of patients admitted with influenza-like symptoms had respiratory viruses other than influenza A. A high proportion of patients were treated with antibiotics and pH1N1 infection had higher mortality compared to other respiratory viruses.     

Attitudes toward and uptake of H1N1 vaccine among health care workers during the 2009 H1N1 pandemic

Background

Though recommended by many and mandated by some, influenza vaccination rates among health care workers, even in pandemics, remain below optimal levels. The objective of this study was to assess vaccination uptake, attitudes, and distinguishing characteristics (including doctor-nurse differences) of health care workers who did and did not receive the pandemic H1N1 influenza vaccine in late 2009.

Methodology/Principal Findings

In early 2010 we mailed a self-administered survey to 800 physicians and 800 nurses currently licensed and practicing in Minnesota. 1,073 individuals responded (cooperation rate: 69%). 85% and 62% of Minnesota physicians and nurses, respectively, reported being vaccinated. Accurately estimating the risk of vaccine side effects (OR 2.0; 95% CI 1.5–2.7), agreeing with a professional obligation to be vaccinated (OR 10.1; 95% CI 7.1–14.2), an ethical obligation to follow public health authorities'' recommendations (OR 9.9; 95% CI 6.6–14.9), and laws mandating pandemic vaccination (OR 3.1; 95% CI 2.3–4.1) were all independently associated with receiving the H1N1 influenza vaccine.

Conclusions/Significance

While a majority of health care workers in one midwestern state reported receiving the pandemic H1N1 vaccine, physicians and nurses differed significantly in vaccination uptake. Several key attitudes and perceptions may influence health care workers'' decisions regarding vaccination. These data inform how states might optimally enlist health care workers'' support in achieving vaccination goals during a pandemic.     

Antiviral therapy and outcomes of patients with pneumonia caused by influenza A pandemic (H1N1) virus

Background

There is limited data on the clinical outcome of patients with pandemic H1N1 (pH1N1) pneumonia who received oseltamivir treatment, especially when the treatment was administered more than 48 hours after symptom onset.

Methods

During the pandemic in 2009, a cohort of pH1N1 influenza pneumonia was built in China, and their clinical information was collected systematically, and analyzed with Cox models.

Results

920 adults and 541 children with pneumonia who didn''t receive corticosteroids were analyzed. In-hospital mortality was higher in adults who did not receive antiviral therapy (18.2%) than those with who received oseltamivir ≤ 2days (2.9%), between 2–5 days (4.6%) and >5 days after illness onset (4.9%), p<0.01. A similar trend was observed in pediatric patients. Cox regression showed that at 60 days after symptoms onset, 11 patients (10.8%) who did not receive antivirals died versus 4 (1.8%), 18 (3.3%), and 23 (3.7%) patients whose oseltamivir treatment was started ≤ 2days, between 2–5days, and >5 days, respectively. For males patients, aged ≥ 14 years and baseline PaO₂/FiO₂<200, oseltamivir administration reduced the mortality risk by 92.1%, 88% and 83.5%, respectively. Higher doses of oseltamivir (>3.8 mg/kg/d) did not improve clinical outcome (mortality, higher dose 2.5% vs standard dose 2.8%, p>0.05).

Conclusions

Antiviral therapy might reduce mortality of patients with pH1N1 pneumonia, even when initiated more than 48 hours after onset of illness. Greater protective effects might be in males, patients aged 14–60 years, and patients with PaO₂/FiO₂<200.     

Dynamic patterns of circulating seasonal and pandemic A(H1N1)pdm09 influenza viruses from 2007-2010 in and around Delhi, India

Influenza surveillance was carried out in a subset of patients with influenza-like illness (ILI) presenting at an Employee Health Clinic (EHS) at All India Institute of Medical Sciences (AIIMS), New Delhi (urban) and pediatric out patients department of civil hospital at Ballabhgarh (peri-urban), under the Comprehensive Rural Health Services Project (CRHSP) of AIIMS, in Delhi region from January 2007 to December 2010. Of the 3264 samples tested, 541 (17%) were positive for influenza viruses, of which 221 (41%) were pandemic Influenza A(H1N1)pdm09, 168 (31%) were seasonal influenza A, and 152 (28%) were influenza B. While the Influenza viruses were detected year-round, their types/subtypes varied remarkably. While there was an equal distribution of seasonal A(H1N1) and influenza B in 2007, predominance of influenza B was observed in 2008. At the beginning of 2009, circulation of influenza A(H3N2) viruses was observed, followed later by emergence of Influenza A(H1N1)pdm09 with co-circulation of influenza B viruses. Influenza B was dominant subtype in early 2010, with second wave of Influenza A(H1N1)pdm09 in August-September, 2010. With the exception of pandemic H1N1 emergence in 2009, the peaks of influenza activity coincided primarily with monsoon season, followed by minor peak in winter at both urban and rural sites. Age group analysis of influenza positivity revealed that the percent positivity of Influenza A(H1N1)pdm09 influenza virus was highest in >5–18 years age groups (OR 2.5; CI = 1.2–5.0; p = 0.009) when compared to seasonal influenza. Phylogenetic analysis of Influenza A(H1N1)pdm09 from urban and rural sites did not reveal any major divergence from other Indian strains or viruses circulating worldwide. Continued surveillance globally will help define regional differences in influenza seasonality, as well as, to determine optimal periods to implement influenza vaccination programs among priority populations.     

Minor changes in the hemagglutinin of influenza A(H1N1)2009 virus alter its antigenic properties

Background

The influenza A(H1N1)2009 virus has been the dominant type of influenza A virus in Finland during the 2009–2010 and 2010–2011 epidemic seasons. We analyzed the antigenic characteristics of several influenza A(H1N1)2009 viruses isolated during the two influenza seasons by analyzing the amino acid sequences of the hemagglutinin (HA), modeling the amino acid changes in the HA structure and measuring antibody responses induced by natural infection or influenza vaccination.

Methods/Results

Based on the HA sequences of influenza A(H1N1)2009 viruses we selected 13 different strains for antigenic characterization. The analysis included the vaccine virus, A/California/07/2009 and multiple California-like isolates from 2009–2010 and 2010–2011 epidemic seasons. These viruses had two to five amino acid changes in their HA1 molecule. The mutation(s) were located in antigenic sites Sa, Ca1, Ca2 and Cb region. Analysis of the antibody levels by hemagglutination inhibition test (HI) indicated that vaccinated individuals and people who had experienced a natural influenza A(H1N1)2009 virus infection showed good immune responses against the vaccine virus and most of the wild-type viruses. However, one to two amino acid changes in the antigenic site Sa dramatically affected the ability of antibodies to recognize these viruses. In contrast, the tested viruses were indistinguishable in regard to antibody recognition by the sera from elderly individuals who had been exposed to the Spanish influenza or its descendant viruses during the early 20^th century.

Conclusions

According to our results, one to two amino acid changes (N125D and/or N156K) in the major antigenic sites of the hemagglutinin of influenza A(H1N1)2009 virus may lead to significant reduction in the ability of patient and vaccine sera to recognize A(H1N1)2009 viruses.     

Effectiveness of the AS03-adjuvanted vaccine against pandemic influenza virus A/(H1N1) 2009--a comparison of two methods; Germany, 2009/10

During the autumn wave of the pandemic influenza virus A/(H1N1) 2009 (pIV) the German population was offered an AS03-adjuvanted vaccine. The authors compared results of two methods calculating the effectiveness of the vaccine (VE). The test-negative case-control method used data from virologic surveillance including influenza-positive and negative patients. An innovative case-series methodology explored data from all nationally reported laboratory-confirmed influenza cases. The proportion of reported cases occurring in vaccinees during an assumed unprotected phase after vaccination was compared with that occurring in vaccinees during their assumed protected phase. The test-negative case-control method included 1,749 pIV cases and 2,087 influenza test-negative individuals of whom 6 (0.3%) and 36 (1.7%), respectively, were vaccinated. The case series method included data from 73,280 cases. VE in the two methods was 79% (95% confidence interval (CI) = 35–93%; P = 0.007) and 87% (95% CI = 78–92%; P<0.001) for individuals less than 14 years of age and 70% (95% CI = −45%–94%, P = 0.13) and 74% (95% CI = 64–82%; P<0.001) for individuals above the age of 14. Both methods yielded similar VE in both age groups; and VE for the younger age group seemed to be higher.     

Detection of resistance mutations to antivirals oseltamivir and zanamivir in avian influenza A viruses isolated from wild birds

The neuraminidase (NA) inhibitors oseltamivir and zanamivir are the first-line of defense against potentially fatal variants of influenza A pandemic strains. However, if resistant virus strains start to arise easily or at a high frequency, a new anti-influenza strategy will be necessary. This study aimed to investigate if and to what extent NA inhibitor–resistant mutants exist in the wild population of influenza A viruses that inhabit wild birds. NA sequences of all NA subtypes available from 5490 avian, 379 swine and 122 environmental isolates were extracted from NCBI databases. In addition, a dataset containing 230 virus isolates from mallard collected at Ottenby Bird Observatory (Öland, Sweden) was analyzed. Isolated NA RNA fragments from Ottenby were transformed to cDNA by RT-PCR, which was followed by sequencing. The analysis of genotypic profiles for NAs from both data sets in regard to antiviral resistance mutations was performed using bioinformatics tools. All 6221 sequences were scanned for oseltamivir- (I117V, E119V, D198N, I222V, H274Y, R292K, N294S and I314V) and zanamivir-related mutations (V116A, R118K, E119G/A/D, Q136K, D151E, R152K, R224K, E276D, R292K and R371K). Of the sequences from the avian NCBI dataset, 132 (2.4%) carried at least one, or in two cases even two and three, NA inhibitor resistance mutations. Swine and environmental isolates from the same data set had 18 (4.75%) and one (0.82%) mutant, respectively, with at least one mutation. The Ottenby sequences carried at least one mutation in 15 cases (6.52%). Therefore, resistant strains were more frequently found in Ottenby samples than in NCBI data sets. However, it is still uncertain if these mutations are the result of natural variations in the viruses or if they are induced by the selective pressure of xenobiotics (e.g., oseltamivir, zanamivir).     

Safety and reactogenicity of canarypox ALVAC-HIV (vCP1521) and HIV-1 gp120 AIDSVAX B/E vaccination in an efficacy trial in Thailand

Background

A prime-boost vaccination regimen with ALVAC-HIV (vCP1521) administered intramuscularly at 0, 4, 12, and 24 weeks and gp120 AIDSVAX B/E at 12 and 24 weeks demonstrated modest efficacy of 31.2% for prevention of HIV acquisition in HIV-uninfected adults participating in a community-based efficacy trial in Thailand.

Methodology/Principal Findings

Reactogenicity was recorded for 3 days following vaccination. Adverse events were monitored every 6 months for 3.5 years, during which pregnancy outcomes were recorded. Of the 16,402 volunteers, 69% of the participants reported an adverse event any time after the first dose. Only 32.9% experienced an AE within 30 days following any vaccination. Overall adverse event rates and attribution of relatedness did not differ between groups. The frequency of serious adverse events was similar in vaccine (14.3%) and placebo (14.9%) recipients (p = 0.33). None of the 160 deaths (85 in vaccine and 75 in placebo recipients, p = 0.43) was assessed as related to vaccine. The most common cause of death was trauma or traffic accident. Approximately 30% of female participants reported a pregnancy during the study. Abnormal pregnancy outcomes were experienced in 17.1% of vaccine and 14.6% (p = 0.13) of placebo recipients. When the conception occurred within 3 months (estimated) of a vaccination, the majority of these abnormal outcomes were spontaneous or elective abortions among 22.2% and 15.3% of vaccine and placebo pregnant recipients, respectively (p = 0.08). Local reactions occurred in 88.0% of vaccine and 61.0% of placebo recipients (p<0.001) and were more frequent after ALVAC-HIV than AIDSVAX B/E vaccination. Systemic reactions were more frequent in vaccine than placebo recipients (77.2% vs. 59.8%, p<0.001). Local and systemic reactions were mostly mild to moderate, resolving within 3 days.

Conclusions/Significance

The ALVAC-HIV and AIDSVAX B/E vaccine regimen was found to be safe, well tolerated and suitable for potential large-scale use in Thailand.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00223080","term_id":"NCT00223080"}}NCT00223080     

Field effectiveness of pandemic and 2009-2010 seasonal vaccines against 2009-2010 A(H1N1) influenza: estimations from surveillance data in France

Background

In this study, we assess how effective pandemic and trivalent 2009-2010 seasonal vaccines were in preventing influenza-like illness (ILI) during the 2009 A(H1N1) pandemic in France. We also compare vaccine effectiveness against ILI versus laboratory-confirmed pandemic A(H1N1) influenza, and assess the possible bias caused by using non-specific endpoints and observational data.

Methodology and Principal Findings

We estimated vaccine effectiveness by using the following formula: VE  =  (PPV-PCV)/(PPV(1-PCV)) × 100%, where PPV is the proportion vaccinated in the population and PCV the proportion of vaccinated influenza cases. People were considered vaccinated three weeks after receiving a dose of vaccine. ILI and pandemic A(H1N1) laboratory-confirmed cases were obtained from two surveillance networks of general practitioners. During the epidemic, 99.7% of influenza isolates were pandemic A(H1N1). Pandemic and seasonal vaccine uptakes in the population were obtained from the National Health Insurance database and by telephonic surveys, respectively. Effectiveness estimates were adjusted by age and week. The presence of residual biases was explored by calculating vaccine effectiveness after the influenza period. The effectiveness of pandemic vaccines in preventing ILI was 52% (95% confidence interval: 30–69) during the pandemic and 33% (4–55) after. It was 86% (56–98) against confirmed influenza. The effectiveness of seasonal vaccines against ILI was 61% (56–66) during the pandemic and 19% (−10–41) after. It was 60% (41–74) against confirmed influenza.

Conclusions

The effectiveness of pandemic vaccines in preventing confirmed pandemic A(H1N1) influenza on the field was high, consistently with published findings. It was significantly lower against ILI. This is unsurprising since not all ILI cases are caused by influenza. Trivalent 2009-2010 seasonal vaccines had a statistically significant effectiveness in preventing ILI and confirmed pandemic influenza, but were not better in preventing confirmed pandemic influenza than in preventing ILI. This lack of difference might be indicative of selection bias.     

Optimizing vaccine allocation at different points in time during an epidemic

Background

Pandemic influenza A(H1N1) 2009 began spreading around the globe in April of 2009 and vaccination started in October of 2009. In most countries, by the time vaccination started, the second wave of pandemic H1N1 2009 was already under way. With limited supplies of vaccine, we are left to question whether it may be a good strategy to vaccinate the high-transmission groups earlier in the epidemic, but it might be a better use of resources to protect instead the high-risk groups later in the epidemic. To answer this question, we develop a deterministic epidemic model with two age-groups (children and adults) and further subdivide each age group in low and high risk.

Methods and Findings

We compare optimal vaccination strategies started at various points in time in two different settings: a population in a developed country where children account for 24% of the population, and a population in a less developed country where children make up the majority of the population, 55%. For each of these populations, we minimize mortality or hospitalizations and we find an optimal vaccination strategy that gives the best vaccine allocation given a starting vaccination time and vaccine coverage level. We find that population structure is an important factor in determining the optimal vaccine distribution. Moreover, the optimal policy is dynamic as there is a switch in the optimal vaccination strategy at some time point just before the peak of the epidemic. For instance, with 25% vaccine coverage, it is better to protect the high-transmission groups before this point, but it is optimal to protect the most vulnerable groups afterward.

Conclusions

Choosing the optimal strategy before or early in the epidemic makes an important difference in minimizing the number of influenza infections, and consequently the number of influenza deaths or hospitalizations, but the optimal strategy makes little difference after the peak.