Reference viruses for seasonal and pandemic influenza vaccine preparation

The production of seasonal and pandemic influenza vaccines depends on the timely availability of suitable reference viruses. Seasonal vaccines are traditionally produced from high‐growth reassortant viruses, which have been derived empirically using well‐established techniques. However, it is not possible to use such approaches in deriving vaccine reference viruses from highly pathogenic H5N1 viruses and alternative techniques such as reverse genetics must be employed.     

HIV virological suppression influences response to the AS03‐adjuvanted monovalent pandemic influenza A H1N1 vaccine in HIV‐infected children

Design

Children with HIV are especially susceptible to complications from influenza infection, and effective vaccines are central to reducing disease burden in this population. We undertook a prospective, observational study to investigate the safety and immunogenicity of the inactivated split-virion AS03-adjuvanted pandemic H1N1(2009) vaccine in children with HIV.

Setting

National referral centre for Paediatric HIV in Ireland.

Sample

Twenty four children with HIV were recruited consecutively and received two doses of the vaccine. The serological response was measured before each vaccine dose (Day 0 and Day 28) and 2 months after the booster dose. Antibody titres were measured using a haemagglutination inhibition (HAI) assay. Seroprotection was defined as a HAI titre ≥ 1:40; seroconversion was defined as a ≥ fourfold increase in antibody titre and a postvaccination titre ≥ 1:40.

Main outcome measures

The seroconversion rates after prime and booster doses were 75% and 71%, respectively. HIV virological suppression at the time of immunization was associated with a significantly increased seroconversion rate (P = 0·009), magnitude of serological response (P = 0·02) and presence of seroprotective HAI titres (P = 0·017) two months after the booster dose. No other factor was significantly associated with the seroconversion/seroprotection rate. No serious adverse effects were reported. Vaccination had no impact on HIV disease progression. The AS03-adjuvanted pandemic H1N1 vaccine appears to be safe and immunogenic among HIV-infected children. A robust serological response appears to be optimized by adherence to a HAART regimen delivering virological suppression.     

Statistical estimates of respiratory admissions attributable to seasonal and pandemic influenza for Canada

Please cite this paper as: Schanzer et al. (2012) Statistical estimates of respiratory admissions attributable to seasonal and pandemic influenza for Canada. Influenza and Other Respiratory Viruses DOI: 10.1111/irv.12011. Background  The number of admissions to hospital for which influenza is laboratory confirmed is considered to be a substantial underestimate of the true number of admissions due to an influenza infection. During the 2009 pandemic, testing for influenza in hospitalized patients was a priority, but the ascertainment rate remains uncertain. Methods  The discharge abstracts of persons admitted with any respiratory condition were extracted from the Canadian Discharge Abstract Database, for April 2003–March 2010. Stratified, weekly admissions were modeled as a function of viral activity, seasonality, and trend using Poisson regression models. Results  An estimated 1 out of every 6·4 admissions attributable to seasonal influenza (2003–April 2009) were coded to J10 (influenza virus identified). During the 2009 pandemic (May–March 2010), the influenza virus was identified in 1 of 1·6 admissions (95% CI, 1·5–1·7) attributed to the pandemic strain. Compared with previous H1N1 seasons (2007/08, 2008/09), the influenza‐attributed hospitalization rate for persons <65 years was approximately six times higher during the 2009 H1N1 pandemic, whereas for persons 75 years or older, the pandemic rate was approximately fivefold lower. Conclusions  Case ascertainment was much improved during the pandemic period, with under ascertainment of admissions due to H1N1/2009 limited primarily to patients with a diagnosis of pneumonia.     

The 1918 influenza pandemic in New York City: age‐specific timing,mortality, and transmission dynamics

Background

The 1918 influenza pandemic caused disproportionately high mortality among certain age groups. The mechanisms underlying these differences are not fully understood.

Objectives

To explore the dynamics of the 1918 pandemic and to identify potential age-specific transmission patterns.

Methods

We examined 1915–1923 daily mortality data in New York City (NYC) and estimated the outbreak duration and initial effective reproductive number (R_e) for each 1-year age cohort.

Results

Four pandemic waves occurred from February 1918 to April 1920. The fractional mortality increase (i.e. ratio of excess mortality to baseline mortality) was highest among teenagers during the first wave. This peak shifted to 25- to 29-year-olds in subsequent waves. The distribution of age-specific mortality during the last three waves was strongly correlated (r = 0·94 and 0·86). With each wave, the pandemic appeared to spread with a comparable early growth rate but then attenuate with varying rates. For the entire population, R_e estimates made assuming 2-day serial interval were 1·74 (1·27), 1·74 (1·43), 1·66 (1·25), and 1·86 (1·37), respectively, during the first week (first 3 weeks) of each wave. Using age-specific mortality, the average R_e estimates over the first week of each wave were 1·62 (95% CI: 1·55–1·68), 1·68 (1·65–1·72), 1·67 (1·61–1·73), and 1·69 (1·63–1·74), respectively; R_e was not significantly different either among age cohorts or between waves.

Conclusions

The pandemic generally caused higher mortality among young adults and might have spread mainly among school-aged children during the first wave. We propose mechanisms to explain the timing and transmission dynamics of the four NYC pandemic waves.     

Risk factors for death from pandemic influenza in 1918–1919: a case–control study

Background

Despite the persisting threat from future influenza pandemics, much is still unknown about the risk factors for death from such events, and especially for the 1918–1919 influenza pandemic.

Methods

A case–control study was performed to explore possible risk factors for death from pandemic influenza among New Zealand military personnel in the Northern Hemisphere in 1918–1919 (n = 218 cases, n = 221 controls). Data were compiled from a Roll-of-Honour dataset, a dataset of nearly all military personnel involved in the war and archived individual records.

Results

In the fully adjusted multivariable model, the following were significantly associated with increased risk of death from pandemic influenza: age (25–29 years), pre-pandemic hospitalisations for a chronic condition (e.g. tuberculosis), relatively early year of military deployment, a relatively short time from enlistment to foreign service, and having a larger chest size (e.g. adjusted odds ratio for 90–99 cm versus <90 cm was 2·45; 95% CI=1·47–4·10). There were no significant associations in the fully adjusted model with military rank, occupational class at enlistment, and rurality at enlistment.

Conclusions

This is one of the first published case–control studies of mortality risk factors for the 1918–1919 influenza pandemic. Some of the findings are consistent with previous research on risk factors (such as chronic conditions and age groups), but others appear more novel (e.g., larger chest size). As all such historical analyses have limitations, there is a need for additional studies in other settings as archival World War One records become digitalised.     

Phase II,randomized, open,controlled study of AS03‐adjuvanted H5N1 pre‐pandemic influenza vaccine in children aged 3 to 9 years: follow‐up of safety and immunogenicity persistence at 24 months post‐vaccination

Background

An AS03-adjuvanted H5N1 influenza vaccine elicited broad and persistent immune responses with an acceptable safety profile up to 6 months following the first vaccination in children aged 3–9 years.

Methods

In this follow-up of the Phase II study, we report immunogenicity persistence and safety at 24 months post-vaccination in children aged 3–9 years. The randomized, open-label study assessed two doses of H5N1 A/Vietnam/1194/2004 influenza vaccine (1·9 μg or 3·75 μg hemagglutinin antigen) formulated with AS03_A or AS03_B (11·89 mg or 5·93 mg tocopherol, respectively). Control groups received seasonal trivalent influenza vaccine. Safety was assessed prospectively and included potential immune-mediated diseases (pIMDs). Immunogenicity was assessed by hemagglutination-inhibition assay 12 and 24 months after vaccination; cross-reactivity and cell-mediated responses were also assessed. ({"type":"clinical-trial","attrs":{"text":"NCT00502593","term_id":"NCT00502593"}}NCT00502593).

Results

The safety population included 405 children. Over 24 months, five events fulfilled the criteria for pIMDs, of which four occurred in H5N1 vaccine recipients, including uveitis (n = 1) and autoimmune hepatitis (n = 1), which were considered to be vaccine-related. Overall, safety profiles of the vaccines were clinically acceptable. Humoral immune responses at 12 and 24 months were reduced versus those observed after the second dose of vaccine, although still within the range of those observed after the first dose. Persistence of cell-mediated immunity was strong, and CD4⁺ T cells with a T_H1 profile were observed.

Conclusions

Two doses of an AS03-adjuvanted H5N1 influenza vaccine in children showed low but persistent humoral immune responses and a strong persistence of cell-mediated immunity, with clinically acceptable safety profiles up to 24 months following first vaccination.     

The PFA‐100®: a potential rapid screening tool for the assessment of platelet dysfunction

The PFA‐100^® is a device that simulates high shear dependent platelet function in vitro and thus is particularly useful for screening for von Willebrand's disease (VWD). The aim of this study was to assess the overall potential of the PFA‐100^® as a primary clinical screening tool using the wide spectrum of clinical samples assessed for platelet function within our institution. The PFA‐100^® test was performed using both collagen/ADP (CADP) and collagen/epinephrine (CEPI) cartridges on samples from 337 patients with a wide variety of haemostatic defects. One hundred and eighty‐two patients were defined as having normal platelet function based on classical laboratory tests and von Willebrand factor levels. The overall clinical sensitivity of the PFA‐100^® for platelet abnormalities (including VWD) was 81% for CADP and 86% for CEPI. The overall specificity was found to be 82% for CADP and 80% for CEPI. When utilizing both cartridges in combination (with both results either higher or lower than the upper cutoff of the normal ranges), the overall false positive and false negative rates were 12% and 6%, respectively. The PFA‐100^® proved to be sensitive in detecting classical defects by giving prolonged closure times in samples from patients with major platelet function defects (e.g. von Willebrand's disease, Glanzmann's thrombasthenia and Bernard Soulier syndrome). However, there were a small number of false negative results (6%) obtained with various milder platelet defects (e.g. Hermansky Pudlak syndrome, storage pool and release defects, type I VWD and macrothrombocytopenia). The PFA‐100^® test provides a useful rapid screening tool and should increase the efficiency and reduce the cost of the routine diagnosis of platelet dysfunction.     

Safety and tolerability of a 6‐week course of oseltamivir prophylaxis for seasonal influenza in children

Please cite this paper as: Reisinger et al. Safety and tolerability of a 6‐week course of oseltamivir prophylaxis for seasonal influenza in children. Influenza and Other Respiratory Viruses DOI: 10.1111/j.1750‐2659.2012.00367.x. In an open‐label study, 49 children aged 1–12 years received oseltamivir (30–75 mg once daily depending on bodyweight) for 6 weeks for influenza prophylaxis. Seventeen participants reported 22 adverse events (AEs); in three participants, AEs were considered probably drug related (nausea or vomiting). No serious AEs were reported. The tolerability profile was similar to pooled safety data from treatment studies (duration of 5 days) in children.     

Preventable and non‐preventable risk factors for influenza transmission and hygiene behavior in German influenza households,pandemic season (H1N1) 2009/2010

Background To date, little is known about the role of behavioral risk factors for influenza transmission as well as hygiene behavior in the household setting during the influenza pandemic (H1N1) 2009. In a household‐based study conducted during 2008/2009, we identified several behavioral risk factors for influenza transmission; 30% of index patients and 30% of household contacts reported increased hand cleaning frequency in the week after symptom onset of the index patient. We conducted another household‐based study during the pandemic season 2009/2010. Methods We identified index patients with laboratory confirmed influenza infection and interviewed household members after illness day 8 of the index patient. Outcome was influenza‐like illness (ILI) in a household contact. Results We included 108 households. Overall secondary attack rate was 10·1% (27/267) and decreased with increasing age. Apart from being in close daily proximity with the index patient for at least 9 hours, no other behavioral risk factor was associated with secondary ILI. Of all index patients and household contacts, 49% and 55%, respectively, cleaned their hands more often in the week after symptom onset of the index patient (in comparison with 2008/2009 P‐value for both <0·01). Conclusions While the study was hampered by its relatively limited size, data suggest that a significantly larger proportion of influenza households practiced good hand hygiene compared to the last pre‐pandemic season. This may have led to a different risk factor profile and a delay of the time threshold necessary for transmission among household members with close contact.     

The influenza pandemic of 1918–1919 in Sri Lanka: its demographic cost,timing, and propagation

Background

As an island and a former British colony, Sri Lanka is a case of special interest for the study of 1918–1919 influenza pandemic because of its potential for isolation from as well as integration into the world epidemiologic system.

Objectives

To estimate population loss attributable to the influenza pandemic and weekly district-level excess mortality from the pandemic to analyze its spread across the island.

Methods

To measure population loss, we estimated a population growth model using a panel of 100 district-level observations on population for five consecutive censuses from 1891 to 1931, allowing for a one-time drop in population in 1918–1919. To estimate weekly excess mortality from the pandemic, we estimated a seasonally adjusted weekly time series of district-specific mortality estimates from vital registration records, ranked them, and plotted the ranks on weekly maps to create a picture of the geographic pattern of propagation across Sri Lanka.

Results

Total loss of population from the influenza pandemic was 307 000 or approximately 6·7% of the population. The pandemic peaked in two discrete (northern and southern) regions in early October of 1918 and in a third (central) region in early March 1919.

Conclusions

The population loss estimate is significantly higher than earlier estimates of mortality from the pandemic in Sri Lanka, suggesting underreporting of influenza-attributable deaths and a role for influenza-related fertility declines. The spatial pattern of peak mortality indicates the presence of two distinct entry points and three distinct epidemiologic regions, defined by population density and ethnicity, in colonial Sri Lanka.     

Genetic characterization of seasonal influenza A (H3N2) viruses in Ontario during 2010–2011 influenza season: high prevalence of mutations at antigenic sites

Background

The direct effect of antigenic site mutations in influenza viruses on antigenic drift and vaccine effectiveness is poorly understood.

Objective

To investigate the genetic and antigenic characteristics of human influenza A (H3N2) viruses circulating in Ontario during the early 2010–2011 winter season.

Study design

We sequenced the hemagglutinin (HA) and neuraminidase (NA) genes from 41 A(H3N2) viruses detected in nasopharyngeal specimens. Strain typing was performed by hemagglutination inhibition (HI) assay. Molecular and phylogenetic tree analyses were conducted.

Results

HA and NA genes showed high similarity to the 2010–2011 vaccine strain, A/Perth/16/2009 (H3N2)-like virus (97·7–98·5% and 98·7–99·5% amino acid (AA) identity, respectively). Compared to A/Perth/16/2009 strain, HA gene mutations were documented at 28 different AA positions across all five H3 antigenic sites, with a range of 5–11 mutations in individual viruses. Thirty-six (88%) viruses had 8 AA substitutions in common; none of these had reduced HI titer. Among Ontario isolates, 11 antigenic site AAs were positively selected with an increase in glycosylation sites.

Conclusion

The presence of antigenic site mutations with high frequency among 2010–2011 influenza H3N2 isolates confirms ongoing adaptive H3N2 evolution. These may represent early phylogenetic changes that could cause antigenic drift with further mutations. Clinical relevance of antigenic site mutations not causing drift in HI assays is unknown and requires further investigation. In addition, viral sequencing information will assist with vaccine strain planning and may facilitate early detection of vaccine escape.     

Modified vaccinia virus Ankara expressing the hemagglutinin of pandemic (H1N1) 2009 virus induces cross‐protective immunity against Eurasian ‘avian‐like’ H1N1 swine viruses in mice

Objectives

To examine cross-reactivity between hemagglutinin (HA) derived from A/California/7/09 (CA/09) virus and that derived from representative Eurasian “avian-like” (EA) H1N1 swine viruses isolated in Italy between 1999 and 2008 during virological surveillance in pigs.

Design

Modified vaccinia virus Ankara (MVA) expressing the HA gene of CA/09 virus (MVA-HA-CA/09) was used as a vaccine to investigate cross-protective immunity against H1N1 swine viruses in mice.

Sample

Two classical swine H1N1 (CS) viruses and four representative EA-like H1N1 swine viruses previously isolated during outbreaks of respiratory disease in pigs on farms in Northern Italy were used in this study.

Setting

Female C57BL/6 mice were vaccinated with MVA/HA/CA/09 and then challenged intranasally with H1N1 swine viruses.

Main outcome measures

Cross-reactive antibody responses were determined by hemagglutination- inhibition (HI) and virus microneutralizing (MN) assays of sera from MVA-vaccinated mice. The extent of protective immunity against infection with H1N1 swine viruses was determined by measuring lung viral load on days 2 and 4 post-challenge.

Results and Conclusions

Systemic immunization of mice with CA/09-derived HA, vectored by MVA, elicited cross-protective immunity against recent EA-like swine viruses. This immune protection was related to the levels of cross-reactive HI antibodies in the sera of the immunized mice and was dependent on the similarity of the antigenic site Sa of H1 HAs. Our findings suggest that the herd immunity elicited in humans by the pandemic (H1N1) 2009 virus could limit the transmission of recent EA-like swine HA genes into the influenza A virus gene pool in humans.     

Laboratory detection of strongyloidiasis: IgG‐, IgG4‐ and IgE‐ELISAs and cross‐reactivity with lymphatic filariasis

Enzyme‐linked immunosorbent assays (ELISAs) were developed for the detection of IgG, IgG₄ and IgE antibodies against Strongyloides stercoralis. A commercial ELISA (IVD Research, USA) was also used, and the sensitivities and specificities of the four assays were determined. Serum samples from 26 patients with S. stercoralis infection and 55 patients with other infections or no infection were analysed. Sensitivities of the IgG₄, IgG, IgE and IgG (IVD) assays were 76·9%, 84·6%, 7·7% and 84·6%, respectively, while the specificities were 92·7%, 81·8%, 100% and 83·6%, respectively. If filariasis samples were excluded, the specificities of the IgG₄‐ELISA and both IgG‐ELISAs increased to 100% and 98%, respectively. A significant positive correlation was observed between IgG‐ and IgG₄‐ELISAs (r = 0·4828; P = 0·0125). IgG‐ and IgG‐ (IVD) ELISAs (r = 0·309) were positively correlated, but was not significant (P = 0·124). Meanwhile there was no correlation between IgG₄‐ and IgG‐ (IVD) ELISAs (r = 0·0042; P = 0·8294). Sera from brugian filariasis patients showed weak, positive correlation between the titres of antifilarial IgG₄ and the optical densities of anti‐Strongyloides IgG₄‐ELISA (r = 0·4544, P = 0·0294). In conclusion, the detection of both anti‐Strongyloides IgG₄ and IgG antibodies could improve the serodiagnosis of human strongyloidiasis. Furthermore, patients from lymphatic filariasis endemic areas who are serologically diagnosed with strongyloidiasis should also be tested for filariasis.