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.     

Simple models to include influenza vaccination history when evaluating the effect of influenza vaccination

BackgroundMost reports of influenza vaccine effectiveness consider current-season vaccination only.AimWe evaluated a method to estimate the effect of influenza vaccinations (EIV) considering vaccination history.MethodsWe used a test-negative design with well-documented vaccination history to evaluate the average EIV over eight influenza seasons (2011/12–2018/19; n = 10,356). Modifying effect was considered as difference in effects of vaccination in current and previous seasons and current-season vaccination only. We also explored differences between current-season estimates excluding from the reference category people vaccinated in any of the five previous seasons and estimates without this exclusion or only for one or three previous seasons.ResultsThe EIV was 50%, 45% and 38% in people vaccinated in the current season who had previously received none, one to two and three to five doses, respectively, and it was 30% and 43% for one to two and three to five prior doses only. Vaccination in at least three previous seasons reduced the effect of current-season vaccination by 12 percentage points overall, 31 among outpatients, 22 in 9–65 year-olds, and 23 against influenza B. Including people vaccinated in previous seasons only in the unvaccinated category underestimated EIV by 9 percentage points on average (31% vs 40%). Estimates considering vaccination of three or five previous seasons were similar.ConclusionsVaccine effectiveness studies should consider influenza vaccination in previous seasons, as it can retain effect and is often an effect modifier. Vaccination status in three categories (current season, previous seasons only, unvaccinated) reflects the whole EIV.     

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.     

MF59®‐adjuvanted vaccines for seasonal and pandemic influenza prophylaxis

Abstract Influenza is a major cause of worldwide morbidity and mortality through frequent seasonal epidemics and infrequent pandemics. Morbidity and mortality rates from seasonal influenza are highest in the most frail, such as the elderly, those with underlying chronic conditions and very young children. Antigenic mismatch between strains recommended for vaccine formulation and circulating viruses can further reduce vaccine efficacy in these populations. Seasonal influenza vaccines with enhanced, cross‐reactive immunogenicity are needed to address these problems and can confer a better immune protection, particularly in seasons were antigenic mismatch occurs. A related issue for vaccine development is the growing threat of pandemic influenza caused by H5N1 avian strains. Vaccines against strains with pandemic potential offer the best approach for reducing the potential impact of a pandemic. However, current non‐adjuvanted pre‐pandemic vaccines offer suboptimal immunogenicity against H5N1. For both seasonal and pre‐pandemic vaccines, the addition of adjuvants may be the best approach for providing enhanced cross‐reactive immunogenicity. MF59^®, the first oil‐in‐water emulsion licensed as an adjuvant for human use, can enhance vaccine immune responses through multiple mechanisms. A trivalent MF59‐adjuvanted seasonal influenza vaccine (Fluad^®) has shown to induce significantly higher immune responses to influenza vaccination in the elderly, compared with non‐adjuvanted vaccines, and to provide cross‐reactive immunity against divergent influenza strains. Similar results have been generated with a MF59‐adjuvanted H5N1 pre‐pandemic vaccine, which showed higher and broader immunogenicity compared with non‐adjuvanted pre‐pandemic vaccines.     

A vaccine manufacturer’s approach to address medical needs related to seasonal and pandemic influenza viruses

Abstract Vaccination is considered to be one of the most effective tools to decrease morbidity as well as mortality caused by influenza viruses.For the prevention of seasonal influenza, Fluarix ™ and FluLaval™ have been marketed since 1987 and 1992, respectively. Both vaccines have consistently been shown to meet or exceed the regulatory criteria for immunogenicity against the three strains H1N1, H3N2 and B, have a good safety profile, and are recommended for vaccinating children and adults of all ages.For the prevention of pandemic influenza, GlaxoSmithKline (GSK) has obtained licensure of a pre‐pandemic vaccine, Prepandrix ™. This split‐virus H5N1 adjuvanted with AS03, a proprietary oil‐in‐water emulsion‐based adjuvant system, has demonstrated broad immunity against drifted H5N1 strains and has been shown to be effective in preventing mortality and viral shedding in animal studies.The influenza vaccine portfolio of GSK addresses specific medical needs related to seasonal or pandemic influenza viruses, which remain an important public health threat worldwide.     

Seroprevalence of pandemic (H1N1) 2009 influenza and effectiveness of 2010/2011 influenza vaccine during 2010/2011 season in Beijing, China

Please cite this paper as: Yang et al. (2011) Seroprevalence of pandemic (H1N1) 2009 influenza and effectiveness of 2010/2011 influenza vaccine during 2010/2011 season in Beijing, China. Influenza and Other Respiratory Viruses 6(6), 381–388. Background In the post‐pandemic period, pandemic (H1N1) 2009 virus was expected to circulate seasonally and was introduced into trivalent influenza vaccine during 2010/2011 season in the Northern Hemisphere. Objectives The aim of this study was to examine the evolution of herd immunity against pandemic (H1N1) 2009 virus in Beijing, China, during 2010/2011 season and effectiveness of the 2010/2011 trivalent vaccine. Methods Two serological surveys were conducted before and after 2010/2011 season in Beijing. A case–control study was used to investigate vaccine effectiveness against influenza‐like illness (ILI) and lower respiratory tract infection (LRI). Results A total of 4509 and 4543 subjects participated in the pre‐ and post‐season surveys, respectively. The standardized seroprevalence of pandemic (H1N1) 2009 influenza increased from 22·1% pre‐season to 24·3% post‐season (P < 0·001). Significant elevation in seroprevalence appeared in the ≥60 years age‐group (P < 0·001), but not in others. The 2010/2011 trivalent vaccine contributed to the higher post‐seasonal seroprevalence in unvaccinated individuals (P = 0·024), but not in those vaccinated with monovalent pandemic vaccine (P = 0·205), as well as in those without prior immunity versus those with immunity. The adjusted effectiveness of the 2010/2011 trivalent vaccine was 79% protection against ILI (95% CI, 61–89%) and 95% against LRI (95% CI: 59–99%). Conclusions A slight increase in herd immunity against pandemic (H1N1) 2009 influenza was observed in Beijing, China, during the 2010/2011 season. Prior vaccination and immunity had a suppressive impact on immune response toward this novel influenza virus, elicited by 2010/2011 trivalent vaccine. This trivalent vaccine conferred good protection against ILI and LRI.     

Response to avian influenza and preparedness for pandemic influenza: Thailand's experience

Thailand has been struggling to control and prevent H5N1 avian influenza on both the animal health and public health fronts. Prevention and control programs for animals and humans are improving, with infections in poultry currently under control and no human cases seen in 2007. In awareness of the risk of an influenza pandemic, Thailand is joining global efforts in pandemic influenza preparedness. The national preparedness plan highlights building of national capacity for self-reliance and regional/international cooperation. Public health response to avian influenza and pandemic preparedness benefit significantly from the experience of responses to severe acute respiratory syndrome. This underlines the need to strengthen infrastructure and manpower, ensure public confidence and cooperation, secure maximum government advocacy and support, and forge multi-sector and international cooperation.     

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.     

Lessons from the first year of the WAIVE study investigating the protective effect of influenza vaccine against laboratory-confirmed influenza in hospitalised children aged 6–59 months

Please cite this paper as: Dixon et al. (2010) Lessons from the first year of the WAIVE study investigating the protective effect of influenza vaccine against laboratory-confirmed influenza in hospitalised children aged 6–59 months. Influenza and Other Respiratory Viruses 4(4), 231–234. Background Influenza is major cause of paediatric hospitalisation. Influenza vaccine was offered to all children aged 6–59 months resident in Western Australia in 2008, and we wished to evaluate the effectiveness of this immunisation programme. Objectives To assess the practicalities of a nested matched case–control design to estimate the protective effect of inactivated influenza vaccination in hospitalised children aged 6–59 months. Methods Cases were hospitalised children with laboratory-confirmed influenza, while matched controls were recruited from children admitted for an acute non-respiratory illness. We estimated influenza vaccine effectiveness (VE) against influenza as 1 – the adjusted odds ratio from multivariate logistic regression. Results The 2008 influenza season was characterised by a late peak and a predominance of influenza virus B. We recruited 26 hospitalised patients with laboratory-confirmed influenza and 50 matched controls. The proportion of cases who were fully vaccinated was 7% versus 30% of controls giving an adjusted VE of 83% (95% CI −54 to 98). Conclusions Recruiting sufficient controls was problematic and in the future, we will select controls hospitalised for an influenza-like-illness but influenza negative by laboratory PCR testing. The VE estimate was high but non-significant, reflecting the low number of cases.     

Patterns of early transmission of pandemic influenza in London - link with deprivation

Please cite this paper as: Balasegaram et al. (2012) Patterns of early transmission of pandemic influenza in London – link with deprivation. Influenza and Other Respiratory Viruses 6(3), e35–e41. Background  During the early containment phase in England from April to June 2009, the national strategy for H1N1 pandemic influenza involved case investigation and treatment, and tracing and prophylaxis of contacts. Objective  To describe the relationship between early transmission of H1N1 pandemic influenza in London and age and socio‐economic status. Methods  Epidemiological data on cases of pandemic flu in London reported to the London Flu Response Centre were analysed to determine patterns of transmission. Results  There were 3487 reported cases (2202 confirmed, 1272 presumed and 14 probable) from 20 April to 28 June 2009, during the ‘containment’ period. The highest report rate of 206 per 100 000 (95% CI 195–218) was seen in primary school–age children (5−11 years) followed by 129 (95% CI 119–139) in secondary school–age children (12–18 years). Reports of cases were initially concentrated in affluent areas but overall showed a clear trend with deprivation and risk ratio of 2·32 (95% CI 1·94–2·78) between the most deprived and the least deprived. Conclusion  Early transmissions were highest amongst school‐aged children but linked with socio‐economic deprivation across all age groups.     

Assessment of the benefits of seasonal influenza vaccination: Elements of a framework to interpret estimates of vaccine effectiveness and support robust decision‐making and communication

Systematic reviews and meta‐analyses confirm that influenza vaccination reduces the risk of influenza illness by between about 40% and 60% in seasons when circulating influenza stains are well matched to vaccine strains. Influenza vaccine effectiveness (IVE) estimates, however, are often discordant and a source of confusion for decision makers. IVE assessments are increasingly publicized and are often used by policy makers to make decisions about the value of seasonal influenza vaccination. But there is limited guidance on how IVE should be interpreted or used to inform policy. There are several limitations to the use of IVE for decision‐making: (a) IVE studies have methodological issues that often complicate the interpretation of their value; and (b) the full impact of vaccination will almost always be greater than the impact assessed by a point estimate of IVE in specific populations or settings. Understanding the strengths and weaknesses of study methodologies and the fundamental limitations of IVE estimates is important for the accuracy of interpretations and support of policy makers’ decisions. Here, we review a comprehensive set of issues that need to be considered when interpreting IVE and determining the full benefits of influenza vaccination. We propose that published IVE values should be assessed using an evaluative framework that includes influenza‐specific outcomes, types of VE study design, and confounders, among other factors. Better interpretation of IVE will improve the broader assessment of the value of influenza vaccination and ultimately optimize the public health benefits in seasonal influenza vaccination.     

Mortality burden of the 1918–1919 influenza pandemic in Europe

Background The origin and estimated death toll of the 1918–1919 epidemic are still debated. Europe, one of the candidate sites for pandemic emergence, has detailed pandemic mortality information. Objective To determine the mortality impact of the 1918 pandemic in 14 European countries, accounting for approximately three‐quarters of the European population (250 million in 1918). Methods We analyzed monthly all‐cause civilian mortality rates in the 14 countries, accounting for approximately three‐quarters of the European population (250 million in 1918). A periodic regression model was applied to estimate excess mortality from 1906 to 1922. Using the 1906–1917 data as a training set, the method provided a non‐epidemic baseline for 1918–1922. Excess mortality was the mortality observed above this baseline. It represents the upper bound of the mortality attributable to the flu pandemic. Results Our analysis suggests that 2·64 million excess deaths occurred in Europe during the period when Spanish flu was circulating. The method provided space variation of the excess mortality: the highest and lowest cumulative excess/predicted mortality ratios were observed in Italy (+172%) and Finland (+33%). Excess‐death curves showed high synchrony in 1918–1919 with peak mortality occurring in all countries during a 2‐month window (Oct–Nov 1918). Conclusions During the Spanish flu, the excess mortality was 1·1% of the European population. Our study highlights the synchrony of the mortality waves in the different countries, which pleads against a European origin of the pandemic, as was sometimes hypothesized.