Lessons from pandemic influenza A(H1N1): The research-based vaccine industry's perspective

AbstractAs A(H1N1) influenza enters the post-pandemic phase, health authorities around the world are reviewing the response to the pandemic. To ensure this process enhances future preparations, it is essential that perspectives are included from all relevant stakeholders, including vaccine manufacturers. This paper outlines the contribution of R&D-based influenza vaccine producers to the pandemic response, and explores lessons that can be learned to improve future preparedness.The emergence of 2009 A(H1N1) influenza led to unprecedented collaboration between global health authorities, scientists and manufacturers, resulting in the most comprehensive pandemic response ever undertaken, with a number of vaccines approved for use three months after the pandemic declaration. This response was only possible because of the extensive preparations undertaken during the last decade.During this period, manufacturers greatly increased influenza vaccine production capacity, and estimates suggest a further doubling of capacity by 2014. Producers also introduced cell-culture technology, while adjuvant and whole virion technologies significantly reduced pandemic vaccine antigen content. This substantially increased pandemic vaccine production capacity, which in July 2009 WHO estimated reached 4.9 billion doses per annum. Manufacturers also worked with health authorities to establish risk management plans for robust vaccine surveillance during the pandemic. Individual producers pledged significant donations of vaccine doses and tiered-pricing approaches for developing country supply.Based on the pandemic experience, a number of improvements would strengthen future preparedness. Technical improvements to rapidly select optimal vaccine viruses, and processes to speed up vaccine standardization, could accelerate and extend vaccine availability. Establishing vaccine supply agreements beforehand would avoid the need for complex discussions during a period of intense time pressure.Enhancing international regulatory co-operation and mutual recognition of approvals could accelerate vaccine supply, while maintaining safety standards. Strengthening communications with the public and healthcare workers using new approaches and new channels could help improve vaccine uptake. Finally, increasing seasonal vaccine coverage will be particularly important to extend and sustain pandemic vaccine production capacity

Antibody induction by influenza vaccines in the elderly: a review of the literature

Conflicting results have been reported concerning the association between high age and response to influenza vaccines. Some authors have found a reduced response in aged subjects, others have found no difference or even better results as compared with younger control subjects. Seventeen papers were selected from international literature published in the period 1968-1988 for a review of the anti-haemagglutinin-IgG sero-response following vaccination: among 30 cases in which vaccine components could be studied independently, ten revealed a better immune response in young subjects than in the elderly, four found more favourable results in the elderly, and 16 could not detect any significant between-group-differences, the latter most probably because of a high type-2-error. Nine of these 16 cases tended to favour young subjects. These results were relativated by the finding that each paper had at least one of three methodological limitations: (1) the failure to exclude subjects with illnesses or using drugs influencing the immune system, (2) the failure to exclude subjects with previous vaccinations against influenza, (3) the failure to exclude subjects with high prevaccination antibody titres. The direction of these biases is such that failure to address any one issue will lead to an underestimate of the response of aged subjects. In view of the failure to control these biases, it was not surprising that the papers reviewed presented a heterogeneous picture. Thus, the association between high age per se and response to influenza vaccines, if any, has not yet been established. Suggestions are made for future studies in which admission criteria should control health state and previous exposure to influenza antigens

Influenza vaccines: the effect of vaccine dose on antibody response in primed populations during the ongoing interpandemic period. A review of the literature.

Health authorities tend to favour an increase of the antigen dose in inactivated influenza vaccines from or = 75%) for a 10 micrograms HA dose of influenza A vaccine components. For both response and protection rates, an increase of the antigenic load from 10 to 15 micrograms HA was not associated with a meaningful increase of seroresponse: in 38 out of 39 stratification groups, the increase of response and/or protection rate varied between -9% and +8%, with a median of 1.5%. These results do not justify the expectation that a vaccine dose of 15 micrograms HA per strain would be clinically superior to a dose of 10 micrograms HA. Only in a group of immune-compromised patients on chronic intermittent haemodialysis were results in favour of a higher dose found, which may justify further evaluation in this special population

Nineteenth annual New England Intercollegiate Geological Excursion: October 12 and 13, 1923, Massachusetts

Locality 1: Cut on Bow Street, south of Turkey Hill, northwest corner of Arlington; Locality 2: Blueberry Mountain, southeast border of Woburn between Woburn and East Woburn; Locality 3: Shore west of West Manchester, on Gloucester branch of the Boston and Maine R.R., third of the way from Beverly to Glouceste

Mismatch between the 1997/1998 influenza vaccine and the major epidemic A (H3N2) virus strain as the cause of an inadequate vaccine-induced antibody response to this strain in the elderly.

The success of influenza vaccination depends largely on the antigenic match between the influenza vaccine strains and the virus strains actually circulating during the season. In the past, this match has proved to be satisfactory in most seasons. In the 1997/1998 season, however, hemagglutination inhibition (HI) assays with ferret antisera indicated a considerable mismatch between the H3N2 vaccine component and the most prevalent epidemic influenza A(H3N2) virus. The results from antigenic analyses using pre- and postvaccination serum samples from volunteers of various ages, including residents of nursing homes who were more than 60 years of age, were in good agreement with the results obtained with ferret antisera. Homologous serum antibody responses to the H3N2 vaccine component as well as the cross-reactivity of the induced antibodies to the epidemic H3N2 strain, declined with increasing age of the vaccinees. As a consequence of these two effects, 84% of the vaccinees over 75 years of age did not develop HI antibody titers >/= 40 against the major H3N2 virus variant of 1997/1998, suggesting that they were not protected against infection with this virus variant. These findings support the current policy of the World Health Organization (WHO), which is to base worldwide influenza virus surveillance on results predominantly obtained by antigenic analyses of influenza virus isolates with ferret antisera in HI tests. If an antigenic mismatch is observed, the protective efficacy of the vaccine, especially for the elderly, may be insufficient. The observations also support the current policy to include the elderly in serologic efficacy trials

Gender differences in local and systemic reactions to inactivated influenza vaccine, established by a meta-analysis of fourteen independent studies

In order to determine whether there is a difference between genders in reported adverse reactions to inactivated influenza vaccine, a computerized database of serological studies was investigated. A standardized questionnaire was used to evaluate vaccine reactogenicity. A total of 1,800 vaccinees in 14 studies were analyzed separately for two age groups ( or = 60 years of age). Females reported significantly more local reactions than males. The pooled odds ratio for the outcome measure "any local reaction" was 0.32 (95% confidence interval, 0.26-0.40, significant) and 0.54 (95% Cl, 0.41-0.70, significant) for young and elderly adults, respectively. Similar results were obtained for the outcome measure "any systemic reaction." Previous exposure to influenza or influenza vaccine had no influence on reactogenicity. There were no gender differences in sero-responses. In conclusion, gender should be regarded as a predictor of reported reactions to influenza vaccine in both young and elderly adults and should be addressed in future study designs

Adjuvancy and reactogenicity of N-acetylglycosaminyl-N-acetylmuramyl-dipeptide (GMDP) orally administered just prior to trivalent influenza subunit vaccine. A double-blind placebo-controlled study in nursing home residents.

One hundred and fifty-three nursing home residents received 0, 5, 25 or 50 mg N-acetylglucosaminyl-N-acetylmuramyl-dipeptide (GMDP) orally, and trivalent influenza subunit vaccine intramuscularly. One day after intervention, there was a strong increase of total leucocytes, monocytes and neutrophils in the groups receiving 25 or 50 mg GMDP. A GMDP dose dependent increase in systemic, but not in local, vaccine side-effects was observed. No significant differences in post-vaccination haemagglutination inhibiting serum antibody titres were observed between the four groups, indicating that oral administration of GMDP together with influenza vaccination, does not lead to a higher vaccine efficacy

Effects of repeated annual influenza vaccination on vaccine sero-response in young and elderly adults

Three cohort studies in adults were performed during the period from 1986 to 1989. Eight hundred and eighty-four subjects were, one or more times, immunized with influenza vaccines, and pre- and post-vaccination antibody titres were determined by hemagglutination inhibition tests. One thousand and one hundred and nineteen vaccination events in 681 subjects could be analysed by a comparison, per trial and per influenza (sub)type, between groups with and without influenza vaccination in previous years. Effect size, odds ratio and protection rate difference, were used as effect measures. Subjects with previous vaccination showed higher pre-vaccination antibody than those without. The average change of the post-vaccination proportion of subjects with high antibody titre value to previous vaccination, was +9.4% (95% CI: +5.3 to 13.6%) for A-H3N2 vaccine components, -2.1% (-8.1 to 3.9%, not significant) for A-H1N1 and -10.6% (-16.5% to -4.8%) for B. In a linear regression model, pre-vaccination titres and the status of previous vaccination were identified as factors significantly influencing post-vaccination titres. These findings are discussed in the context of a short review of the literature. It is concluded that the status of previous vaccination should always be addressed as an independent factor in serological vaccination studies

Association between vaccine adjuvant effect and pre-seasonal immunity. Systematic review and meta-analysis of randomised immunogenicity trials comparing squalene-adjuvanted and aqueous inactivated influenza vaccines

The immunogenicity benefit of inactivated influenza vaccine (IIV) adjuvanted by squalene over non-adjuvanted aqueous IIV was explored in a meta-analysis involving 49 randomised trials published between 1999 and 2017, and 22,470 eligible persons of all age classes. Most vaccines contained 15 μg viral haemagglutinin per strain. Adjuvanted IIV mostly contained 9.75 mg squalene per dose. Homologous pre- and post-vaccination geometric mean titres (GMTs) of haemagglutination-inhibition (HI) antibody were recorded for 290 single influenza (sub-)type arms. The adjuvant effect was expressed as the ratio of post-vaccination GMTs between squalene-IIV and aqueous IIV (GMTR, 145 estimates). GMTRs > 1.0 favoured squalene-IIV over aqueous IIV. For all influenza (sub-)types, the adjuvant effect proved negatively associated with pre-vaccination GMT and mean age. The adjuvant effect appeared most pronounced in young children (mean age < 2.5 years) showing an average GMTR of 3.7 (95% CI: 2.5 to 5.5). With increasing age, GMTR values gradually decreased towards 1.4 (95% CI: 1.0 to 1.9) in older adults. Heterologous antibody titrations simulating mismatch between vaccine and circulating virus (30 GMTR estimates) again showed a larger adjuvant effect at young age. GMT values and their variances were converted to antibody-predicted protection rates using an evidence-based clinical protection curve. The adjuvant effect was expressed as the protection rate differences, which showed similar age patterns as corresponding GMTR values. However for influenza B, the adjuvant effect lasted longer than for influenza A, possibly due to a generally later influenza B virus exposure. Collectively, this meta-analysis indicates the highest benefit of squalene-IIV over aqueous IIV in young children and decreasing benefit with progressing age. This trend is similar for seasonal influenza (sub-)types and the 2009 pandemic strain, by both homologous and heterologous titration. The impact of pre-seasonal immunity on vaccine effectiveness, and its implications for age-specific vaccination recommendations, are discussed