Abraham Palache

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.

Cold-adapted live influenza vaccine versus inactivated vaccine: systemic vaccine reactions, local and systemic antibody response, and vaccine efficacy A meta-analysis

Since the 1940s, influenza vaccines are inactivated and purified virus or virus subunit preparations (IIV) administered by the intramuscular route. Since decades, attempts have been made to construct, as an alternative, attenuated live influenza vaccines (LIV) for intranasal administration. Presently, the most successful LIV is derived from the cold-adapted master strains A/Ann Arbor/6/60 (H2N2) and B/Ann Arbor/1/66 (AA-LIV, for Ann-Arbor-derived live influenza vaccine). It has been claimed that AA-LIV is more efficacious than IIV. In order to assess differences between the two vaccines with respect to systemic reactogenicity, antibody response, and efficacy, we performed a meta-analysis on eighteen randomised comparative clinical trials involving a total of 5000 vaccinees of all ages. Pooled odds ratios (AA-LIV versus IIV) were calculated according to the random effects model. The two vaccines were associated with similarly low frequencies of systemic vaccine reactions (pooled odds ratio: 0.96, 95% confidence interval: 0.74-1.24). AA-LIV induced significantly lower levels of serum haemagglutination inhibiting antibody and significantly greater levels of local IgA antibody (influenza virus-specific respiratory IgA assayed by ELISA in nasal wash specimens) than IIV. Yet, although they predominantly stimulate different antibody compartments, the two vaccines were similarly efficacious in preventing culture-positive influenza illness. In all trials assessing clinical efficacy, the odds ratios were not significantly different from one (point of equivalence). The pooled odds ratio for influenza A-H3N2 was 1.50 (95% CI: 0.80-2.82), and for A-H1N1, 1.03 (95% CI: 0.58-1.82). The choice between the two vaccine types should be based on weighing the advantage of the attractive non-invasive mode of administration of AA-LIV, against serious concerns about the biological risks inherent to large-scale use of infectious influenza virus, in particular the hazard of gene reassortment with non-human influenza virus strains.

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.

Comparison of serology and reactogenicity between influenza subunit vaccines and whole virus or split vaccines. A review and meta-analysis of the literature

SummaryCurrently three different inactivated influenza vaccine types are available: whole virus (WV), split (SPL) and subunit (SU) vaccines. Physicians and patients at risk for influenza complications may wonder whether there are important differences between the vaccine types with respect to antibody induction (serology) and adverse effects (reactogenicity). A literature review (1975 to 1995) was performed to evaluate the serology and reactogenicity of SU vaccines in comparison with either split or whole virus vaccines. 22 publications with randomised allocation were identified describing a total of 5416 serological observations, 2858 observations of local reactions, and 2990 observations of systemic reactions. Subjects included those from all age groups from children to the elderly. Absolute protection and reaction rate differences (RD) were calculated for the comparisons SU vs SPL or SU vs WV vaccine. These were subjected to a method of meta-analysis, resulting in pooled rate differences and their 95% confidence intervals. With the exception of the comparison SU vs WV vaccine in subjects born after 1957 and unexposed to the reappearing H1N1 subtype after 1977, no evidence was found to suggest relevant differences in seroresponse among the three currently available inactivated influenza vaccine types. Although insufficient data were available in the meta-analysis for vaccines in children for whom specific recommendations concerning these vaccines exist, adverse events after administration of any of the three vaccine types were generally mild and transitory; however, SU vaccines were associated with a lower frequency of local and systemic reactions.

Improvement of the immunoglobulin subclass response to influenza vaccine in elderly nursing-home residents by the use of high-dose vaccines

To investigate the effects of age and antigen dose (10, 20, 60 micrograms) on the immunoglobulin (sub) class distribution following influenza vaccination, antibody responses in 79 elderly nursing home residents were compared with the responses in 100 young subjects. At a 10 micrograms dose the IgM, IgG3 and IgA1 responses were comparable in both age groups, whereas the IgG, IgG1 and haemagglutination inhibition (HI) responses were twofold lower in the elderly. A 20 micrograms dose increased the IgG, IgG1 and HI levels in the elderly to the levels in the young and the IgA1 to significantly higher levels. A 60 micrograms dose increased antibody levels in the young, but did not further increase the response in the elderly. The 20 micrograms dose might represent a higher level of protection in the elderly.

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 (<60 and ≥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 seroresponses. 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.

Immunogenicity and safety of inactivated influenza vaccines in primed populations: a systematic literature review and meta-analysis.

Several inactivated influenza vaccine formulations for systemic administration in man are currently available for annual (seasonal) immunization: split virus and subunit (either plain-aqueous, or virosomal, or adjuvanted by MF59). From a literature search covering the period 1978-2009, 33 articles could be identified, which described randomized clinical trials comparing at least two of the four vaccine formulations with respect to serum hemagglutination inhibition (HI) antibody response, local and systemic vaccine reactions and serious adverse events after vaccination, and employing seasonal vaccine components and doses. In total, 9121 vaccinees of all ages, either healthy or with underlying diseases, were involved. Most vaccinees were primed or had been vaccinated in previous years. For immunogenicity, homologous post-vaccination geometric mean HI titers (GMTs) were analyzed by a random effects model for continuous data. Unreported standard deviations (SD) were addressed by imputing assumed SD-values. Age and health state of the vaccinees appeared to have little influence on the outcome. The immunogenicity of split, aqueous and virosomal subunit formulations were similar, with geometric mean ratio values (GMR, quotient of paired GMT-values) varying around one (0.93-1.24). The MF59-adjuvanted subunit vaccine induced, on average, larger antibody titers than the non-adjuvanted vaccine formulations, but the absolute increase was small (GMR-values varying between 1.25 and 1.40). Vaccine reactions were analyzed using a random effects model for binary data. Local and systemic reactogenicity was similar among non-adjuvanted formulations. The adjuvanted subunit formulation was more frequently associated with local reactions than the non-adjuvanted formulations (rate ratio: 2.12, significant). Systemic reactions were similar among all vaccine formulations. The original articles emphasized the mild and transient character of the vaccine reactions and the absence of serious vaccine-related adverse events. This adequate amount of evidence led to the conclusion that all the currently available inactivated influenza vaccine formulations are safe, well tolerated and similarly effective to control seasonal influenza outbreaks across primed populations and age ranges.

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 = 10 micrograms haemagglutinin (HA) per vaccine strain to 15 micrograms HA/strain. The increased dose is expected to yield a meaningful increase in the number of subjects to be protected after vaccination. To verify this expectation, we have reviewed 20 published reports (1978-1991) of serological studies in which anti-HA-IgG antibody after different doses was measured. In the review, stratification groups of previously primed subjects were formed and the antibody response was estimated for doses of 10 and 15 micrograms HA by linear k*2-chi 2 model. Despite a considerable heterogenicity of study populations, study designs, vaccine types and strains, and antibody assays, the results were consistent in revealing high protection rates (> 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.

Seasonal influenza vaccine dose distribution in 195 countries (2004–2013): Little progress in estimated global vaccination coverage

Seasonal influenza is an important disease which results in 250,000-500,000 annual deaths worldwide. Global targets for vaccination coverage rates (VCRs) in high-risk groups are at least 75% in adults ≥65 years and increased coverage in other risk groups. The International Federation of Pharmaceutical Manufacturers and Associations Influenza Vaccine Supply (IFPMA IVS) International Task Force developed a survey methodology in 2008, to assess the global distribution of influenza vaccine doses as a proxy for VCRs. This paper updates the previous survey results on absolute numbers of influenza vaccine doses distributed between 2004 and 2013 inclusive, and dose distribution rates per 1000 population, and provides a qualitative assessment of the principal enablers and barriers to seasonal influenza vaccination. The two main findings from the quantitative portion of the survey are the continued negative trend for dose distribution in the EURO region and the perpetuation of appreciable differences in scale of dose distribution between WHO regions, with no observed convergence in the rates of doses distributed per 1000 population over time. The main findings from the qualitative portion of the survey were that actively managing the vaccination program in real-time and ensuring political commitment to vaccination are important enablers of vaccination, whereas insufficient access to vaccination and lack of political commitment to seasonal influenza vaccination programs are likely contributing to vaccination target failures. In all regions of the world, seasonal influenza vaccination is underutilized as a public health tool. The survey provides evidence of lost opportunity to protect populations against potentially serious influenza-associated disease. We call on the national and international public health communities to re-evaluate their political commitment to the prevention of the annual influenza disease burden and to develop a systematic approach to improve vaccine distribution equitably.

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

As 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.