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Doubt about the serologic efficacy of annually repeated influenza vaccination prompted investigations into the course of hemagglutination-inhibiting (HI), IgG, and IgA antibody titers and the IgG and IgA avidity index to influenza A/Taiwan/1/86 and A/Beijing/353/89 after annual vaccination. Fifty-four healthy elderly persons >70 years of age and 24 healthy young adults <30 years of age received standard influenza vaccine during 3 consecutive years. On average, prevaccination HI, IgG, and IgA titers to both influenza virus strains increased >=4 fold between the first and the third vaccination (analysis of variance, P<.001). The postvaccination HI and IgG titers remained unchanged after annual vaccination. The avidity index of IgG and IgA antibodies increased somewhat after annual vaccination, although the increase was statistically significant only in the young subjects. These data indicate that annual influenza vaccination of healthy elderly and young subjects results in an overall increase in protective antibodies. Copyright © 1999 The University of Chicago Copyright © 1999 The University of Chicago [ABSTRACT FROM AUTHOR]

Who Universal Trial Numbers (utns): U1111-1174-4615 and U1111-1174-4698., Clinicaltrials.gov: NCT04210349 and NCT03430089.

Between 1982 and 2006, 76 clinical studies (including the annual update studies required for licensing in Europe) were performed with the trivalent inactivated subunit influenza vaccine Influvac. In all, 6415 subjects were vaccinated, of whom 5034 were eligible for safety evaluation and 4534 for efficacy evaluation. Treatment-emergent adverse events occurred in 13.7% of subjects. Transient mild-to-moderate local and systemic reactions occurred in up to half of subjects. Post-marketing surveillance confirmed the well-established safety profile reported for inactivated influenza vaccines. All three serological criteria for immunogenicity of the Committee for Medicinal Products for Human Use (CHMP) were met for all three virus strain (sub)types in healthy adults, elderly (over 60 years), nursing home residents, and those at high risk of influenza-related complications. In an additional trial in children aged 3 -- 12 years, all three CHMP criteria for adults were met for all three virus strains. Influvac is thus immunogenic and safe, and is a suitable vaccine to combat the annually recurring medical and economic burden of influenza epidemics.

HI titers measure anti-HA antibody concentrations in sera. By the way they are defined standard titers underestimate the true amounts of antibody. A new definition is proposed, the mid-value definition. Under mild conditions mid-value titers are on average closer to the true value than standard titers.

In a well-know CHMP Note for Guidance criteria are given for evaluation the results of annual-update studies. Now and then it sometimes is suggested that these criteria can be improved by the use of confidence intervals. Here it is argued that this is based on a misinterpretation of what confidence intervals are. These intervals require that subjects are chosen at random from a population. In influenza studies this is never the case.

Several approaches are currently being pursued in order to improve the efficacy of influenza vaccines in elderly individuals and others who have impaired immune responses to conventional influenza vaccines. There are two influenza vaccines available for elderly subjects: Fluad (Chiron) and Invivac (Solvay Pharmaceuticals). The present clinical study was a randomized, endpoint-blind, parallel group study in elderly subjects aged 61 years and older to investigate the safety and immunogenicity of these vaccines as compared to a standard influenza vaccine Invivac (Solvay Pharmaceuticals). The three vaccines had similar immunogenicity results, whereas the tolerability profile of Invivac was better as compared to Fluad.

Current available influenza vaccines are safe and effective in preventing influenza. Nevertheless, there is a need for influenza vaccines with improved efficacy in the elderly. This need is underscored by both the observation that influenza has a major clinical and economic impact in the elderly and the fact that currently available vaccines are generally less effective in elderly than in younger subjects. Several approaches are currently being pursued in order to improve the efficacy of influenza vaccines in elderly individuals and others who have impaired immune responses to conventional influenza vaccines. A novel antigen-presenting strategy to overcome impaired immune responses is the use of virosomes. Previously, data on safety and reactogenicity have been published regarding the use of virosomal influenza vaccines. Data from three recent clinical trials are presented here. The first of these was a comparative study of a virosomal vaccine and a conventional subunit vaccine in "at-risk" adults with underlying chronic illness. The virosomal vaccine demonstrated comparable tolerability to the subunit vaccine, with about 98% of patients reporting tolerability to be good or very good. The vast majority of adverse events reported were mild to moderate in severity. With both vaccine types, mean HI titres decreased with age for both the A-H1N1 and B influenza virus strains, but for the A-H3N2 strain (the most virulent of the three strains), mean HI titres did not decrease with age, suggesting a better response with the virosomal vaccine when compared to the subunit vaccine. All three studies explored the long-term persistence of antibodies after vaccination with virosomal influenza vaccines. Immunogenicity declined over time but remained high at 4, 6 and 12 months post-vaccination compared to baseline, indicating that adequate seroprotection is achievable for the duration of the influenza season. Virosomal vaccines may induce better immunity in elderly subjects and may be more effective in reducing morbidity and mortality in this age group.

In 14 clinical studies, various efficacy and safety aspects of a new virosomal influenza vaccine (Invivac) were assessed in 2865 subjects. The virosomal influenza vaccine fully complies with the Committee for Proprietary Medicinal Products (CPMP) requirement for immunogenicity of influenza vaccines. In particular, in a subset of subjects with low pre-vaccination titers (thus those persons who actually need protection by a vaccine), between 76 and 99% of subjects (dependent on age, health status and vaccine components) achieved protective hemagglutination inhibiting (HI) antibody titers after vaccination with the virosomal influenza vaccine. Acceptable frequencies of well-known local and systemic reactions were observed in healthy adults and risk subjects in clinical studies and in a post-marketing study population. These reactions were transient and generally not severe, and did not cause major inconvenience. In conclusion, Invivac is an efficacious and safe vaccine for the protection against influenza in healthy and chronically ill adult subjects. The vaccine is especially efficacious in subjects with low pre-vaccination immunity.

Background: According to common recommendations, influenza vaccination should be performed annually. It has been suggested that vaccination in previous years reduces vaccine efficacy in the long term., Objective: To determine whether the protection of influenza vaccine decreases when vaccination is repeated annually., Methods: Articles published between 1966 and 1997 were selected from MEDLINE. The end point for field studies was the influenza-related morbidity or mortality during influenza outbreaks (resulting in field protection rates). The end point for serologic studies was exceeding a protective postvaccination hemagglutination-inhibition titer (serologic protection rates). Protection rate differences between groups with single and multiple vaccinations were subjected to meta-analysis., Results: Seven field studies (including 13 trials) supported the hypothesis that protection in multiple-vaccination groups is at least as good as that in single-vaccination groups. Ten trials with 5117 observations could be subjected to meta-analysis. The pooled protection-rate difference was close to 0 (1.1%; 95% confidence interval, -0.2% to 2.4%), thus detecting no difference between single or multiple vaccination. Twelve serologic studies (including 53 trials) showed heterogeneous results: 9 trials were significantly in favor of single vaccination, and 7 were in favor of multiple vaccination, but in most cases, there was no significant difference between the 2 vaccination groups. The pooled serologic protection-rate difference from 52 trials (12341 observations) was again close to 0 (1.7%; 95% confidence interval, -1.3% to 4.8%)., Conclusions: We did not detect any evidence for a decreasing protection with annually repeated influenza vaccination. Annual vaccination should not be discouraged in populations at risk.

Three papers by Hoskins and collaborators published in The Lancet in the 70s, have been challenging the common policy to annually vaccinate people at risk with inactivated influenza virus vaccine. From an analysis of a vaccination campaign in adolescent pupils of a boarding school and four influenza outbreaks in the period 1970-76, Hoskins et al. concluded that annually repeated vaccinations would not confer protection against epidemic influenza in the long-term ('Hoskins' Paradox'). A review of the papers revealed, however, that most of the study subjects were not consequently vaccinated every year and that most of the presented data were, therefore, not relevant for the problem of annually repeated influenza vaccination. When applying strict definitions of single vaccination (immunised immediately prior to the epidemic, but not in the years before) and multiple vaccination (immunised immediately prior to the epidemic, and also in the year(s) before), only two of four epidemics (A/England/42/72 (H3N2) in 1972/73 and A/Port Chalmers/1/73 (H3N2) in 1973/74) could be evaluated: in one case, no negative effect of repeated vaccination could be detected, in the second case, the attack rate difference between groups with single and multiple vaccination was of borderline significance. Data on two other epidemics (B/Hong Kong/8/73 in 1973/74 and A/Victoria/3/75 (H3N2) in 1975/76) could not be interpreted because of incomplete vaccination strategies. In conclusion, Hoskins' Paradox cannot be substantiated by Hoskins' own data. Considering other published data on the subject, it is suggested that no negative effect of annually repeated vaccination on protection against epidemic influenza exists.

To determine the influence of ageing per se as well as of priming histories on the antibody response to influenza vaccination, haemagglutination inhibition (HI), ELISA IgG, IgA, IgM and neutralizing antibody titres were studied in 43 healthy young subjects (mean age 23 years) and 55 healthy elderly people (mean age 79 years). The HI and ELISA lgG responses to the A/Guizhou/54/89 strain (H3N2) for which both the young and the elderly had similar priming histories were equal. By contrast, the HI and IgG responses to A/Taiwan/1/86 (H1N1), where the priming histories were different, were lower in the elderly (P < 0.05). Influenza-specific IgA responses in the elderly tended to be higher for all vaccine strains. Influenza-specific postvaccination IgM titres were similar or tended to be higher in the elderly. A subgroup of elderly subjects (18%) who did not express HI activity to the A/Taiwan/1/86 (H1N1) vaccine strain, reacted in the HI assay with the closely related A/Singapore/6/86 (H1N1) strain. These elderly people, however, produced lgG antibodies which neutralized A/Taiwan/1/86 virus in vitro. It is concluded that the elderly are capable of mounting antibody responses similar to those observed in the young. Moreover, the observed age-related differences in antibody responses to H1N1 strains are probably not due to ageing of the immune system itself, but are determined by differences in priming histories.

The benefit of annually repeated influenza vaccination on antibody formation is still under debate. In this study the effect of annually repeated influenza vaccination on haemagglutination inhibiting (HI) antibody formation in the elderly is investigated. Between 1990 and 1993 healthy young and elderly, both selected by the SENIEUR protocol, were vaccinated consecutively with commercially available influenza vaccines. The elderly had a lower HI antibody response after one vaccination as compared to the young against the A/Taiwan/1/86 (HINI), B/Yamagata/16/88 and B/Panama/45/90 strains. Annually repeated vaccination did not result in a decrease of the HI antibody titres against the A and B vaccine strains in both age groups. Moreover, the elderly had a significantly higher HI titre against the B strains after the second vaccination as compared to the first, resulting in comparable HI titres for young and elderly. Thus, annually repeated vaccination has a beneficial effect on the antibody titre against influenza virus and can contribute to a better antibody-response in the elderly.