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Variable efficacy of repeated annual influenza vaccination.

ABSTRACT: Conclusions have differed in studies that have compared vaccine efficacy in groups receiving influenza vaccine for the first time to efficacy in groups vaccinated more than once. For example, the Hoskins study [Hoskins, T. W., Davis, J. R., Smith, A. J., Miller, C. L. & Allchin, A. (1979) Lancet i, 33-35] concluded that repeat vaccination was not protective in the long term, whereas the Keitel study [Keitel, W. A., Cate, T. R., Couch, R. B., Huggins, L. L. & Hess, K. R. (1997) Vaccine 15, 1114-1122] concluded that repeat vaccination provided continual protection. We propose an explanation, the antigenic distance hypothesis, and test it by analyzing seven influenza outbreaks that occurred during the Hoskins and Keitel studies. The hypothesis is that variation in repeat vaccine efficacy is due to differences in antigenic distances among vaccine strains and between the vaccine strains and the epidemic strain in each outbreak. To test the hypothesis, antigenic distances were calculated from historical hemagglutination inhibition assay tables, and a computer model of the immune response was used to predict the vaccine efficacy of individuals given different vaccinations. The model accurately predicted the observed vaccine efficacies in repeat vaccinees relative to the efficacy in first-time vaccinees (correlation 0.87). Thus, the antigenic distance hypothesis offers a parsimonious explanation of the differences between and within the Hoskins and Keitel studies. These results have implications for the selection of influenza vaccine strains, and also for vaccination strategies for other antigenically variable pathogens that might require repeated vaccination.

SUBMITTER: Smith DJ

PROVIDER: S-EPMC24180 | biostudies-literature | 1999 Nov

REPOSITORIES: biostudies-literature

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Variable efficacy of repeated annual influenza vaccination.

Smith D J DJ Forrest S S Ackley D H DH Perelson A S AS

Proceedings of the National Academy of Sciences of the United States of America 19991101 24

Conclusions have differed in studies that have compared vaccine efficacy in groups receiving influenza vaccine for the first time to efficacy in groups vaccinated more than once. For example, the Hoskins study [Hoskins, T. W., Davis, J. R., Smith, A. J., Miller, C. L. & Allchin, A. (1979) Lancet i, 33-35] concluded that repeat vaccination was not protective in the long term, whereas the Keitel study [Keitel, W. A., Cate, T. R., Couch, R. B., Huggins, L. L. & Hess, K. R. (1997) Vaccine 15, 1114-1 ...[more]

PMID: 10570188

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Project description:Annual seasonal influenza vaccination is recommended for high-risk populations and often occupational groups such as healthcare workers (HCWs). Repeated annual vaccination has been reported to either have no impact or reduce antibody responses or protection. However, whether repeated vaccination influences T-cell responses has not been sufficiently studied, despite the increasing evidence of the protective roles of T-cell immunity. Here, we explored the impact of repeated annual vaccination with the same vaccine strain (H1N1pdm09) over multiple seasons in the post-2009 pandemic era and showed that repeated vaccination increased both T-cell and humoral responses. Using the T-cell FluroSpot and intracellular cytokine-staining, the hemagglutination inhibition (HI), and the memory B-cell (MBC) ELISpot assays, we investigated pre- and postvaccination T cells, antibodies, and MBCs in a cohort of HCWs repeatedly vaccinated with H1N1pdm09 for 5 years (pandemic vaccination in 2009 and subsequently annual seasonal vaccination containing H1N1pdm09 during 2010-2013). We found that the prevaccination H1N1pdm09-specific T cells, antibodies, and MBCs were significantly increased after 3-4 repeated vaccinations and maintained at high levels throughout seasons 2012 and 2013. The cross-reactive IFN-?-secreting CD4+ cells recognizing conserved viral external or internal epitopes were also maintained throughout 2012 and 2013. Repeated vaccination improved the multifunctional memory CD4+ responses. Particularly, the IFN-?+TNF-?+CD4+ T cells were boosted following each vaccination. HI antibodies were significantly induced after each vaccination over 5 years. Our findings indicate a broad impact of repeated annual vaccination, even with the same vaccine component, on the influenza-specific T-cell and humoral immunity and support the continuing recommendation of annual influenza vaccination. Despite the widespread implementation of annual influenza vaccination, the effect of repeated vaccinations on the immune response in subsequent seasons is poorly understood. A team led by Rebecca Jane Cox at the University of Bergen examined the humoral and T-cell response elicited by 2009's H1N1pdm09 seasonal vaccine. Since the H1N1pdm09 strain continued to circulate in subsequent years it was included in later vaccine formulations and the authors could therefore examine the effects of repeated annual vaccination over multiple seasons. They observed that H1N1pdm09-specific polyfunctional T-cell responses and antibodies were enhanced by multiple annual vaccinations. In particular, T cells showed progressive skewing to IFN-?+TNF+ double producers, but the magnitude of the T-cell response tended to plateau after 3-4 repeated vaccinations. The findings suggest that including the same component in subsequent annual vaccines can significantly impact the influenza immune response.

Project description:Antibodies to influenza surface protein neuraminidase (NA) have been found to reduce disease severity and may be an independent correlate of protection. Despite this, current influenza vaccines have no regulatory requirements for the quality or quantity of the NA antigen and are not optimized for induction of NA-specific antibodies. Here we investigate the induction and durability of NA-specific antibody titers after pandemic AS03-adjuvanted monovalent H1N1 vaccination and subsequent annual vaccination in health care workers in a five-year longitudinal study. NA-specific antibodies were measured by endpoint ELISA and functional antibodies measured by enzyme-linked lectin assay (ELLA) and plaque reduction naturalisation assay. We found robust induction of NA inhibition (NAI) titers with a 53% seroconversion rate (>4-fold) after pandemic vaccination in 2009. Furthermore, the endpoint and NAI geometric mean titers persisted above pre-vaccination levels up to five years after vaccination in HCWs that only received the pandemic vaccine, which demonstrates considerable durability. Vaccination with non-adjuvanted trivalent influenza vaccines (TIV) in subsequent influenza seasons 2010/2011 – 2013/2014 further boosted NA-specific antibody responses. We found that each subsequent vaccination increased durable endpoint titers and contributed to maintaining the durability of functional antibody titers. Although the trivalent influenza vaccines boosted NA-specific antibodies, the magnitude of fold-increase at day 21 declined with repeated vaccination, particularly for functional antibody titers. High levels of pre-existing antibodies were associated with lower fold-induction in repeatedly vaccinated HCWs. In summary, our results show that durable NA-specific antibody responses can be induced by an adjuvanted influenza vaccine, which can be maintained and further boosted by TIVs. Although NA-specific antibody responses are boosted by annual influenza vaccines, high pre-existing titers may negatively affect the magnitude of fold-increase in repeatedly vaccinated individuals. Our results support continued development and standardization of the NA antigen to supplement current influenza vaccines and reduce the burden of morbidity and mortality.

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Variable efficacy of repeated annual influenza vaccination.

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Variable efficacy of repeated annual influenza vaccination.

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