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Repeated Influenza Vaccination Boosts and Maintains H1N1pdm09 Neuraminidase Antibody Titers

ABSTRACT: 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.

SUBMITTER: Hansen L

PROVIDER: S-EPMC8551669 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Immune responses induced by currently licensed inactivated influenza vaccines are mainly directed against the hemagglutinin (HA) glycoprotein, the immunodominant antigen of influenza viruses. The resulting antigenic drift of HA requires frequent updating of the vaccine composition and annual revaccination. On the other hand, the levels of antibodies directed against the neuraminidase (NA) glycoprotein, the second major influenza virus antigen, vary greatly. To investigate the potential of the more conserved NA protein for the induction of subtype-specific protection, vesicular stomatitis virus-based replicons expressing a panel of N1 proteins from prototypic seasonal and pandemic H1N1 strains and human H5N1 and H7N9 isolates were generated. Immunization of mice and ferrets with the replicon carrying the matched N1 protein resulted in robust humoral and cellular immune responses and protected against challenge with the homologous influenza virus with an efficacy similar to that of the matched HA protein, illustrating the potential of the NA protein as a vaccine antigen. The extent of protection after immunization with mismatched N1 proteins correlated with the level of cross-reactive neuraminidase-inhibiting antibody titers. Passive serum transfer experiments in mice confirmed that these functional antibodies determine subtype-specific cross-protection. Our findings illustrate the potential of NA-specific immunity for achieving broader protection against antigenic drift variants or newly emerging viruses carrying the same NA but a different HA subtype.IMPORTANCE Despite the availability of vaccines, annual influenza virus epidemics cause 250,000 to 500,000 deaths worldwide. Currently licensed inactivated vaccines, which are standardized for the amount of the hemagglutinin (HA) antigen, primarily induce strain-specific antibodies, whereas the immune response to the neuraminidase (NA) antigen, which is also present on the viral surface, is usually low. Using NA-expressing single-cycle vesicular stomatitis virus replicons, we show that the NA antigen conferred protection of mice and ferrets against not only the matched influenza virus strains but also viruses carrying NA proteins from other strains of the same subtype. The extent of protection correlated with the level of cross-reactive NA-inhibiting antibodies. This highlights the potential of the NA antigen for the development of more broadly protective influenza vaccines. Such vaccines may also provide partial protection against newly emerging strains with the same NA but a different HA subtype.

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:UnlabelledWe infected mice with the 2009 influenza A pandemic virus (H1N1pdm09), boosted with an inactivated vaccine, and cloned immunoglobulins (Igs) from HA-specific B cells. Based on the redundancy in germline gene utilization, we inferred that between 72-130 unique IgH VDJ and 35 different IgL VJ combinations comprised the anti-HA recall response. The IgH VH1 and IgL VK14 variable gene families were employed most frequently. A representative panel of antibodies were cloned and expressed to confirm reactivity with H1N1pdm09 HA. The majority of the recombinant antibodies were of high avidity and capable of inhibiting H1N1pdm09 hemagglutination. Three of these antibodies were subtype-specific cross-reactive, binding to the HA of A/South Carolina/1/1918(H1N1), and one further reacted with A/swine/Iowa/15/1930(H1N1). These results help to define the genetic diversity of the influenza anti-HA antibody repertoire profile induced following infection and vaccination, which may facilitate the development of influenza vaccines that are more protective and broadly neutralizing.ImportanceProtection against influenza viruses is mediated mainly by antibodies, and in most cases this antibody response is narrow, only providing protection against closely related viruses. In spite of this limited range of protection, recent findings indicate that individuals immune to one influenza virus may contain antibodies (generally a minority of the overall response) that are more broadly reactive. These findings have raised the possibility that influenza vaccines could induce a more broadly protective response, reducing the need for frequent vaccine strain changes. However, interpretation of these observations is hampered by the lack of quantitative characterization of the antibody repertoire. In this study, we used single-cell cloning of influenza HA-specific B cells to assess the diversity and nature of the antibody response to influenza hemagglutinin in mice. Our findings help to put bounds on the diversity of the anti-hemagglutinin antibody response, as well as characterizing the cross-reactivity, affinity, and molecular nature of the antibody response.

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Repeated Influenza Vaccination Boosts and Maintains H1N1pdm09 Neuraminidase Antibody Titers

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