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.
Highlights
Influenza is an acute respiratory disease that is annually estimated to cause 3 – 5 million cases of severe illness and 290 000 – 650 000 deaths worldwide [1, 2]
Recent studies have emphasized the importance of NA-specific antibodies in protection against influenza disease and found that it may be an independent correlate of protection [6, 7]
Antibody titers were boosted after repeated vaccination, the magnitude of fold-induction declined, which was most prominent for functional NA inhibition (NAI) and PRNT50 titers
Summary
Influenza is an acute respiratory disease that is annually estimated to cause 3 – 5 million cases of severe illness and 290 000 – 650 000 deaths worldwide [1, 2]. Hemagglutinin (HA) is the major surface glycoprotein on the virus that mediates viral entry by binding to sialic acid receptors on the surface of host cells. Antibodies that target the HA globular head and block binding to sialic acids are considered the classical mediators of protection against influenza infection. These antibodies are measured by hemagglutination inhibition (HI) assay and the HI titer has been the gold standard for measuring vaccine immunogenicity for many years. Despite NA being an antigenic target for induction of protective antibody responses, the quantity and quality of NA is not regulated in current influenza vaccines. Studies have reported variable seroconversion rates for NA-specific antibody responses after vaccination with inactivated influenza vaccines, ranging between 23 – 64% [7, 10, 11]
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