Abstract
The effectiveness of influenza vaccines against circulating A(H1N1)pdm09 viruses was modest for several seasons despite the absence of antigenic drift of hemagglutinin (HA), the primary vaccine component. Since antibodies against HA and neuraminidase (NA) contribute independently to protection against disease, antigenic changes in NA may allow A(H1N1)pdm09 viruses to escape from vaccine-induced immunity. In this study, analysis of the specificities of human NA-specific monoclonal antibodies identified antigenic sites that have changed over time. The impact of these differences on in vitro inhibition of enzyme activity was not evident for polyclonal antisera until viruses emerged in 2013 without a predicted glycosylation site at amino acid 386 in NA. Phylogenetic and antigenic cartography demonstrated significant antigenic changes that in most cases aligned with genetic differences. Typical of NA drift, the antigenic difference is observed in one direction, with antibodies against conserved antigenic domains in A/California/7/2009 (CA/09) continuing to inhibit NA of recent A(H1N1)pdm09 viruses reasonably well. However, ferret CA/09-specific antiserum that inhibited the NA of A/Michigan/45/2015 (MI/15) very well in vitro, protected mice against lethal MI/15 infection poorly. These data show that antiserum against the homologous antigen is most effective and suggest the antigenic properties of NA should not be overlooked when selecting viruses for vaccine production.IMPORTANCE The effectiveness of seasonal influenza vaccines against circulating A(H1N1)pdm09 viruses has been modest in recent years, despite the absence of antigenic drift of HA, the primary vaccine component. Human monoclonal antibodies identified antigenic sites in NA that changed early after the new pandemic virus emerged. The reactivity of ferret antisera demonstrated antigenic drift of A(H1N1)pdm09 NA from 2013 onward. Passive transfer of serum raised against A/California/7/2009 was less effective than ferret serum against the homologous virus in protecting mice against a virus with the NA of more recent virus, A/Michigan/45/2015. Given the long-standing observation that NA-inhibiting antibodies are associated with resistance against disease in humans, these data demonstrate the importance of evaluating NA drift and suggest that vaccine effectiveness might be improved by selecting viruses for vaccine production that have NAs antigenically similar to those of circulating influenza viruses.
Highlights
The effectiveness of influenza vaccines against circulating A(H1N1) pdm09 viruses was modest for several seasons despite the absence of antigenic drift of hemagglutinin (HA), the primary vaccine component
While there is evidence in a ferret model that antigenic changes can be selected under conditions fo immune pressure [4], antigenic drift of HA was not observed with ferret antisera [5, 6], and it was the loss of human serum reactivity [7] which prompted the recommendation to update the A(H1N1)pdm09 virus component of influenza vaccines
Multiple studies have shown increases in NA inhibition antibody titers following vaccination with either inactive or live attenuated vaccines [23,24,25], and clinical challenge studies demonstrate a correlation between NA inhibition titers and reduced symptoms of disease [26]. These results demonstrate the importance of considering NA drift when selecting viruses for vaccine production and suggest the antigenic changes in NA may have contributed to past vaccine failures
Summary
The effectiveness of influenza vaccines against circulating A(H1N1) pdm viruses was modest for several seasons despite the absence of antigenic drift of hemagglutinin (HA), the primary vaccine component. Ferret CA/09-specific antiserum that inhibited the NA of A/Michigan/45/2015 (MI/15) very well in vitro, protected mice against lethal MI/15 infection poorly These data show that antiserum against the homologous antigen is most effective and suggest the antigenic properties of NA should not be overlooked when selecting viruses for vaccine production. In a past study of NA drift, it was noted that differences in antigenicity measured by the classical “two-way” analysis with ferret antisera are often observed to occur in one direction only [10] such that antiserum against one of a pair of viruses reacts against NAs of both viruses, while the other antiserum reacts poorly with the nonhomologous virus This raises the possibility that antigenic drift may not always result in a loss of immunity. In spite of being used at similar titers, NA-specific antibodies in polyclonal antiserum raised against CA/09 were not as effective as those raised in response to A/Michigan/45/15 (MI/15), a more recent A(H1N1)pdm virus which contains an NA that has experienced antigenic drift
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