Author Correction: A pan-influenza antibody inhibiting neuraminidase via receptor mimicry.
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ABSTRACT:
SUBMITTER: Momont C
PROVIDER: S-EPMC10356599 | biostudies-literature | 2023 Jul
REPOSITORIES: biostudies-literature
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Author Correction: A pan-influenza antibody inhibiting neuraminidase via receptor mimicry.
Momont Corey C Dang Ha V HV Zatta Fabrizia F Hauser Kevin K Wang Caihong C di Iulio Julia J Minola Andrea A Czudnochowski Nadine N De Marco Anna A Branch Kaitlin K Donermeyer David D Vyas Siddhant S Chen Alex A Ferri Elena E Guarino Barbara B Powell Abigail E AE Spreafico Roberto R Yim Samantha S SS Balce Dale R DR Bartha Istvan I Meury Marcel M Croll Tristan I TI Belnap David M DM Schmid Michael A MA Schaiff William Timothy WT Miller Jessica L JL Cameroni Elisabetta E Telenti Amalio A Virgin Herbert W HW Rosen Laura E LE Purcell Lisa A LA Lanzavecchia Antonio A Snell Gyorgy G Corti Davide D Pizzuto Matteo Samuele MS
Nature 20230701 7970
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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.
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Project description:Neuraminidase (NA)-based immunity to influenza can be useful for protecting against novel antigenic variants. To develop safe and effective tools to assess NA-based immunity, we generated a baculovirus-based pseudotyped virus, N1-Bac, that expresses the full-length NA of the influenza A/California/07/2009 (H1N1)pdm09 strain. We evaluated the level of NA-inhibiting (NI) antibodies in the paired blood sera of influenza patients by means of an enzyme-linked lectin assay (ELLA) using the influenza virus or N1-Bac. Additionally, we evaluated the level of NA antibodies by means of the enzyme-linked immunosorbent assay (ELISA) with an N1-expressing Sf21 culture. We detected a strong correlation between our results from using the influenza virus and NA-Bac pseudoviruses to detect NI antibodies and a medium-strong correlation between NI antibodies and NA antibodies determined by an N1-cell ELISA, indicating that baculovirus-based platforms can be successfully used to evaluate NI or NA antibodies. Furthermore, animal experiments showed that immunization with N1-Bac protected against infection with a drift variant of the A/H1N1pdm09 influenza virus. Our results demonstrate that recombinant baculovirus can be an effective influenza pseudotype to evaluate influenza serologic immunity and protect against influenza virus infection.
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Project description:Influenza viruses present a significant health challenge each year, as in the H3N2 epidemic of 2012-2013. Here we describe an antibody, F045-092, that possesses broadly neutralizing activity against the entire H3 subtype and accommodates the natural variation and additional glycosylation in all strains tested from 1963 to 2011. Crystal structures of F045-092 in complex with HAs from 1975 and 2011 H3N2 viruses reveal the structural basis for its neutralization breadth through insertion of its 23-residue HCDR3 into the receptor-binding site that involves striking receptor mimicry. F045-092 extends its recognition to divergent subtypes, including H1, H2 and H13, using the enhanced avidity of its IgG to overcome lower-affinity Fab binding, as observed with other antibodies that target the receptor-binding site. This unprecedented level of antibody cross-reactivity against the H3 subtype can potentially inform on development of a pan-H3 vaccine or small-molecule therapeutics.
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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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Project description:[This corrects the article DOI: 10.1038/s42003-019-0536-x.].
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