Original antigenic sin priming of influenza virus hemagglutinin stalk antibodies

Abstract

<jats:p>Immunity to influenza viruses can be long-lived, but reinfections with antigenically distinct viral strains and subtypes are common. Reinfections can boost antibody responses against viral strains first encountered in childhood through a process termed “original antigenic sin.” It is unknown how initial childhood exposures affect the induction of antibodies against the hemagglutinin (HA) stalk domain of influenza viruses. This is an important consideration since broadly reactive HA stalk antibodies can protect against infection, and universal vaccine platforms are being developed to induce these antibodies. Here we show that experimentally infected ferrets and naturally infected humans establish strong “immunological imprints” against HA stalk antigens first encountered during primary influenza virus infections. We found that HA stalk antibodies are surprisingly boosted upon subsequent infections with antigenically distinct influenza A virus subtypes. Paradoxically, these heterosubtypic-boosted HA stalk antibodies do not bind efficiently to the boosting influenza virus strain. Our results demonstrate that an individual’s HA stalk antibody response is dependent on the specific subtype of influenza virus that they first encounter early in life. We propose that humans are susceptible to heterosubtypic influenza virus infections later in life since these viruses boost HA stalk antibodies that do not bind efficiently to the boosting antigen.</jats:p>

Dynamics of neutralizing antibody titers in the months after SARS-CoV-2 infection

“…Acute infection is always associated with an initial peak in antibody titers due to a burst of short-lived antibody-secreting cells [38]. For many other infections, titers decline from this initial peak but then reach a stable plateau that is maintained for years or even decades by long-lived plasma cells and memory B cells that can be recalled during subsequent infections [12][13][14][15][16]18,39,40].…”

Mapping the Antibody Repertoires in Ferrets with Repeated Influenza A/H3 Infections: Is Original Antigenic Sin Really “Sinful”?

“…While our current work was focused on HA head-specific antibodies, it does not consider antibodies directed towards the HA stem and neuraminidase that have also been shown to exhibit OAS and may influence the dynamics of this system. 40,41 Future work that refines these antibody trajectories across multiple infections and multiple regions of an influenza virus may facilitate the development of more effective influenza vaccines.…”

The Power of First Impressions: Can Influenza Imprinting during Infancy Inform Vaccine Design?

“…Additionally, this study also showed that those who were imprinted with H3 strains which would have been circulating during their birth year, would not be afforded cross-protective responses against an H5 virus. More recently, Arevalo et al showed that natural H1N1 imprinting in childhood was able to elicit HA stem specific antibodies that were recalled at reinfection and unable to bind efficient to the reinfecting strain suggesting an imprinting event specifically on HA stem epitopes [ 51 ]. Although a report by Tesini and colleagues indicated that the antibody and memory B cell responses during vaccination in a previously infected host is dynamic with several outcomes [ 52 ].…”