Targeting the SARS-CoV-2 spike: The surface of severe acute respiratory syndrome–coronavirus 2 (SARS-CoV-2) is decorated with trimeric spikes that bind to host cell receptors. These spikes also elicit an antibody response, so understanding antibody recognition may aid in vaccine design. Yuan et al. determined the structure of CR3022, a neutralizing antibody obtained from a convalescent SARS-CoV–infected patient, in complex with the receptor-binding domain of the SARS-CoV-2 spike. The antibody binds to an epitope conserved between SARS-CoV-2 and SARS-CoV that is distinct from the receptor-binding site. CR3022 likely binds more tightly to SARS-CoV because its epitope contains a glycan not present in SARS-CoV-2. Structural modeling showed that the epitope is only revealed when at least two of the three spike proteins are in a conformation competent to bind the receptor. Science , this issue p. 630

Egg-adaptive mutations in influenza hemagglutinin (HA) often emerge during the production of egg-based seasonal influenza vaccines, which contribute to the largest share in the global influenza vaccine market. While some egg-adaptive mutations have minimal impact on the HA antigenicity (e.g. G186V), others can alter it (e.g. L194P). Here, we show that the preference of egg-adaptive mutation in human H3N2 HA is strain-dependent. In particular, Thr160 and Asn190, which are found in many recent H3N2 strains, restrict the emergence of L194P but not G186V. Our results further suggest that natural amino acid variants at other HA residues also play a role in determining the preference of egg-adaptive mutation. Consistently, recent human H3N2 strains from different clades acquire different mutations during egg passaging. Overall, these results demonstrate that natural mutations in human H3N2 HA can influence the preference of egg-adaptation mutation, which has important implications in seed strain selection for egg-based influenza vaccine.

Vaccine development against SARS‐CoV‐2 has drawn attention around the globe due to the exploding pandemic. Although COVID‐19 is caused by a new coronavirus, SARS‐CoV‐2, previous research on other coronavirus vaccines, such as FIPV, SARS, and MERS, has provided valuable information for the rapid development of COVID‐19 vaccine. However, important knowledge gaps remain — some are specific to SARS‐CoV‐2, others are fundamental to immunology and vaccinology. Here, we discuss areas that need to be addressed for COVID‐19 vaccine development, and what can be learned from examples of vaccine development in the past. Since the beginning of the outbreak, the research progress on COVID‐19 has been remarkable. We are therefore optimistic about the rapid development of COVID‐19 vaccine.

Seasonal influenza viruses cause significant global illness and death annually, and the potential spillover of avian H5N1 poses a serious pandemic threat. Traditional influenza vaccines target the variable hemagglutinin (HA) protein, necessitating annual vaccine updates, while the slower-evolving neuraminidase (NA) presents a promising target for broader protection. We investigated the breadth of anti-NA B cell responses to seasonal influenza vaccination in humans. We screened plasmablast-derived monoclonal antibodies (mAbs) from three donors, identifying 11 clonally distinct NA mAbs from 268 vaccine-specific mAbs. Among these, mAb-297 showed exceptionally broad NA inhibition, effectively protecting mice against lethal doses of influenza A and B viruses, including H5N1. We show that mAb-297 targets a common binding motif in the conserved NA active site. Our findings show that while B cell responses against NA following conventional, egg-derived influenza vaccines are rare, inducing broadly protective NA antibodies through such vaccination remains feasible, highlighting the importance of improving NA immunogens to develop a more broadly protective influenza vaccine.

Immune imprinting¹ or original antigenic sin² is a phenomenon whereby the immune system preferentially recalls its initial response to a related, often evolving pathogen after subsequent exposure. Despite its important implications for vaccine development, the causes of imprinting remain unclear. Here, to understand the basis and impact of imprinting by influenza A viruses, we characterized the B cell responses of young children after consecutive first infections with divergent H1N1 and H3N2 strains of influenza. Children had a primary but otherwise similar B cell response to that of adults. Adult B cells commonly cross-reacted with past strains using more stereotyped and mutated immunoglobulin genes, indicating substantial homosubtypic imprinting. In children, after consecutive heterosubtypic primary infections, up to 6% of memory B cells are H1/H3 cross-reactive and bind to the highly conserved central stalk epitope—a lead target for broadly protective vaccine candidates. Over 90% of these B cells had a higher affinity for the imprinting H3N2 strain, resulting in reduced breadth and neutralization potency against H1N1 strains. Mechanistically, the imprinting H3 strains and affected H1 strains shared a residue change in the stalk epitope (D46N) that was central to the nearly universal shift in reactivity, despite differing by only a single atomic group. In conclusion, imprinting by influenza viruses can cause a deleterious shift of nearly the entire memory recall response against key, conserved epitopes.

Understanding how immune history influences influenza immunity is essential for developing effective vaccines and therapeutic strategies. This study examines the antigenic imprinting of influenza hemagglutinin (HA) and neuraminidase (NA) using a mouse model with sequential infections by H1N1 virus strains exhibiting substantial antigenic differences in HA. In our pre-2009 influenza infection model, we observed that mice with more extensive infection histories produced higher levels of functional NA-inhibiting antibodies (NAI). However, following further infection with the 2009 pandemic H1N1 strain, these mice demonstrated a reduced NAI to the challenged virus. Interestingly, prior exposure to older strains resulted in a lower HA antibody response (neutralization and HAI) to the challenged virus in both pre- and post-2009 scenarios, potentially due to faster viral clearance facilitated by immune memory recall. Overall, our findings reveal distinct trajectories in HA and NA immune responses, suggesting that immune imprinting can differentially impact these proteins based on the extent of antigenic variation in influenza viruses. IMPORTANCE: Influenza viruses continue to pose a significant threat to human health, with vaccine effectiveness remaining a persistent challenge. Individual immune history is a crucial factor that can influence antibody responses to subsequent influenza exposures. While many studies have explored how pre-existing antibodies shape the induction of anti-HA antibodies following influenza virus infections or vaccinations, the impact on anti-NA antibodies has been less extensively studied. Using a mouse model, our study demonstrates that within pre-2009 H1N1 strains, an extensive immune history negatively impacted anti-HA antibody responses but enhanced anti-NA antibody responses. However, in response to the 2009 pandemic H1N1 strain, which experienced an antigenic shift, both anti-HA and anti-NA antibody responses were hindered by antibodies from prior pre-2009 H1N1 virus infections. These findings provide important insights into how antigenic imprinting affects both anti-HA and anti-NA antibody responses and underscore the need to consider immune history in developing more effective influenza vaccination strategies.