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PURPOSE The immunogenicity and reactogenicity of SARS-CoV-2 vaccines in patients with cancer are poorly understood. METHODS We performed a prospective cohort study of adults with solid-organ or hematologic cancers to evaluate anti–SARS-CoV-2 immunoglobulin A/M/G spike antibodies, neutralization, and reactogenicity ≥ 7 days following two doses of mRNA-1273, BNT162b2, or one dose of Ad26.COV2.S. We analyzed responses by multivariate regression and included data from 1,638 healthy controls, previously reported, for comparison. RESULTS Between April and July 2021, we enrolled 1,001 patients; 762 were eligible for analysis (656 had neutralization measured). mRNA-1273 was the most immunogenic (log10 geometric mean concentration [GMC] 2.9, log10 geometric mean neutralization titer [GMT] 2.3), followed by BNT162b2 (GMC 2.4; GMT 1.9) and Ad26.COV2.S (GMC 1.5; GMT 1.4; P < .001). The proportion of low neutralization (< 20% of convalescent titers) among Ad26.COV2.S recipients was 69.9%. Prior COVID-19 infection (in 7.1% of the cohort) was associated with higher responses ( P < .001). Antibody titers and neutralization were quantitatively lower in patients with cancer than in comparable healthy controls, regardless of vaccine type ( P < .001). Receipt of chemotherapy in the prior year or current steroids were associated with lower antibody levels and immune checkpoint blockade with higher neutralization. Systemic reactogenicity varied by vaccine and correlated with immune responses ( P = .002 for concentration, P = .016 for neutralization). In 32 patients who received an additional vaccine dose, side effects were similar to prior doses, and 30 of 32 demonstrated increased antibody titers (GMC 1.05 before additional dose, 3.17 after dose). CONCLUSION Immune responses to SARS-CoV-2 vaccines are modestly impaired in patients with cancer. These data suggest utility of antibody testing to identify patients for whom additional vaccine doses may be effective and appropriate, although larger prospective studies are needed.

The immunogenicity of SARS-CoV-2 vaccines in cancer patients receiving radiotherapy is unknown. This prospective cohort study demonstrates that anti-SARS-CoV-2 spike antibody and neutralization titers are reduced in a subset of thoracic radiotherapy patients, possibly due to immunosuppressive conditions. Antibody testing may be useful to identify candidates for additional vaccine doses.

After BNT162b2 messenger RNA vaccination, antibody levels to spike, receptor-binding domain, and virus neutralization were examined in 149 nursing home residents and 110 healthcare worker controls. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)–naive nursing home residents’ median post–second vaccine dose antibody neutralization titers are one-quarter that of SARS-CoV-2–naive healthcare workers.

High COVID-19 mortality among nursing home (NH) residents led to their prioritization for SARS-CoV-2 vaccination; most NH residents received BNT162b2 mRNA vaccination under the Emergency Use Authorization due to first to market and its availability. With NH residents’ poor initial vaccine response, the rise of NH breakthrough infections and outbreaks, characterization of the durability of immunity to inform public health policy on the need for boosting is needed. We report on humoral immunity from 2 weeks to 6-months post-vaccination in 120 NH residents and 92 ambulatory healthcare worker controls with and without pre-vaccination SARS-CoV-2 infection. Anti-spike and anti-receptor binding domain (RBD) IgG, and serum neutralization titers, were assessed using a bead-based ELISA method and pseudovirus neutralization assay. Anti-spike, anti-RBD and neutralization levels dropped more than 84% over 6 months’ time in all groups irrespective of prior SARS-CoV-2 infection. At 6 months post-vaccine, 70% of the infection-naive NH residents had neutralization titers at or below the lower limit of detection compared to 16% at 2 weeks after full vaccination. These data demonstrate a significant reduction in levels of antibody in all groups. In particular, those infection-naive NH residents had lower initial post-vaccination humoral immunity immediately and exhibited the greatest declines 6 months later. Healthcare workers, given their younger age and relative good-health, achieved higher initial antibody levels and better maintained them, yet also experienced significant declines in humoral immunity. Based on the rapid spread of the delta variant and reports of vaccine breakthrough in NH and among younger community populations, boosting NH residents may be warranted.

Background Understanding immunogenicity and effectiveness of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines is critical to guide rational use. Methods We compared the immunogenicity of mRNA-1273, BNT-162b2, and Ad26.COV2.S in healthy ambulatory adults. We performed an inverse-variance meta-analysis of population-level effectiveness from public health reports in > 40 million individuals. Results A single dose of either mRNA vaccine yielded comparable antibody and neutralization titers to convalescent individuals. Ad26.COV2.S yielded lower antibody concentrations and frequently undetectable neutralization titers. Bulk and cytotoxic T-cell responses were higher in mRNA1273 and BNT162b2 than Ad26.COV2.S recipients. Regardless of vaccine, Conclusions Variation in the immunogenicity correlates with variable effectiveness of the 3 vaccines deployed in the United States.

Eliciting antibodies to surface-exposed viral glycoproteins can lead to protective responses that ultimately control and prevent future infections. Targeting functionally conserved epitopes may help reduce the likelihood of viral escape and aid in preventing the spread of related viruses with pandemic potential. One such functionally conserved viral epitope is the site to which a receptor must bind to facilitate viral entry. Here, we leveraged rational immunogen design strategies to focus humoral responses to the receptor binding motif (RBM) on the SARS-CoV-2 spike. Using glycan engineering and epitope scaffolding, we find an improved targeting of the serum response to the RBM in context of SARS-CoV-2 spike imprinting. Furthermore, we observed a robust SARS-CoV-2-neutralizing serum response with increased potency against related sarbecoviruses, SARS-CoV, WIV1-CoV, RaTG13-CoV, and SHC014-CoV. Thus, RBM focusing is a promising strategy to elicit breadth across emerging sarbecoviruses and represents an adaptable design approach for targeting conserved epitopes on other viral glycoproteins.One Sentence SummarySARS-CoV-2 immune focusing with engineered immunogens

Vaccination elicits immune responses capable of potently neutralizing SARS-CoV-2. However, ongoing surveillance has revealed the emergence of variants harboring mutations in spike, the main target of neutralizing antibodies. To understand the impact of these variants, we evaluated the neutralization potency of 99 individuals that received one or two doses of either BNT162b2 or mRNA-1273 vaccines against pseudoviruses representing 10 globally circulating strains of SARS-CoV-2. Five of the 10 pseudoviruses, harboring receptor-binding domain mutations, including K417N/T, E484K, and N501Y, were highly resistant to neutralization. Cross-neutralization of B.1.351 variants was comparable to SARS-CoV and bat-derived WIV1-CoV, suggesting that a relatively small number of mutations can mediate potent escape from vaccine responses. While the clinical impact of neutralization resistance remains uncertain, these results highlight the potential for variants to escape from neutralizing humoral immunity and emphasize the need to develop broadly protective interventions against the evolving pandemic., Graphical abstract, Analyses of sera from individuals vaccinated with one or two doses of mRNA vaccines against 10 circulating variants of SARS-CoV-2 show that P.1 and B.1.351 in particular exhibit limited neutralization by vaccine-induced humoral immunity. This escape was found to be largely mediated by mutations in the receptor-binding domain of SARS-CoV-2 spike.

Initial exposure to a pathogen elicits an adaptive immune response to control and eradicate the threat. Interrogating the abundance and specificity of the naive B cell repertoire drives understanding of how to mount protective responses. Here, we isolated naive B cells from eight seronegative human donors targeting the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) receptor binding domain (RBD). Single-cell B cell receptor (BCR) sequencing identified diverse gene usage and no restriction on complementarity determining region length. A subset of recombinant antibodies produced by naive B cell precursors bound to SARS-CoV-2 RBD and engaged circulating variants including B.1.1.7, B.1.351, and B.1.617.2, as well as preemergent bat-derived coronaviruses RaTG13, SHC104, and WIV1. By structural characterization of a naive antibody in complex with SARS-CoV-2 spike, we identified a conserved mode of recognition shared with infection-induced antibodies. We found that representative naive antibodies could signal in a B cell activation assay, and by using directed evolution, we could select for a higher-affinity RBD interaction, conferred by a single amino acid change. The minimally mutated, affinity-matured antibodies also potently neutralized SARS-CoV-2. Understanding the SARS-CoV-2 RBD–specific naive repertoire may inform potential responses capable of recognizing future SARS-CoV-2 variants or emerging coronaviruses, enabling the development of pan-coronavirus vaccines aimed at engaging protective germline responses.

Effective countermeasures are needed against emerging coronaviruses of pandemic potential, similar to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Designing immunogens that elicit broadly neutralizing antibodies to conserved viral epitopes on the major surface glycoprotein, spike, such as the receptor binding domain (RBD) is one potential approach. Here, we report the generation of homotrimeric RBD immunogens from different sarbecoviruses using a stabilized, immune-silent trimerization tag. In mice, we find that a cocktail of these homotrimeric sarbecovirus RBDs elicits antibodies to conserved viral epitopes outside of the ACE2 receptor binding motif (RBM). Importantly, these responses neutralize all sarbecovirus components even in context of prior SARS-CoV-2 imprinting. We further show that a substantial fraction of the neutralizing antibodies elicited after vaccination in humans also engages non-RBM epitopes on the RBD. Collectively, our results suggest a strategy for eliciting broadly neutralizing responses leading to a pan-sarbecovirus vaccine.Author summaryImmunity to SARS-CoV-2 in the human population will be widespread due to natural infection and vaccination. However, another novel coronavirus will likely emerge in the future and may cause a subsequent pandemic. Humoral responses induced by SARS-CoV-2 infection and vaccination provide limited protection against even closely related coronaviruses. We show immunization with a cocktail of trimeric coronavirus receptor binding domains induces a neutralizing antibody response that is broadened to related coronaviruses with pandemic potential. Importantly, this broadening occurs in context of an initial imprinted SARS-CoV-2 spike immunization showing that preexisting immunity can be expanded to recognize other related coronaviruses. Our immunogens focused the serum antibody response to conserved epitopes on the receptor binding domain outside of the ACE2 receptor binding motif; this contrasts with current SARS-CoV-2 therapeutic antibodies, which predominantly target the receptor binding motif.