ABSTRACT
Since the COVID-19 pandemic began in 2020, viral sequencing has documented 131 individual mutations in the viral spike protein across 48 named variants. To determine the ability of vaccine-mediated humoral immunity to keep pace with continued SARS-CoV-2 evolution, we assessed the neutralization potency of sera from 76 vaccine recipients collected after 2 to 6 immunizations against a comprehensive panel of mutations observed during the pandemic. Remarkably, while many individual mutations that emerged between 2020 and 2022 exhibit escape from sera following primary vaccination, few escape boosted sera. However, progressive loss of neutralization was observed across newer variants, irrespective of vaccine doses. Importantly, an updated XBB.1.5 booster significantly increased titers against newer variants but not JN.1. These findings demonstrate that seasonal boosters improve titers against contemporaneous strains, but novel variants continue to evade updated mRNA vaccines, demonstrating the need for novel approaches to adequately control SARS-CoV-2 transmission.
Subject(s)
COVID-19ABSTRACT
Multivalent antigen display is a well-established design principle to enhance humoral immunity elicited by subunit vaccines. Protein-based virus-like particles (VLPs) are an important vaccine platform that implements this principle but also contain thymus-dependent off-target epitopes, thereby generating neutralizing and defocused antibody responses against the scaffold itself. Here, we present DNA origami as an alternative platform to display the receptor binding domain (RBD) of SARS-CoV-2. DNA-based scaffolds provide nanoscale control over antigen organization and, as thymus-independent antigens, are expected to induce only extrafollicular B-cell responses. Our icosahedral DNA-based VLPs elicited valency-dependent BCR signaling in two reporter B-cell lines, with corresponding increases in RBD-specific antibody responses following sequential immunization in mice. Mouse sera also neutralized the Wuhan strain of SARS-CoV-2--but did not contain boosted, DNA-specific antibodies. Thus, multivalent display using DNA origami can enhance immunogenicity of protein antigens without generating scaffold-directed immunological memory and may prove useful for rational vaccine design.
ABSTRACT
ABSTRACT The SARS-CoV-2 Omicron variant (B.1.1.529) contains mutations that mediate escape from infection and vaccine-induced antibody responses, although the extent to which these substitutions in spike and non-spike proteins affect T cell recognition is unknown. Here we show that T cell responses in individuals with prior infection, vaccination, both prior infection and vaccination, and boosted vaccination are largely preserved to Omicron spike and non-spike proteins. However, we also identify a subset of individuals (∼21%) with a >50% reduction in T cell reactivity to the Omicron spike. Evaluation of functional CD4 + and CD8 + memory T cell responses confirmed these findings and reveal that reduced recognition to Omicron spike is primarily observed within the CD8 + T cell compartment. Booster vaccination substantially enhanced T cell responses to Omicron spike. In contrast to neutralizing immunity, these findings suggest preservation of T cell responses to the Omicron variant, although with reduced reactivity in some individuals.
ABSTRACT
SUMMARY Recent surveillance has revealed the emergence of the SARS-CoV-2 Omicron variant (BA.1/B.1.1.529) harboring up to 36 mutations in spike protein, the target of vaccine-induced neutralizing antibodies. Given its potential to escape vaccine-induced humoral immunity, we measured neutralization potency of sera from 88 mRNA-1273, 111 BNT162b, and 40 Ad26.COV2.S vaccine recipients against wild type, Delta, and Omicron SARS-CoV-2 pseudoviruses. We included individuals that were vaccinated recently (<3 months), distantly (6-12 months), or recently boosted, and accounted for prior SARS-CoV-2 infection. Remarkably, neutralization of Omicron was undetectable in most vaccinated individuals. However, individuals boosted with mRNA vaccines exhibited potent neutralization of Omicron only 4-6-fold lower than wild type, suggesting that boosters enhance the cross-reactivity of neutralizing antibody responses. In addition, we find Omicron pseudovirus is more infectious than any other variant tested. Overall, this study highlights the importance of boosters to broaden neutralizing antibody responses against highly divergent SARS-CoV-2 variants.
Subject(s)
COVID-19ABSTRACT
Eliciting antibodies to surface-exposed viral glycoproteins can generate protective responses that control and prevent future infections. Targeting conserved sites may reduce the likelihood of viral escape and limit spread of related viruses with pandemic potential. Here, we leveraged rational immunogen design to focus humoral responses on conserved epitopes. Using glycan engineering and epitope scaffolding, we directed murine serum antibody responses to conserved receptor binding motif (RBM) and domain (RBD) epitopes in the context of SARS-CoV-2 spike imprinting. Whereas all engineered immunogens elicited a robust SARS-CoV-2-neutralizing serum response, the RBM-focusing immunogens exhibited increased potency against related sarbecoviruses, SARS-CoV, WIV1-CoV, RaTG13-CoV, and SHC014-CoV; structural characterization of representative antibodies defined a conserved epitope. Furthermore, the RBM-focused sera conferred protection against SARS-CoV-2 challenge. Thus, RBM focusing is a promising strategy to elicit breadth across emerging sarbecoviruses without compromising SARS-CoV-2 protection. Broadly, these engineering strategies are adaptable to other viral glycoproteins for targeting conserved epitopes.Funding: We acknowledge funding from NIH R01s AI146779 (AGS), AI124378, AI137057 and AI153098 (DL), R01 AI157155 (MSD) and a Massachusetts Consortium on Pathogenesis Readiness (MassCPR) grant (AGS); training grants: NIGMS T32 GM007753 (BMH, TMC); T32 AI007245 (JF); F31 Al138368 (MS); F30 AI160908 (BMH). ABB is supported by the National Institutes for Drug Abuse (NIDA) Avenir New Innovator Award DP2DA040254, the MGH Transformative Scholars Program as well as funding from the Charles H. Hood Foundation (ABB). This independent research was supported by the Gilead Sciences Research Scholars Program in HIV (ABB). JBC is supported by a Helen Hay Whitney Foundation postdoctoral fellowship.Declaration of Interests: BMH, TMC, and AGS have filed a provisional patent for the described immunogens. MSD is a consultant for Inbios, Vir Biotechnology, and Carnival Corporation, and on the Scientific Advisory Boards of Moderna and Immunome. The Diamond laboratory has received unrelated funding support in sponsored research agreements from Vir Biotechnology, Moderna, and Emergent BioSolutions.Ethics Approval Statement: All experiments were conducted with institutional IACUC approval (MGH protocol 2014N000252). Animal studies were carried out in accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. The protocols were approved by the Institutional Animal Care and Use Committee at the Washington University School of Medicine (assurance number A3381–01).
Subject(s)
HIV Infections , Multiple Sclerosis , Emergencies , Multiple Sulfatase Deficiency DiseaseABSTRACT
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.
Subject(s)
Pulmonary Disease, Chronic Obstructive , Infections , Breakthrough Pain , COVID-19ABSTRACT
Background Understanding immunogenicity and effectiveness of SARS-CoV-2 vaccines is critical to guide rational use. Methods We compared the immunogenicity of mRNA-1273, BNT-162b2 or Ad26.COV2.S in ambulatory adults in Massachusetts, USA. To correlate immunogenicity with effectiveness of the three vaccines, 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 negative neutralization titers. Bulk and cytotoxic T-cell responses were higher in mRNA1273 and BNT162b2 than Ad26.COV2.S recipients, and <50% of vaccinees demonstrate CD8+ T-cell responses to spike peptides. Antibody concentrations and neutralization titers increased comparably after the first dose of either vaccine, and further in recipients of a second dose. Prior infection was associated with high antibody concentrations and neutralization even after a single dose and regardless of vaccine. Neutralization of beta, gamma and delta strains were poorer regardless of vaccine. Relative to mRNA1273, the effectiveness of BNT162b2 was lower against infection and hospitalization; and Ad26COV2.S was lower against infection, hospitalization and death. Conclusions Variation in the immunogenicity correlates with variable effectiveness of the three FDA EUA vaccines deployed in the USA.