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.
ABSTRACT
Multivalent antigen display is a well-established principle to enhance humoral immunity. Protein-based virus-like particles (VLPs) are commonly used to spatially organize antigens. However, protein-based VLPs are limited in their ability to control valency on fixed scaffold geometries and are thymus-dependent antigens that elicit neutralizing B cell memory themselves, which can distract immune responses. Here, we investigated DNA origami as an alternative material for multivalent antigen display in vivo, applied to the receptor binding domain (RBD) of SARS-CoV2 that is the primary antigenic target of neutralizing antibody responses. Icosahedral DNA-VLPs elicited neutralizing antibodies to SARS-CoV-2 in a valency-dependent manner following sequential immunization in mice, quantified by pseudo- and live-virus neutralization assays. Further, induction of B cell memory against the RBD required T cell help, but the immune sera did not contain boosted, class-switched antibodies against the DNA scaffold. This contrasted with protein-based VLP display of the RBD that elicited B cell memory against both the target antigen and the scaffold. Thus, DNA-based VLPs enhance target antigen immunogenicity without generating off-target, scaffold-directed immune memory, thereby offering a potentially important alternative material for particulate vaccine design.
ABSTRACT
BACKGROUND: The BNT162b2 SARS-CoV-2 mRNA vaccination has mitigated the burden of COVID-19 among residents of long-term care facilities considerably, despite being excluded from the vaccine trials. Data on reactogenicity (vaccine side effects) in this population are limited. AIMS: To assess reactogenicity among nursing home (NH) residents. To provide a plausible proxy for predicting vaccine response among this population. METHODS: We enrolled and sampled NH residents and community-dwelling healthcare workers who received the BNT162b2 mRNA vaccine, to assess local or systemic reactogenicity and antibody levels (immunogenicity). RESULTS: NH residents reported reactions at a much lower frequency and lesser severity than the community-dwelling healthcare workers. These reactions were mild and transient with all subjects experiencing more local than systemic reactions. Based on our reactogenicity and immunogenicity data, we developed a linear regression model predicting log-transformed anti-spike, anti-receptor-binding domain (RBD), and neutralizing titers, with a dichotomous variable indicating the presence or absence of reported reactions which revealed a statistically significant effect, with estimated shifts in log-transformed titers ranging from 0.32 to 0.37 (all p < 0.01) indicating greater immunogenicity in subjects with one or more reported reactions of varying severity. DISCUSSION: With a significantly lower incidence of post-vaccination reactions among NH residents as reported in this study, the BNT162b2 mRNA vaccine appears to be well-tolerated among this vulnerable population. If validated in larger populations, absence of reactogenicity could help guide clinicians in prioritizing vaccine boosters. CONCLUSIONS: Reactogenicity is significantly mild among nursing home residents and overall, subjects who reported post-vaccination reactions developed higher antibody titers.
