Preliminary Analysis of Safety and Immunogenicity of a SARS-CoV-2 Variant Vaccine Booster

Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of a global pandemic of coronavirus disease 2019 (COVID-19) that has led to more than 3 million deaths worldwide. Safe and effective vaccines are now available, including the mRNA-1273 prototype vaccine, which encodes for the Wuhan SARS-CoV-2 Spike protein stabilized in the prefusion conformation by 2 proline substitutions. This vaccine showed 94% efficacy in prevention of symptomatic COVID-19 disease in a phase 3 clinical study. Recently, SARS-CoV-2 variants have emerged, some of which have shown decreased susceptibility to neutralization by vaccine-induced antibody, most notably the B.1.351 variant, although the overall impact on vaccine efficacy remains to be determined. In addition, recent evidence of waning antibody levels after infection or vaccination point to the need for periodic boosting of immunity. Here we present the preliminary evaluation of a clinical study on the use of the prototype mRNA-1273 or modified COVID-19 mRNA vaccines, designed to target emerging SARS-CoV-2 variants as booster vaccines in participants previously vaccinated approximately 6 months earlier with two doses of the prototype vaccine, mRNA-1273. The modified vaccines include a monovalent mRNA-1273.351 encoding for the S protein found in the B.1.351 variant and multivalent mRNA-1273.211 comprising a 1:1 mix of mRNA-1273 and mRNA-1273.351. As single 50 μg booster vaccinations, both mRNA-1273 and mRNA-1273.351 had acceptable safety profiles and were immunogenic. Antibody neutralization titers against B.1.351 and P.1 variants measured by SARS-CoV-2 pseudovirus neutralization (PsVN) assays before the booster vaccinations, approximately 6 to 8 months after the primary series, were low or below the assay limit of quantification, although GMTs versus the wild-type strain remained above levels likely to be protective. Two weeks after the booster vaccinations, titers against the wild-type original strain, B.1.351, and P.1 variants increased to levels similar to or higher than peak titers after the primary series vaccinations. Although both mRNA-1273 and mRNA-1273.351 boosted neutralization of the wild-type original strain, and B.1.351 and P.1 variants, mRNA-1273.351 appeared to be more effective at increasing neutralization of the B.1.351 virus versus a boost with mRNA-1273. The vaccine trial is ongoing and boosting of clinical trial participants with the multivalent mRNA-1273.211 is currently being evaluated.

Broad neutralization against SARS-CoV-2 variants induced by a modified B.1.351 protein-based COVID-19 vaccine candidate

“…There did not appear to be significant differences in neutralizing antibody titers if the booster dose given was Prototype S-Trimer or B.1.351 S-Trimer. These findings appear to be consistent with preliminary Phase 1 clinical trial data evaluating booster doses of mRNA vaccine candidates based on either the original strain or B.1.351 variant ( 26 ). If these findings are further evaluated and confirmed in humans, greater flexibility in effective boosting strategies could be employed based on the supply of prototype and variant vaccines available at a given time.…”

SARS-CoV-2 mRNA Vaccine Induces Robust Specific and Cross-reactive IgG and Unequal Strain-specific Neutralizing Antibodies in Naïve and Previously Infected Recipients

“…Widely administered booster immunizations against reference/variants will expose a previously vaccinated and sensitized population to risk of vaccine reaction with attendant risks and discomforts 61 . Our data shows that previous SARS-CoV-2 exposure either from infection or vaccine results in greater symptoms in response to a second exposure to SARS-CoV-2 antigens; however, a recent small scale study which looked at booster vaccinations with one of the two mRNA vaccines reported no more than moderate symptoms in just 15% of subjects 62 .…”

The origins and potential future of SARS-CoV-2 variants of concern in the evolving COVID-19 pandemic

“…Fortunately, updating mRNA vaccines to target new variants is relatively straightforward, and clinical studies are already underway for variant-specific vaccines. For example, Moderna recently reported on phase 2 trials with mRNA-1273.351, a vaccine that matches changes in Spike observed in the B.1.351 variant 58 . That said, the results showed very modest increases in antibodies targeting B.1.351 following two doses of the standard Moderna vaccine with mRNA-1273.351, suggesting that variant-specific vaccines may primarily boost previous immune responses rather than convey new immune responses to the variant epitopes.…”