Variant SARS-CoV-2 mRNA vaccines confer broad neutralization as primary or booster series in mice

Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of a global pandemic that has led to more than 2.8 million deaths worldwide. Safe and effective vaccines are now available, including Moderna's COVID-19 vaccine (mRNA-1273) that showed 94% efficacy in prevention of symptomatic COVID-19 disease in a phase 3 clinical study. mRNA-1273 encodes for a prefusion stabilized full length spike (S) protein of the Wuhan-Hu-1 isolate. However, the emergence of SARS-CoV-2 variants has led to concerns of viral escape from vaccine-induced immunity. Several emerging variants have shown decreased susceptibility to neutralization by vaccine induced immunity, most notably the B.1.351 variant, although the overall impact on vaccine efficacy remains to be determined. Here, we present the initial evaluation in mice of two updated COVID-19 mRNA vaccines designed to target emerging SARS-CoV-2 variants: (1) monovalent mRNA-1273.351 encodes for the S protein found in the B.1.351 lineage and (2) mRNA-1273.211 comprising a 1:1 mix of mRNA-1273 and mRNA-1273.351. Both vaccines were evaluated as a 2-dose primary series in mice; mRNA-1273.351 was also evaluated as a booster dose in animals previously vaccinated with 2-doses of mRNA-1273. The results demonstrated that a primary vaccination series of mRNA-1273.351 was effective at increasing neutralizing antibody titers against the B.1.351 lineage, while mRNA-1273.211 was most effective at providing broad cross-variant neutralization in mice. In addition, these results demonstrated a third dose of mRNA-1273.351 significantly increased both wild-type and B.1.351-specific neutralization titers. Both mRNA-1273.351 and mRNA-1273.211 are currently being evaluated in additional pre-clinical challenge models and in phase 1/2 clinical studies.

Stabilization of the SARS-CoV-2 Spike Receptor-Binding Domain Using Deep Mutational Scanning and Structure-Based Design

“…While the stabilizing mutations reported here are not expected to impact the effectiveness of RBD-based vaccines, the improvements in manufacturability, stability, and solution properties we observe could have a significant impact on the manufacturing and distribution of protein-based vaccines for SARS-CoV-2. As SARS-CoV-2 vaccines are already being updated in response to antigenic drift (83), such improvements could be crucial for maximizing the scale and speed of vaccine production and buffering against unanticipated changes in the stability or solution properties of antigens derived from novel SARS-CoV-2 isolates. Moreover, improved resistance to denaturation and shelf-life stability at various temperatures could be particularly impactful for reliable distribution in developing countries that lack cold chain infrastructure.…”

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

“…Importantly, two doses of B.1.351 S-Trimer was also able to fully back-neutralize against the original SARS-CoV-2 strain, as well as neutralize the B.1.1.7 variant. In contrast, an mRNA COVID-19 vaccine candidate based on the B.1.351 variant spike protein (containing all mutations found in B.1.351) appeared to induce approximately 6-fold lower neutralizing antibody titers against the original SARS-CoV-2 strain compared to the prototype mRNA vaccine in mice ( 21 ).…”

An AAV-based, room-temperature-stable, single-dose COVID-19 vaccine provides durable immunogenicity and protection in non-human primates

“…Additionally, new SARS-CoV-2 strains are emerging, and the immune escape of new variants is of concern (Garcia-Beltran et al, 2021;Wu et al, 2021b). Efficacy of re-vaccination against the emerging variants has also been explored (Alter et al, 2021;Collier et al, 2021;Liu et al, 2021;Wu et al, 2021a). Viral vector vaccines that elicit an immune response against the vector might show reduced efficacy after several doses due to the neutralization of the vector.…”