A third SARS-CoV-2 spike vaccination improves neutralization of variants-of-concern

Abstract

The emergence of SARS-CoV-2 variants that are more resistant to antibody-mediated neutralization pose a new hurdle in combating the COVID-19 pandemic. Although vaccines based on the original Wuhan sequence have been shown to be effective at preventing COVID-19, their efficacy is likely to be decreased against more neutralization-resistant variants-of-concern (VOC), in particular, the Beta variant originating in South Africa. We assessed, in mice, rabbits, and non-human primates, whether a third vaccination with experimental Wuhan-based Spike vaccines could alleviate this problem. Our data show that a third immunization improves neutralizing antibody titers against the variants-of-concern, Alpha (B.1.1.7), Beta (B.1.351), Gamma (P.1), and Delta (B.1.617.2). After three vaccinations, the level of neutralization against Beta was similar to the level of neutralization against the original strain after two vaccinations, suggesting that simply providing a third immunization could nullify the reduced activity of current vaccines against VOC.

Immunogenicity of SARS-CoV-2 spike antigens derived from Beta & Delta variants of concern

“…As the SARS-CoV-2 pandemic continues, we will be better able to assess the ability of reference strain-based vaccines to control existing and future VOCs. We and others have previously shown that repeated immunization with reference strain-based vaccine formulations can induce neutralizing activity to VOCs 6 , 10 . In addition, initial data indicates that subjects receiving a third dose of a reference strain-based vaccine may be better protected from infection by VOCs such as Delta 21 .…”

“…As currently approved vaccines are based on the reference spike antigen, their efficacy against certain VOCs may be reduced 4 , 5 . Different vaccine-based approaches to combat these VOCs include (1) increasing antigen-specific antibody levels through additional boosts with reference strain-based vaccines to generate sufficient cross-neutralizing activity, (2) inducing T-cell responses to spike or other SARS-CoV-2 antigens (e.g., nucleocapsid and membrane proteins) and/or (3) utilizing spike-based antigens based on the VOC sequence to generate more efficient neutralizing activity against the targeted VOC 6 – 8 . While it may seem likely that the latter approach would generate better neutralization activity against a VOC, mutational differences in antigen sequence and/or quaternary structure could potentially reduce immunogenicity against critical spike regions, such as the receptor-binding domain.…”

A potent, broadly protective vaccine against SARS-CoV-2 variants of concern

“…All subsequent variants were established on the basis of the D614G substitution 15,16 . (2) N501Y: This mutation in the RBD was firstly detected in Alpha variant, which carries deletions at positions 69-70 and 144 in the NTD with increased infectivity 17 . The N501Y mutation also appeared in Omicron.…”

“…(3) K417N and E484K: The Beta and Gamma variants, which originated in South Africa and Brazil, respectively, carry the K417N/T and E484K amino acid changes in the RBD in addition to N501Y. Mutations in Beta variant decreased the neutralization sensitivity of convalescent and vaccine sera by approximately six-fold (ranging from 4 to 42), while mutations in Gamma decreased neutralizing activity by approximately three-fold (range: 2-7) 17 . These two substitutions simulate a structure that enhances the spectrum of neutralizing activity.…”

The rapid progress in COVID vaccine development and implementation

“…A range of studies reported in NPJ Vaccines have shown that antibodies to the Wuhan spike protein are able to neutralize a range of variants, including the Omicron variant, albeit with reduced potency towards some variants 9 , which is mostly due to mutations in the RBD of variants 5 . The reduced neutralizing activity of antibodies towards variants can, to some extent, be addressed using a third immunizing dose 10 .…”