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To the Editor: The emergence and rapid propagation of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants — in particular, the B.1.1.529 (omicron) sublineages, which have mutations that increase transmissibility and evasiveness against vaccine-induced immunity — can substantially reduce the efficacy of approved vaccines. The degree to which ancestral strain–based vaccines induced immunity against variants depends on the ability of the vaccine to induce broadly cross-reactive antibodies. The NVX-CoV2373 vaccine (Novavax) consists of full-length, prefusion, recombinant spike (rS) protein trimers with epitopes conserved across variants and is coformulated with a saponin-based adjuvant, Matrix-M, which may enhance antibody avidity, affinity maturation, and epitope spreading. As part of an ongoing phase 2, randomized, placebo-controlled clinical trial of NVX-CoV2373 that is being conducted in Australia and the United States (ClinicalTrials.gov number, NCT04368988), two doses of NVX-CoV2373 were administered to participants 21 days apart, followed initially by a single booster dose after approximately 6 months.1 The trial protocol is available with the full text of this letter at NEJM.org. In a continuation of this trial, a second booster dose of the vaccine was administered after another 6 months. Only participants who received four doses of NVX-CoV2373 were included in this analysis.

oster dose after approximately 6 months.1 The trial protocol is available with the full text of this letter at NEJM.org. In a continuation of this trial, a second booster dose of the vaccine was administered after another 6 months. Only participants who received four doses of NVX-CoV2373 were included in this analysis. Antigenic cartography, a method that is frequently used to help evaluate the potential effectiveness of influenza vaccination against variant strains and to guide vaccine-strain composition, provides a direct visualization of the effect of multiple doses on vaccine-induced immunogenicity. The anti-rS IgG and neutralization titers increased after the third and fourth doses of NVX-CoV2373 and showed a reduction in the antigenic distance between the ancestral SARS-CoV-2 strain and the forward-drifted BA.1 and BA.4 or BA.5 variants (Figure 1). When we compared the antigenic distance between omicron subvariants and the ancestral strain, the factor difference in IgG titers against the ancestral strain and the BA.5 variant (4.4) after the second dose decreased to 1.8 after the fourth dose, and the factor difference in neutralization titers against the ancestral strain and the BA.4 or BA.5 variant (33.5) after the second dose decreased to 3.5 after the fourth dose.

difference in IgG titers against the ancestral strain and the BA.5 variant (4.4) after the second dose decreased to 1.8 after the fourth dose, and the factor difference in neutralization titers against the ancestral strain and the BA.4 or BA.5 variant (33.5) after the second dose decreased to 3.5 after the fourth dose. These data indicate that boosting with the NVX-CoV2373 vaccine resulted in enhanced cross-reactive immunity to SARS-CoV-2 variants, a decreased gap between immune recognition of the variants and the ancestral strain, and the induction of a potentially more universal-like response against SARS-CoV-2 variants. We believe that this phenomenon may be driven by the conserved epitopes found on the recombinant protein vaccine, whereby expression of the full-length trimers of the S protein present epitopes that are conserved across variants for recognition by the immune system.4 This process may be further enhanced by the saponin-based Matrix-M adjuvant by means of epitope spreading.5 Whether the observed antibody responses to additional boosting with the ancestral sequence that was used in the NVX-CoV2373 vaccine translate into meaningful protection against emerging SARS-CoV-2 variants will require clinical studies of efficacy.