Discussion
infection, E484K/A, subvariants
VIRUS, SARS-COV-2 INFECTION, DISEASE, INFECTION, SOMATIC MUTATION
The continued emergence of SARS-CoV-2 VOCs led to a recommendation to update COVID-19 vaccinesFirst, our findings support that mRNA and adjuvanted protein variant vaccines elicit substantial crossreactive neutralizing antibodies to D614G and to B.1.351, 1.617.2, Omicron BA.1, Omicron BA.4/5 and other Omicron subvariants, regardless of prior SARS-CoV-2 infection history and age. This is probably due to ongoing antibody somatic mutation, memory B cell clonal turnover and development of antibodies that are resistant to SARS-CoV-2 spike protein RBD mutationsSecond, our ANCOVA modeling demonstrated that the mRNA variant vaccines offered a clear serologic advantage over the wild-type/prototype vaccines against B.1.351, BA.1 and BA.4/5 that persisted up to 3 months after vaccination. Moreover, vaccine candidates without Omicron BA.1 variant, such as the Pfizer mRNA Beta vaccine, still provided superior heterologous coverage to Omicron BA.1 and BA.4/5 when compared with the wild-type vaccine, which was probably due to the common mutations in the spike RBD (K417N, E484K/A and N501Y) between B.1.351 and these Omicron variants. Although a serologic advantage to BA.1 was not seen in ANCOVA modeling with the Sanofi Beta or Beta + prototype protein vaccine candidates, perhaps due to small sample size or undetected prior infection, a similar serologic benefit of boosting with the Beta monovalent vaccineThe antibody landscapes visualizing the neutralization profile after vaccination further support inclusion of variants in booster vaccines. After vaccination, the antibody landscape rises with variant vaccine candidates, especially against more recent variants, and flattens the antibody landscape more than the prototype vaccine, suggesting there may be higher titers of neutralizing antibodies with variant-containing vaccines against future VOCs, especially if they emerge near B.1.351, Omicron BA.1 and BA.4/5 (ref. Although specific correlates of protection for infection with recent Omicron subvariants are not well understood, neutralizing antibody titers have been used to infer protection during the D614G wave of the pandemic, when the circulating virus closely matched the vaccine strainFor all vaccine candidates, including vaccine products not containing prototype, the antibody titers were higher against D614G compared with the VOCs, supporting the hypothesis of back-boosting to the ancestral strain seen in previous studiesNotably, although variant vaccines improved neutralizing activity against Omicron subvariants, these titers decreased for more recent Omicron subvariants. Although the serum inhibitory dilution required for 50% neutralization (IDOur study has several limitations. First, the sample size is small for certain subgroups of interest, such as prior infection (27%) and adults older than 65 years (31%). Second, T cell responses and antibody effector functions, which may be critical to preventing severe diseaseIn conclusion, these data demonstrate that updating vaccines to target recent variants provides modestly improved and broadly crossprotective neutralizing antibody responses against diverse SARS-CoV-2 variants without sacrificing boosting immunity to the ancestral strain. The precise degree to which the enhanced antibody response elicited by updated vaccines will restore protection against disease after infection with heterologous or homologous strains needs further confirmation by real-world effectiveness studies. Our study incorporating both antigenic distances and serologic landscapes serve as a framework for objectively guiding decisions for future vaccine updates.