Deep immunological imprinting due to the ancestral spike in the current bivalent COVID-19 vaccine (preprint)

With the aim of broadening immune responses against the evolving SARS-CoV-2 Omicron variants, bivalent COVID-19 mRNA vaccines that encode the ancestral and Omicron BA.5 spike proteins have been authorized for clinical use, supplanting the original monovalent counterpart in numerous countries. However, recent studies have demonstrated that administering either a monovalent or bivalent vaccine as a fourth vaccine dose results in similar neutralizing antibody titers against the latest Omicron subvariants, raising the possibility of immunological imprinting. Utilizing binding immunoassays, pseudotyped virus neutralization assays, and antigenic mapping, we investigated antibody responses from 72 participants who received three monovalent mRNA vaccine doses followed by either a bivalent or monovalent booster, or who experienced breakthrough infections with the BA.5 or BQ subvariant after vaccinations with an original monovalent vaccine. Compared to a monovalent booster, the bivalent booster did not yield noticeably higher binding titers to D614G, BA.5, and BQ.1.1 spike proteins, nor higher virus-neutralizing titers against SARS-CoV-2 variants including the predominant XBB.1.5 and the emergent XBB.1.16. However, sera from breakthrough infection cohorts neutralized Omicron subvariants significantly better. Multiple analyses of these results, including antigenic mapping, made clear that inclusion of the ancestral spike prevents the broadening of antibodies to the BA.5 component in the bivalent vaccine, thereby defeating its intended goal. Our findings suggest that the ancestral spike in the current bivalent COVID-19 vaccine is the cause of deep immunological imprinting. Its removal from future vaccine compositions is therefore strongly recommended.

SARS-CoV-2 Neutralizing Antibodies After Bivalent vs. Monovalent Booster (preprint)

Bivalent mRNA vaccine boosters expressing Omicron BA.5 spike and ancestral D614G spike were introduced to attempt to boost waning antibody titers and broaden coverage against emerging SARS-CoV-2 lineages. Previous reports showed that peak serum neutralizing antibody (NAb) titers against SARS-CoV-2 variants following bivalent booster were similar to peak titers following monovalent booster. It remains unknown whether these antibody responses would diverge over time. We assessed serum virus-neutralizing titers in 41 participants who received three monovalent mRNA vaccine doses followed by bivalent booster, monovalent booster, or BA.5 breakthrough infection at one month and three months after the last vaccine dose or breakthrough infection using pseudovirus neutralization assays against D614G and Omicron subvariants (BA.2, BA.5, BQ.1.1, and XBB.1.5). There was no significant difference at one month and three months post-booster for the two booster cohorts. BA.5 breakthrough patients exhibited significantly higher NAb titers at three months against all Omicron subvariants tested compared against monovalent and bivalent booster cohorts. There was a 2-fold drop in mean NAb titers in the booster cohorts between one and three month time points, but no discernible waning of titers in the BA.5 breakthrough cohort over the same period. Our results suggest that NAb titers after boosting with one dose of bivalent mRNA vaccine are not higher than boosting with monovalent vaccine. Perhaps inclusion of D614G spike in the bivalent booster exacerbates the challenge posed by immunological imprinting. Hope remains that a second bivalent booster could induce superior NAb responses against emerging variants.