Comparison of bivalent and monovalent SARS-CoV-2 variant vaccines: the phase 2 randomized open-label COVAIL trial

Abstract

Vaccine protection against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection wanes over time, requiring updated boosters. In a phase 2, open-label, randomized clinical trial with sequentially enrolled stages at 22 US sites, we assessed safety and immunogenicity of a second boost with monovalent or bivalent variant vaccines from mRNA and protein-based platforms targeting wild-type, Beta, Delta and Omicron BA.1 spike antigens. The primary outcome was pseudovirus neutralization titers at 50% inhibitory dilution (ID50 titers) with 95% confidence intervals against different SARS-CoV-2 strains. The secondary outcome assessed safety by solicited local and systemic adverse events (AEs), unsolicited AEs, serious AEs and AEs of special interest. Boosting with prototype/wild-type vaccines produced numerically lower ID50 titers than any variant-containing vaccine against all variants. Conversely, boosting with a variant vaccine excluding prototype was not associated with decreased neutralization against D614G. Omicron BA.1 or Beta monovalent vaccines were nearly equivalent to Omicron BA.1 + prototype or Beta + prototype bivalent vaccines for neutralization of Beta, Omicron BA.1 and Omicron BA.4/5, although they were lower for contemporaneous Omicron subvariants. Safety was similar across arms and stages and comparable to previous reports. Our study shows that updated vaccines targeting Beta or Omicron BA.1 provide broadly crossprotective neutralizing antibody responses against diverse SARS-CoV-2 variants without sacrificing immunity to the ancestral strain. ClinicalTrials.gov registration: NCT05289037.

Predicting COVID-19 booster immunogenicity against future SARS-CoV-2 variants and the benefits of vaccine updates

“…Of the 28 studies we identified, only two studies 1,3 contained data that could be used to contribute to all four comparisons, however no study contained data for both the old and updated immunogens across all four comparisons. In addition, 1 study could not be used in our analysis as it did not include titres after one of the relevant immunogens 9 , leaving 27 studies that could contribute to one or more of the comparisons identified in Figure 2A.…”

“…Secondly, there were a limited number of studies 2,3,5,6,14,17,19,20,23,24 that provided a head-to-head comparison of in vitro neutralisaEon Etres elicited by different booster immunogens (Table 1).…”

“…For example, 9 studies 5-9,20-22,28 that we idenEfied were sponsored by the companies producing the vaccines. We therefore performed an analysis on a subset of studies [2][3][4]10,11,14,17,19,24 that reported both pre-and post-boost neutralisaEon Etres and had no pharmaceuEcal company involvement and found a similar benefit of updaEng the booster immunogen to that described above (update advantage of 1.39-fold [95% CI 1.04-1.84], Supplementary Table 7). AddiEonally, in our mulEple regression analysis when we included pharmaceuEcal involvement as a potenEal factor, we found this variable was not significant.…”

“…That is, the infection and vaccination history of an individual are thought to contribute to their current cross-recognition profile of different variant strains 35 . Further, boosting with a variant antigen leads to increased recognition of the vaccine strain (and antigenically similar strains) 3 .…”

“…That is, the infecEon and vaccinaEon history of an individual are thought to contribute to their current cross-recogniEon profile of different variant strains 35 . Further, boosEng with a variant anEgen leads to increased recogniEon of the vaccine strain (and anEgenically similar strains) 3 . How effecEve this is at improving responses to a future variant is thought to be dependent on the similarity between the booster anEgen and a future circulaEng variant (anEgenic distance) 36 .…”