Bivalent COVID-19 booster vaccines and the absence of BA.5-specific antibodies

Vaccination against COVID-19 increased immunity in the population, which reduced viral transmission and protected against severe disease. However, continuous emergence of SARS-CoV-2 variants required the implementation of bivalent boosters including the wild-type (D614G) and omicron (BA.5) spike. Improved effectiveness of the bivalent booster versus monovalent booster against omicron subvariants has been reported;¹ however, few differences in the immune response have been detected.2, 3

We investigated whether a bivalent COVID-19 booster vaccine that included wild-type spike and BA.5 spike induced detectable BA.5-specific antibody responses in serum. 16 serum samples collected at mean 31 days (SD 63 [range 0–260]) before and a mean 16 days (8 [6–31]) after receiving the bivalent booster were tested for antibody binding and avidity to the receptor binding domain (RBD) of wild-type and BA.5 SARS-CoV-2. Neutralisation of wild-type and BA.5 viruses was determined. Omicron-specific antibodies were measured by depletion of wild-type RBD reactive antibodies and assessment of depleted serum samples against BA.5 RBD.

A substantial increase in antibody binding to wild-type and BA.5 RBD as well as in neutralisation of wild-type and BA.5 viruses was seen in serum samples after receiving the bivalent booster (figure , appendix p 6). There were substantial differences in binding of post-booster serum samples between wild-type and BA.5 RBDs; however, differences in neutralisation were not significant. Pre-booster and post-booster RBD antibody avidity was lower against BA.5 RBD than wild-type RBD, which prompted us to look for BA.5 specific antibodies. Wild-type RBD depleted serum samples had undetectable reactivity to wild-type RBD—as expected—and to BA.5 RBD, suggesting that a single exposure to BA.5 antigens by the administration of bivalent vaccine boosters does not elicit robust concentrations of BA.5 specific serum antibodies.

Figure.

Serum samples depleted of wild-type RBD have no reactivity to BA.5 RBD

Reactivity of pre-bivalent booster vaccination serum samples is shown in blue and reactivity of post-bivalent booster vaccination serum samples is shown in red for both (A) wild-type RBD protein and (B) BA.5 RBD protein. Samples were depleted of wild-type RBD antibodies and reactivity was measured to (A) wild-type RBD (to confirm complete depletion) and to (B) BA.5 RBD (to determine if omicron-specific antibodies were present). Samples depleted of wild-type RBD antibodies are shown as dashed lines and samples not depleted of wild-type RBD antibodies are shown as continuous lines. OD is shown on the y axis and reciprocal serum dilutions (100–12 800 with two-fold dilution series) are shown on the x axis. The sample size was 16. RBD=receptor binding domain. OD=optical density.

Reduced sensitivity of antibody tests based on wild-type viral antigens was detected in previously SARS-CoV-2 antigen naive individuals after omicron infection.⁴ However, most of the global population has been infected with ancestral strains or exposed to wild-type antigens through vaccination, hence our results are relevant for the current immune status of the population worldwide. Moreover, our data align with results from April, 2023, which indicate that a monovalent booster with BA.1 vaccine elicits robust spike-specific germinal centre B-cell responses but very low numbers of de-novo B cells targeting variant-specific epitopes.⁵ Whether further exposures to omicron antigens will boost these responses to make them detectable in serum remains to be explored. Importantly, it is probable that cross-reactive antibodies towards omicron-antigens contribute to protection.