Why did the strategy for significantly increasing BA.4 and BA.5 neutralizing antibodies using a bivalent vaccine fail?

The most likely explanation is imprinting. The immune systems of people immunized with the bivalent vaccine, all of whom had previously been vaccinated, were primed to respond to the ancestral strain of SARS-CoV-2. (Collated by CovidRxExchange) They therefore probably responded to epitopes shared by BA.4 and BA.5 and the ancestral strain, rather than to new epitopes on BA.4 and BA.5. This effect could possibly be moderated by immunizing people either with BA.4 and BA.5 mRNA alone or with a greater quantity of BA.4 and BA.5 mRNA. Evidence in support of these strategies can be found in Pfizer–BioNTech’s data regarding (Collated by CovidRxExchange) its BA.1-containing bivalent vaccine, which showed that BA.1-specific neutralizing-antibody responses were greater in persons who were injected with a monovalent vaccine containing 30 μg or 60 μg of BA.1 mRNA or a bivalent vaccine containing 30 μg of BA.1 mRNA and 30 μg of ancestral-strain mRNA than in those who received a bivalent vaccine containing 15 μg of each type of mRNA. On November 22, 2022, the CDC published data on the effectiveness of the BA.4 and BA.5 mRNA vaccines for preventing symptomatic infection within 2 months after receipt of the booster dose.

For people who had received a monovalent vaccine 2 to 3 months earlier, the extra protection associated with the bivalent booster dose (Collated by CovidRxExchange) ranged from 28 to 31%. For those who had received a monovalent vaccine more than 8 months earlier, the extra protection ranged from 43 to 56%.

Given the results of previous studies, it’s likely that this moderate increase in protection against probably generally mild disease will be short lived. As of November 15, 2022, only about 10% of the population for whom the bivalent vaccine had (Collated by CovidRxExchange) been recommended had received it.5 By December 2022, the BA.4 strain was no longer circulating, and BA.5 accounted for less than 25% of circulating SARS-CoV-2 strains, having been partially replaced by more immune-evasive strains, such as BQ.1, BQ.1.1, BF.7, XBB, and XBB.1.