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When the FDA authorized bivalent COVID-19 vaccines, there were no published data comparing their efficacy with monovalent vaccines. In an industry-supported study, Winokur et al. randomized 1846 participants older than 55 who previously received three doses of BNT162b2 (12.6% with evidence of prior SARS-CoV-2 infection) to receive 30 µg or 60 µg of BNT162b2 containing the ancestral strain, 30 or 60 µg of monovalent Omicron BA.1 vaccine, or 30 or 60 µg of bivalent vaccine (Omicron BA.1 and ancestral). They assessed immunogenicity of the Omicron BA.1–adapted vaccines compared with the ancestral vaccine at 1 month post-immunization.
Relative to the 30-µg dose of BNT162b2, geometric mean ratios (GMRs) of neutralizing antibodies (Abs) against Omicron BA.1 were 2.23-fold and 3.15-fold higher for the 30-µg and 60-µg monovalent BA.1 vaccines, respectively; and the corresponding GMRs for the bivalent BA.1 vaccines were 1.56 (30-µg) and 1.97 (60-µg). All tested vaccines yielded comparable Ab responses against the ancestral strain, with increases from 4.3-fold to 5.6-fold over prevaccination levels. Immunization with 30-µg BNT162b2 or 30-µg bivalent vaccines resulted in geometric mean Ab titers of 155 and 167 against BA.4/5, and 89 and 108 against BA.2.75.
Collier et al. evaluated responses against BA.4/5 in a study of 15 participants who received an ancestral monovalent mRNA booster and 18 who received the bivalent mRNA booster (BA.4/5 and ancestral). All participants had previously received a median of three previous doses, and 33% were previously infected. Neutralizing Ab titers were 2829 and 3693 against the BA.4/5 strain and 21,507 and 40,515 against the ancestral strain in the monovalent and bivalent groups, respectively. Ancestral and BA.4/5 strain-specific CD4+ and CD8+ responses were comparable between groups.
Wang et al. evaluated the breadth of antibody responses in individuals who received three or four doses of monovalent vaccine, those who received a bivalent fourth dose (BA.4/5 and ancestral), and those with BA.4/5 infection after 3 to 4 doses of monovalent vaccine. Tested strains included SARS-CoV-2 ancestral, several sublineages (e.g., BA.1, BA.2, BA.4/5), and other sarbecoviruses (e.g., SARS-CoV). The highest neutralizing Ab titers were observed in the convalescent group. Titers against the tested Omicron variants did not differ for the fourth dose of monovalent vs. bivalent vaccine. The four-dose monovalent vaccine group had higher neutralizing Ab titers against the tested sarbecoviruses than the four-dose bivalent vaccine group.
Winokur P et al. Bivalent omicron BA.1–adapted BNT162b2 booster in adults older than 55 years. N Engl J Med 2023 Jan 19; 388:214. (https://doi.org/10.1056/NEJMoa2213082)
Collier AY et al. Immunogenicity of BA.5 bivalent mRNA vaccine boosters. N Engl J Med 2023 Jan 11; [e-pub]. (https://doi.org/10.1056/NEJMc2213948)
Wang Q et al. Antibody response to omicron BA.4–BA.5 bivalent booster. N Engl J Med 2023 Jan 11; [e-pub]. (https://doi.org/10.1056/NEJMc2213907)
Comment
Under randomized controlled conditions, Winokur et al. demonstrated that, by replacing or combining the ancestral strain with BA.1, a higher level of antibodies was produced against the BA.1 strain; however, the breadth of response against subsequently emerging strains was not improved. In a convenience sampling approach that likely comprised mostly infected persons (whether knowingly and unknowingly), the two studies by Wang and Collier found no meaningful differences in serologic or cellular responses between the bivalent BA.4/5 booster and monovalent ancestral booster. Given that additional strains continue to arise beyond those tested here, the serologic and clinical additive value of a bivalent COVID-19 vaccine remains to be demonstrated.