Efficacy of a Fourth Dose of Covid-19 mRNA Vaccine against Omicron
In this open-label, nonrandomized clinical study, we assessed the immunogenicity and safety of a fourth dose of either BNT162b2 (Pfizer–BioNTech) or mRNA-1273 (Moderna) administered 4 months after the third dose in a series of three BNT162b2 doses (ClinicalTrials.gov numbers, NCT05231005 and NCT05230953; the protocol is available with the full text of this letter at NEJM.org).
Of the 1050 eligible health care workers enrolled in the Sheba HCW COVID-19 Cohort,1,2 154 received the fourth dose of BNT162b2 and, 1 week later, 120 received mRNA-1273. For each participant, two agematched controls were selected from the remaining eligible participants (Fig. S1 in the Supplementary Appendix, available at NEJM.org). After the fourth dose, both messenger RNA (mRNA) vaccines induced IgG antibodies against the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) receptor-binding domain (Fig. 1A) and increased neutralizing antibody titers (Fig. S3); each measure was increased by a factor of 9 to 10, to titers that were slightly higher than those achieved after the third dose, with no significant difference between the two vaccines. Concurrently, antibody levels in the control group continued to wane (Table S5). Both vaccines induced an increase in live neutralization of the B.1.1.529 (omicron) variant and other viral strains by a factor of approximately 10 (Fig. 1B), similar to the response after the third dose.3 We found that the fourth dose did not lead to substantial adverse events despite triggering mild systemic and local symptoms in the majority of recipients (Fig. S2 and Table S4A and S4B).