ABSTRACT
Background Booster vaccination is important because of waning immunity and variant immune evasion. We conducted a single-blinded, randomized trial to evaluate the safety, reactogenicity, and immunogenicity of heterologous booster vaccination in health care workers (HCW) who had received two doses of ChAdOx1 nCov-19. Methods and findings HCW at least 90 days after the second dose were enrolled to receive one of the four vaccines: BNT162b2, half-dose mRNA-1273, mRNA-1273, and MVC-COV1901. The primary outcomes were humoral and cellular immunogenicity and the secondary outcomes safety and reactogenicity 28 days post-booster. 340 HCW were enrolled: 83 received BNT162b2 (2 excluded), 85 half-dose mRNA-1273, 85 mRNA-1273, and 85 MVC-COV1901. mRNA vaccines had more reactogenicity than protein vaccine. Anti-spike IgG increased by a fold of 8.4 for MCV-COV1901, 32.2 for BNT162b2, 47.6 for half-dose mRNA-1273 and 63.2 for mRNA1273. The live virus microneutralization assay (LVMNA) against the wild type, alpha and delta variants were consistent with anti-spike IgG for all booster vaccines. The LVMNA in the four groups against omicron variant were 6.4 to 13.5 times lower than those against the wild type. Serum neutralizing antibody against omicron variant was undetectable in 60% of the participants who received MCV-COV1901 as a booster by LVMNA. By using pseudovirus neutralizing assay, we found that neutralization activity in the four groups against omicron variant were 4.6 to 5.2 times lower than that against the D614G. All booster vaccines induced comparable T cell response. Conclusions Third dose booster not only increases neutralizing antibody titer but also enhances antibody capacity against SARS-CoV-2 variants. mRNA vaccines are preferred booster vaccines for those after primary series of ChAdOx1 nCov-19.