Titers and breadth of neutralizing antibodies against SARS-CoV-2 variants after heterologous booster vaccination in health care workers primed with two doses of ChAdOx1 nCov-19: A single-blinded, randomized clinical trial

Abstract

Objectives: 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: HCW who had at least 90 days after the second dose were enrolled to receive one of the four vaccines: BNT162b2 (30 μg), half-dose mRNA-1273 (50 μg), mRNA-1273 (100 μg), and MVC-COV1901 (15 μg). The primary outcomes were humoral and cellular immunogenicity and secondary outcomes assessed safety and reactogenicity at 28 days post-booster.

Results: MVC-COV1901 Three hundred and forty 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. The fold-rise of anti-spike IgG geometric mean titer was 8.4 (95% CI 6.8-10.4) for MVC-COV1901, 32.2 (27.2-38.1) for BNT162b2, 47.6 (40.8-55.6) for half-dose mRNA-1273 and 63.2 (53.6-74.6) for mRNA-1273. The live virus microneutralization assays (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 BA.1 variant were 6.4 to 13.5 times lower than those against the wild type. All booster vaccines induced a comparable T cell response.

Conclusions: Third dose booster not only increases neutralizing antibody titer but also enhances antibody breadth against SARS-CoV-2 variants. mRNA vaccines are preferred booster vaccines for those who received primary series of ChAdOx1 nCov-19.

Trial registration: ClinicalTrials.gov NCT05132855.

Keywords: COVID-19; Heterologous booster; Immunogenicity; Safety; Third dose; Vaccine.

Graphical abstract

Fig. 1

Study population and analysis. 340 participants were enrolled and randomly assigned to 4 groups. Two participants had detectable anti-nucleocapsid protein IgG antibody at baseline and during follow-up and were excluded for analysis.

Fig. 2

Severity of systemic and local reactions after booster vaccination. The percentage of participants with local symptoms (pain, redness, or swelling at the injection site) and the percentage of participants with systemic symptoms (fever, fatigue, myalgia, headache, nausea, or diarrhea) after booster vaccination are demonstrated. These reactions were monitored in the 7 days after the administration of the booster. The toxicity grading scale represents the highest grade of severity during the seven days. Grade 1 means mild reaction, grade 2 moderate reaction and grade 3 severe reaction. gray: BNT162b2; red: half-dose mRNA-1273; yellow: mRNA-1273; blue: MVC—COV1901.

Fig. 3

SARS-CoV-2 spike protein–specific immune responses before and after booster vaccination. A, Levels of SARS-CoV-2 spike protein-specific IgG antibodies at baseline (before booster vaccination) and after booster vaccination in the four groups. B, Levels of surrogate neutralizing antibodies by ELISA at baseline and after booster vaccination in the four groups. C, Levels of neutralizing antibodies at baseline and after booster vaccination, as assessed with a live virus microneutralization assay (LVMNA) in the four groups. D, Levels of neutralizing antibodies at baseline and after booster vaccination, as assessed with a SARS-CoV-2 pseudovirus neutralization assay (PNA) in the four groups. E, SARS-CoV-2 spike protein-specific T-cell response at baseline and after booster vaccination in the four groups, as measured by interferon-γ levels produced peripheral blood mononuclear cells after ex vivo stimulation. The P values on the top of figure were the comparison of the immune responses between groups. The dashed line indicated cutoff value.

Fig. 4

Correlation between anti-spike IgG and neutralizing antibodies after booster vaccination. The correlations between anti-spike IgG and neutralizing antibodies against the wild type by LVMNA (Spearman's correlation coefficient, 0.79, 95% CI 0.69–0.86; P < 0.001) (n = 120), neutralizing antibodies against the alpha variant by LVMNA (Spearman's correlation coefficient, 0.79, 95% CI 0.69–0.86; P < 0.001) (n = 120), neutralizing antibodies against the delta variant by LVMNA (Spearman's correlation coefficient, 0.72, 95% CI 0.59–0.81; P < 0.001), and neutralizing antibodies against the omicron BA.1 by LVMNA (Spearman's correlation coefficient, 0.85, 95% CI 0.79–0.89; P < 0.001) (n = 120) are demonstrated. The gray shaded areas indicate the 95% CI of the best-fit line. Each dot in the figure represents an individual participant.