Immune Response and Reactogenicity After Immunization With a Suboptimal Two-Dose mRNA Vaccine Followed by a Full Vaccination With a Standard mRNA Vaccine Compared to a Prime-Boost Regimen of a Standard mRNA Vaccine: A Multicenter Cohort Study

Abstract

Background: There is no evidence to date on immunogenic response and dynamics in individuals who participated in clinical trials of experimental COVID-19 vaccines, thus being redirected to receive standard courses included in national vaccination programs.

Methods: This multicentre, prospective controlled cohort study included subjects primed with a non-authorised experimental COVID-19 vaccine (test group, TG) and subjects who did not receive any active COVID-19 vaccine earlier (control group, CG), selected among individuals to be vaccinated at study sites according to the Spanish vaccination program. All subjects from TG had received the experimental CVnCoV vaccine previously. All study subjects received BNT162b2 as a standard vaccine of the national program but 8 (from CG) who received mRNA-1273 and were excluded from immunogenicity analyses. Anti-RBD antibodies titres, and neutralising titres (NT50) against G614 (reference), Beta, Mu, Delta and Omicron variants were analysed. Reactogenicity was also assessed.

Findings: 130 participants (TG: 92; CG: 38) completed standard vaccination. Mean (SD) interval between CVnCoV and BNT162b2 vaccines was 110 (15·4) days (only TG), while interval between BNT162b2 doses was 21 days (SD 2·3 [TG] and 0·9 [CG]). In the TG, median (IQR) titres of anti-RBD antibodies after first BNT162b2 dose were 10740·0 BAU/mL (4466·0-12500) compared to 29·8 BAU/mL (14·5-47·8) in the CG (p <0·0001). Median NT50 (IQR) of G614 variant was 2674·0 (1865·0-3997·0) in the TG and 63·0 (16·0-123·1) in the CG (p <0·0001). After second BNT162b2 dose, anti-RBD antibody titres increased to ≥12500 BAU/mL (11625·0-12500) in the TG compared to 1859·0 BAU/mL (915·4-3820·0) in the CG (p <0·0001). NT50 was 2626·5 (1756·0-5472·0) and 850·4 (525·1-1608·0), respectively (p <0·0001). Variant-specific response in the CG showed 8·2-, 5·5-, and 16·8-fold decrease of GM NT50 against Beta, Mu, and Omicron variants, respectively, compared to G614 variant, while in the TG it was 2·6, 2·4, and 4·7 folds, respectively. Most frequent adverse reactions were headache and myalgia (systemic), and pain (local). No severe AEs were reported.

Interpretation: Results suggest that heterologous BNT162b2 as third and fourth doses in previously suboptimal immunized individuals elicit stronger immune response than obtained with standard prime-boost BNT162b2 regimen. This apparent benefit was also observed in variant-specific response. No safety concerns arose.

Trial Registration Details: The study is registered with the Spanish Register of Clinical Studies (REEC–code: 0061-2021-OBS).

Funding Information: Partly funded by the Institute of Health Carlos III (Instituto de Salud Carlos III – ISCIII –), (grant numbers PI19CIII/00004 and PI21CIII/00025), and COVID-19 FUND (grants COV20/00679 and COV20/00072) and CIBERINFEC, co-financed by the European Regional Development Fund (FEDER) “A way to make Europe”.