Heterologous COVID-19 vaccine schedule with protein-based prime (NVX-CoV2373) and mRNA boost (BNT162b2) induces strong humoral responses: Results from COV-BOOST trial

Abstract

Background

Heterologous schedules of booster vaccines for COVID-19 following initial doses of mRNA or adenoviral vector vaccines have been shown to be safe and immunogenic. There are few data on booster doses following initial doses of protein nanoparticle vaccines.

Methods

Participants of the phase 3 clinical trial of the COVID-19 vaccine NVX-CoV2373 (EudraCT 2020–004123-16) enroled between September 28 and November 28, 2020, who received 2 doses of NVX-CoV2373 administered 21 days apart were invited to receive a third dose booster vaccine of BNT162b2 (wild type mRNA vaccine) as a sub-study of the COV-BOOST clinical trial, and were followed up for assessment of safety, reactogenicity and immunogenicity to day 242 post-booster.

Results

The BNT162b2 booster following two doses of NVX-COV2373 was well-tolerated. Most adverse events were mild to moderate, with no serious vaccine-related adverse events reported. Immunogenicity analysis showed a significant increase in spike IgG titres and T-cell responses post-third dose booster. Specifically, IgG levels peaked at day 14 with a geometric mean concentration (GMC) of 216,255 ELISA laboratory units (ELU)/mL (95% CI 191,083–244,743). The geometric mean fold increase from baseline to day 28 post-boost was 168.6 (95% CI 117.5–241.8). Spike IgG titres were sustained above baseline levels at day 242 with a GMC of 58,686 ELU/mL (95% CI 48,954–74,652), with significant decay between days 28 and 84 (geometric mean ratio 0.58, 95% CI 0.53–0.63). T-cell responses also demonstrated enhancement post-booster, with a geometric mean fold increase of 5.1 (95% CI 2.9–9.0) at day 14 in fresh samples and 3.0 (95% CI 1.8–4.9) in frozen samples as measured by ELISpot. In an exploratory analysis, participants who received BNT162b2 after two doses of NVX-COV2373 exhibited higher anti-spike IgG at Day 28 than those who received homologous three doses of BNT162b2, with a GMR of 5.02 (95% CI: 3.17–7.94). This trend remained consistent across all time points, indicating a similar decay rate between the two schedules.

Conclusions

A BNT162b2 third dose booster dose in individuals primed with two doses of NVX-COV2373 is safe and induces strong and durable immunogenic responses, higher than seen in other comparable studies. These findings support the use and investigation of heterologous booster strategies and early investigation of heterologous vaccine technology schedules should be a priority in the development of vaccines against new pathogens.