Safety and immunogenicity of heterologous versus homologous prime-boost schedules with an adenoviral vectored and mRNA COVID-19 vaccine (Com-COV): a single-blind, randomised, non-inferiority trial

Abstract

Background Use of heterologous prime-boost COVID-19 vaccine schedules could facilitate mass COVID-19 immunisation. However, we have previously reported that heterologous schedules incorporating an adenoviral vectored vaccine (ChAdOx1 nCoV-19, AstraZeneca; hereafter referred to as ChAd) and an mRNA vaccine (BNT162b2, Pfizer–BioNTech; hereafter referred to as BNT) at a 4-week interval are more reactogenic than homologous schedules. Here, we report the safety and immunogenicity of heterologous schedules with the ChAd and BNT vaccines. Methods Com-COV is a participant-blinded, randomised, non-inferiority trial evaluating vaccine safety, reactogenicity, and immunogenicity. Adults aged 50 years and older with no or well controlled comorbidities and no previous SARS-CoV-2 infection by laboratory confirmation were eligible and were recruited at eight sites across the UK. The majority of eligible participants were enrolled into the general cohort (28-day or 84-day prime-boost intervals), who were randomly assigned (1:1:1:1:1:1:1:1) to receive ChAd/ChAd, ChAd/BNT, BNT/BNT, or BNT/ChAd, administered at either 28-day or 84-day prime-boost intervals. A small subset of eligible participants (n=100) were enrolled into an immunology cohort, who had additional blood tests to evaluate immune responses; these participants were randomly assigned (1:1:1:1) to the four schedules (28-day interval only). Participants were masked to the vaccine received but not to the prime-boost interval. The primary endpoint was the geometric mean ratio (GMR) of serum SARS-CoV-2 anti-spike IgG concentration (measured by ELISA) at 28 days after boost, when comparing ChAd/BNT with ChAd/ChAd, and BNT/ChAd with BNT/BNT. The heterologous schedules were considered non-inferior to the approved homologous schedules if the lower limit of the one-sided 97·5% CI of the GMR of these comparisons was greater than 0·63. The primary analysis was done in the per-protocol population, who were seronegative at baseline. Safety analyses were done among participants receiving at least one dose of a study vaccine. The trial is registered with ISRCTN, 69254139. Findings Between Feb 11 and Feb 26, 2021, 830 participants were enrolled and randomised, including 463 participants with a 28-day prime-boost interval, for whom results are reported here. The mean age of participants was 57·8 years (SD 4·7), with 212 (46%) female participants and 117 (25%) from ethnic minorities. At day 28 post boost, the geometric mean concentration of SARS-CoV-2 anti-spike IgG in ChAd/BNT recipients (12 906 ELU/mL) was non-inferior to that in ChAd/ChAd recipients (1392 ELU/mL), with a GMR of 9·2 (one-sided 97·5% CI 7·5 to ∞). In participants primed with BNT, we did not show non-inferiority of the heterologous schedule (BNT/ChAd, 7133 ELU/mL) against the homologous schedule (BNT/BNT, 14 080 ELU/mL), with a GMR of 0·51 (one-sided 97·5% CI 0·43 to ∞). Four serious adverse events occurred across all groups, none of which were co...

Robust Neutralizing Antibody Levels Detected after Either SARS-CoV-2 Vaccination or One Year after Infection

“…In our study, this effect might be altered due to the difference in time of application of the booster vaccination and due to different vaccines used for prime vaccination. Earlier data had already shown similar results to those presented here when comparing an AZD1222/BNT162b2 combination with a homologous BNT162b2 prime-boost vaccination [33].…”

The anti-SARS-CoV-2 immunoglobulin G levels and neutralising capacities against alpha and delta virus variants of concern achieved after initial immunisation with vector vaccine followed by mRNA vaccine boost are comparable to those after double immunisation with mRNA vaccines

“…The results of a single-blind randomised British study, in which the four possible vaccine combinations of AZD1222 and BNT162b2 were compared with one another, are very interesting and promising. These researchers report about 9-fold higher mean anti-S IgG titres in sera from heterologous AZD1222/BNT162b2 vaccinees compared to individuals immunised twice with AZD1222 [19] which is largely in accordance to our results. In a study from Sweden, markedly higher anti-S and anti-RBD IgG titres were observed after heterologous vaccination (AZD1222/mRNA-1273) compared to the homologues AZD1222 scheme.…”

“…The results presented by us on the antibody response after heterologous SARS-CoV-2 vaccination are consistent with the few available clinical studies [17, 19, 21, 16, 18, 20]. In June 2021, a randomised study from Spain has already demonstrated that the heterologous vaccination scheme is suitable for generating a robust immune response.…”

Enhancement of the HIV-1-Specific Immune Response Induced by an mRNA Vaccine through Boosting with a Poxvirus MVA Vector Expressing the Same Antigen

“…In fact, recruitment for phase I/II clinical trials with the AstraZeneca and Pfizer mRNA SARS-CoV-2 vaccine combination is currently ongoing. Clinical trials with individuals that received the first dose from AstraZeneca and the second dose of Pfizer mRNA vaccine revealed potentiation of the immune responses, as measured by increased S protein binding antibodies and enhanced neutralizing antibody levels [17,18]. Thus, heterologous combinations of vaccines might provide an advantage for vaccination.…”