The Oxford-AstraZeneca ChAdOx1 nCoV-19 vaccine (ChAdOx1) was widely used globally, but concerns arose regarding its association with thrombosis and thrombocytopenia syndrome (TTS). This led to exploring alternative immunization strategies, including heterologous prime-boost regimens. This study aimed to evaluate the safety and immunogenicity of a heterologous prime-boost strategy using ChAdOx1 followed by the protein-based subunit vaccine MVC-COV1901. The rationale behind using a heterologous approach is the potential for enhanced and broader immune responses compared to homologous vaccination, particularly in addressing concerns about the lower efficacy of ChAdOx1 against certain variants and the risk of TTS. A successful heterologous strategy would offer a valuable tool in mass COVID-19 immunization efforts, especially for individuals who have already received a first dose of ChAdOx1. The study’s importance lies in its contribution to understanding alternative vaccination strategies to improve COVID-19 vaccine efficacy and safety.

Prior research demonstrated that ChAdOx1, while effective against severe COVID-19, had lower efficacy compared to mRNA and protein-based vaccines. Concerns about TTS further highlighted the need for alternative strategies. Studies on mix-and-match vaccination approaches using ChAdOx1 as a prime and mRNA vaccines as a boost showed improved immunogenicity. This existing literature supported the investigation of a heterologous prime-boost strategy using ChAdOx1 followed by a protein-based subunit vaccine like MVC-COV1901, aiming to leverage the advantages of both vaccine platforms to enhance immune responses while potentially mitigating the risks associated with ChAdOx1 alone. The review of the literature also informed the choice of endpoints, specifically focusing on neutralizing antibody titers and cellular immune responses, which were known to be crucial in COVID-19 protection.

This study employed a participant-blinded, randomized, non-inferiority trial (NCT05054621) design. 100 healthy adults (aged 20–70) who had received a single dose of ChAdOx1 were randomly assigned (1:1) to receive a booster dose of either ChAdOx1 (homologous group, n=50) or MVC-COV1901 (heterologous group, n=50) at an interval of 4–6 or 8–10 weeks. Participants were stratified by prime-boost interval. The primary objective was to determine if the neutralizing antibody titer at day 28 post-boost in the heterologous group was non-inferior to the homologous group. Safety was assessed by recording solicited and unsolicited adverse events (AEs) within one week and 28 days post-boost, respectively. Immunogenicity was assessed by measuring neutralizing antibody titers (using an ELISA-based assay and a live virus neutralization assay), spike-specific antibody-secreting B cells (ELISpot), and spike-specific T cell responses (IFN-γ ELISpot). Statistical analyses included t-tests, Mann-Whitney tests, and one-way ANOVA, with appropriate adjustments for multiple comparisons.

At day 28 post-boost, the heterologous MVC-COV1901 group showed significantly higher neutralizing antibody geometric mean titers (GMTs) against the wild-type SARS-CoV-2 (GMT ratio 2.1, 95% CI 1.4–2.9) and Delta variant (GMT ratio 2.6, 95% CI 1.8–3.5) compared to the homologous ChAdOx1 group. Both spike-specific antibody-secreting B cell and T cell responses were substantially enhanced in the heterologous group. The shorter prime-boost interval (4–6 weeks) showed a tendency toward higher antibody responses in both groups. Common solicited AEs (injection site pain, fatigue, headache, myalgia) were similar between groups, with no serious AEs reported. The ELISA-based neutralizing antibody assay showed high correlation with the live virus neutralization assay.

The significantly higher neutralizing antibody titers and enhanced cellular immune responses observed in the heterologous ChAdOx1/MVC-COV1901 group support the use of this prime-boost strategy. The superior immunogenicity against both the wild-type and Delta variant suggests improved protection compared to a homologous ChAdOx1 regimen. The findings align with other studies demonstrating the benefits of heterologous prime-boost schedules using ChAdOx1 followed by mRNA vaccines. The observation that shorter prime-boost intervals tended to be associated with higher antibody responses requires further investigation, although it might be influenced by differences in the timing of the study relative to the prevalence of natural infections in the study setting. The generally good safety profile of the heterologous strategy adds to its appeal. Future studies should examine the long-term durability of the immune response and assess the effectiveness of this strategy against emerging SARS-CoV-2 variants.

This randomized controlled trial demonstrated that a heterologous prime-boost regimen using ChAdOx1 followed by MVC-COV1901 elicits significantly superior humoral and cellular immune responses compared to homologous ChAdOx1 vaccination. This strategy shows promise for improving COVID-19 vaccine efficacy and safety, particularly in populations already primed with ChAdOx1. Future studies should focus on long-term immune response durability and effectiveness against emerging variants.

The relatively small sample size limits the generalizability of the findings. The study was conducted in a single center in Taiwan, potentially limiting the generalizability to other populations. The study focused on immunogenicity; assessing real-world effectiveness in preventing COVID-19 infection and severe disease would be valuable. The short follow-up period may not fully capture the long-term effects of the vaccination strategy.