Heterologous Prime-boost-boost Vaccine Combinations for Long-term Humoral and Cellular Immunity Against COVID-19

The COVID-19 pandemic has spurred vaccine development and phase 1/2/3 clinical trials in record time. In Singapore, novel mRNA vaccines produced by Pfizer-BioNTech (BNT162b2) and Moderna (mRNA-1273) were the first COVID-19 vaccines to receive interim authorisation under the Pandemic Special Access Route (PSAR). Vaccination in Singapore started first for frontline and healthcare workers with BNT162b2 at the end of December 2020. Over the following months this vaccine program was extended first to older adults and then the general population, while mRNA-1273 was also introduced alongside BNT162b2.

While the pivotal phase 3 clinical trials of BNT162b2 and mRNA-1273 have reported a vaccine efficacy of >95% against symptomatic and severe disease, waning antibody levels and the emergence of variants of concern (VOCs) capable of evading protective immunity (from a wildtype SARS-CoV-2 virus vaccine) have raised the need for a long term COVID-19 immunisation strategy. The emergence of the highly transmissible Omicron VOC in November 2021 heralded a shift in booster vaccination policy in Singapore and overseas. First, recommendations for a third dose of an mRNA vaccine were strengthened and in Singapore receipt of a booster dose within 9 months of completing the primary vaccine series was mandated for maintenance of vaccinated status. Following these efforts booster vaccination uptake increased markedly, and currently 79% of the total population in Singapore has received their first booster vaccination dose. Secondly, recommendations changed to advise that individuals complete the standard vaccination regimen even if they have had prior COVID-19.

Although the original monovalent COVID-19 vaccines have proven effective at preventing death and severe disease, breakthrough infections and reinfections have become more common in the face of an evolving virus. The ever-mutating Omicron virus has resulted in several sublineages such as BA.1, BA.2, BA.4 and BA.5 that have caused surges in COVID-19 cases worldwide. Lab studies consistently suggest that antibodies triggered by vaccines (targeting the ancestral SARS-CoV-2 strain) are less effective at blocking BA.4 and BA.5 than earlier Omicron strains BA.1 and BA.2. This could leave previously infected and/or vaccinated and boosted individuals vulnerable to multiple Omicron infections. Thus, pharmaceutical companies have moved towards developing variant-based vaccines to ensure individuals maintain a high level of protection. On 31 August 2022, the US FDA authorized the bivalent formulations of the Moderna and Pfizer-BioNTech vaccines for use as a single booster dose at least two months following primary or booster vaccination. Since the first detection of the XBB Omicron subvariant in August 2022 in India, it has been detected in more than 17 countries to-date including Singapore, Australia, Bangladesh, Denmark, Japan and the US. To combat the rising COVID-19 infections and reinfections in Singapore, the bivalent Moderna/Spikevax and bivalent Pfizer-BioNTech vaccines were added to the National Vaccination Programme from October 2022.

Third-dose boosters increase humoral and cellular immunity, but the rapid waning of protection against symptomatic infection with VOCs such as Omicron has prompted countries to call for a fourth-dose vaccination program. However, the clinical need, effectiveness and timing of a fourth-dose vaccine booster remain to be assessed.

This study will assess the immunogenicity and safety of heterologous boost COVID-19 vaccine regimens compared with a homologous boost regimen. In the early phases of this study (Phase A to C) volunteers who previously received a homologous primary vaccine series with BNT162b2 (Comirnaty/Pfizer-BioNTech) or mRNA-1273 (Moderna) were enrolled. With robust data now available about the benefits of a first booster dose of the vaccine, phase D of the study will shift to investigating the second booster dose and will simplify eligibility criteria to reflect heterogeneity in vaccinations received among the Singapore population to date, and the high prevalence of COVID-19 infection during the Omicron wave.