Safety and Immunogenicity of Fractional Doses of COVID-19 Vaccines among Nigerian Adults- A Randomised Non-Inferiority trial

The shortage of COVID-19 vaccines posed a significant challenge in optimal response to the COVID-19 pandemic. Fractional doses of vaccine with adequate immunogenic response and proven safety profile emerged as potential strategy to extend the limited vaccine doses. This study was aimed to evaluate the immunogenicity and safety of fractional doses of the ChadOx1, Ad26.COV2.S, and BNT162B2 vaccines among healthy Nigerian adults. A non-inferiority multi-site triple-blind clinical trial was undertaken in Nigeria. Healthy Nigerian adults (18-65 years) who met the inclusion criteria were enrolled in the study. Participants were block-randomized into three vaccine arms (ChadOx1 quarter, half, and full dose; Ad26.COV2.S: quarter, half and full dose; and BNT162B2: half and full dose) . Participants, clinical staff (clinicians and nurses) and laboratory personnel were blinded. The primary objective of the study was to evaluate non-inferiority in seroconversion rates, defined as geometric mean fold rise (GMFR) [≥] 2.5 in serum anti-spike IgG titre at 28 days post-vaccination by ELISA. Immunogenicity analysis included use of serum neutralization assays using pseudotyped virus bearing spike from Wu-1 and Omicron variants. A total of 1891 participants were enrolled between June 21, 2022, and January 25, 2023. 320 participants in the fractional dose group and 220 in the standard dose group completed follow-up and were included in the analysis. SARS-CoV-2 seropositivity at baseline was high, at 68% (365/539). Seroconversion (geometric mean fold rise) was comparable between standard and fractional doses. For ChAdOx1, 31% achieved [≥] 2.5 fold change increase in serum binding antibody in the standard dose arm (16/52), 28% in half dose (15/53), and 34% in quarter dose (18/53). For Ad26.COV2.S, the proportions were 27% (28/105) in standard dose, 32% (22/68) in half dose, and 30% (21/71) in quarter dose arms respectively. For BNT162N2, the proportions were 43% (27/63) in standard dose and 39% (29/75) in half dose. Subset analysis of binding and neutralization responses in (n=64) participants demonstrated high degree of of prior exposure to SARS-CoV-2 ancestral and Omicron lineage variants prior to vaccination. Serum neutralization responses showed [≥]2-fold response to both full and fractional doses indicating immunogenic responses to the vaccine dosing regimens. There was no report of serious adverse events. Fractional vaccine doses showed potential to generate non-inferior immune responses compared to standard doses in the context of a population with high rate of previous exposure to SARS-CoV-2 infection. The three vaccines are safe and well tolerated. Fractional dose should be considered to boost herd immunity and prevent outbreaks of SARS-COV-2.