Immunogenicity and Reactogenicity of Fractional vs. Full Booster Doses of COVID-19 Vaccines: A Non-Inferiority, Randomized, Double-Blind, Phase IV Clinical Trial in Pakistan

Background: Vaccine dose fractionation has been explored as a potential dose-sparing strategy to expand vaccine access. We conducted a randomized controlled trial to evaluate the immunogenicity and safety of fractional doses of SARS-CoV-2 booster vaccines compared to full doses in adults aged 18-60 primed with full series of Sinovac, AZD1222, or Natural Infection in Sindh, Pakistan.
Methods: This observer-blind, randomized, phase IV non-inferiority study was conducted from February 2023 to January 2024. Participants received one-third, half, or full doses of BNT162b2, or a full dose of Sinovac. Eligible immunocompetent individuals were assigned to one of 10 study arms based on their primary vaccine series. Participants were followed for 6 months, with in-person visits for blood collection and safety evaluation at baseline (day 0), day 28, day 84 and day 182 timepoints. The primary endpoint of seroresponse rate defined as >4-fold rise in anti-Spike IgG level 28 days from baseline, measured by binding ELISA, was compared between full and fractional doses within a priming arm, using a 10% non-inferiority threshold.
Results: In total, 903 participants received booster vaccines. The BNT162b2 fractional doses were found to be non-inferior to the full Sinovac booster, with a seroresponse rate 47.2% (90% CI: 34.7 to 57.5%) and 50.3% (90% CI: 37.6 to 61.2%) lower with a full Sinovac dose as compared to the 1/2 and 1/3 doses of BNT162b2, respectively. No other comparisons we considered were found to be non-inferior. The magnitude and duration of antibody titers were similar between the BNT162b2 full and fractional doses during six months of follow-up. Local and systemic adverse events occurred in all groups, but none were serious within 28 days. Both full and fractional BNT162b2, and full Sinovac doses were well tolerated.
Conclusions: Fractional BNT162b2 doses were non-inferior to the full Sinovac dose, but not to the full BNT162b2 dose in any priming group. Given these findings and considering the need for further research on antibody thresholds to fully understand the protection provided by fractional doses, we recommend using full BNT162b2 doses as boosters for those primed with Sinovac. If full BNT162b2 doses are not available, fractional BNT162b2 doses may be considered, but another Sinovac dose should be avoided.