Safety and immunogenicity of booster vaccination and fractional dosing with Ad26.COV2.S or BNT162b2 in Ad26.COV2.S-vaccinated participants
Authors: Riou Catherine , Bhiman Jinal N. , Ganga Yashica , Sawry Shobna , Ayres Frances , Baguma Richard , Balla Sashkia R. , Benede Ntombi , Bernstein Mallory , Besethi Asiphe S. , Cele Sandile , Crowther Carol , Dhar Mrinmayee , Geyer Sohair , Gill Katherine , Grifoni Alba , Hermanus Tandile , Kaldine Haajira , Keeton Roanne S. , Kgagudi Prudence , Khan Khadija , Lazarus Erica , Le Roux Jean , Lustig Gila , Madzivhandila Mashudu , Magugu Siyabulela F. J. , Makhado Zanele , Manamela Nelia P. , Mkhize Qiniso , Mosala Paballo , Motlou Thopisang P. , Mutavhatsindi Hygon , Mzindle Nonkululeko B. , Nana Anusha , Nesamari Rofhiwa , Ngomti Amkele , Nkayi Anathi A. , Nkosi Thandeka P. , Omondi Millicent A. , Panchia Ravindre , Patel Faeezah , Sette Alessandro , Singh Upasna , van Graan Strauss , Venter Elizabeth M. , Walters Avril , Moyo-Gwete Thandeka , Richardson Simone I. , Garrett Nigel , Rees Helen , Bekker Linda-Gail , Gray Glenda , Burgers Wendy A. , Sigal Alex , Moore Penny L. , Fairlie Lee 
Published: April 2024

We report the safety and immunogenicity of fractional and full dose Ad26.COV2.S and BNT162b2 in an open label phase 2 trial of participants previously vaccinated with a single dose of Ad26.COV2.S, with 91.4% showing evidence of previous SARS-CoV-2 infection. A total of 286 adults (with or without HIV) were enrolled >4 months after an Ad26.COV2.S prime and randomized 1:1:1:1 to receive either a full or half-dose booster of Ad26.COV2.S or BNT162b2 vaccine. B cell responses (binding, neutralization and antibody dependent cellular cytotoxicity-ADCC), and spike-specific T-cell responses were evaluated at baseline, 2, 12 and 24 weeks post-boost. Antibody and T-cell immunity targeting the Ad26 vector was also evaluated. No vaccine-associated serious adverse events were recorded. The full- and half-dose BNT162b2 boosted anti-SARS-CoV-2 binding antibody levels (3.9- and 4.5-fold, respectively) and neutralizing antibody levels (4.4- and 10-fold). Binding and neutralizing antibodies following half-dose Ad26.COV2.S were not significantly boosted. Full-dose Ad26.COV2.S did not boost binding antibodies but slightly enhanced neutralizing antibodies (2.1-fold). ADCC was marginally increased only after a full-dose BNT162b2. T-cell responses followed a similar pattern to neutralizing antibodies. Six months post-boost, antibody and T-cell responses had waned to baseline levels. While we detected strong anti-vector immunity, there was no correlation between anti-vector immunity in Ad26.COV2.S recipients and spike-specific neutralizing antibody or T-cell responses post-Ad26.COV2.S boosting. Overall, in the context of hybrid immunity, boosting with heterologous full- or half-dose BNT162b2 mRNA vaccine demonstrated superior immunogenicity 2 weeks post-vaccination compared to homologous Ad26.COV2.S, though rapid waning occurred by 12 weeks post-boost.
Trial Registration: The study has been registered to the South African National Clinical Trial Registry (SANCTR): DOH-27-012022-7841. The approval letter from SANCTR has been provided in the up-loaded documents.