Lenart K, Hellgren F, Ols S, Yan X, Cagigi A, Cerveira RA, Winge I, Hanczak J, Mueller SO, Jasny E, Schwendt K, Rauch S, Petsch B, Loré K
Mol Ther Methods Clin Dev - (-) - [2022-10-06; online 2022-10-06]
A third vaccine dose is often required to achieve potent, long-lasting immune responses. We investigated the impact of three 8 μg doses of CVnCoV, CureVac's SARS-CoV-2 vaccine candidate containing sequence-optimized unmodified mRNA encoding spike (S) glycoprotein, administered at 0, 4 and 28 weeks on immune responses in rhesus macaques. Following the third dose S-specific binding and neutralizing antibodies increased 50-fold compared with post-dose 2 levels, with increased responses also evident in the lower airways and against the SARS-CoV-2 B.1.1.7 (Alpha), B.1.351 (Beta), P.1 (Gamma) and B.1.617.2 (Delta) variants. Enhanced binding affinity of serum antibodies after the third dose correlated with higher somatic hypermutation in S-specific B cells, corresponding with improved binding properties of monoclonal antibodies expressed from isolated B cells. Administration of low dose mRNA led to fewer cells expressing antigen in vivo at the injection site and in the draining lymph nodes compared with a tenfold higher dose, possibly reducing the engagement of precursor cells with the antigen and resulting in the suboptimal response observed following two-dose vaccination schedules in phase IIb/III clinical trials of CVnCoV. However, when immune memory is established, a third dose efficiently boosts the immunological responses as well as improves antibody affinity and breadth.