A third dose of the unmodified COVID-19 mRNA vaccine CVnCoV enhances quality and quantity of immune responses

Abstract

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.

Graphical abstract

Abstract

Lenart et al show significant improvement in magnitude and quality of vaccine-specific responses with the third low dose mRNA immunization. In biodistribution studies, low dose vaccines drained to fewer lymph node clusters compared to high dose, likely targeting fewer naïve lymphocytes and thus requiring multiple doses for induction of high-quality responses.