Discussion
RBD, Selected SARS-CoV-2 RBD, beta variant RBD, beta RBD
RECRUITMENT, VIRUS, SARS-COV-2 INFECTION, SECONDARY
This Phase I study provides evidence of the safety and tolerability of recombinant protein and mRNA-LNP vaccines directed at the beta variant RBD of SARS-CoV-2. The data also show that in a highly immunised cohort with a substantial degree of prior SARS-CoV-2 infection, robust boosting of antibody levels is achieved. The dose–response relationship for boosting, as measured by GMT, was approximately linear for both the Protein-RBD and mRNA-RBD vaccines. However, when examining GMFR relative to baseline responses that were higher in the intermediate and higher dose groups, dose relationships were less apparent and even reversed for the mRNA vaccine. Similarly, while there was evidence of CD4Breadth of immune responses boosted by the beta RBD vaccines was demonstrated against BA.5 for ELISA and all neutralisation assays, and in sVNT and pVNT assays also for more recent omicron subvariants (BA.1, BA.2, XBB, XBB.1.5 and BQ.1.1). This possibly reflects the benefit of beta variant-directed candidates and focussed RBD presentation that is less susceptible to immunological imprinting targeting conserved and non-neutralising epitopes.RBD-reactive CD4The nature of the evolution of the SARS-CoV-2 virus has required updating of the vaccine due to the development of VOC. This resulted in calls for RBD-based COVID vaccines that would potentially reduce the risk of vaccine escape and imprinting, and provide a more efficient basis for mass production to meet global vaccine needs.Several RBD protein vaccines are now in various stages of development or implementation,Selected SARS-CoV-2 RBD vaccine candidates in later-stage development or licensure.All but three are targeted at ancestral strain RBD—a beta variant version of the V-01 vaccine that was tested in a pilot study, the HIPRA candidate has a beta RBD target (as alpha/beta heterodimer), and ARVAC CG uses the gamma variant RBD.Preclinical (mouse) studies of our Protein-RBD vaccine showed that the RBD presented as an Fc-linked dimer produced superior primary and secondary immune responses compared to RBD monomers and single-chain RBD dimers.Recognising that this is a Phase I trial, there are some limitations which will need to be addressed in subsequent studies. There were no elderly participants (65 y+) because of ethical constraints around placebo receipt in the context of public health booster recommendations at the time of recruitment. Nevertheless, other licensed COVID-19 vaccines have not shown reduction in efficacy with increasing age.In summary, this Phase I study interim analysis identified no safety concerns and the reactogenicity profile was mild and similar to licensed COVID-19 vaccines. Both protein and mRNA beta RBD vaccines boosted immune responses against beta, ancestral and omicron BA.5 strains based on ELISA, microneutralisation, sVNT and pVNT assays, with optimal vaccine doses of 45 μg and possibly 50 μg respectively. Based on sVNT and/or pVNT data, neutralising antibody titres against several other variants, including alpha, delta, lambda, delta