Adjuvanting a subunit COVID-19 vaccine to induce protective immunity

Abstract

R us se ll -L od ri gue, C hr is to ph er Monjure,

Phase 1 randomized trial of a plant-derived virus-like particle vaccine for COVID-19

“…In contrast, when CoVLP was adjuvanted with AS03, the response was faster and more balanced with evidence of both Th1-and Th2-type activation. These differential effects of the adjuvants are generally consistent with a recent study that compared responses to a recombinant S protein administered with several adjuvants in non-human primates, including AS03 and CpG1018 + alum 48 , as well our own observations in Indian rhesus macaques (S.P. et al, unpublished data).…”

“…Again, IFN-γ responses were strongest in the AS03-adjuvanted groups, particularly at lower CoVLP dose levels. Although such IFN-γ responses could theoretically be mediated by other cells (for example, natural killer or CD8 T cells) 43 , our previous observations with plant-derived influenza vaccine candidates [29][30][31][32][45][46][47] and recent experience with an AS03-adjuvanted S protein vaccine in non-human primates 48 suggest that this production is most likely attributable to CD4 + T cells. The IL-4 ELISpot responses were also consistently higher in the AS03-adjuvanted groups than the unadjuvanted and CpG1018-adjuvanted groups, rising to near equivalence with the IFN-γ response with the second dose.…”

Stabilization of the SARS-CoV-2 Spike Receptor-Binding Domain Using Deep Mutational Scanning and Structure-Based Design

“…While monomeric and trimeric RBDs tend to be stable in solution, multivalent display on self-assembling protein nanoparticles has in some cases exposed a latent tendency of the RBD to aggregate (25,39). We have previously reported that I53-50-based nanoparticle immunogens displaying the wild-type SARS-CoV-2 RBD elicited potent neutralizing antibody responses and protective immunity in mice and NHPs (25,37). In those studies, excipients such as glycerol, L-arginine, and the detergent 3-[(3-cholamidopropyl)dimethylammonio]-1propanesulfonate (CHAPS) were used to stabilize preparations of the nanoparticle immunogens.…”

“…The SARS-CoV-2 RBD is more structurally homogeneous than metastable S ectodomains, with far higher expression yields (25,26). RBD-based immunogens in various oligomeric states have been investigated as genetic or protein-based vaccines for SARS-CoV-2, including monomers (27)(28)(29)(30)(31), dimers (32), trimers (33)(34)(35) and highly multivalent nanoparticles (25,(36)(37)(38)(39), several of which are now being evaluated in clinical trials. Although the RBD comprises only a minority of the total mass and antigenic surface of S and could in principle be more susceptible to escape mutations, this theoretical disadvantage may be mitigated by both functional constraints and the elicitation of antibodies targeting multiple distinct neutralizing epitopes in the RBD by infection or vaccination (25,(40)(41)(42)(43).…”

“…Indeed, the vast majority of neutralizing activity elicited by SARS-CoV-2 infection and currently approved S-based vaccines targets the RBD (40,(44)(45)(46)(47)(48), as do most clinical-stage monoclonal antibodies (49). Furthermore, preclinical studies have shown similar reductions in heterologous neutralizing titers against SARS-CoV-2 variants of concern, such as B.1.351, for RBD nanoparticle immunogens and S-based immunogens (37,50). Finally, RBD antigens can be leveraged to elicit neutralizing responses against the sarbecovirus subgenus through multivalent display on nanoparticles (36,50) and have recently been shown to be targeted by broadly neutralizing monoclonal antibodies (42,(51)(52)(53)(54)(55)(56).…”