Safety, immunogenicity and protection provided by unadjuvanted and adjuvanted formulations of recombinant plant-derived virus-like particle vaccine candidate for COVID-19 in non-human primates

Abstract

Although antivirals are important tools to control the SARS-CoV-2 infection, effective vaccines are essential to control the current pandemic. Plant-derived virus-like particle (VLP) vaccine candidates have previously demonstrated immunogenicity and efficacy against influenza. Here we report the immunogenicity and protection induced in macaques by intramuscular injections of VLP bearing SARS-CoV-2 spike protein (CoVLP) vaccine candidate formulated with or without Adjuvant System 03 (AS03) or cytosine phosphoguanine (CpG) 1018. Although a single dose of unadjuvanted CoVLP vaccine candidate stimulated humoral and cell-mediated immune responses, booster immunization (at 28 days after prime) and adjuvants significantly improved both responses with a higher immunogenicity and protection provided by AS03 adjuvanted CoVLP. Fifteen microgram CoVLP adjuvanted with AS03 induced a balanced IL-2 driven response along with IL-4 expression in CD4 T cells and mobilization of CD4 follicular helper cells (Tfh). Animals were challenged by multiple routes (i.e. intratracheal, intranasal and ocular) with a total viral dose of 106 plaque forming units of SARS-CoV-2. Lower viral replication in nasal swabs and broncho-alveolar lavage (BAL) as well as fewer SARS-CoV-2 infected cells and immune cell infiltrates in the lungs concomitant with reduced levels of pro-inflammatory cytokines and chemotactic factors in BAL were observed in the animals immunized with CoVLP adjuvanted with AS03. No clinical, pathologic or virologic evidences of vaccine associated enhanced disease (VAED) were observed in vaccinated animals. CoVLP adjuvanted with AS03 was therefore selected for vaccine development and clinical trials.

Medical imaging of pulmonary disease in SARS-CoV-2-exposed non-human primates

“…Although most human CXR examinations are inconclusive during the early stages of COVID-19 [37], 28 studies of SARS-CoV-2-exposed NHPs detected CXR abnormalities early after exposure [9,[13][14][15][16][17][20][21][22][23]26,27,29,32,35,[44][45][46]. However, CXR imaging was inconclusive in other studies [12,13,[23][24][25]28] and was generally found to be uncorrelated with the degree of lung abnormalities at necropsy (Figure 1).…”

“…Multiple routes [9,13,16,20,23,26,28,29,31,33,34,46] lead to SARS-CoV-2 shedding. However, although infection is not necessarily dependent on respiratory tract exposure, it is plausible that the route of exposure impacts the progression of disease.…”

“…In general, BAL and imaging should be concurrently used with caution, as BAL may produce CXR or CT imaging artifacts when performed on consecutive days [72], interfere with pulmonary pathogenesis (within-lung spread), and potentially confound histopathology. Of the 41 NHP SARS-CoV-2 studies examined, 24 used BAL during the infection phase and included imaging [12][13][14][15][16]20,[22][23][24][27][28][29][30]33,35,50,51,53,54,56,65,73,74]. Eight included single BAL immediately before or at necropsy [12,20,22,33,54,57,65,73].…”

Broad neutralization against SARS-CoV-2 variants induced by ancestral and B.1.351 AS03-Adjuvanted recombinant Plant-Derived Virus-Like particle vaccines

“…Although many consider NAb levels to be a good candidate for a correlate of protection [81] , this is a fairly limited evaluation of vaccine-induced immunity and it is very likely that non-neutralizing but functional antibodies and cellular responses also contribute to vaccine-induced protection [82] . Data from a large non-human primate study [83] as well as ongoing clinical trials [27] , [65] , [84] demonstrate that AS03-adjuvanted CoVLP stimulates multiple arms of the adaptive response to SARS-CoV-2. Results from Medicago’s ongoing pivotal Phase 3 efficacy study [25] (NCT04636697), performed in different regions of the world where several VOCs have been circulating, demonstrated a good protection of the CoVLP vaccine (targeting the ancestral strain) against several VOCs such as B.1.617.2 and P.1.…”