A Capsid Virus-Like Particle-Based SARS-CoV-2 Vaccine Induces High Levels of Antibodies and Protects Rhesus Macaques

Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a worldwide pandemic. Here, we present non-human primate immunogenicity and protective efficacy data generated with the capsid virus-like particle (cVLP)-based vaccine ABNCoV2 that has previously demonstrated immunogenicity in mice. In rhesus macaques, a single vaccination with either 15 or 100 μg ABNCoV2 induced binding and neutralizing antibodies in a dose-dependent manner, at levels comparable to those measured in human convalescents. A second vaccine administration led to a >50-fold increase in neutralizing antibodies, with 2-log higher mean levels in the 100-μg ABNCoV2 group compared with convalescent samples. Upon SARS-CoV-2 challenge, a significant reduction in viral load was observed for both vaccine groups relative to the challenge control group, with no evidence of enhanced disease. Remarkably, neutralizing antibody titers against an original SARS-CoV-2 isolate and against variants of concern were comparable, indicating a potential for broad protection afforded by ABNCoV2, which is currently in clinical testing.

Keywords: COVID-19; SARS-CoV-2; broad neutralizing antibodies; corona; non-human primates (NHP); protection; variants of concern (VOCs); virus-like particles (VLP).

Figure 1

Experimental design and immunogenicity of ABNCoV2. (A) Schematic study design with non-human primates (NHP) (N = 6 per group) vaccinated intramuscularly with 100 or 15 μg ABNCoV2 in weeks 0 and 14 and challenged with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in week 20. Four (4) additional non-vaccinated NHP were added as controls. At regular intervals as indicated, animals were bled. (B) RBD-specific IgG was measured by ELISA, and (C) SARS-CoV-2 neutralizing antibodies were assessed by PRNT. For comparison, 10 human plasma samples positive for SARS-CoV-2 antibodies (human convalescents, gray symbols) were analyzed as well. Filled circles represent individual values and columns depict the geometric mean (ELISA, B) or geometric mean titers (PRNT, C) of the group +/geometric standard deviation. The horizontal dotted line in (B) represents the mean + 2 times the standard deviation of 50 untreated naive NHP to indicate background responses.

Figure 2

Chemokine changes following SARS-CoV-2 challenge. NHP (N = 6 per group) were vaccinated intramuscularly with 100 μg ABNCoV2 (red symbols) or 15 μg ABNCoV2 (blue symbols) in weeks 0 and 14 and challenged by the combined intranasal/intratracheal route with SARS-CoV-2 in week 20. As controls, four non-vaccinated rhesus macaques (black symbols) were challenged at the same time. CXCL10 (top graphs) and CXCL11 (bottom graphs) were measured in serum (A) and bronchoalveolar lavage (BAL) (B) on the days post-challenge as indicated. Each curve represents an individual animal. The symbol shapes identify individual animals as stated and the same symbols are used for the same animals throughout all post-challenge data.

Figure 3

Viral load in bronchoalveolar lavage following SARS-CoV-2 challenge. Rhesus macaques were vaccinated and challenged as described in Figure 2 . sgRNA was measured in bronchoalveolar lavage on days 2, 4, and 6 post-challenge. (A) sgRNA copies per ml BAL are shown for each animal in the 100-μg ABNCoV2 group by red symbols, in the 15-μg ABNCoV2 group by blue symbols, and in the non-vaccinated control group by black symbols. The symbol shapes identify individual animals; the same symbols are used for the same animals throughout all post-challenge data. Horizontal bars depict geometric mean values. (B) Total amount of sgRNA in BAL per animal (symbols) and median values (horizontal bars) are calculated as area under the curve (AUC). Significant differences by Mann–Whitney test were seen between each vaccinated group compared with the control group (p = 0.0095).

Figure 4

Immune responses following SARS-CoV-2 challenge. Rhesus macaques were vaccinated and challenged as described in Figure 2 . SARS-CoV-2 neutralizing antibodies (A) were measured at the time of challenge (week 20) and 2 weeks post-challenge (week 22) by PRNT, and RBD-specific IFN-γ T-cell responses (B) were measured 2 weeks post-challenge by ELISpot. (A) Symbols represent individual PRNT50 titers; horizontal bars depict the GMT of the group. For comparison, PRNT50 titers and GMT of 10 human plasma samples positive for SARS-CoV-2 antibodies (human convalescents) are shown. (B) Symbols represent individual spot-forming units (SFU) per one million PBMCs; horizontal bars depict mean SFU per one million PBMCs. Different symbol shapes represent individual animals, and the same symbol shapes are used for the same animals throughout all post-challenge data.

Figure 5

Neutralization of SARS-CoV-2 variants of concern. (A) NHP were vaccinated as described in Figure 1 . Two weeks following the second administration, vaccine-induced antibodies were tested for their capacity to neutralize Wuhan-like SARS-CoV-2 (FR-4286) as well as the alpha (B.1.1.7), beta (B.1.351), and delta variants (B1.617.2) by PRNT. Filled circles represent PRNT50 titers of individual NHP, and columns depict the GMT of the group +/geometric standard deviation. Kruskal–Wallis test showed no statistically significant differences between the neutralization of Wuhan-like FR-4286 and the variants. (B) Ten human plasma samples positive for SARS-CoV-2 antibodies (human convalescents) were analyzed for comparison.