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. 2022 Mar 18;8(11):eabl6015.
doi: 10.1126/sciadv.abl6015. Epub 2022 Mar 16.

SARS-CoV-2 receptor binding domain displayed on HBsAg virus-like particles elicits protective immunity in macaques

Neil C Dalvie  1   2 , Lisa H Tostanoski  3 , Sergio A Rodriguez-Aponte  2   4 , Kawaljit Kaur  5 , Sakshi Bajoria  5 , Ozan S Kumru  5 , Amanda J Martinot  3   6 , Abishek Chandrashekar  3 , Katherine McMahan  3 , Noe B Mercado  3 , Jingyou Yu  3 , Aiquan Chang  3   7 , Victoria M Giffin  3 , Felix Nampanya  3 , Shivani Patel  3 , Lesley Bowman  8 , Christopher A Naranjo  2 , Dongsoo Yun  2 , Zach Flinchbaugh  9 , Laurent Pessaint  9 , Renita Brown  9 , Jason Velasco  9 , Elyse Teow  9 , Anthony Cook  9 , Hanne Andersen  9 , Mark G Lewis  9 , Danielle L Camp  2 , Judith Maxwell Silverman  10 , Gaurav S Nagar  11 , Harish D Rao  11 , Rakesh R Lothe  11 , Rahul Chandrasekharan  11 , Meghraj P Rajurkar  11 , Umesh S Shaligram  11 , Harry Kleanthous  12 , Sangeeta B Joshi  5 , David B Volkin  5 , Sumi Biswas  8   13 , J Christopher Love  1   2   14 , Dan H Barouch  3   7   14   15
Affiliations

SARS-CoV-2 receptor binding domain displayed on HBsAg virus-like particles elicits protective immunity in macaques

Neil C Dalvie et al. Sci Adv. .

Abstract

Authorized vaccines against SARS-CoV-2 remain less available in low- and middle-income countries due to insufficient supply, high costs, and storage requirements. Global immunity could still benefit from new vaccines using widely available, safe adjuvants, such as alum and protein subunits, suited to low-cost production in existing manufacturing facilities. Here, a clinical-stage vaccine candidate comprising a SARS-CoV-2 receptor binding domain-hepatitis B surface antigen virus-like particle elicited protective immunity in cynomolgus macaques. Titers of neutralizing antibodies (>104) induced by this candidate were above the range of protection for other licensed vaccines in nonhuman primates. Including CpG 1018 did not significantly improve the immunological responses. Vaccinated animals challenged with SARS-CoV-2 showed reduced median viral loads in bronchoalveolar lavage (~3.4 log10) and nasal mucosa (~2.9 log10) versus sham controls. These data support the potential benefit of this design for a low-cost modular vaccine platform for SARS-CoV-2 and other variants of concern or betacoronaviruses.

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Figures

Fig. 1.
Fig. 1.. Design and analysis of the RBD-VLP drug product.
(A) Schematic of protein expression and conjugation. (B) Reduced SDS-PAGE analysis of the formulated RBD-VLP vaccine samples. Alum-bound protein antigen (with and without CpG) was separated by centrifugation and desorbed from the alum using an elution buffer combined with heat treatment before SDS-PAGE.
Fig. 2.
Fig. 2.. Humoral and cellular immune response to the RBD-VLP vaccine.
(A) Design of the nonhuman primate study in cynomolgus macaques. (B) Titers of RBD-specific antibody binding in animal sera. (C) Titers of SARS-CoV-2 pseudovirus–neutralizing antibody in animal sera. NT50, end point of 50% reduction of virus expression. (D) Expression of IFN-γ from cells stimulated with S1 protein peptides. Statistical significance was determined by a Kolmogorov-Smirnov test. n.s., not significant (P > 0.1). Black bars represent median values. Gray dotted line represents limit of detection. PBMCs, peripheral blood mononuclear cells.
Fig. 3.
Fig. 3.. Challenge with SARS-CoV-2.
(A and C) Peak levels of SARS-CoV-2 sgRNA after challenge for each animal from nasal swabs (A) or BAL (C). Statistical significance was determined by a Kolmogorov-Smirnov test. n.s., not significant (P > 0.1). Black bars represent median values. Gray dotted line represents limit of detection. (B and D) Levels of sgRNA after challenge from nasal swabs (B) or BAL (D). Each thin line represents one animal. Thick black lines represent median values. (E and F) Correlation of RBD-specific antibody titer and pseudovirus-neutralizing antibody titer from week 5 animal sera with peak sgRNA levels in nasal swabs (E) and BAL (F). R was calculated by Spearman correlation. (G) Pathology scores for individual lung samples and cumulative scores for each animal. (H) Titers of RBD-specific antibody and SARS-CoV-2 pseudovirus–neutralizing antibody in animal sera at week 7 (2 weeks after challenge). Statistical significance was determined by a Kolmogorov-Smirnov test. n.s., not significant (P > 0.1). Black bars represent median values.
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