Preclinical evaluation of a COVID-19 vaccine candidate based on a recombinant RBD fusion heterodimer of SARS-CoV-2

Abstract

Since the genetic sequence of SARS-CoV-2 became available in January 2020, new vaccines have been developed at an unprecedented speed. The current vaccines have been directly associated with a decline in new infection rates, prevention of severe disease and an outstanding decrease in mortality rates. However, the pandemic is still far from being over. New Variants of Concern (VoCs) are continuously evolving. Thus, it is essential to develop accessible second-generation COVID-19 vaccines against known and future VoCs to mitigate the current pandemic. Here, we provide preclinical data showing the immunogenicity, efficacy, and safety results in mice of a receptor-binding domain (RBD)-based recombinant protein vaccine candidate (PHH-1V) which consists of a novel RBD fusion heterodimer containing the B.1.1.7 (alpha) and B.1.351 (beta) variants of SARS-CoV-2, formulated with an oil-based adjuvant equivalent to MF59C.1. BALB/c and K18-hACE2 mice were immunized with different doses of recombinant RBD fusion heterodimer, following a two-dose prime-and-boost schedule. Upon 20 μg RBD fusion heterodimer/dose immunization, BALB/c mice produced RBD-binding antibodies with neutralising activity against the alpha, beta, gamma, and delta variants. Furthermore, vaccination elicited robust activation of CD4+ and CD8+ T cells with early expression of Th1 cytokines upon in vitro restimulation, along with a good tolerability profile. Importantly, vaccination with 10 μg or 20 μg RBD fusion heterodimer/dose conferred 100% efficacy preventing mortality and bodyweight loss upon SARS-CoV-2 challenge in K18-hACE2 mice. These findings demonstrate the feasibility of this novel recombinant vaccine strategy, allowing the inclusion of up to 2 different RBD proteins in the same vaccine. Most importantly, this new platform is easy to adapt to future VoCs and has a good stability profile, thus ensuring its global distribution.

Safety and immunogenicity of the protein-based PHH-1V compared to BNT162b2 as a heterologous SARS-CoV-2 booster vaccine in adults vaccinated against COVID-19: a multicentre, randomised, double-blind, non-inferiority phase IIb trial

“…SARS-CoV-2 delta, and mostly omicron (BA.1), were the most concerning variants circulating at the time this trial was started. PHH-1V has consistently showed good response against each new variant in many animal models 21 , a result which has been confirmed in the data presented here. These data indicate that PHH-1V is superior to BNT162b2 in terms of neutralizing antibodies against SARS-CoV-2 for the beta and omicron variants, and non-inferior against delta variant (or even superior on day 98) and Wuhan-Hu-1 (on day 98).…”

“…PHH-1V is a protein-based vaccine intended for the prevention of COVID-19 caused by SARS-CoV-2. This vaccine is based on a fusion heterodimer consisting of the spike RBD sequence from the SARS-CoV-2 beta (B.1.351) and alpha (B.1.1.7) variants 21 , formulated with an oil-in-water based adjuvant produced by HIPRA known as SQBA, and prepared as an emulsion for intramuscular administration. PHH-1V comprises three key mutations of high relevance for previously and currently circulating SARS-CoV-2 variants: K417N, E484K and N501Y 22 .…”

Immunogenicity mechanism of mRNA vaccines and their limitations in promoting adaptive protection against SARS-CoV-2

“…Recently, a RBD-based recombinant protein vaccine, the HIPRA PHH-1 V vaccine, which consists of a novel RBD fusion heterodimer containing the Alpha (B.1.1.7) and Beta (B.1.351) variants of SARS-CoV-2 has been developed. The vaccine showed promising results in protecting mice from COVID-19 infection, with robust activation of CD4 + and CD8 + T cells ( Barreiro et al, 2021 ). Although many potent nAbs bind to RBD ( Ju et al, 2020 ; Yang et al, 2020 ), other neutralizing epitopes that are present on the full-length S glycoprotein are absent in the RBD-derived vaccine, which may render the vaccine more prone to impact from antigenic drift and lead to reduced effectiveness.…”

Safety and Immunogenicity of a Recombinant Protein RBD Fusion Heterodimer Vaccine against SARS-CoV-2: preliminary results of a phase 1-2a dose-escalating, randomized, double-blind clinical trial

“…This new candidate also elicited a cross-reactive response and neutralization against heterologous pseudoviruses Wuhan strain, P·1 and B·1·617·2 in pre-clinical studies. 13 Different adjuvants, alone or combined, were assayed. Based on non-clinical studies, the oil-in-water emulsion adjuvant SQBA was selected.…”