Researchers in the United States and Taiwan have demonstrated the potential of a novel protein-peptide vaccine to protect against infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) – the agent that causes coronavirus disease 2019 (COVID-19).
Image Credit: https://www.biorxiv.org/content/10.1101/2020.11.30.399154v1.full.pdf
Chang Yi Wang from United Biomedical Inc Asia in Taipei and colleagues say the vaccine, called UB-612, is the first “multitope” protein-peptide vaccine to be developed against SARS-CoV-2.
UB-612 comprises several components designed to induce high levels of neutralizing antibodies and a broad immune cellular response, including a viral fusion protein, and five synthetic SARS-CoV-2-derived peptides.
Studies in guinea pigs, rats, mice, and rhesus macaques confirmed the immunogenicity and efficacy of UB-612, while toxicity tests in rats indicated the vaccine is safe and well-tolerated.
With the First in Human (FIH) clinical trials of UB-612 having started in Taiwan and future trials planned globally, UB-612 represents a highly promising vaccine candidate for the prevention of SARS-CoV-2 transmission and COVID-19 disease, say Wang and the team.
A pre-print version of the paper is available on the server bioRxiv*, while the article undergoes peer review.
Researchers race to develop a vaccine
Since the COVID-19 outbreak began in Wuhan, China late last year (2019), this unprecedented global public health crisis has prompted urgent efforts by researchers worldwide to design a vaccine against SARS-CoV-2.
Hundreds of candidate vaccines have been developed, some of which have already reached the late phases of clinical trials.
SARS-CoV-2 has a large viral RNA genome, of around 30kb in length, that encodes 29 proteins. Four of these proteins are the structural spike (S), membrane (M), envelope (E), and nucleocapsid (N) proteins.
The main structural protein SARS-CoV-2 uses to infect cells is a spike (S), a class I fusion glycoprotein that is divided into two functionally distinct subunits.
Subunit 1 (S1) contains the receptor-binding domain (RBD) that directly engages the human host cell receptor angiotensin-converting enzyme 2 (ACE2). S1, therefore, determines viral tissue tropism (the specific targeting of particular host tissue) and the degree of pathogenicity.
Subunit 2 (S2) bears the fusion peptide that drives viral and hosts membrane fusion to enable the delivery of viral RNA into the host cell.
Most of the vaccines currently being evaluated in clinical trials target only the full-length S protein, with the aim of inducing a neutralizing antibody response.
Targeting spike alone could present problems
“A neutralizing response against the S protein alone is unlikely to provide lasting protection against SARS-CoV-2 and its emerging variants with mutated B-cell epitopes,” write Wang and colleagues. “The induction of T cell responses would be limited compared to responses generated by natural multigenic SARS-CoV-2 infections.”
The S1-RBD is a critical component of SARS-CoV-2. This domain is required for host cell attachment and is the primary immunogen for the induction of neutralizing antibodies and a memory B cell response.
A long-lasting cellular response could augment the initial neutralizing response (through memory B cell activation) and provide a much greater duration of immunity as antibody titers wane,”
Due to the clear advantages of a vaccine having a strong S1-RBD vaccine component, the team developed three S1-RBD binding constructs that were then subjected to immunogenicity testing in guinea pigs.
The most potent immunogen was S1-RBD-sFc
Of the three candidates, the most potent immunogen was S1-RBD-sFc – where S1-RBD is fused to a single chain fragment crystallizable region (sFc) of human immunoglobulin 1.
This construct elicited antibodies with the strongest functional activity, as quantified by inhibition of viral binding to ACE2 and neutralization of live SARS-CoV-2.
“Based on these results, the S1-RBD-sFc protein was selected as the lead candidate for our B cell component of the vaccine,” says the team.
To provide immunogens to elicit T cell responses, a literature search was performed to identify T helper (Th) and cytotoxic T cell (CTL) epitopes derived from the S, N, and M proteins of SARS-CoV-2. Five peptides were selected and subjected to additional design.
Tests of the leading candidate S1-RBD-sFc construct, further formulated with Th and CTL peptides were then performed in rats, mice, and rhesus macaques, which confirmed the immunogenicity and efficacy of UB-612.
Furthermore, the results of good laboratory practice (GLP) repeated-dose toxicology study in rats indicated that the UB-612 vaccine was safe and well-tolerated.
A “highly promising” vaccine candidate
“We showed extremely high levels of neutralizing antibodies and Th1 prone immune response induced by the vaccine that protected animals, challenged by a high dose of SARS-CoV-2, without induction of immunopathology in the lungs,” say Wang and the team.
Overall, the researchers say they have demonstrated proof-of-concept for UB-612, the first multitope protein, and a peptide-based vaccine against SARS-CoV-2.
With the phase 1 trial ongoing in Taiwan and additional trials planned worldwide, UB-612 is a highly promising and differentiated vaccine candidate for the prevention of SARS-CoV-2 transmission and COVID-19 disease,”
bioRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.
Wang CY, et al. A Novel SARS-CoV-2 Multitope Protein/Peptide Vaccine Candidate is Highly Immunogenic and Prevents Lung Infection in an Adeno Associated Virus Human Angiotensin-Converting Enzyme 2 (AAV hACE2) Mouse Model. bioRxiv, 2020. doi: https://doi.org/10.1101/2020.11.30.399154