Researchers in the United States have developed a modular protein subunit vaccine against Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), which induced a strong immune response in macaques and prevented animals from developing coronavirus disease 2019 (COVID-19 ) to develop.
The vaccine, which contains the SARS-CoV-2 spike protein receptor binding domain (RBD) presented on a hepatitis B virus-like particle (VLP), was developed using the SpyTag / SpyCatcher covalent peptide-mediated coupling system constructed.
The spike RBD mediates the initial stage of the SARS-CoV-2 infection process when it binds to the angiotensin-converting enzyme 2 of the host cell receptor. This RBD is a primary target of neutralizing antibodies following natural infection or vaccination.
Dan Barouch of Harvard Medical School in Boston, Massachusetts and colleagues say the RBD-VLP antigen elicits significantly higher levels of neutralizing antibodies than other approved vaccines in non-human primates.
The vaccine also reduced the viral load in the animals’ upper and lower airways after infection with SARS-CoV-2.
In addition, both the Spike RBD and Hepatitis B (VLPs) protein components are produced in yeast, potentially providing a cost-effective manufacturing process for low- and middle-income countries where access to vaccination is limited.
“Because of these promising data, this vaccine candidate is currently being tested in clinical trials,” said Barouch and colleagues.
A pre-print version of the research paper is available on the site bioRxiv* Server while the article is being peer reviewed.
Access to vaccines is limited in low and middle income countries
The mass adoption of COVID-19 vaccination in many industrialized countries has been shown to be very effective in lowering SARS-CoV-2 infection rates and preventing symptomatic COVID-19.
However, the availability of vaccines in low and middle income countries is limited due to inadequate supplies, high costs and cold storage requirements.
New vaccines that could be manufactured by existing local manufacturers could minimize the costly infrastructure required to distribute vaccines to achieve global immunity to SARS-CoV-2.
Protein subunit vaccines represent a promising solution because they can be made on a large scale using local fermentation equipment, do not usually require cold storage, and are known to be used with adjuvants.
What did the team do?
Now Barouch and colleagues have outlined the design and preclinical testing of the protein subunit vaccine – RBD-VLP – which is currently being manufactured at the Serum Institute of India manufacturing facility.
“Both protein components are made in yeast, making this vaccine a promising, low-cost intervention for low- and middle-income countries,” the team says.
The researchers used a polypeptide-based system called SpyTag-SpyCatcher to covalently attach the antigen to the VLP, previously shown to increase antigen-specific antibody titers in mice.
“The modularity of the SpyTag SpyCatcher system allows each component of the final particle to be independently expressed and purified to maximize yield and quality,” they explain.
The RBD-VLP antigen has been formulated with one of two adjuvants: aluminum hydroxide (alum) and a combination of alum with CpG1018 – a potent commercial adjuvant known to cause T-helper-1-type (Th1) cytokine responses evokes.
Cynomolgus macaques were immunized with two doses of either the vaccine formulation or a placebo separated by a three week interval. Spike-specific antibody titers were measured after each dose.
Design and Analysis of the RBD-VLP Drug Product A) Scheme 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 a heat treatment prior to SDS-PAGE.
What did the study find out?
The researchers say they observed neutralizing antibody titers in the immunized animals that were more than 10,000 times the range of protection provided by other approved vaccines previously tested on non-human primates.
The pure alum formulation elicited significantly higher antibody levels than the combination adjuvant. However, the combination of alum plus CpG1018 improved the cellular immune response compared to alum alone.
“The cellular response appeared to be stronger when alum and CpG1018 were formulated together, which is consistent with previous reports on the influence of CpG1018 as an adjuvant in vaccines,” the team says.
The researchers say that CpG adjuvants with hepatitis B surface antigen vaccines have previously been shown to enhance the Th1 cell response and complement the Th2 cell response induced by alum alone.
“Consistent with these previous reports, we observed a higher Th1 cell response to the RBD-VLP formulated with both alum and CpG1018 compared to alum alone,” they write.
The vaccine reduced the viral load in the airways
The researchers infected the macaques with SARS-CoV-2 two weeks after the second dose of the vaccine or placebo.
Among the animals immunized there were approximately 3.4 and 2.9 logs10 Reduction of the median virus content of the bronchoalveolar lavage supernatants or nasal samples compared to the control animals.
Animals given the sham vaccine showed evidence of interstitial inflammation, syncytial cells and type II pneumocyte hyperplasia in the lungs and a higher mean cumulative pathology score compared to the immunized animals.
“Notably, the post-exposure levels of humoral immunity conferred by the vaccine did not differ significantly between the two vaccine formulations,” the team says.
What did the authors conclude?
Barouch and colleagues say the results taken together suggest that the RBD-VLP vaccine candidate protects against SARS-CoV-2 infection.
“Based on these promising data, this vaccine candidate is currently being tested in clinical trials (ANZCTR registration number ACTRN12620000817943),” they write.
bioRxiv publishes preliminary scientific reports that are not peer-reviewed and therefore are not considered conclusive, guide clinical practice / health-related behavior, or should be treated as established information.