India's COVID-19 Vaccine Candidate Covaxin Or BBV152, Which Uses Inactivated Whole-Virion Shows Better Prospects Than RNA Vaccines
: Indian researchers from vaccine developer Bharat Biotech International Ltd in collaboration with researchers National Institute of Virology-Indian Council of Medical Research have conducted a preclinical study demonstrating the safety and efficacy of a new candidate vaccine against the SARS-CoV-2 coronavirus, the pathogen that causes the COVID-19 disease.
The Covaxin vaccine is composed of an inactivated whole SARS-CoV-2 virion with one of two different adjuvants: either aluminum hydroxide gel (Algel) or a novel TLR7/8 agonist adsorbed Algel.
Lead clinical researcher from Bharat Biotech International Ltd, Dr Krishna Mohan Vadrevu said that both forms of the vaccine, called BBV152, induced high titers of neutralizing antibodies in mice, rabbits, and rats, without any safety concerns.
The study results were published on a preprint server and are currently being peer-reviewed. https://www.biorxiv.org/content/10.1101/2020.09.09.285445v2
Significantly the formulation containing the TLR7/8 agonist also induced a distinct T helper cell 1 (Th1) biased antibody response with increased levels of SARS-CoV-2-specific interferon-gamma (IFN-γ)+ CD4 cells.
Many other international researchers are also in agreement that India’s approached in using a whole inactivated virion might be more beneficial compared to many of the current candidates in phase three trials that are RNA based vaccines or ‘genetic’ vaccines that focuses on using primarily spike proteins or the RBD proteins of the SARS-CoV-2 coronavirus.
The study team says the findings provide evidence to support the testing of BBV152 in phase I clinical trials.
The team says that a number of vaccines are currently in various stages of preclinical and clinical trials, but producing the billions of doses needed globally will require a collective effort to validate and manufacture effective vaccines.
They added that inactivated virions have been licensed as safe vaccines for decades, and the availability of well-established vero cell manufacturing platforms for testing these agents has helped to expedite vaccine development.
The study team lead by Dr Vadrevu used a well-characterized strain of SARS-CoV-2 and an established vero cell platform called CCL-81 to generate large-scale good manufacturing practice (GMP) grade, highly purified BBV152.
Importantly a key critical challenge researchers face when developing a safe coronavirus vaccine is the vaccine-induced disease that occurs in animal models when Th2-like immunity develops.
The study team says some preclinical studies of inactivated SARS-CoV-1 and Middle East respiratory syndrome coronavirus (MERS-CoV) adjuvanted with alum have resulted in Th2 responses that cause eosinophilic infiltration in the lungs.
In order to circumvent the Th-2 bias and to develop a safe vaccine, the study team formulated a new proprietary adjuvant that contains an imidaquizoquinoline class TLR7/8 agonist adsorbed to Algel.
The study team explained that this type of agonist
induces a potent type I interferon response from dendritic cells and monocyte-macrophages that help to drive Th1-biased immunity rather than the pathogenic Th2-biased immunity.
In the research, the BBV152 vaccine with the two different adjuvants was administered to rats, rabbits, and mice at concentrations of 3µg and 6µg.
It was observed that at both concentrations, the vaccine-induced the production of high antigen-binding and neutralizing antibody titers in all three animal models.
The team added that the neutralizing antibody titers did not statistically differ between the 3µg and 6µg concentrations or between the two types of adjuvant use, with all formulations exhibiting excellent immunogenicity.
It was observed however that the formulation containing the TLR7/8 agonist also induced Th1-biased antibody responses with an elevated immunoglobulin 2a (IgG2a)-to-IgG1 ratio and increased levels of SARS-CoV-2-specific IFN-γ+ CD4 T cells.
It must be noted that safety testing showed no pathological changes or systemic toxicity and only minimal to no adverse events.
However the only side effect observed was a local reaction that is consistent with the reaction previously described in the literature for these adjuvants. Dr Vadrevu and colleagues say the reaction is a physiological response to injection rather than an adverse event.
The study findings support further development of the vaccine for clinical trials. The study team said, “The study findings show that these vaccine formulations induced significantly elevated titers of antigen binding and neutralizing antibodies in all animal models tested without any safety concerns and this support further development for Phase I/II clinical trials in human.”
In another study by the same team of which the study results are not published yet, the Covaxin again demonstrated encouraging and positive results in another animal trial involving 20 monkeys in India. The monkeys were administered two doses of Covaxin in a span of 14 days.
In the study, the monkeys were divided into four groups in which three groups were given the vaccination and one group was not vaccinated. The three vaccinated groups did not develop pneumonia, while the non-vaccination group developed pneumonia.
Bharat Biotech said the vaccine candidate was found to generate robust immune responses. Thus, preventing infection and disease in the primates upon high amounts of exposure to live SARS-CoV-2 virus.
The human phase I/II clinical trial are already being conducted on 1,125 patients at 12 institutes across India, including All India Institute of Medical Sciences in New Delhi and Patna, King George Hospital in Visakhapatnam, Nizam’s Institute of Medical Sciences in Hyderabad and PGIMS in Rohtak.
Covaxin has demonstrated protective efficacy and immunogenicity in non-human primates in Phase I clinical trials in India. According to the official note released by Bharat Biotech, there have not been any adverse side-effects noted in the animal trials.
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