Serum’s Covishield and Bharat Biotech’s Covaxin are examples of atmanirbhar (self-reliance) but have an element of non-Indian science — and at least to me that is fine, says Dr. Gagandeep Kang. Though Covaxin uses inactivated virus, neutralising antibodies against the spike protein are critical for reinfection. So if Covaxin is based on an old viral strain, will it continue to work? We will just have to wait for data from humans and from the laboratory to know that, she clarifies. Once clinical efficacy data are available and have been reviewed by the regulator, will have no issues at all with taking the vaccine, Dr. Kang stresses.
A year after the first outbreak of novel coronavirus (SARS-CoV-2) in the Chinese city of Wuhan was reported by the World Health Organization, the virus has spread to 191 countries and all continents, including Antarctica. So far nearly 86.4 million cases and 1.8 million deaths have been reported from across the world. Since allowing the virus to infect a sizable percentage of the world population to bring the COVID-19 pandemic to an end is a dangerous proposition and has been rightly ruled out, all efforts have been to develop a safe and effective vaccine.
Scientists, manufacturers and drug regulators have been speeding up the timelines to develop, test and approve vaccines for emergency use. Three safe and efficacious vaccines from Pfizer, Moderna and AstraZeneca have already been greenlighted. China and Russia were the first two countries to approve a vaccine developed domestically but without waiting for efficacy data from phase-3 trials.
Perils of haste
In India, the Hyderabad-based Bharat Biotech has been working feverishly to develop and test a COVID-19 vaccine, Covaxin, that uses a time-tested inactivated vaccine platform; but the haste shown by the Indian drug regulator to approve it even in the absence of efficacy data has taken the shine off an indigenously developed lifesaver.
“Bharat Biotech has data from animal challenge studies which are supportive of efficacy, but that is not an automatic bridge to human efficacy,” Dr. Gagandeep Kang who has extensive experience in vaccine research and is Professor of Microbiology at CMC Vellore says in an email. From humans, Bharat Biotech must be following up their phase-1 and phase-2 participants for safety and immunogenicity, and may have some data, but that is not going to be sufficient, she says. The company really will need efficacy data from its phase-3 trial and is in the process of recruitment, vaccination and data collection. But that interim data, crucial for an approval, will still take a few weeks or months to come by.
Approval contradicts regulator’s guidance
The approval granted to Bharat Biotech’s Covaxin flies in the face of the regulator’s own guidance to vaccine manufacturers. The September 2020 guidance explicitly mentions that 50% efficacy would be considered acceptable for emergency use approval. But it appears that our expert committee has followed a path similar to the Russian and Chinese regulators in not requiring human efficacy data for approval, Dr. Kang says.
The urgency to approve the vaccine even in the absence of efficacy data would have been permissible if COVID-19 has been life-threatening with a very high likelihood of death in those who are infected, as in the case of Ebola and Nipah. “For a disease with a low mortality rate and a population-wide vaccination strategy, it makes more sense to wait and have an efficacious vaccine instead of wide use of a vaccine that might not work,” she emphasises.
Not sure what ‘clinical trial mode’ means
While granting permission, the regulator had said the vaccine will be used in a ‘clinical trial mode’, a phrase never before used in any vaccine approval. “I really do not know what ‘clinical trial mode’ after approval means,” says Dr. Kang. “I am not sure what is planned for consent post-introduction and I am not clear about whether these studies and medical expenses in case of serious adverse events will be the responsibility of the company or the government. If it is the company, it is not clear to me how expanding their studies from thousands to lakhs or millions with the increased requirements benefits the company in its goal to full licensure.”
The assertion that Covaxin will be effective against mutant strains even in the absence of efficacy data is based on the premise that using the whole virus that is inactivated might provide increased protection unlike other vaccines because it would induce immune responses to many more proteins. The flip side is that neutralising antibodies against the spike protein are critical for reinfection. So if Covaxin is based on an old viral strain, will it continue to work? We will just have to wait for data from humans and from the laboratory to know that, she clarifies.
Idea of self-reliance to be blamed?
With Prime Minister Narendra Modi emphasising on atmanirbhar (self-reliance), one wonders if that is what prompted the regulator to approve the vaccine even in the absence of any supporting efficacy data. “Covaxin, Covishield and many other vaccines are made in India, and we should be proud of our vaccine companies. But if the question is — did Indian science make the vaccine candidate and did Indian companies develop it, then the answer to the first part is variable and to the second is always yes,” Dr. Kang says. “Covaxin is based on an Indian strain and a proven technology that Bharat Biotech has used for many vaccines, but has a new adjuvant that was developed in the U.S. Covishield’s viral vector construct was developed by the University of Oxford and then transferred by AstraZeneca to India. So, both are examples of atmanirbhar but have an element of non-Indian science — and at least to me that is fine.”
There is a real danger that the non-transparent manner in which the approval was granted to Covaxin even without efficacy data might lead to increased vaccine hesitancy. “Even without missteps, we have misinformation, and any grounds for concern will be blown up into much larger conspiracy theories,” warns Dr. Kang. “We are not yet as badly affected with vaccine hesitance as the West, but we do have a growing problem. We ignore this at our own peril. Decreased trust in vaccines can lead to an inability to achieve our public health goals of decreasing mortality and preventing spread.”
No to Covaxin now
Given that the inactivated vaccine platform is time-tested and Bharat Biotech has developed many vaccines using this platform, animal studies show promise and the vaccine appears to be safe, will Dr. Kang be willing to take Covaxin even in the absence of efficacy data? “I have no problem with volunteering for the Covaxin trial, because I think it is potentially a good vaccine, but unfortunately CMC Vellore is not a centre. I would go through the process as a volunteer and could get a vaccine or placebo and I am fine with that because I would be contributing to the generation of scientific data that would inform vaccine development,” says Dr. Kang. “But if the vaccine were to be offered to me under conditions of ‘restricted use’, as a matter of ‘abundant caution’, in ‘clinical trial mode’, I would not take the vaccine without efficacy data, because it makes no sense to me. Once clinical efficacy data are available and have been reviewed by the regulator, [I have] no issues at all with taking the vaccine.”