JOIN USCovid-19: A vaccine by diktat?
Nearly 35 years ago, Maharaj Kishan Bhan, a young medical researcher at the All-India Institute of Medical Sciences stumbled upon a new virus strain during a regular check of the slum kids in South Delhi. The discovery of that strain (116E) was the first step in making an indigenous commercial rotavirus vaccine, which was released in 2015 after Bhan, who rose to become the longest-serving Secretary of the Department of Biotechnology, had retired from government service.
The rotavirus vaccine is just one example. It’s the same story with other shots like polio, smallpox or pneumonia that were developed in the 1950s and 1960s. All of them took years, if not decades, for development and testing. In fact, the Sabin oral polio vaccine was not even used in the US because by the time it was ready for testing, the US had started using the inactivated Salk polio vaccine. It was given to Russia for testing, and the rest is history on how the oral polio vaccine has helped in eradicating polio from most of the world.
The world is a very different place now from both a technology and knowledge point of view because within six months of SARS-CoV-2 appearing on the scene, over 140 vaccine candidates are in the pipeline and clinical trials are on for more than 20 such candidates. No doubt, the vaccine against Covid-19 will take less time to develop. Nevertheless, proper testing will take time even if the developers follow the accelerated testing plans approved by the World Health Organisation and the US Food and Drug Administration.
The Indian Council of Medical Research’s ambitious target of readying the indigenous Covid-19 vaccine Covaxin, developed by Bharat Biotech, Hyderabad, for public release within 42 days needs to be seen in this context.
Vaccine development requires scientifically executed clinical trials in a phased manner. These trials involve evaluation of safety (Phase 1 trial), efficacy and side effects at different dose levels (Phase 2 trial) and confirmation of safety and efficacy in thousands of healthy people (Phase 3 trial) before its release for public use. Since it requires participation of healthy human volunteers, several ethical and regulatory approvals are to be obtained prior to the initiation of a trial in humans.
“While administrative approvals for such trials can be expedited to some extent, the scientific processes of experimentation and data collection have a natural time span that can’t be hastened without compromising standards of scientific rigour,” the Indian Academy of Sciences said in a statement.
For example, immune responses usually take several weeks to develop, and relevant data should not be collected earlier. Moreover, data collected in one phase must be adequately examined before the next phase can be initiated. If the data from any phase is unacceptable, then the clinical trial is required to be immediately aborted. If the data collected from Phase 1 of the clinical trial shows that the vaccine is not adequately safe, then Phase 2 cannot be initiated, and the candidate vaccine must be discarded.
The approval process itself can take time. One of the essential preconditions for initiating a clinical trial is to get permission from an institute ethics committee that scrutinises the trial protocol. This can take time because the investigators have to convince the ethics panel on the trial protocol.
“You can’t ask an ethics panel to give approval within a pre-fixed date. The ethics committee needs time to look at the protocol. I understand that the ethics panel at AIIMS Delhi (one of the 12 sites for the trial) has raised several queries on the Covaxin trial protocol, and rightly so,” said Anant Bhan, researcher, global health, bioethics and health policy and past president of the International Association of Bioethics.
Ethics approvals are pending at least in two other sites, SRM Hospital and Research Centre at Kancheepuram and King George Hospital at Visakhapatnam.
In addition, Bharat Biotech is yet to receive government certification on the batches it produced. At the Central Drugs Laboratory, Kasauli, bio-safety and bio-sterility tests are being conducted on the vaccine to make sure no harm is done to the people who would receive the jab. Typically, the process takes 14 days and only if there is no adverse report, the company would start shipping the vaccine for the trial.
To determine the final dose, both single and double dose regimens are to be tried during the clinical trials. For the two-dose regimen, the vaccine is to be given on the first and 14th days and the immune responses are to be checked after 28 days. Taking all these factors into account, it looks logical to conclude that, at best, only Phase 1 of the trial would be completed by Independence Day.
“To launch a vaccine, we must get a vaccine, it must be proven to be a vaccine. Proof is needed for both safety and efficacy. Just because a vaccine candidate is proven safe in Phase 1, it cannot be launched as a vaccine. By August 15, only Phase 1 results will be available. The Phase 2 results may come by October-November,” said veteran virologist Dr T Jacob John, a former professor at the Christian Medical College, Vellore.
Globally, no vaccine is expected to complete Phase 3 trial before the first quarter of 2021.
A week after Covaxin, a second indigenous vaccine, ZyCov-D -- developed by Ahmedabad-based Zydus Cadila -- received regulatory approval for Phase 1 and 2 clinical trials, subject to certain conditions. This is a DNA vaccine, funded by the Department of Biotechnology. When the proposal was discussed by an expert panel within the Central Drug Standard Control Organisation on July 1, the CDSCO panel asked the company to make four specific changes in the clinical trial protocol while granting them permissions to carry out Phase 1 and Phase 2 clinical trials.
There is now a thought within the Indian scientific community to invoke the World Health Organisation’s MEURI (Monitored Emergency Use of Unregistered and Investigational Interventions) protocol to expedite the trial of at least the inactivated Indian vaccine (Covaxin), as was done with an experimental Ebola vaccine last year.
“Ebola has a Case Fatality Rate of over 70%, while Covid-19 has a global CFR of about 5% and for India about 2.8%. Ebola is therefore not a very good example to justify injecting a premature Covid-19 vaccine into humans,” said Shahid Jameel, senior virologist and CEO of the Wellcome Trust/DBT India Alliance, a public charity that invests in building biomedical sciences and health research framework.
“India should do proper testing for both safety and efficacy. There are many ethical considerations that come up in fast-tracked trials. It’s best to avoid such fast-tracking. We should have a global outlook and be global leaders in vaccine development and manufacture. Cutting corners will undermine our credibility.”
The procedure adopted for the Ebola vaccine, argued Dr John, couldn’t be extended to Covid-19 vaccine because of the huge difference in death rates.
“The vaccine has to be safe and effective and shown to be so with credible evidence. With a 5% case fatality ratio, a vaccine has to be shown not to increase the CFR by any unexpected immunological mechanism. There is no case for a compassionate use of any experimental vaccine with Covid-19,” he summed up.
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