How Safe is Covaxin when Phase 3 Clinical Trial is Not Over?

The hurried approval given to Bharat Biotech's Covaxin vaccine is worrying as its Phase 3 trial is still going on. Vaccine development takes years and even though the regulatory framework has been relaxed, surely due processes should be followed. There are concerns whether Bharat Biotech could really have proceeded to the human-trial phase of vaccine development within just 50 days of receiving the inactivated virus from the National Institute of Virology. While there are many questions, few have been answered, writes DR KAFEEL KHAN.  

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As we enter into the New Year, Covid-19 continues to be a threat. However, there was good news on January 3, 2021, with the Drug Controller General of India (DGCI) approving two vaccines for restrictive emergency usage in India. This spells hope in these dire times. 

The first one was Oxford-AstraZeneca's Covishield, which is produced in India by Serum Institute of India. The second one by Bharat Biotech, in collaboration with the National Institute of Virology (NIV) and the Indian Council of Medical Research (ICMR), is Covaxin. This comes after an expert panel of the drug regulator, Subject Expert Committee, gave its recommendation on January 1, 2021, for emergency use authorisation.

While Covishield is developed with a master seed from Oxford-AstraZeneca, Covaxin, derived from a strain of SARS-CoV-2 virus, was isolated at NIV, Pune. Both vaccines will be administered in two doses 3-12 weeks apart and can be transported and stored at normal refrigeration temperatures.

Serious Worries

Approval of Covaxin, which is still undergoing Phase 3 clinical trial, has raised serious questions. The DCGI said Covaxin was approved in public interest as an abundant precaution in "clinical trial mode" in order to have more options for vaccinations, especially in cases of infection by mutant strains. The clinical trial will continue. 

Prime Minister Narendra Modi touted the approval as a "game changer". Dr Harsh Vardhan, Minister of Health and Family Welfare, said Covaxin's approval is a "monitored approval" and "clinical trial mode" would mean that all vaccine recipients will be tracked as if they're in a trial.

When asked what "clinical trial mode" means, Gagandeep Kang, a reputed microbiology professor at Christian Medical College, Vellore, reportedly said: "I have no clue. I have never seen anything like this before. I'm completely unaware of any data that suggests that Covaxin has any efficacy against any strain of Covid-19, let alone special efficacy against the variant (UK) strain"

Health watchdog All India Drug Action Network said it was "shocked", while Opposition parties questioned the speed and the manner of approval. The decision to approve an incompletely studied vaccine, even under accelerated process, raises more questions than answers.

Also read: The COVID-19 Vaccine Frenzy and the Long Journey Ahead

To answer this, let us first understand what is a vaccine? A vaccine uses the body's natural defences to build resistance to specific infections by training the immune system to create antibodies, just as it does when it's exposed to a disease. However, because vaccines contain only killed or weakened forms of germs, they do not cause the disease or put one at risk of its complications. The immune system remembers the disease and if one is exposed to the germ in future, it can quickly destroy it before one becomes unwell.

While Covishield is based on the virus's genetic instructions for building the spike protein using double-stranded DNA added to another virus (adenovirus), Covaxin is an inactivated vaccine (one that uses dead virus).

Normal Vaccine Development

Vaccine development has to go through different phases, which usually takes years, but due to Covid-19's enormous ill-effects on health, the regulatory framework have been relaxed. The following are the normal trails a vaccine undergoes: 

For me, "clinical trial mode" is similar to a Phase 3 trial where the efficacy of the vaccine is tested on consented volunteers. If an experimental vaccine is given to people, there should be informed consent explaining the potential risks and benefits of it and post-vaccination follow-up. In case there is any serious adverse reaction, the recipient may also be eligible for compensation. Critics and the government are on the same page that Covaxin is still in Phase 3 trials, but then, what is the hurry? 

From the beginning, the speed at which Covaxin has been manufactured to be dispensed has raised so many unanswered questions. ICMR transferred the strain which NIV had isolated to Biotech Bharat on May 9, 2020. It takes at least three months to do animal trials to establish the safety of the vaccine. The company published its results on June 29, 2020. So there were only 50 days in between, during which time the company should have developed the inactivated vaccine, conducted preclinical animal trials (with mice and hamsters) and sent the reports to be evaluated and approved by DCGI.

Issue of Animal Trials

A related issue is that animal trials for Covid-19 can only be conducted with hACE2 transgenic mice, as normal mice can't get infected with the novel coronavirus. These mice need to be shipped from the US, Europe or China. These issues, therefore, raised initial concerns about whether Bharat Biotech could really have proceeded to the human-trial phase of vaccine development within just 50 days of receiving the inactivated virus from NIV.

ICMR's Dr Balram Bhargava had earlier too created an uproar when he wrote a letter to Bharat Biotech in early August 2020 saying: "It is envisaged to launch the vaccine for public health use latest by 15th August 2020 after completion of all clinical trials." 

Also read: Patent and Patient Rights in COVID-19: Is the Right to Exclusivity a Hamlet Question?

Covaxin's Phase 3 efficacy trial was initiated in India on 25,800 volunteers on November 6, 2020.  In a December 22 statement, it was said that 13,000 people were recruited or half of the target, for these trials. Now the regulator says that till date, 22,500 participants have been vaccinated across the country and the vaccine has been found to be safe, but it didn't provide further details. 

It is not possible that matters could have been speeded up so fast. Volunteers needs two shots of the vaccine 3-12 weeks apart, they need to be tracked and tested until enough of them have contracted Covid-19 to allow the vaccine's efficacy to be analysed. There is no clarity on whether there is data from Phase 3 trials to meet the criteria for an interim analysis on the vaccine's efficacy. 

Vague Assurances

ICMR said that Covaxin has the potential to mount resistance against new mutants of SARS-CoV-2. No data has been shared by the regulator or the company to support this claim. Words such as "likely", "restricted use" and "backup plan" have created more confusion.

The DGCI should have given more time to Bharat Biotech to complete Phase 3 trial of the vaccine. It should not be seen pushing for any announcements on Republic Day at the cost of common citizens. Approving the vaccine before trials are complete is a matter of concern irrespective of how safe or effective it eventually turns out to be. The government's decision not to release data on the vaccine's efficacy for peer review is worrying. The government needs to be more transparent about the authorisation process because the success of the Covid-19 vaccine programme depends on public trust. It should not lead to people being hesitant to take the vaccine as India is already struggling with anti-vaccine and anti-scientific views. 

Bharat Biotech is a reputed drug manufacturer that delivers four billion doses around the world for infections such as rotavirus, hepatitis, Zika, Japanese encephalitis and others. The method it has chosen is a very old and tested method–using inactivated virus—and there are high hopes  riding on this. 

Let us first start with the Covishield vaccine as it is already being given in the UK. Let Bharat Biotech first finish its Phase 3 trial. Clinical trials and safety and additional efficacy data continue to be collected, so let participants continue to be monitored for long-term protection and safety.

Remember, a vaccine will complement the other tools we have, not replace them. Contact tracing, testing more and more people, isolation, and quarantine will have to be continued. At the same time, people will need to follow social distancing norms, mask wearing and hand hygiene practices.

Also read: Statement by Indian Civil Society: Need for open innovation and knowledge sharing for COVID-19 healthcare through Indian IP laws

(Dr Kafeel Khan is Assistant Professor, Department of Paediatrics, BRD Medical College, Gorakhpur, UP. The views expressed are personal.)