Covaxin Completes a Half-Marathon With WHO Approval, Time To Boost Production

India needs to reinforce its capacity for conducting large trials and ramp up production vaccines.

The Technical Advisory Group of the World Health Organization (WHO) has recommended Emergency Use Listing (EUL) status for Bharat Biotech's Covaxin, the health body tweeted on Wednesday, 3 November.

(Photo: The Quint/Abhilash Mallick)

The World Health Organization (WHO) appeared to have decided that Diwali was the auspicious moment to give the India-made Covaxin COVID-19 vaccine Emergency Use Listing (EUL) status. After several weeks of suspenseful waiting, during which many questions were raised about the WHO’s process and the presentation of data by Bharat Biotech, the EUL has finally been granted.

Many Indians, who were nail-bitingly anxious about their eligibility for intended international travel, heaved a huge sigh of relief. Other Covaxin recipients (including myself) felt vindicated about our choice of the vaccine.

After a string of stringent reviews that called for several clarifications of the data presented by Bharat Biotech, the WHO panel affirmed that the vaccine had demonstrated an efficacy of 78 percent against symptomatic COVID-19 of any severity.

This was observed at 14 days after the second dose, which was administered four weeks after the first dose. No safety concern was noted. Use for all adults, 18 years old and above, was permitted. Data related to safety or efficacy in pregnant women were found to be insufficient for any conclusion or recommendation related to vaccine use in that group.

Big Win for Indian Science

Despite the controversies that dogged this vaccine since it received emergency authorisation from Indian regulators in early January 2021, the vaccine scores a big win for Indian science. The SARS-CoV-2 virus was isolated, cultured, and inactivated at the National Institute of Virology (NIV) in Pune.

Immunogenicity and safety of the inactivated virus were assessed in animal models at the NIV. The disabled virus cannot replicate in the human cells, like the live virus, but can still stimulate an immune response which involves both antibody production (involving B lymphocytes) and cellular immunity (involving T lymphocytes). The inactivated virus passed the laboratory tests of immunogenicity.

The Indian Council of Medical Research (ICMR), which governs the NIV, shared the vaccine with an Indian company (Bharat Biotech) for further development, evaluation, and manufacture. Addition of an important adjuvant (Alhydroxyquim-II), by Bharat Biotech, enhanced the immunogenicity of the vaccine by activating two T lymphocyte cellular receptors (TLR7 and TLR8) in the lymph nodes.

The different phases of the clinical trials (phases 1-3) were then conducted across multiple centres in India, to assess the efficacy and safety of the vaccine.

As storage of the live virus prior to its inactivation is a very important biosafety requirement, only a production facility with a high biosafety level (BSL 3 or 4) could be used.

All of these are very creditworthy accomplishments of Indian scientists and industry. While critics panned the approval granted by the Indian regulatory agency to the vaccine, even as the Phase 3 trial was still underway, the potential of an inactivated vaccine to protect against emerging variants of the virus was cited as a reason for granting expedited clearance for mass vaccination. By then, the alpha variant had already entered India from the United Kingdom, where it was reported to show 60-70 percent higher infectivity when compared to the ancestral wild virus.

Why is a vaccine made with an inactivated virus likely to prove more effective against variants than others which emerged from different platforms and demonstrated higher levels of efficacy in clinical trials? The reason lies in the fact that this whole virus vaccine presents several antigens to the human immune system, eliciting a broadband immune response.

Even if the virus tries to evade the immune response, by developing form-altering mutations of the spike protein (which lies on the outer surface of the virus), immunity directed against other antigens (which are internally located in the virus) will still overcome the microbe and thwart its intent to exploit the human body for its replication.

Most other vaccines, which are currently in use, present only the spike protein antigen to the human body. They elicit a high level of immune response to the spike protein. That efficacy was very impressive (over 90 percent for the mRNA vaccines) in the trials which were conducted when the ancestral virus was in circulation.

However, the efficacy of spike protein focused vaccines diminished when pitted against the variants that emerged after their clinical trials were completed. There was some loss of efficacy against the alpha variant and even more against the delta variant.

There was comfort in the finding that, while overall efficacy in preventing all forms of COVID-19 was diminished, there was still a fairly high level of protection against severe disease, hospitalisation, and death. That was so even against the delta variant, which is the reigning world champion among the spooky spikers.

However, what would happen if the virus develops other spike protein mutations, which help it to escape recognition by the immunity that was crafted by a vaccine with a different spike protein configuration? As Katherine Wu wrote in The Atlantic, such a ‘monogamous relationship’ of most available vaccines to the spike protein could pose a problem.

The theoretical construct that a whole but inactivated virus offers a more dependable defence against variants with shape-changing mutations of the spike protein, has been validated by the NIV scientists who demonstrated the ability of this vaccine to effectively neutralise many of the SARS-CoV-2 virus variants, including the dreaded delta and delta-plus variants. Real-life evidence, on breakthrough infection rates, is still awaited. That may take time to gather as the pandemic has entered a quiescent phase in India.

If indeed the inactivated virus vaccine demonstrates greater efficacy in countering new variants that may still emerge in different parts of the world, there will be a greater demand for the vaccine from other countries. Even as of now, it is an attractive option for many countries due to its affordable pricing and lack of stringent temperature requirements for storage and transport.

However, the production volume will be difficult to ramp up fast, because of the biosafety requirements of handling the whole virus. Many more facilities will have to be established in India, with BSL3 laboratories. The Department of Biotechnology (DBT) is supporting the development of more such facilities in India. The recently unveiled Pradhan Mantri Ayushman Bharat Health Infrastructure Mission (PM ABHIM) proposes to have 15 such facilities in India.

EUL Done, Now Focus on Ramping Up Production

As we set out to build on our reputation for vaccine development, in addition to vaccine production, we need to reinforce our capacity for conducting large vaccine trials in India, with dedication to both purpose and process. DBT is also supporting the development of several demographic surveillance sites where such community-based trials can be ethically conducted with due attention to methodological integrity and high data quality.

Accurate data collection, collation, analysis, and timely presentation to domestic and international regulatory agencies must become the acclaimed norm of such trials.

Technical capacity in microbiology, immunology, biotechnology, epidemiology, biostatistics, and data management must be enhanced along with integration of health economics, social and behavioural sciences, and medical and public health ethics.

We also need to revisit the structure of our regulatory bodies and review their composition and competence in examining complex technical and ethical issues specifically related to vaccine trials.

Covaxin has completed the half-marathon and has deservedly been handed a bouquet at that stage. It still has to emerge as a major contributor to the COVID-19 vaccination programme in India. Its contribution to the global vaccine supply chain thereafter will depend on its ability to ramp up production to high volume.

To win the coveted medal at the finishing line of the full COVID-19 marathon, it needs to demonstrate real-world clinical efficacy against new variants and breakthrough infections while ramping up production to meet Indian and global supply chain requirements. If it can demonstrate that style and speed as it advances on the COVID-19 marathon run, it can have a podium finish. Even as of now, it serves to inspire Indian science with the taste of success that innovation and application can bring.

(Prof K Srinath Reddy, a cardiologist and epidemiologist, is President, Public Health Foundation of India (PHFI). He is the author of ‘Make Health in India: Reaching a Billion Plus’.)

(This is an opinion piece. The views expressed are the author’s own. The Quint neither endorses nor is responsible for them.)