Is the drug regulator doing its job?

Vaccine approvals seem shrouded in secrecy. Has DCGI sought evidence of efficacy of vaccines against newer virus variants? Does it have data on ADE?

Covid-19 vaccines have been a powerful tool in addressing the fear and panic caused by the pandemic. Unfortunately, they are increasingly being used to create a smokescreen of safety, to evade public accountability on the public health concerns around them. The Drugs Controller General of India (DCGI), the apex regulator for all pharmaceuticals, has been used to hurriedly authorise emergency approvals for several drugs and vaccines that lack sufficient evidence to substantiate their safety and efficacy. This may pose serious public health risks, considering the fact that the SARS-CoV-2, the coronavirus causing Covid-19, has been evolving quite dramatically.

First is the lack of transparency in approving vaccines. Let us take the example of the latest entrant to the mass vaccination campaign, Corbevax, which was developed in 2020 against the ancestral Wuhan-strain of SARS-CoV-2. It is a sub-unit type vaccine, which uses a portion of the S-protein called the Receptor Binding Domain (RBD) along with an adjuvant to elicit immunity in the human body through the generation of vaccinal antibodies.

The Phase I/II trials for Corbevax were completed in April 2021 but the results of the study are yet to be published. By November 2021, the Omicron variant had begun to emerge as the dominant strain and was immediately declared by the WHO as a ‘Variant of Concern’ due to the unusually high number of mutations present in it. On December 13, 2021, two independent teams of researchers from University Hospital Frankfurt and the Rockefeller University showed that the mutations on Omicron variant enable it to escape vaccine as well as infection-elicited antibodies and therapeutic monoclonal antibodies. In other words, immunity gained from prior Covid-19 infection and/or vaccination were not sufficient to fight off Omicron.

Yet, two weeks later, on December 28, 2021, the DCGI approved Corbevax without any publicly available evidence or peer-reviewed publications of its Phase I/II & III clinical studies, much less its effectiveness in providing immunity against Omicron.

This lack of transparency and accountability, which is not unique to Corbevax’s case, begs the question, why are the approvals issued by the DCGI shrouded in secrecy? Also, at a time when caution ought to be exercised on the use of any vaccine developed against the ancestral strain, why did the DCGI approve a new vaccine without having received any data on its effectiveness against Omicron? The non-disclosure of clinical trial data impedes independent evaluation and troubleshooting of adverse events in real-time, which does not bode well for the science and innovation ecosystem in India.

Second is the apparent apathy to the potential risks of using sub-optimal vaccines. The virus enters the human cell by anchoring its S-protein onto the ACE-2 receptor present in the human cell and takes over the cellular machinery to make millions of viral copies, thus causing disease. Any given B-cell vaccine (all vaccines currently in use belong to this category) produces a plethora of antibodies, some of them bind perfectly to the S-protein (i.e., antigen) on the viral surface, thereby blocking it from anchoring to the ACE-2 receptors and entering the cells. This acts as a cue for immune cells (such as the macrophages) to bind to the other end of the antibody and swallow up the virus, thereby neutralising it. Yet some other antibodies do not bind perfectly to the viral S-protein. In such cases, the macrophages bound to the antibodies do not neutralise the virus. On the contrary, these non-neutralising or sub-optimally neutralising antibodies mediate viral entry into the macrophages, where the virus begins replicating itself. As a result, the virus gets access to more cells to replicate itself from, causing more severe illness. This is termed Antibody-Dependent Enhancement (ADE) of disease.

The Omicron variant is highly mutated (32 mutations in the S-protein). Emerging variants may have even more mutations, which means antibodies from vaccines currently in use will have a greatly reduced effect on them, potentially increasing the risk of ADE. Emerging studies have demonstrated that SARS-CoV-2 antibodies bind to two types of immune cells, macrophages and mast cells, which may represent two different mechanisms for ADE in patients. This calls for an urgent need to develop safe vaccines such as T-cell-eliciting SARS-CoV-2 vaccines that are not dependent on antibodies. Does the DCGI ask for evidence of ADE and other vaccine-associated risks before approving a vaccine? If so, why has this evidence never been made public? More importantly, why hasn’t the government or its agencies issued any public notification on the potential risks involved in taking the vaccines currently in use? Lastly, why hasn’t the government invested in, encouraged, nor incentivised the development of safe, effective, evidence-based therapeutics for Covid-19?

Third is the non-redressal of misinformation and malpractices. It appears that from the very beginning of this pandemic, the DCGI and its departments have cut corners and issued approvals due to political pressure. Riding on this lapse of public duty, the pharmaceutical industry seems more focused on profiteering and has failed to issue disclosures on the safety and efficacy of their products. Even the DRDO pushed for the approval of its 2-DG (2-Deoxy-D-glucose) drug without furnishing any evidence on the safety of its use in patients. It claimed that the drug would cure patients of Covid-19 by starving the virus to death but forgot to add that 2-DG would starve the patient’s cells, too, in the process. If it had a way around this glitch, we are yet to hear of it.

In a recent hearing in the Supreme Court, no less than the Additional Advocate General of Tamil Nadu made irresponsible submissions stating that unvaccinated people are the cause of viral mutants, and the counsel for a vaccine manufacturer felt that only the regulatory authority has the right to access data on clinical trials. Academicians rarely call out malpractices of the industry, public officials and regulatory authorities, nor do they sufficiently address misinformation, or advocate in the spirit of open science or communicate essential but missing information to the public. Worse, even as evidence is totally lacking, several experts have made exaggerated claims on the future course of the pandemic or made misleading statements on the safety of vaccines, leaving the public befuddled.

The one solution for all these concerns lies in depoliticising the pandemic, more so the vaccines involved. With more rigorous and transparent regulation, greater public debate and incentivising evidence-based innovations, we will be in a much better place than we are today.

(The writer is an independent researcher and former senior science adviser to the UK government)