Perceptions and sentiments embed themselves deeper in the mind than logic. A day after he received the Covaxin shot, Tamil cinema’s iconic comedy actor Vivek succumbed to clogged arteries. Vaccine sceptics glossed over the arteries and blamed the death on the shot, giving muscle to the narrative, howsoever unfounded, that vaccines have bad side-effects, sometimes fatal.

Could scientists not come up with a vaccine that has no side effects at all? Well, yes, they can.

Earlier this month, a tiny but significant news emerged, which got swept aside by the Covid second wave. The government of India said in a press release that it had approved Pune-based Gennova Biopharmaceuticals, a subsidiary of Emcure Pharmaceuticals, that produces recombinant drugs, to go ahead with Phase I and II human clinical trials of its vaccine called HGCO19. If Gennova gets it right, it would win global recognition and stand shoulder-to-shoulder with Pfizer and Moderna.

Gennova’s vaccine is of a type that is being hailed as a rising star in the world of vaccinology — ‘mRNA’ (messenger RNA), which is a fruit of three decades of research.

Why is mRNA different — and better?

Conventional vaccines are essentially weakened pathogens (or disease-causing microbes) introduced into the body to provoke the immune system to launch a response — namely, produce the appropriate antibodies (aka immunoglobulins, which are Y-shaped proteins that engulf the invaders and destroy them). While doing so, the immune system learns all about the pathogen; now it is ready for a real attack.

Since you are introducing a disease causer, side effects are inevitable.

But mRNA works entirely differently.

Take a pathogen like a virus, which has a ‘core’ of genes made of DNA or RNA (SARS-CoV-2 has RNA). These genes are wrapped in a coat of proteins. To make the coat, the DNA or RNA genes of the virus make a ‘messenger RNA’, which contains the instructions for it. An mRNA of a particular pathogen makes a protein of a particular structure. In the case of SARS-CoV-2, the coat has ‘spike’ proteins.

Now, mRNA vaccine developers make this particular mRNA in the lab. You inject this synthetic mRNA, you trick the immune system into believing that it is actually a pathogen. An immune response is triggered, antibodies are produced. Job done.

What works

There are many advantages with the mRNA vaccine. It introduces no attenuated pathogen into the body, so no side-effect. As the government’s press release notes, it is synthesised in the lab, requiring no host such as eggs or bacteria, so scaling up is easy. The mRNA vaccines are also believed to help produce ‘adjuvants’ — substances that enhance the immune system’s response.

Then there are the diseases where conventional vaccines have failed — HIV-1, herpes simplex virus and respiratory syncytial virus (RSV). Furthermore, development of a vaccine up to the marketing stage takes time; diseases overwhelm us before we find one, as seen in the case of Ebola and Zika viruses.

Norbert Pardy et al of University of Pennsylvania write in a 2018 paper in Nature that “preclinical studies have created hope that mRNA vaccines will fulfil many aspects of an ideal clinical vaccine”. They note that mRNA vaccines can be produced relatively easily and quickly. Pfizer and Moderna have since come up with mRNA vaccines and others, such as Gennova, are working on it for Covid-19. Some others are bringing mRNA vaccines for other diseases (Argo Therapeutics, Erasmus, Massachusetts General Hospital and McGill University for HIV-1; Moderna for Zika and Influenza).

Many Indian vaccine manufacturers have mRNA in their to-do list. But experts have also cautioned against explosive optimism. There are still some challenges.

For instance, its ‘immunogenicity’ — the ability to provoke an immune response — is yet to be fully understood. Will it trigger unwanted immune response? The stability of mRNA inside the cells has also been a challenge, as it quickly disappears. Another unknown is whether the mRNA vaccine will create immunity that lasts as long as conventional vaccines? What kind of refrigeration and handling would mRNA vaccines require?

Current research is on tackling these challenges. Some success has been achieved in areas such as delivery into cells and refrigeration.

Cutting edge

Antony Komaroff, Editor-in-Chief, Harvard Health Letter, who finds mRNA “exciting”, tells Quantum that “there is really not much of a track record (of mRNA vaccines) beyond their remarkable success with Covid-19”.

Observers note Indian companies are not far behind in this cutting-edge technology. “A year back, this was a new technology and never used for vaccine manufacturing in India,” notes Renu Swarup, Secretary, Department of Biotechnology and Chairperson of the government’s Biotechnology Industry Research Assistance Council (BIRAC). She points out that BIRAC, “believing in the potential of this technology”, provided seed funding to Gennova.

Gennova was already into mRNA when the pandemic broke out. “Gennova focused on the development of the Covid vaccine on the already established mRNA platform,” Dr Sanjay Singh, CEO, Gennova, tells Quantum .

When other companies too jump in, it would do a world of good, because mRNA is good for both infectious and non-infectious diseases, notably cancer. “Cancer cells make proteins, which can also be targeted by mRNA vaccines,” observes Komaroff.

By all accounts, the time for the mRNA vaccine seems to have arrived. Experts like Komaroff and Pardy stress that while mRNA’s use as a vaccine was deduced decades ago, the convergence of disparate technologies (engineering and manufacturing mRNA in a lab, delivery into cells, storage) is happening now, making the vaccine practicable.

“The future of mRNA vaccines is extremely bright, and the clinical data and resources provided by companies and other institutions are likely to substantially build on and invigorate basic research into mRNA-based therapeutics,” says Pardy.

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