Explained: Booster COVID shots and the immunity puzzle

There’s a dreary sense of deja-vu as the year draws to a close with the twin threats of Omicron and Delta driving, as WHO chief Tedros Adhanom Ghebreyesus put it, “a tsunami of cases globally”. And, after 12 months of a vaccination blitzkrieg, we are back to discussing immunity — booster doses are now part of the response being mounted in many countries. India as well, beginning January 10, will start administering a third ‘precautionary’ shot to healthcare and frontline workers and elderly people with co-morbidities.

Booster shots, as we know, are meant to provide added protection. But how exactly?

Do they rally more antibodies to the trenches – for Covid, that would be the respiratory tract through which the virus enters. Or, do they fire up the T cells which look for virus-infected cells and kill them, thereby preventing severe disease? Or do they teach the body a new trick or two?

It could be all three, ideally – and that’s where the catch lies. Chandrakant Lahariya, a public policy and health systems expert, frames the situation thus: “The entire discourse on a third shot is more nuanced. It’s not that we are looking at one criteria, we need to find the right balance.”

For that, evidence will have to come from studies, many of which are ongoing at the moment. Immune responses vary across vaccines though all COVID vaccines available at the moment are known to protect from severe disease and mortality. “In the case of an ongoing pandemic when natural infection is also happening, every setting is very different,” says Lahariya.

So far, there has been more data available for messenger RNA (mRNA) vaccines, which are being used in several countries including the US and UK, than other platforms. Even though these vaccines could be less effective against Omicron because of its spike mutations, the way mRNA vaccine platforms work – by producing a suffusion of antibodies — probably explains their utility as a third shot, say experts.

An mRNA booster shot, therefore, would be akin to a bouncer outside a nightclub calling in reinforcements to deal with a troublemaker, explains Prof K Srinath Reddy, president of the Public Health Foundation of India (PHFI). “They will give a huge surge and even if antibodies are not fully competent against the spike protein there’s such a crowd of antibodies, the surge itself will be able to capture it. That’s the general principle,” he says.

That same mechanism was also seen to confer mRNA vaccines with some role in preventing transmission – because of the likelihood that antibodies could neutralise the virus at localised sites such as the nose and throat.

“Certainly in the short term their protective efficacy is higher,” says biophysicist Raghavan Varadarajan from the Indian Institute of Science. But in the long term, that difference in efficacy over other vaccines narrows down. “It still confers higher efficacy but the difference is not as large,” he says.

“So any vaccine, if a subsequent dose is given, would increase the quantum of antibodies. But mRNA-based vaccines result in a far greater increase in the quantum of antibodies. That’s why they are considered a better booster shot than other vaccines,” says Lahariya. “Many of the countries which are giving third shots are also looking to prevent mild infection and reduce transmission.” But that’s not the case for India which doesn’t have mRNA vaccines yet, he says.

How third shots hold up in countries that are facing a surge in cases will only be known from further data.

Last week, four countries — USA, the UK, France and Spain – contributed to 58 percent of global COVID cases.

The immune response

However, protection against severe disease and death cannot be measured by antibodies alone.

“This virus elicits three kinds of responses. One is antibody-mediated, the second is cell-mediated immunity and then there is immunological memory,” explained Balram Bhargava, director-general of the Indian Council of Medical Research (ICMR) at a press briefing on Thursday. “And, measurement of antibody titre alone does not capture the entire protection. So, that is very clear.”

Antibody-mediated, or humoral immunity, refers to the mechanism of antibodies produced by the body to target an infectious agent. Cell-mediated immunity component involves specific cells – such as T cells and B cells – that are the police force which identify and destroy infected cells besides retaining the memory of all this so as to mount an attack the next time an infection takes place.

“In the long course when there is an infection, you have to have good T cell immunity, particularly CD8 type of cells, to prevent the person from going into complications. They attenuate the infection and the symptoms,” explains paediatrician Dr Vipin M Vashishtha. “On the other hand, if you want prevention of infection, you need neutralising antibodies, just the T cells will not work.”

Cell-mediated immunity is much harder to measure and hence there is less data on it compared to antibodies.

The conservative estimate from overall evidence pointed to immunity persisting for nine months, said Bhargava. Hybrid immunity – that is, from both a previous infection and vaccination – typically prompted a slightly stronger response that also lasted longer.

So far, about 63 percent of India’s adult population is fully vaccinated with two doses. “The objective should be to give two doses to as many people as possible,” says Vashishtha.

Currently, extensive debates on the precautionary dose are ongoing. “A precautionary dose is primarily to mitigate severity of infections, hospitalisation and death. This is very important for individuals who are elderly, immunocompromised, on chemotherapy or patients of chronic obstructive lung disease,” said Bhargava at the briefing. “We are analysing all the data that is available in terms of which vaccine can be given, whether it is going to be the same one or it is going to be a different one. Before January 10 we will have clear-cut recommendations on the same,” he said.

Heterologous booster

With two more vaccines added this week to India’s basket of COVID vaccines, there’s been considerable discussion about the optimal third shot – that is, will it be more beneficial to continue with the same vaccine that a person received previously or offer a new one (termed as a heterologous booster).

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The new vaccines in India — Covovax, manufactured by Serum Institute of India, and Corbevac, developed by Biological E – are both protein sub-unit vaccines, meaning that they contain a specific protein from the virus.

“If you follow with a vaccine developed on a different platform it increases the breadth of the immune response. But not in all cases,” says Vashishtha.

Some of the evidence for mix-and-match comes from the CovBOOST study in the UK which investigated seven different Covid vaccines given as a third dose to candidates 2-3 months after they had received doses of either the AstraZeneca (Covishield in India) or Pfizer vaccines — the study found that all the vaccines ‘showed acceptable side-effect profiles, although some schedules were more reactogenic than others’.

Novavax (which is labelled as Covovax in India) was among the seven vaccines evaluated by CovBOOST.

Also read: Booster shot or additional dose? Experts mull ways to tackle Omicron

While studies on third doses are ongoing in India, the only local evidence for mix-and-match comes from an inadvertent mix-up in Uttar Pradesh this year where some people accidentally received a second shot of Covaxin instead of Covishield. A limited study of that episode had suggested that the mixing turned out to be safe and that antibody response was significantly high.

At the moment, there’s a lot of grey area, many unanswered questions and limited evidence, says Lahariya. “If we are giving a booster shot, we should select the right vaccine and optimise the opportunity to get the maximum out of it.”