Expert Speak Health Express
Published on May 19, 2022 Updated 3 Days ago
Would a one-size-fits-all booster policy be a sound decision in the long run?
Booster shots for COVID-19: A moving target

What is a booster dose?

For someone who has completed the primary vaccination process, giving additional doses to reawaken the immune response is commonly referred to as a booster dose.

A common example is the case of influenza, commonly referred to as the flu. However, unlike SARS CoV2 which is a single virus, influenza is caused by several different types and subtypes of viruses. Every year, before the flu season, a quadrivalent vaccine is put together to target those four influenza-causing viruses that are expected to circulate later that year.

Influenza viruses are prone to antigenic shift, which is abrupt wholesale changes in the antigenic structure. SARS CoV2 is yet to exhibit that behaviour and is instead showing a more gradual albeit non-uniform change, called antigenic drift. However, Some researchers believe, that Omicron’s remarkable set of mutations might qualify as an antigenic shift.

Why are boosters needed for COVID-19?

When the pandemic unfolded, many people hoped it would be a once-in-a-lifetime infection that could be prevented by a once-in-a-lifetime vaccination. As months passed, it became clear that this virus is capable of infecting people who were fully vaccinated or previously infected, or both. In other words, the immune response generated by our body was not good enough to stop the virus from infecting us again.

Influenza viruses are prone to antigenic shift, which is abrupt wholesale changes in the antigenic structure. SARS CoV2 is yet to exhibit that behaviour and is instead showing a more gradual albeit non-uniform change, called antigenic drift.

The reasons for this phenomenon are three-fold:

Firstly, the virus has shown a continuous adaptive capability in its new-found host, that is human beings. After quickly figuring out the human antibody response pattern, the virus found ways to escape this by making tiny changes in its amino acid sequence. This is called an immune escape. For example, Omicron has a considerable ability to leap past any prior immunity.

Secondly, the vaccines in current use are the injectable type, which generates a durable and multipronged systemic immune response, that protects against organ damage. But, unlike natural infections, vaccines are not good at protecting the main gate of entry of this virus, the mucosal lining of our nose and throat. Besides, the initial high levels of neutralising antibodies start falling after two months or so. This sets up the stage for repeated infections, and is often loosely called ‘waning of immunity’. The drop is more pronounced after each additional dose.

Third, which is perhaps the least discussed, is human behaviour. People grew tired of the public health measures instituted to stem the spread of the virus. Increased mingling without masks, especially in indoor settings gave the virus a free run. This occurred even in highly vaccinated and boosted communities that had relatively recent waves, for instance, in western Europe in early 2022.

As a result, it became necessary to provide additional doses of vaccine to shore up the immune response. Since most deaths from COVID-19 occur in people over the age of 60, this group, along with immune-compromised individuals are at the highest priority to receive such additional protection. In other words, the risk-benefit equation for boosters is not the same for all groups of people.

People grew tired of the public health measures instituted to stem the spread of the virus. Increased mingling without masks, especially in indoor settings gave the virus a free run.

Much of the available evidence on boosters are about mRNA vaccines. There is evidence that people who received mRNA booster doses had fewer infections in the following few months and fewer deaths as a group. The decrease in death rate is likely the expected result of a decrease in the total number of infections occurring during that period in higher-risk segments. In younger and healthier individuals, in whom the death risk is much lower, the additional death protection achieved by a third dose has been unremarkable so far.

Reduction in infection risk has other advantages such as reduction in Long COVID, and fewer disruptions at the workplace. This can also be achieved with non-pharma interventions such as masks and better indoor ventilation.

Vaccine protection is multipronged. Although we commonly hear about antibodies, there are other components of our immune system that cannot be effectively or easily measured. It is believed that long-lived memory cells of the B and T cell genre will rise to the occasion whenever required, reducing the damage to our internal organs—even if the circulating level of antibodies is low. Whether additional vaccine doses will specifically augment these is unclear at this time.

What is indisputable though is that in the initial few months following a booster dose, there is a remarkable but temporary rise in neutralising antibodies, which correlates with a reduced risk of getting infected. This window, unfortunately, is short-lived, which raises the question of further additional doses. However, studies on the fourth dose of mRNA vaccine have shown that the protection achieved is shorter-lived than with the third dose.

Whether human beings can and should receive repeated booster doses every few months is a question that has no clear answer. The world of science is divided on this topic, with some invoking the principle of Minimum Effective Dose, while others assert that there is no alternative.

Is it time to upgrade the vaccine based on Omicron?

Complicating the above equation is the fact that variants emerge every few months, and they are not predictable upgrades of the previous dominant variant. Instead, new variants like delta and omicron took birth from remote branches of the genomic tree. Once a new variant dominates, we are seeing numerous sub-lineages as offshoots in the weeks that follow.

The decrease in death rate is likely the expected result of a decrease in the total number of infections occurring during that period in higher-risk segments.

Thus, the theoretical solution of variant-specific vaccines runs into certain difficulties.

First, the relatively narrow range of immune responses generated by Omicron-based vaccines tested so far has not shown superiority over the original vaccine, with the latter providing a more broad-based response that is capable of covering multiple variants. This dilemma is especially relevant for first-time-vaccine recipients, who would want the broadest range of protection possible for the longest duration.

Second, by the time a variant-specific vaccine is developed, tested, and made available for general use, a whole new variant may have taken over.

Third, Omicron sub-lineages are now specifically adapting to escape immune protection from earlier versions of Omicron. This broadly means that a vaccine based on the BA.1 version of Omicron might only be good against BA.1 - and not against other Omicron sub-lineages such as BA.4 or BA.5.

There are several initiatives in the works, these include intranasal or oral mucosal vaccines, pan-corona vaccines, and bivalent vaccines that are designed to target more than one variant. Although these mechanisms appear impressive on paper, they are not without challenges. We do not know yet how effective these will be in the real world and will have to wait for the results.

Boosters do not mean ‘bulletproof’

Receiving a booster dose does not guarantee protection from infection. Separately published studies from Italy and the Faroe Islands show that two-thirds of healthcare workers who went to social gatherings got infected with Omicron despite recent boosting with mRNA vaccine. This shows that a sufficiently large virus exposure load can easily get past booster protection. This is the reason why air hygiene measures like masks cannot be side-lined; this is especially important for keeping vulnerable individuals safe.

The relatively narrow range of immune responses generated by Omicron-based vaccines tested so far has not shown superiority over the original vaccine, with the latter providing a more broad-based response that is capable of covering multiple variants.

The India scenario

Meanwhile, from India’s perspective, both the widely used vaccines have shown to be effective as a third dose. Covishield, also known as ChAdOx1 in the UK, is at least as good as mRNA vaccine when used as a third dose. Covaxin has been shown to generate an immune response when used as a third dose. A recent nationwide survey showed that there was no difference between these vaccines in the percentage of people who got infected during the third wave. Studies on the mixing of doses will be published shortly.

Other potential options, yet to be authorised as booster doses are two protein subunit vaccines manufactured in India, Corbevax, and Covovax. Although published data on the use of Corbevax as a booster is not available, Novavax (the US version of Covovax) has been shown to generate an immune response when used as the third dose in England.

A large number of people in the world have had natural infections by now, many of them more than once. Some parts of India had already attained levels of seroprevalence as high as 97 percent even before the arrival of Omicron. Most of this was silent spread, with only 25 percent of people with serological evidence of infection in rural India recalling any symptoms.

Hybrid immunity level in India is expected to be high after achieving 87 percent adult vaccination coverage, and having gone through three large waves. Each bout of infection recalls long-lived memory cells and generates an immune response, albeit of varying intensity.

The precise role of boosters in a setting of widespread breakthrough infections in well-vaccinated populations needs to be defined further. With so much heterogeneity amongst the decision-making factors, it is unlikely we will have a one-size-fits-all booster policy.

The views expressed above belong to the author(s). ORF research and analyses now available on Telegram! Click here to access our curated content — blogs, longforms and interviews.

Contributor

Rajeev Jayadevan

Rajeev Jayadevan

Dr Rajeev Jayadevan MD DNB MRCP (UK) ABIM (Medicine New York) is a former president of the Cochin Chapter of the Indian Medical Association. He ...

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