Photo: Swarnavo Chakrabarti/Unsplash
- The immunity induced by a vaccine, in terms of its quality and durability, depends on whether the vaccine is ‘live’ or contains only non-living matter.
- It has been the experience in vaccinology that non-replicating vaccines need to be given in multiple doses to obtain prolonged duration of immunity.
- As of mid-September, India’s stance was that boosters are not necessary. This is the right stance, but we don’t know if experts arrived at it with the proper considerations.
The dawn of the novel coronavirus’s delta variant, the global devastation it wreaked and the fear of waning immunity because of its capacity to cause breakthrough infections in vaccinated individuals prompted certain countries to include a third dose in their COVID-19 vaccination programmes.
In August this year, the US Food and Drug Administration (FDA) authorised an ‘additional’ vaccine dose for certain groups of individuals with weakened immune systems. In September, it also authorised a ‘booster’ dose for older people (65 years+) and for adults (18-64 years) at high risk of COVID-19 exposure and severe disease.
In October, the European Medicines Agency (EMA) also recommended additional doses for people with weakened immune systems and booster doses for all adults. Earlier this week, there were reports that the WHO’s Strategic Advisory Group of Experts had recommended that people with weakened immune systems be considered for an additional dose of a COVID-19 vaccine.
Additional v. booster doses
The third COVID-19 vaccine dose – for most vaccines except the Johnson & Johnson vaccine and Sputnik Light, which are single-dose – could either be an additional dose or a booster dose, depending on the specific immune health status of the vaccinated person. This is evident from the way the EMA and the FDA have made their additional and booster dose recommendations.
Many populations of people may have a weakened immune system because of certain immune system-affecting disease or because of immune-suppression drugs they may be taking for specific medical conditions. Their immune systems don’t respond to vaccination as robustly as those of healthy people do. This is true for COVID-19 vaccines as well. This may leave them vulnerable to SARS-CoV-2 and its variants. Experts believe that a third dose of the COVID-19 vaccine in such people may compensate for the deficit and enhance their immunity. Such a dose is an ‘additional’ one. It is to be given 28 days after the second dose.
On the other hand, healthy people who receive a two-dose COVID-19 vaccine regimen mount a robust immune response – but it wanes over time. In these cases, after immunity has waned considerably, a third dose can help extend the duration of protection. These doses qualify as ‘booster’ doses. They are typically to be administered six months after the second dose.
For simplicity’s sake, this article will refer to the third dose as a booster dose.
Nature of vaccine-induced immunity
The immunity induced by a vaccine, in terms of its quality and durability, depends on whether the vaccine is ‘live’ or contains only non-living matter.
Consider the chickenpox vaccine, which contains a weakened version of the chickenpox virus. It is known as a replicating vaccine because the weakened virus retains the ability to multiply, but at significantly lower efficiency, so that it doesn’t cause chickenpox disease. The body’s immune system encounters more of this weakened virus than the amount the vaccine first introduces. This stimulates in a potent way the two components of the immune system: B cells, which produce virus-inactivating antibodies, and T cells, which can kill and eliminate virus-infected cells. This vaccine usually elicits potent and long-lasting immunity.
On the other hand, vaccines such as the hepatitis B shot contain a purified coat-protein of the virus. This active matter is lifeless and is an example of a non-replicating vaccine. In turn, the immune system is not stimulated as much as in the case of replicating vaccines. Another catch with a non-replicating vaccine is that it’s not very good at stimulating T cells, which are important for long-lasting immunity.
It has been the experience in vaccinology that non-replicating vaccines need to be given in multiple doses to obtain prolonged duration of immunity. The initial dose is called the priming dose. Subsequent doses given months later are called the booster doses. Giving a booster dose stimulates the memory B cells persisting from the previous dose. Such boosting allows the body to produce more antibodies and also promote a process called affinity maturation, whereby the antibodies gain greater potency.
In the context of COVID-19, it’s possible that immunity and protection may wane over time and newer variants of the virus may emerge, against which current vaccine-induced immunity may not be effective. So booster doses may ultimately be required. We need to carefully determine the need to boost and the timing for each vaccine, however.
EMA’s and FDA’s evidence
Support for a booster dose of a COVID-19 vaccine for people with weakened immune systems is based on studies with people who have received organ transplants and are on immune-suppressing medication (to prevent the body from rejecting the new organ).
For example, a French study in August 2021 reported that the immune response in such people improved significantly following a third dose versus after the second. In September, a Canadian study enrolled 120 transplant recipients who had already received two doses of a COVID-19 vaccine and assigned them randomly to two groups: one received a third dose and one didn’t. It also found that a third dose helped better the antibody response.
However, neither study provided any information on protection against severe COVID-19 in people of these groups.
The case for booster doses for everyone is based mostly on a recent study from Israel. On July 30 this year, the small Middle-Eastern nation authorised booster doses for its senior citizens who had completed the standard two-dose Pfizer vaccine regimen at least five months earlier.
This decision followed an increased incidence of breakthrough infections among Israel’s vaccinated population. A team of scientists evaluated over a million of these senior citizens in the first month of the booster-dose campaign. They concluded that, at 12 days after the booster, the risk of getting severe COVID-19 had been reduced almost 20x compared to those who hadn’t received the booster.
Another piece of evidence comes from Johnson & Johnson’s vaccine. The company reported on September 21 that a booster dose given six months after the first dose increased antibody levels 12x.
(Note that companies projecting booster requirements for their vaccines may not be purely for public health reasons.)
After Israel, the US, the UK, Canada, Russia, China and several European, South American and Southeast Asian countries, among others, have followed suit with booster shots. But don’t let this rush by itself convince you that the scientific data that is available is also conclusive. These countries have likely been more motivated by politics and business, fueled in turn by the unfounded anxieties of many of their peoples.
There are several critical gaps in the available information. Expert opinion suggests that the scientific evidence at this time is weak on several counts. Most studies on boosters are preliminary and suffer from confounding and selective reporting. Also, the efficacy of all vaccines approved thus far against severe COVID-19 is significantly greater than against infection itself. And vaccination that protects against severe disease from the main variants essentially negates any urgent need to administer booster doses to the general population.
The general population may perceive a decision to roll out booster doses without the proper justification as a sign of vaccine failure. Data from clinical trials and epidemiological studies should inform the decision to administer boosters and their timings.
The decision should take into account the durability of boosting, number of severe COVID-19 cases that it can prevent, its efficacy against prevalent variants and potential safety risks. COVID-19 vaccines based on adenoviral vectors and mRNA have been linked to potentially serious side effects. Boosting may exacerbate these side effects and may even fuel vaccine hesitancy.
The perception that vaccine-induced immunity wanes over time is being driven by observations that suggest antibody levels drop with time. This is a natural process and happens with any vaccine. Antibody decline is not necessarily synonymous with decline in protection – as protection can also be mediated by memory B cells and T cells. In fact, no study so far has shown that protection against severe COVID-19 declines significantly with time.
Such gaps in our knowledge make it difficult for us to assess the need for booster doses at this time. Experts have said that there must be an antibody threshold below which protection may be lost. There is a likely threshold of the T cell response as well. These relationships are called correlates of protection.
Researchers around the world are yet to identify a correlate of protection for COVID-19 to this day. Without this information, we can’t make decisions about booster doses with 100% certainty.
In the first week of April, the Drug Controller General of India reportedly permitted Bharat Biotech to begin testing a third dose of its Covaxin among a subset of clinical trial volunteers, six months after they had received the second dose. There were also reports in the last week of July that the National Technical Advisory Group on Immunisation and the National Expert Group on Vaccine Administration for COVID-19 were deliberating issues related to boosting schedules.
But as of mid-September, the Indian government’s stance appeared to be that boosters are not central to its vaccination strategy. This is the right stance, but we don’t know if experts in government arrived at it with the proper facts and considerations.
Scientifically, there is at present no evidence that booster shots will be useful for any of the vaccines authorised for use in India. Given the high seroprevalence of COVID-19 in the country, surely a significant amount of natural boosting, through viral exposure, must be happening. We need to investigate and understand this phenomenon and factor in such knowledge into any decisions on the feasibility of boosting.
India’s COVID-19 vaccination campaign has been dominated by the adenoviral vector vaccine Covishield, manufactured by Pune-based Serum Institute of India. Adenovirus vector-based vaccines have been associated with Guillain-Barré syndrome, a rare and untreatable disorder in which the body’s immune system attacks the nerves, leading to muscle weakness and paralysis. Covishield has also been associated with numerous complaints of debilitating cardiac effects, leading up to death.
Given these risks, we need to carefully investigate the effects of a third dose of Covishield.
We will also need to re-estimate the relative benefit of boosting to the immune response. This is because an adenoviral vector will elicit a potent immune response to itself – called anti-vector immunity – apart from the spike protein, which it encodes. After two doses of Covishield, anti-vector immunity will be very high, and will eliminate the vaccine before it has a chance to boost immunity against the virus. This phenomenon led to the failure of an AIDS vaccine several years ago.
From an ethical viewpoint, wealthier nations that opt for third doses for their citizens will essentially deprive poorer nations of their second or even first doses. This blatantly promotes vaccine inequity. About 6.6 billion doses of COVID-19 vaccines have been administered worldwide so far, but only 0.5% have been administered in low-income countries.
But from a practical viewpoint, India just can’t afford to roll out boosters when a significant fraction of its population remains unvaccinated. Approximately 50% of India’s estimated 94-crore adult population has received at least one dose of a COVID-19 vaccine. About 20% have received two doses. India hopes to vaccinate all of its adult population by the end of December 2021 – but is likely to miss this target, thanks to unrealistic supply projections. This is all the more reason India doesn’t need booster shots.
In sum, science, ethics and practice all say the answer to the question ‘Does India need booster doses?’ is ‘no’.
S. Swaminathan is a retired scientist based in Hyderabad. The views expressed here are the author’s own.