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A healthcare worker prepares a dose of a COVID-19 vaccine at a vaccination centre in San Salvador, July 13, 2021. Photo: Reuters/Jose Cabezas
There are two important arguments against distributing booster doses for all: slow pace of vaccination in poorer countries and lack of evidence for boosting.
We can avail booster doses for certain sections of the population, especially those older than 60 years of age.
Underlying this whole debate is a question about the immune correlates of protection against COVID-19.
The COVID 19 pandemic created a global emergency and prompted the scientific community worldwide to develop and test several vaccines. By July 2021, 99 vaccines were reportedly undergoing human clinical trials, and 33 of them had qualified for the final stage.
On June 1, a month earlier, seven vaccines were listed in the WHO emergency-use listing, and the bulk of them were to be administered in one or two doses.
Now, a booster dose refers to another dose of a vaccine given to someone who has built up enough protection after the first or regular dosing schedule, to augment the protection that would have waned over time.
The conversation around the need for a booster dose has been gaining momentum amid rising concerns over the effectiveness of the vaccines currently in use, vis-à-vis new variants of the novel coronavirus. The surge in cases due to the delta variant in particular has created a sense of urgency. Some nations appear to perceive more keenly the waning of vaccine-induced immunity, and have fully vaccinated individuals may need to take a booster dose.
While still awaiting real-world data and definitive recommendations on booster doses, many nations have started providing them at the same time.
The idea of booster doses is not new. The demand for them grew louder when Pfizer announced in mid-August its plan to meet with US health officials and request approval for a third dose of its COVID-19 vaccine. The evidence for booster doses, according to drug-makers, comes from early data from a company study that showed greater increase in antibody levels after a third dose than after the second dose.
Data from Israel also showed that a booster dose of this vaccine was efficacious vis-à-vis reducing the risk of symptomatic infection and severe disease. The studies from Pfizer have not been released, and the data from Israel has not been peer-reviewed.
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There are no moral grounds on which we can justify booster doses for already protected individuals. In addition, many people in low- and middle-income nations (LMICs) are still waiting for the first dose.
In addition, one would also expect a more sound scientific basis for booster doses. The need for such a dose depends on how rapidly the vaccine-induced immunity is waning, whether existing vaccines can protect existing and future variants, and if the booster doses will work. It is also imperative that we understand if a breakthrough infection in a fully immunised individual is the result of an infectious variant or because the vaccine’s protection is fading. (The clinical implications of waning antibodies are indeterminate due to confounding factors like age, dosing interval and population size.)
Before we set ahead, we must understand how the different kinds of vaccines work, which in turn needs us to understand how the body’s immune system works.
When an individual is infected for the first time, the body’s immune cells – white blood cells, macrophages, B lymphocytes and T lymphocytes – generate a primary immune response to fight the infection. The macrophages ingest the germs, and parts of the ingested germs are left behind as ‘antigens’ to be destroyed by antibodies produced by the B lymphocytes. The T lymphocytes kill the infected host cells and activate other immune cells. The primary immune response also leaves behind a pool of ‘memory’ B and T lymphocytes – i.e. they can recognise the pathogen when it infects the body next time, and induce a secondary immune response.
COVID-19 vaccines trigger the primary immune response, and aim to leave behind a pool of ‘memory’ B and T lymphocytes that can mount a secondary immune response when the novel coronavirus shows up. Not all vaccines render protection against infection in the same way, however – but all vaccines eventually provide the body with the right kind of B and T lymphocytes.
In the early stages of an infection, the B lymphocytes turn into antibody-producing plasma cells and continue rendering protection. But months after an infection or vaccination, the number of antibody-producing cells declines.
Booster doses or two doses for everyone?
Currently, there isn’t enough evidence to justify the need for booster doses against COVID-19 for all age groups. Ahead of this, we need to be sure if the decline of antibody levels, induced by a vaccine, also correlates to a drop in the protection against the virus as well. We need data on the immune correlates of protection – the parameters that reliably predict the degree of protection a body has against infection, without the need to conduct whole clinical trials and analyse the outcomes.
We don’t know what the minimum level of circulating antibodies could be that means the body is ‘protected’, and to what extent. We also don’t know the extent to which the drop in the level of neutralising antibodies correlates with a drop in vaccine efficacy. We only know, based on one human model and various animal models, that neutralising antibodies are reasonable correlates of protection.
A study by David Khoury and others, published in May 2021, correlated in vitro1 neutralising antibody titers – or levels – with protection against infection using statistical methods. The data suggested that vaccines starting with initial efficacy of 95% could be expected to be 77% efficacious after 250 days. But vaccines with an initial efficacy of only 70% could drop to 33%, also after 250 days. However, the protection against severe disease and death appeared to persist for longer.
The Pfizer-BioNTech vaccine’s efficacy peaked at 96.2% after the second dose, declining to 83.7% after four months, with an average decline of 6% after every two months. (Despite this slow slide, the vaccine has proven to be highly efficacious at preventing COVID-19 infections.) Data from Pfizer-BioNTech and AstraZeneca have also suggested that antibody levels in infection-naïve individuals (i.e. those who haven’t been infected before) wane three to ten weeks after the second dose of both vaccines.
Let’s consider the data specific to certain variants of concern. In one study, researchers observed that the Moderna two-dose mRNA vaccine could provide over a year of protection against COVID-19 caused by the viruses with the D614G mutation, associated with the B.1 lineage. But in the second year, protection against infection was expected to drop below that accorded by a single-dose.
Researchers studying blood sera samples from people vaccinated with either the Moderna or the Pfizer vaccines found that their neutralisation activity didn’t change against the alpha (B1.1.7) variant but dropped against the beta (B.1.351) variant. The delta variant (B.1.617.2) is nearly 60% more transmissible than the alpha, and spreads much faster than other variants.
In a study to assess the reduced sensitivity of the delta variant to neutralisation by antibodies, scientists found that neutralisation titers were 4-6x lower than they were for the alpha and beta strains. This study also found that the delta variant partially escapes neutralising monoclonal and polyclonal antibodies elicited by a previous infection (natural or vaccine-induced). Another study found that a live virus of the delta variant evaded neutralising antibodies in blood sera from individuals who had received the AstraZeneca and Pfizer-BioNTech vaccines as well as those who had had, and recovered from, COVID-19.
In a retrospective cohort study comparing the incidence of breakthrough infections between early and late vaccinees, researchers analysed the correlation between time from vaccination and protection against breakthrough infections. They reported a possible relative decrease in the long-term protection afforded by the Pfizer-BioNTech vaccine against the delta variant. However, the researchers didn’t measure the effect of time from vaccination on symptomatic infections and hospitalisation, among other limitations.
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All these studies, regarding waning antibodies and novel coronavirus variants, might have paved the way to setting up the need for booster doses, but we can’t overlook certain considerations.
The absence of antibodies is not the same as the absence of a potential immune response. When confronted with the wild virus, a real test is to observe how the immune response changes when antibodies are waning compared to those who have them in ‘full measure’.
To conduct such a study, we need a modified version of human challenge trials – wherein vaccinated participants are intentionally infected with a wild-type variant. The ethics and methods of conducting human challenge trials are governed by WHO regulations.
Rushing into administering booster doses is not wise without conducting these studies (responsibly).
A gamble now
The jury is also out on whether booster doses are necessary for all age groups. Boosters were initially meant for people with a weakened immune system, who were (and are) at higher risk of getting severe COVID-19 if they’re infected, and are prone to breakthrough infections as well. A third dose would improve their response to vaccines. So as such, those aged 60 years and above are among those who most redeserve booster shots.
A study conducted among US veterans showed that the mRNA vaccines were efficacious against COVID-associated hospitalisation in all age groups. However, it was less efficacious among those aged 65 years and above, due to a higher prevalence of underlying medical conditions. In Israel, the government has approved booster doses of the Pfizer-BioNTech vaccine for those older than 60 years. A subsequent study found that participants aged 60+ and who had received both doses of the vaccine plus a booster five months later had 19.5x lower rates of COVID-19 and severe illness – compared to those who didn’t get the booster.
Understanding protection offered by booster doses in the elderly population is crucial to devise strategies to end the pandemic. Researchers have already found that immunogenicity – a vaccine’s ability to evoke an immune response – decreases with increasing age. Studies among organ-transplant patients have also found an increase in protective antibodies after a third, additional dose.
Another study, among kidney-transplant recipients at a hospital in France, found that 28% developed antibodies after receiving a third dose of the vaccine – after developing no antibodies after the second dose.
In sum, a compromised immune system can have various reasons, and from scientists’ and researchers’ point of view, booster doses for all is a gamble right now, given also that many LMICs are still struggling to get a meaningful fraction of their populations vaccinated. This in turn should emphasise the importance of more research into booster doses.
The study by Dan Khoury and others showed that in vitro neutralising antibody titres are immune correlates for protection. It also predicted that immune protection could decline over time as the levels of neutralising antibodies also decline. However, it found vaccines’ protection against severe infection to be durable.
This study suggests that even without boosters, an alternate immune response – such as the cellular immune response – could play a prominent role. Another study found that it is improbable that SARS-CoV-2 mutations can escape T-lymphocyte immunity because a broad array of SARS-CoV-2 epitopes2 have been recognised in humans with COVID-19. Another study, of patients’ health records in New York, found that extant COVID-19 vaccines had been more than 89% effective after two doses against hospitalisation – at a time when the delta variant’s prevalence increased from less than 2% to more than 80% (of all infections) in New York city.
Another study found that mRNA COVID-19 vaccines (of Pfizer-BioNTech and Moderna) are effective against symptomatic COVID-19 among healthcare personnel. Data from real-world settings has also shown that a two-dose regime of the Pfizer-BioNTech vaccine can effectively prevent symptomatic COVID-19 (see here and here).
Similar data from Israel, the UK and other countries have suggested that vaccines have prevented hospitalisation even in cases of the delta variant. So the evidence at present suggests that the vaccines are very protective against severe forms of the disease. And given this, the WHO’s moratorium on booster doses is justifiable.
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We can assess the need for booster doses only after understanding the level of protection provided by an immune response to COVID-vaccines and the infection’s background seroprevalence. Identifying immune markers is crucial to evaluate to the degree to which antibodies protect by neutralising the virus.
We must also bear in mind that more than 80% of the world’s COVID-19 vaccines have thus far been administered in high- and middle-income countries. There are still frontline healthcare workers in many parts of Africa Nigeria who are yet to be inoculated. In the Palestinian territories, less than 12% of the population had got any doses at all, as of early August). In this time, and together with the poor evidence, it is untenable for whole nations to be desperate to get their populations to receive booster doses.
In addition, an isolated response by a few nations to reprime their populations could address challenges posed by the virus, but only for a short time. As the pandemic eases and people move around more once again, the virus will resume spreading if not everyone everywhere has been vaccinated. Eventually, it will still be a threat to fully vaccinated and boosted individuals in the richer countries.
With scant evidence in favour of booster doses for those of all ages, richer nations need to ask themselves if it’s worth persisting with their plans at the cost of undermining the vaccine needs of poorer nations. No part of the world is safe – even with booster doses – as long as the virus continues to circulate in some parts of the world.
It is also troubling, and unethical in fact, that vaccine manufacturers have issued pleas for booster doses. The decision to institute booster doses, or not, should be based on scientific evidence and shouldn’t compromise equitable access.
Hima Bindu Dubasi and Aditi Deshpande are consultants and Giridhara R. Babu is a professor and head of the Department of Epidemiology – all at the Public Health Foundation of India, Bengaluru.
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