The science and politics of boosters

Analysis

By Dylan Barry, GCPPP staff, November 16^th 2021

It is now just shy of a year since the first COVID-19 vaccinations were administered in the United Kingdom, United States and Israel, the world’s vaccine pioneers. In the intervening months, more than half of the world’s population has received at least one dose of an approved COVID-19 vaccine, saving lives and buttressing a stronger-than-expected global economic recovery.

But, although the impact of COVID-19 vaccines has been dramatic, it turns out that the protection they offer is not total and wanes over time. As a consequence, in nations with relatively mature vaccination campaigns, governments are implementing or considering booster shots for vulnerable populations, and, in more and more cases, for all fully-vaccinated individuals. In this ANALYSIS, we review the science behind booster shots and consider whether COVID-19 vaccine booster shots are an appropriate response to waning COVID-19 immunity while so many parts of the world remain largely unvaccinated.

How immunity works

The basic idea behind vaccination is that by exposing a human body to a specially-designed simulacrum of a pathogen, the human immune-system can be primed to rapidly recognise and respond to the pathogen itself in the event of an infection. The human immune-system has a memory. After every new infection, the system in effect files away its study notes on what worked against a pathogen, just in case it needs to take a similar exam in the future.

There are two layers to this immune memory. The first is made up of antibodies, which are Y-shaped proteins designed to bind to special proteins (antigens) on the surface of a specific pathogen, such as a virus or a bacterium. Antibodies come in two relevant types: neutralising antibodies, which directly interfere with the pathogen’s ability to function, neutralising it; and binding antibodies, which flag the pathogen for destruction by immune cells. The number of antibodies in a person’s bloodstream shoots up during and immediately after an infection, offering a strong short-term challenge to the pathogen. But, within a few months, the number of antibodies in circulation begins to fade. How fast depends on the pathogen. For some viruses, like small pox, polio and measles, antibodies fade so slowly that antibody immunity is lifelong. For others, like influenza and the common cold viruses, antibody immunity plummets within months, before levelling off.

Thereafter, the body relies on the second layer of its immune memory,  ‘cellular memory’. This involves a pair of white blood cell types, called B-cells and T-cells. B-cells are the molecular factories which manufacture antibodies. They come in a special subtype called a memory B-cell, which is an inactive B-cell that springs to life the moment it re-encounters the pathogen it is assigned to target. T-cells come in two main types, cytotoxic or ‘killer’ T-cells—assassins that hunt down and kill infected cells—and ‘helper’ T-cells, which stimulate the production of both killer T-cells and antibodies. Both memory B-cells and T-cells persist far longer than circulating antibodies, undergirding the body’s long-term immune memory.

As the number of circulating antibodies begins to fade, one might expect immunity to decline too. Reality, however, is more complex. The advantage of having circulating antibodies is that they respond immediately to the presence of a pathogen, either preventing an infection altogether, or nipping it in the bud early. By comparison, B-cells and T-cells—the immune-system’s heavy hitters—can take a day or two to get up and running. This may give an infection the chance to progress as far as causing mild symptoms, but the heavy artillery is still likely to dispense with it quickly. This means that falling antibody levels may reduce immunity to asymptomatic and mild infection, but immunity to severe disease is likely to stay strong.

The decline in circulating antibodies can also be offset by other effects. For one thing, memory B-cells continue to proliferate long after a pathogen is defeated. So-called germinal B-cells in the body’s lymphoid organs also continue to tinker with their antibody recipe for months post-infection—steadily improving B-cell potency. As a consequence, overall immunity to a pathogen can continue to improve even as the number of antibodies in a person’s bloodstream begins to fall.

How immunity to COVID-19 develops

So what is known about how immunity granted by a COVID-19 vaccine develops over time? Unsurprisingly, given that it is only a matter of months since most individuals received their final dose of a COVID-19 vaccine, the data on long-term immunity is sparse. The available immunological data, however, does suggest that levels of circulating antibodies in vaccinated individuals are declining over time.

A recent study of 122 volunteers published in The Lancet found that, six months after completing a two-dose COVID-19 vaccine regimen, volunteers’ antibody levels had dropped to levels roughly the same as those in people vaccinated with only a single COVID-19 vaccine dose. This suggests that antibody immunity to COVID-19 is more like immunity to influenza than it is to immunity against measles, mumps or chicken pox. Fortunately, other studies show that the major western COVID-19 vaccines—especially of the mRNA variety—continue to provoke strong T-cell and B-cell responses months after full-vaccination, with both the number and quality of memory B-cells still improving past the six-month mark.

The effects on overall immunity remain unclear, however. The strongest evidence comes from Israel—an early leader in COVID-19 vaccination—where rates of COVID-19 plummeted early on in the year before surging in mid-June. This gave researchers the chance to compare COVID-19 infection rates between cohorts of Israeli residents vaccinated with the Pfizer-BioNTech vaccine at different times. The researchers found thatbreakthrough infections occurred roughly 1.6 times more frequently in individuals vaccinated two months earlier than peers in the same age cohort. Research published by the Office for National Statistics (ONS) suggests there has been a similar trend in the United Kingdom. The ONS data indicates that the efficacy of the Pfizer-BioNTech vaccine drops from 92%, at 14 days after full-vaccination, to roughly 90% after 30 days, 85% after 60 days, and 78% after 90 days—consistent with the Israeli figures.

These observational studies must be treated carefully, however. They are not performed in tightly-controlled conditions as in a clinical trial. As a consequence, other confounding effects may explain some of the observed decline in immunity. For example, it is possible that people at greater risk of infection (due to a high-risk occupation or a health condition) were more likely to get vaccinated promptly, while lower-risk individuals waited a little longer. In that case, a higher level of breakthrough infections in high-risk individuals—a natural phenomenon—would look superficially like waning immunity. Alternatively, if wealthy individuals had quicker access to vaccination and also get tested more regularly, an observed high rate of breakthrough infections in that demographic (due to a higher volume of testing) would look like waning immunity too.

These qualms are backed up by what are the only two clinical trials to investigate the long-term protection offered by the Pfizer/BioNTech and Moderna vaccines. These studies suggest that the efficacy of each mRNA vaccine drops by roughly 3 percentage points per month. That is half as fast as implied by the aforementioned observational studies. And even these more trustworthy figures may simply be the result of behavioural changes. With pandemic-fatigue and vaccine-induced complacency setting in, it is plausible that people may be taking fewer precautions and engaging in riskier behaviour as time goes on. That could also explain the observed increase in the rate of breakthrough infections.

Nevertheless, even if the immunity conferred by a COVID-19 vaccine against asymptomatic or mild infection with the virus is waning, there is little evidence that immunity against severe disease has changed much at all. That is just what one might expect from the immunological data, with immunity to initial infection falling as circulating antibodies decline, while immunity to severe infection continues to stay strong due to the persistent presence of T-cells and memory B-cells, the immune system’s heavy artillery.

To boost or not to boost

This is the background against which to address the issue of whether  governments are right to already make booster shots available to fully-vaccinated citizens. That a third shot will eventually be desirable is not controversial: the question is when, and what priority to give to providing extra immunity to already vaccinated citizens relative to spreading protection more widely around the world so as to make the emergence of new variants less likely.

Most clearly, there is a compelling case to be made for offering booster shots to the elderly and the immunocompromised. It is now well-established that the immunity conferred by vaccination wanes unusually rapidly in those demographics and studies appear to confirm that the same is true of COVID-19. Such at-risk groups remain at risk, even after vaccination.

There is also a good case to be made for offering vaccine booster shots to those initially vaccinated with a lower efficacy vaccine or one for which vaccine immunity appears to wane faster. For example, some countries already recommend that people who were vaccinated with a shot of the single-dose Johnson & Johnson vaccine should augment it with a single shot of a higher efficacy vaccine like the Pfizer/BioNTech or Moderna vaccines. The case for this kind of boosting is especially compelling in countries that have vaccinated residents with either of the Sinopharm or Sinovac COVID-19 vaccines developed in China (which account for half of global COVID-19 vaccine output so far). There is a growing body of evidence hinting that the immunity induced by those and similar inactivated-virus vaccines appears to be waning especially quickly.

However, the scientific case for making booster shots immediately available to all fully-vaccinated people is weaker. The current smorgasbord of COVID-19 vaccines, —the mRNA vaccines, in particular, remain remarkably effective against the virus, especially against severe disease, hospitalisation and death.

The real case which is being followed by governments in America, Canada, Japan, Britain and many more is not scientific but political and behavioural: first, that with infection-rates rising again in many countries, governments have to be seen to be “doing something”, and for most of them booster shots are preferable to renewed lockdowns; second, that social behaviour is reverting rapidly to maskless close contact and large gatherings, so that without boosters the absolute numbers of breakthrough infections are bound to climb even as immunity remains high. The fact that these arguments are somewhat circular and are in conflict with governments’ international promises and responsibilities to give priority to the unvaccinated is making little difference.

Many public health experts also worry that overstating the problem of waning vaccine-induced immunity in recommending booster shots for all adults risks further fuelling vaccine hesitancy. A focus on  booster shots for all when they may not be strictly necessary may serve to undermine confidence in the efficacy of the initial two shots of a COVID-19 vaccine.

It may also reinforce the impression that global governance and co-ordination on health is broken beyond repair. The World Health Organisation (WHO) has called for a global moratorium on vaccine boosters until at least the end of the year. Nonetheless, according to the life-sciences intelligence firm Airfinity, 16 countries worldwide are now offering boosters to anyone already vaccinated; 31 are offering them to specified age cohorts; 28 are offering only to high-risk individuals; 10 are offering them based on lower-efficacy initial vaccines; and 17 are offering them according to occupation. The numbers and criteria change by the day. Essentially, the argument for waiting has long since been lost.

According to Our World In Data over recent weeks roughly 10% of all shots being administered worldwide have been boosters; the Oxford-based data provider reckons that the cumulative total of boosters administered is now over 170 million, 50 million of which have been deployed in China. But reporting of this data may not yet be as reliable as that for the primary vaccine doses.

In global perspective

While constrained supply of vaccines is less of an issue than it was in previous months, the reality of very uneven access to vaccines remains crucial, for public health, equity, and strategically. Focussing on boosters for the fully-vaccinated in advanced and the wealthier middle-income economies represents a clear political choice: to take the risk that new variants will emerge in unvaccinated populations and to treat global vaccine inequality as a second-order issue at best.  While over 50% of North Americans and Europeans are fully-vaccinated, fewer than 7% of Africans are vaccinated. This adds a further risk, of social and political instability in unvaccinated countries, which are often fragile and highly indebted, eventually coming back to haunt those currently so eager to rush ahead with boosters.