With more than half the UK population fully vaccinated and the UK government just a little too eager to declare victory, spare a thought for Cameroon. With a population about half the size of England, Cameroon has — according to Our World in Data — administered just 160,000 doses of vaccine. On a good day, the UK manages that many before lunch.
I have a certain romantic attachment to Cameroon, but the west African nation is not alone in lacking vaccines. More than six months into the global vaccination campaign, fewer than a quarter of people around the world have received even a single dose of a vaccine. It is no wonder that more people have already died of Covid in 2021 than died from the disease in 2020.
So what can be done? There has been much talk about vaccine equity, but the main problem is not vaccine hoarding or price-gouging. It is that manufacturers can’t make doses fast enough. (If they could, then India, a huge vaccine producer, would have fully vaccinated more than 5 or 6 per cent of its population by now.)
Global production has been impressive and accelerating: according to Airfinity, a life sciences analytics company, the billion-dose production mark was hit only on April 12. A billion more were produced by May 26 and the third billion by June 22. That’s good. But we need 11 billion doses to fully vaccinate 70 per cent of the world, which may not happen until 2022.
Recently, however, some momentum has built up behind an idea that sounds almost childishly simple: if we reduce the dose size, we can vaccinate more people from each vial of vaccine. Why not give people half doses? What about quarter doses? With quarter doses, we could have already vaccinated the world’s adult population.
The idea seems absurd — you can’t get drunk more cheaply by diluting your beer — but it all depends on how effective lower doses might be. Five years ago, faced with a yellow-fever outbreak and a shortage of vaccines in the Democratic Republic of Congo, seven million people received one-fifth of a dose each. The strategy, endorsed by the WHO, seems to have worked.
Alex Tabarrok, a professor at George Mason University, has been pushing the idea of alternative dosing regimes for several months. Recently, he and other researchers, including vaccine market specialist and Nobel laureate economist Michael Kremer, released a working paper exploring the issue.
At the same time, a letter advocating trials of fractional doses, written by epidemiologists Benjamin Cowling and Wey Wen Lim and a virus evolution specialist Sarah Cobey, has been published in Nature Medicine.
What evidence is there low-dose vaccinations might also work for Covid? From full-scale clinical trials, not much — although there was the serendipitous discovery that the Oxford/AstraZeneca vaccine seemed to work better when the first injection consisted of a half dose. But there is plenty of data on the antibody levels that people produce in response to small doses, and, according to a recent paper in Nature Medicine by David Khoury and colleagues, those antibodies are strongly correlated with real-world protection against Covid.
As Kremer and his colleagues observe, if antibody levels really are a good measure of protection, then the mRNA vaccines (BioNTech/Pfizer and Moderna) may protect as well as the highly effective AstraZeneca vaccine even if they are deployed at two-thirds, 50 per cent or even 25 per cent strength.
A recent preliminary report, yet to be properly reviewed, also finds that a two-dose course of Moderna’s vaccine at 25 per cent strength produces an antibody response comparable with that of a case of Covid. A trial is under way in Belgium exploring alternative doses of the Pfizer vaccine, while Moderna has said it is also investigating lower doses.
The concept of a standard or full dose is fuzzier than one might imagine. These vaccines were developed at great speed, with a focus on effectiveness that meant erring towards high doses. Melissa Moore, a chief scientific officer at Moderna, has acknowledged this. It is plausible that we will come to regard the current doses as needlessly high.
This isn’t to say that we should abandon the standard doses, which have been tried and tested in large clinical trials. But it does suggest that we should test alternatives immediately. Is there a downside? If low-dose vaccines don’t work as well as studies of antibodies suggest, that is a problem that booster shots should be able to fix.
More worrying is the prospect that a large pool of low-dosed people might push the virus to evolve towards vaccine resistance. Cobey acknowledges that risk but argues that if fractional doses help to reduce the number of infected people, that gives the virus fewer opportunities to mutate. Dangerous mutations might be reduced, rather than increased — it is unclear. What is clear is that millions of lives might be saved if fractional dose vaccines are proved to work well.
There is a lesson to be learnt here. While the production and testing of these vaccines has been little short of miraculous, next time we can do better. We should run more trials, earlier, to produce evidence on a wider variety of questions than “Are they safe?” and “Do they work?”
Such trials are expensive; the understanding they produce is worth paying for.
Written for and first published in the Financial Times on 14 July 2021.
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