Ever since the first batch of Covid-19 vaccines became available in the UK last November, questions have lingered about whether two doses will be sufficient to protect against the ongoing threat of SARS-CoV-2, amidst the emergence of new variants which are more infectious and virulent than before.

The NHS is drawing up plans to offer a third dose to more than 30 million of the most vulnerable people across the UK from September. This will include all over 50s, younger, immunocompromised patients, as well as frontline health and social care workers. Public health officials from the Joint Committee on Vaccination and Immunisation (JCVI) feel that it is necessary to administer booster shots alongside winter flu jabs to avoid a surge of hospitalisations from respiratory viruses this autumn.

Scientists are now investigating whether booster doses will be required for the entire UK population, and whether they will need to be continually administered on a seasonal basis as more variants emerge. Among the researchers attempting to answer this is Vincenzo Libri, director of the Covid-19 Vaccine Trial Programme at University College London Hospitals, one of 18 centres across the UK involved in a study called COV-BOOST.

“The more viruses mutate, the more we need booster vaccinations,” Libri says. “The goal is to provide key information to inform future seasonal vaccine campaigns. We’re looking at whether a third dose will continue to clinically protect against the disease, and the outcome will provide NHS England, and the Vaccine Taskforce with the key understanding about how critical it is to initiate a seasonal campaign for boosting individuals on a regular basis.”

Backed by £19.3 million of government funding, the study is following 3,000 people aged over 30, and administering them with a third shot of one of seven different Covid-19 vaccines. Assessments will be made after one month, three months, six months, and 20 months, measuring their antibody levels, and ascertaining how many have been clinically protected from the virus.

Although the UK has agreed to press on with its autumn scheme, there are still a great deal of unknowns about the need for booster shots, and how often they might be required. Recent reports suggest that experts within the World Health Organisation believe annual booster doses could be needed for high risk individuals, with biennial shots for the general population, but there is currently scant evidence to back this up. In contrast, some immunologists have speculated that antibody levels could even hold their own for two years after vaccination, while ongoing clinical trial data from both Pfizer and Moderna indicates that people remain immune for at least six months after their second dose.

While the new Delta variant does appear more resistant to vaccine-driven antibodies in the lab, a hint that the virus is developing ways to flummox the body’s immune defences, some scientists caution that we should not panic into handing out booster doses without fully understanding the safety risks of a third dose.

“You have to make sure you’re doing no harm,” says William Werbel, a physician at John Hopkins University School of Medicine, who has been studying the effects of booster doses in transplant patients. “I don’t want to contribute to vaccine hesitancy, but I’m just very cognisant and cautious that we don’t want to have another hydroxychloroquine situation where sweeping decisions are made on the back of half knowledge.”

Right now, the main populations who are in definitive need of booster doses are the immunocompromised, a spectrum of patients which includes those on dialysis, transplant recipients, cancer patients receiving chemotherapy or immunotherapy, and people with autoimmune diseases. Because their immune systems are compromised, two doses of the vaccine typically results in an insufficient antibody response, and in some cases, no response at all.

Werbel has recently conducted a study in organ transplant patients, which showed that an additional dose can have benefits, although he says that two-thirds of the patients still had very low antibody levels, even after a third dose. “We showed that vaccines which were otherwise extremely immunogenic, turning out tons of antibodies in the general population, were not so effective in transplant patients,” he says. “Only about half of them had any detectable antibodies, after a full two dose vaccine series, and even after a third dose, some didn’t clear that low bar of having detectable antibodies.”

Over the past few months, an increasing amount of attention has been devoted to understanding what is needed to protect these people. Since the end of March, the Department of Health in France has authorised third vaccine doses for all immunocompromised individuals, while scientists at the University of Toronto have just completed enrolment for a clinical trial of a third dose of the Moderna vaccine in transplant patients. Werbel is aware of at least 100 cases in the Baltimore area where transplant doctors have administered an unlicensed third dose to their patients in a desperate attempt to keep them safe.

Nassim Kamar, who heads the organ transplant unit at Toulouse University Hospital, is conducting an ongoing study looking at booster doses in transplant patients, following them over a period of many months, and observing how their antibody levels change. He says that the prevalsence of anti-SARS-CoV-2 antibodies was 40 per cent after the second dose, and this was boosted to 68 per cent after the third dose.

“It’s still much lower than immunocompetent patients,” he says. “Perhaps in non responders, we have to do a fourth dose.” As a result, such doctors are less concerned about the rest of the population, who are likely to remain protected, at least to a reasonable degree, for a while.

“Even if you adjust for novel variants which require ten times more antibodies to defend against them, the vaccines still provide some durable protection for several months,” says Werbel. “The real question is whether it’s six or 12 or 18 months, and that I don't think anybody knows yet. It’s still speculation, and it’s going to take the entirety of the summer for people to get their heads around that.”

There is also an ethical question about whether individuals in high income nations such as the UK and the US – who can afford to purchase access to more vaccine supplies – should be prioritised with a third dose, when much of the world is yet to receive one. Currently only 23.5 per cent of the global population have received a first vaccine dose.

“The fact that we have Covid-19 raging in so many countries around the world with so little access to vaccines ought to drive where vaccines go,” says Steven Joffe, professor of medical ethics and health policy at the University of Pennsylvania Perelman School of Medicine. “If things are relatively well controlled in countries like the United States, then the priority ought to be getting vaccines to vulnerable people in places that have not had them.”

Joffe admits that at the same time, there is a difficult political landscape to navigate for global leaders, especially if the third wave begins to result in mounting hospitalisations. “I sympathise with them, because they have to be accountable to the people of their own countries,” he says. “How do you say to people in within your own country, ‘Boosters are good and they would protect us even further, but on the other hand, around the world, there are places that are so much more at risk?’”

Joseph Ali, an assistant professor at the Johns Hopkins Berman Institute of Bioethics, says that the onus is on vaccine manufacturers to justify their allocationss, particularly in cases where countries such as Brazil or India who have a greater burden of disease, are being overlooked. “It's hard to justify allocating limited supplies of vaccines to populations that may or may not need it,” he says.

However, when it comes to protecting individuals such as immunocompromised patients, who remain extremely vulnerable, even after multiple doses, the ethics are more straightforward. Werbel feels that the main priority should be to increase the protection of these people, before supplying additional doses to the wider population.

“It's a different paradigm than when we're talking about the general population,” he says. “For these people, we’re still trying to get the induction of the first good response.”

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This article was originally published by WIRED UK