Faced with surging coronavirus cases, some European countries are considering whether to change tack and join the U.K. in vaccinating as many people as possible with just one dose rather than the two administered during clinical trials so far.
This issue has been live since December 30, when the U.K. announced its decision to delay second doses by up to 12 weeks when it approved the Oxford/AstraZeneca vaccine for emergency use. The switch also applied to the BioNTech/Pfizer jab.
Just this week, Denmark announced its decision to delay the second dose of both the Pfizer and forthcoming Moderna jabs by up to six weeks. The German health ministry has also confirmed looking into widening vaccination coverage by similar delays between doses.
Meanwhile, the U.S. federal government is in talks with Moderna about halving the recommended dose of the shot to speed up immunization efforts.
Scientists are divided. Some argue delaying could cause further virus mutations and render the shot ineffective. Others question whether recipients will be left more vulnerable, pointing out that allowing larger gaps between doses hasn’t been tested properly.
The pro-delay camp argues that an immediate level of broader, if slightly weaker, protection is better than providing stronger protection in half as many people. U.K. Deputy Chief Medical Officer Jonathan Van-Tam pressed this point in the Mail on Sunday, saying that maximizing coverage with the first dose will “save lives.”
Belgium’s top epidemiologist, Pierre Van Damme, also supports the idea of paused dosing. Speaking to broadcaster VRT last week, he said the strategy would quickly provide protection to more people, and “herd immunity would grow at a much faster rate.” (Belgium’s Health Minister Frank Vandenbroucke has asked the vaccine task force to look into the possibility of delays between doses, but hasn’t yet made a statement, with his spokesperson cautioning that there still isn’t enough evidence for the move.)
With vaccine supplies squeezed and the new U.K. and South African coronavirus variants causing alarm — compounded by overburdened health systems — some politicians are now siding with the latter camp.
The catch: While the U.K.’s approach has been developed and supported by many public health scientists, it lacks the rigor of controlled testing the U.K. is so well-versed in.
Not fully tested
The idea of vaccinating as many people as possible with the Oxford/AstraZeneca vaccine before it was approved for emergency use was first pitched by former Prime Minister Tony Blair in early November. It was quickly rejected by doctors and scientists on the grounds that it would run roughshod over controlled clinical trials already underway for these treatments. Such studies ultimately weed out therapeutic winners (dexamethasone) from losers (hydroxychloroquine).
The debate further shifted this week when the British Society for Immunology tipped its hand on Monday. While their statement placed “utmost value on an evidence-based approach to medical decisions”, they called for a “pragmatic approach in the short-term” given the “unprecedented situation.” The Society backed the delayed two-dose schedule — provided the government develop a “robust program of immune monitoring.”
Sheila Bird, former program leader at Cambridge University’s MRC Biostatistics Unit, went one step further. In an emailed statement Monday, she called on the U.K. to randomize standard and delayed-dosing schedules in order to compare the effectiveness of both approaches.
“Trials would be good for all these variations, although the data we have shows very good protection from one dose of AstraZeneca or Pfizer [vaccines]… The speed and breadth of vaccination is crucial for success,” said Oxford University Professor John Bell, who is also a member of the U.K.’s vaccine task force, in an email.
Single shot data
In their defence of delaying doses, the U.K.’s chief medical officers pointed to data showing that short-term vaccine efficacy from the first dose is around 90 percent with the BioNTech/Pfizer vaccine and around 70 percent with the Oxford/AstraZeneca vaccine. The second dose is likely to be “very important for duration of protection,” they said in a joint letter dated December 31.
Some scientists, however, remain concerned about whether effectiveness could wane beyond the indicated three and four-week periods for second doses of the Pfizer and AstraZeneca vaccines respectively.
Data from the British Society for Immunology on the BioNTech/Pfizer vaccine, for example, shows that antibodies and T cells are neutralized more effectively after the second dose. The society also notes that “similarly, the Oxford/AstraZeneca vaccine shows substantial immunological differences after the second dose at 28 days.”
They concluded, however, that delaying a second dose by eight weeks “would be unlikely to have a negative effect on the overall immune response post-boost.”
Peter English, former editor of the magazine Vaccines in Practice and previous chair of the British Medical Association’s Public Health Medicine Committee, also laid out the case for delays. In an op-ed from Monday, he wrote that decades of experience with other vaccines have shown that, if anything, “increasing the interval will enhance the quality of the booster response.”
Approved single dose coming?
With Johnson & Johnson investigating the question in a large clinical trial, more data on single dose efficacy and duration of protection will likely come to light by the end of the month.
Like the Oxford/AstraZeneca jab, the J&J vaccine is based on adenovirus viral vector technology. This uses a modified cold virus to carry information into the cells, telling them to make the spike protein antigen in order to build an immune response.
J&J, which has experience with pandemic vaccination following the successful approval and launch of its Ebola vaccine, said in November that while a single-dose vaccine “would have significant benefits, particularly in a pandemic setting,” the company’s vaccine program is also testing two doses in a separate trial.
Unpublished early results from a first-stage clinical trial showed that a single dose is effective in generating sufficient antibodies in 98 percent of patients after 29 days, the company said.
Pending positive results, the U.S. drugmaker plans to file for global licenses with data supporting the one-dose schedule. The European Medicines Agency hopes to reach a decision in March.
Final hurdle
The U.K. approach allows the off-label use of both the Pfizer and AstraZeneca vaccines, meaning these jabs can be administered outside of their licensed indication without consequences. This is possible due to instruction from the Joint Committee on Vaccination and Immunization, which offers protection from reprisal.
The same does not apply elsewhere in Europe, where countries will be using EMA-approved vaccines.
“I don’t think health care professionals … in the EU would endorse or otherwise be inclined to promote any kind of off-label use,” said Vincenzo Salvatore, a lawyer at Bonellei Erede and former head counsel at the EMA.
“Any change to [administration] would require a variation to the marketing authorization,” said the EMA, as reported by Reuters, “as well as more clinical data to support such a change. Otherwise it would be considered as ‘off label use.’”
Vaccine manufacturers have also defended clinically approved indications.
“Our Phase 3 clinical trial and U.S. Emergency Use Authorization is associated with 100ug at two doses, 28 days apart,” a Moderna spokesperson said in an email, on the topic of half-doses in the U.S.
BioNTech echoed this sentiment in the FT, reiterating that no data exists to support the administration of two doses of its vaccine given beyond 21 days apart.
English, who is also a consultant in communicable disease control in the U.K, said the benefit of the vaccine committee is that it “views the population and needs in the round.” It includes decades of knowledge on vaccines, the immune system and how they interact — “not just according to trials that were done to get the license.”
He also warned of the deadly risk of limiting the factors affecting these decisions.
“People are dividing into ones who want explicit, narrow, direct empirical evidence and those who are willing to bring in extrapolation from indirect evidence,” he said. “The issue is, lives could be lost if we wait for the narrow direct evidence.”
Charlie Cooper, Hans von der Burchard and Camille Gijs contributed reporting.
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