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The world still needs more — and better — Covid-19 vaccines. But a major hurdle stands in the way of the development of new vaccines, as well as the critical studies needed to determine the best way to use these important tools, the Coalition for Epidemic Preparedness Innovations (CEPI) warned in a letter published Tuesday in the journal Nature.

Unless countries that have purchased vaccine doses and companies that have already brought vaccines into use agree to find ways to resolve the problem, manufacturers that trail the first wave of producers may not be able to prove that their vaccines work. Not only will that slow efforts to vaccinate the planet, it will block development of next-generation vaccines, and it will stymie efforts to answer key public health questions, like whether boosting with a different vaccine would generate better protection, or whether giving smaller — fractional — doses could protect more people more quickly.

The letter was signed by CEPI’s director of vaccine research and development, Melanie Saville.

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In an interview with STAT, CEPI’s U.S. director, Nicole Lurie, said the organization has been trying for months to break the logjam, to no avail. “We’re going round and round in circles.”

The problem stems in part from the fact that at this point in the pandemic, it isn’t considered ethical to test new vaccines against placebos; instead they would have to be tested against one of the existing shots. But getting one’s hands on licensed or authorized vaccines for study purposes is nigh on impossible; all available doses have been snapped up by countries keen to vaccinate as many of their citizens as possible.

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Contracts for those doses contain rigid stipulations about how the vaccines can be deployed. The doses often have to be used in the country that made the purchase; when the Biden administration wanted to share AstraZeneca doses with Canada and Mexico in March, it loaned the doses to get around the restrictions. Contracts also often stipulate that doses that have been purchased must be used for outbreak control, not for research purposes, Lurie said.

There’s little upside for companies to make doses of their vaccines available for study purposes. With global demand vastly exceeding current supply, manufacturers can sell every dose that they can make.

And there are potential downsides. If a clinical trial testing a new vaccine shows it performs better than the vaccine to which it was compared, that doesn’t help future sales of the comparator vaccine. Likewise, if a study showed that it would be better to use a different vaccine as a booster shot — called a heterologous boost — that could undercut plans by manufacturers like Pfizer and Moderna to sell third shots of their vaccines.

There are many questions that need answering about the best way to use Covid vaccines. And the only way to answer them is to conduct studies — studies that would require doses of vaccines like Pfizer-BioNTech’s Comirnaty and Moderna’s Spikevax, as well as the Johnson & Johnson and AstraZeneca vaccines and shots made by manufacturers outside of North America and Europe.

“Whether it’s interval [between doses], whether it’s heterologous prime-boost [studies], whether it’s boosting strategies, fractional dosing, whatever …  you need an authorized vaccine” to test against, Lurie said. “And we can’t get access to vaccines. That’s the basic issue.”

The problem shouldn’t be insurmountable. The South Korean vaccine manufacturer, SK Bioscience, announced recently that it is beginning a Phase 3 trial of a vaccine it is developing in conjunction with vaccine giant GSK, which is supplying a boosting compound known as an adjuvant. The clinical trial will compare the SK vaccine against AstraZeneca’s vaccine. SK Bioscience also produces the AstraZeneca vaccine.

On the health policy studies front, so-called mix-and-match trials are being conducted both in the United States and in Britain. The aim is to see whether using two different vaccines is more effective than using the same vaccine for both priming and boosting doses.

The U.S. trial, being conducted by the National Institute of Allergy and Infectious Diseases, is studying combinations of the three vaccines authorized for use in this country: the Pfizer, Moderna and J&J vaccines. The U.K. trial, being conducted by the University of Oxford, is studying combinations of the Pfizer, Moderna, and AstraZeneca vaccines — which are all authorized for use in Britain — as well as a vaccine made by Novavax, which is in the process of seeking emergency use authorization from the British regulatory authorities.

But in both cases, the trials are only being conducted using vaccines authorized for use in the country in which the study is being conducted. That means that questions that have global ramifications — for instance, could some of the Chinese vaccines be more effective if boosted with a Pfizer, AstraZeneca, or Novavax vaccine? — won’t be answered by these studies. None of the Chinese vaccines has been authorized in either the U.S. or the U.K.

Lurie said CEPI is willing to finance some of these crucial studies, but “moving forward on any of those things is contingent upon us getting vaccine.”

The amount of vaccine doses needed is not massive. A Phase 3 trial of a new vaccine might require 20,000 doses of a comparator vaccine. A Phase 2 trial measuring immunogenicity — the levels of antibodies vaccine doses generate — would need substantially fewer. The British trial, called Com-COV2, is giving just over 1,000 volunteers a third dose of a vaccine that differs from their original vaccination regimen. The U.S. trial is smaller still, involving about 150 people.

Lurie said the problem could be solved, if countries buying vaccine modify the contracts with suppliers. A number have initially indicated willingness, she said, but progress has stalled when they realize the amount of work involved.

“We have a global problem to solve,” Lurie said. “We’re stuck with the vaccines we have unless we can move forward.”

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