There is no clear path to test the three candidate vaccines developed to combat the Ebola Sudan strain now that Uganda’s outbreak is over.

The three candidate vaccines – produced by IAVI (called SUDV), Sabin (ChAD3) and Oxford (ChAdOx1) – were delivered to Uganda with much fanfare in mid-December. But scientists attending a meeting convened by the World Health Organization (WHO) on Thursday could not agree on how to test them now, and discussed options including regulatory approval based on animal-only studies and “immunobridging”.

So far, only one vaccine, BioThrax, developed to protect against anthrax, has been given US Food and Drug Administration approval based solely on animal studies. 

BioThrax had already been licensed in the 1970s to prevent anthrax inhalation but received a futher FDA approval as post-exposure prophylaxis for anthrax exposure in 2015, based on the FDA’s Animal Rule.  

Under the Animal Rule, efficacy is established based on “adequate and well-controlled studies in animal models of the human disease or condition of interest, and safety is evaluated under the pre-existing requirements for drugs and biological products”, according to the FDA.

‘Immunobridging’

There was much discussion about the possibility of immunobridging, an approach that allows scientists to infer a vaccine’s effectiveness to conditions other than those proven in a clinical trial. It has been used during COVID-19 to approach vaccines for different demographic and age groups.

It can also be used to change dose levels and formulation. In some cases, conclusions from animal trials have been extrapolated to humans – including to approve Ebola vaccines and treatment.

Given how lethal Ebola is, the WHO’s Ana Maria Hanao-Restrepo asked participants whether anything could be done with the thousands of doses of the three candidate vaccines currently in Uganda in order to prepare for the next outbreak.

More non-human primate efficacy data, testing the effects of one vaccine dose or two, which vaccine gave rapid protection and which gave long-term protection, and whether efficacy was affected by malaria were some responses.

CEPI’s Bill Dowling said that while efficacy studies in mice and guinea pigs were “not very applicable”, non-human primate studies, particularly in cynomolgus macaques, were similar to human progression and had been used extensively for Ebolavirus Zaire studies.

But having the assays in place to support trials was missing, said Dowling, including reagents for Sudan virus.

Dowling also noted that certain correlates of protection established during trials of the vaccine for Ebolavirus Zaire might be applicable to Sudan.

Pathways to regulatory approval

Several pathways are open to regulatory approval for a vaccine for Sudan, Dowling added.

These include an accelerated approval pathway where efficacy is based on a surrogate endpoint likely to predict clinical benefit, conditional approval, where the benefit of the vaccine’s immediate availability to patients is deemed greater than the risk and an exceptional circumstances pathway, where it is recognised that the sponsor is unable to provide certain data.

“The US animal rule is very stringent, and does not apply if approval can be based on an efficacy standard elsewhere in FDA regulations,” said Dowling, and that it usually entailed “a large number of studies with a large number of animals, and was quite a lengthy process”.

Infectious disease expert Nancy Sullivan, director of Boston University’s National Emerging Infectious Diseases Laboratories, “efficacy data have to be generated in humans”.

“We have to be careful about trying to compare vaccines based on immunogenicity. I think we need those efficacy results and if it requires doing it over multiple trials, we should,” stressed Sullivan.

The University of Marburg’s Stephan Becker agreed: “The most important thing is really the efficacy trials that we can bring up very rapidly during an outbreak.

“Maybe this discussion about immunobridging studies does not help in a situation such as the Sudan Ebola outbreak,” he added. “I think it’s much more important to have all the vaccines ready to go at the beginning of an outbreak. These immunobridging studies are interesting to perform, but in essence, I think we need the efficacy trials.”

Erica Saphire from the La Jolla Institute agreed that “we don’t know a magic number that we need to hit in terms of binding antibody or neutralising antibody to know somebody will or will not be protected [against Sudan]. 

“But we do have the ability to generate useful and informative data on human samples and non-human samples in the meantime so that we have that at the ready for when we do need to deploy a Sudan vaccine during an outbreak,” she added.

Immediate vaccination?

Former FDA official Philip Krause challenged Sullivan and Becker: “If we’re saying the only way to evaluate these vaccines is efficacy trial, that means that a certain number of people are going to receive delayed vaccination versus immediate vaccination. And of course, everybody would rather have immediate vaccination [in an outbreak].”

If it was “reasonably likely” that a vaccine was efficacious, regulators could allow all trialists to get immediate vaccination, he added.

But Sullivan and Becker were convinced that immunobridging could assist to determine efficacy as the different vaccines behave so differently.

Given the lack of clarity and consensus about the way forward, the WHO is conducting further discussions with scientists and collaborators.