Sep 24, 2022Liked by Saloni Dattani

The FDA wouldn't approve covid challenge trials a couple years ago. Healthy young people were eager to volunteer, and the need was dire. The case fatality rate was still high, and at that point we weren't expecting a vaccine for another couple years.

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Yeah, in this case it'll be quite different. The WHO has guidelines to approve challenge trials, and I cite their expert discussion where they agree that challenge trials will be needed for Zika virus.

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Oct 1, 2022Liked by Saloni Dattani

Lots of subtle tricksy things come up with challenge trials that make the regulators wary.

One example: Johns Hopkins and U. of Maryland (and others) have been doing challenge trials for enteric diarrheal diseases for decades. In order to get the "attack rate" high enough for it to be affordable, though, they must use an inoculum dose several logs larger than what is seen in the field. This creates challenges for interpretation, obviously: the model is, in a sense, "biased" against field efficacy because inoculum dose size is (in most diseases) a pretty strong predictor of disease severity.

Another tricksy thing: route of challenge inoculum administration. It is said that zenamavir (a small-molecule antiviral) worked quite well in influenza challenge studies but failed in field trials. It’s thought that this is an experimental artifact: challenge trials administer the challenge inoculum dose with intranasal drops, but in the field it’s thought most infections occur from pulmonary aerosol delivery. (They stopped doing aerosol challenge in the 1970s, I’m told, for ethical reasons: made the study volunteers too sick, apparently.) I believe the better malaria challenge studies today administer the challenge inoculum by having the subject stick their arm into a plexiglass box full of infective mosquitos, perhaps for this reason.

A third consideration: it is very troublesome and expensive to set up a challenge model so they do not match the diversity of strains in the field. The challenge inoculum has to be manufactured/prepared like a drug, with GMP-like controls (so it’s reliable), and requires its own IND application with the FDA (or other regulator) for this reason. This is expensive. Also, both the choice of strain and the inoculum dose (and administration method) must be be characterized with their own clinical trials. So they’re pretty expensive to set up, and for this reason few are set up. This means that they will never match the etiological diversity of the field (or keep up with changing variants). Naturally this introduces questions of external validity since pathogenicity can vary quite a bit from strain to strains, particularly with RNA viruses since they mutate so rapidly. This is compounded by the ethical constraints that in some cases mean that you cannot use the most pathogenic variants—for example the switch in campylobacter studies from 41-176 to CG8421 in recent years, mainly to reduce the risk of Guillain-Barré syndrome. I think this animates a lot of the FDA’s perceived bias against basing approvals on challenge-model data alone.

So lots of traps for the unwary.

But all that aside, there’s progress! hVIVO in London is now offering Covid challenge studies on its website.

And a few years ago the FDA did actually grant approval to Vaxchora’s cholera vaccine on the basis of a three-site challenge study so all these issues can for sure be overcome, which is good news for people living in areas at risk for Zika.

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Oct 1, 2022·edited Oct 1, 2022Author

All great points!

The parts about influenza and campylobacter challenge trials are new to me but that makes sense.

I was reading some of the literature on malaria challenge trials and that confirmed what you mentioned about the mosquito bite model, rather than using the sporozoites directly.

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Oct 2, 2022Liked by Saloni Dattani

This is super informative; thank you!

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