When it comes to clinical trials of a norovirus vaccine – something that has been ongoing since the 1970s, it's the Wild West. The early vaccines were crude and the outcomes has been universally dismal. This could change if Moderna hits the mark with mRNA-1403, its experimental mRNA-based norovirus vaccine. More on this later.
Two types of trials
There are two very different types of trials that are used to determine whether such a vaccine might be efficacious. One isn't too bad and the other is seriously bad. Both involve treated and placebo groups, but the similarity ends there.
In challenge trials, participants are deliberately infected with the virus with one group getting a placebo and the other vaccine. This provides a fast, accurate indication of whether the vaccine works and requires relatively few people. The problem is that the participants are being exposed to a nasty pathogen, something that brings up (pun) some ethical issues. All participants are likely to get sick. (How are they exposed? Let your imagination run wild and see if you can figure out how that is done. It's disgusting.)
In population-based trials, a large number of people are followed over time to see if there is a difference between the vaccination and placebo groups. If they catch the bug they will do so naturally. The numbers will tell the story. This is the protocol that Moderna is employing.
What's going to happen to the participants in a challenge trial?
Let's examine the three possible outcomes:
#1 Placebo group: It's only a matter of how much comes out of a given orifice, when, and for how long. You're doomed.
#2 Vaccine-treated group: Assume that the vaccine will be ineffective. See #1.
#3 Challenge trial treated group with an effective vaccine. There aren't any effective vaccines. See #1.
So, unless your bathroom needs a quick makeover the challenge trial should be avoided.
What is Moderna doing?
A press release from the University of Aberdeen (Britain) asks for help in an innocent enough way :
Join the effort to fight the 'winter vomiting bug'
This may sound pretty bad, but it's not.
The university is participating in one of the worldwide clinical trials of Moderna's mRNA-1403, the only messenger RNA-based vaccine currently in clinical trials. The Nova 301 trial is designed to evaluate the vaccine's efficacy in preventing or minimalizing the effects of norovirus (NoV), the so-called "Stomach Flu (1). Moderna is looking to recruit approximately 25,000 people globally to test the vaccine in Phase 3 clinical trials trial, the final phase before approval (or rejection). This will make or break the vaccine. My prediction? I haven't the slightest idea.
Requirements to be in the Moderna trials
Participants need to be 18 or older, in good health, and not have any of a variety of chronic gastrointestinal diseases. There is compensation for participants but Moderna won't reveal how much, saying only "participants are typically reimbursed for their time and any expenses incurred during the study." That doesn't sound so hot. Neither does this: "The Nova 301 Trial team will be available to support everyone who takes part in the trial." Does this include a mop?
HilleVax goes down in flames
There is ample cause for pessimism. Developing a norovirus vaccine is very far from easy. Norovirus has been a target of vaccine research for a long time and there is little to show. Takeda's TAK-214 (a different name for HilleVax's HIL-214, the same vaccine) (2) shows what happens when it fails.
HilleVax's stock price during the past year. You don't need to be Warren Buffet to figure out what happened on July 8th.
Past "achievements," such as they are
HilleVax's HIL-214 was ineffective by any measure. In its NEST-IN1 trial, a randomized, double-blind, placebo-controlled study a vaccine efficacy of 5% was observed. Nor did 214 show any efficacy in any of the secondary outcomes, hence the stock plunge.
Vaxxart has been developing oral vaccines to protect against the two most common NoV genotypes. It has not gone well so far:
- 29% reduction in infection rates compared to placebo
- 21% reduction in norovirus-associated acute gastroenteritis
- 85% reduction in viral shedding, suggesting the potential to reduce transmission
While the 85% in viral shedding may look interesting I'm not so sure it's meaningful. NoV is one of the most contagious viruses around; it takes only 10-100 viral particles to cause infection. That ain't much, so it's hard to see how suppressing even 85% of viral shedding of any active infection will make a significant difference in transmission.
Bottom line
mRNA technology was spectacularly successful in helping control COVID. Will it repeat this success here? Unfortunately, we won't know the answer for about two years. Nonetheless, I wish them well.
And the rest of you too. The norovirus season is just getting started.
NOTES:
(1) "Stomach flu" is an inaccurate term. Norovirus and influenza are unrelated.
(2) HilleVax did not use live virus in its trials. Instead, virus-like particles, which cannot cause infection were used.
Josh Bloom
Director of Chemical and Pharmaceutical Science
Dr. Josh Bloom, the Director of Chemical and Pharmaceutical Science, comes from the world of drug discovery, where he did research for more than 20 years. He holds a Ph.D. in chemistry.
