COVID-19 Interest Group

November 23, 2020

CIG Bulletin #21

Vaccine Challenge Trials

by Tina Etcheverry - Berkeley Rotary

Vaccines Update - Paused or Halted Trials
Halting clinical trials is not unusual. There can be minor reasons as well as major reasons to halt the enrollment in a trial. These usually result in a pause while the Drug Safety Monitoring Board (an independent set of medical and clinical reviewers) looks at the data in a highly confidential setting. We will hear about their review and conclusions after they write-up a public report. It is reassuring that we are seeing halts in vaccine trials because that means the system is working like it should.

Pfizer–BioNTech paused their vaccine trial to expand enrollment from 30,000 participants to 44,000. This allowed for a broader population of patients (youth under 16 and people with underlying chronic conditions like HIV and Hepatitis). The good news is that this trial amendment provides a better understanding of safety across a broad spectrum of participants.

AstraZeneca/Oxford halted their trials to examine an adverse event. The woman developed symptoms consistent with transverse myelitis, an inflammatory condition of the spinal cord. This could be unrelated to the vaccine, but it is consistent with viruses or a person’s immune response to viral infection. An independent safety panel (Data Safety and Monitoring Board) evaluated the incident. The trail resumed in Europe on September 12thafter they completed the safety review, and will be reopening again soon in the U.S.

More recently, the vaccine trial was halted again when a participant died after contacting COVID-19. The person was on the placebo arm of the trial, and not active vaccine. The question is not one of safety but of bioethics. Did the participant assume they were protected and acted with unsafe behavior? The instructions to participants may require a warning (if not already provided). Or will it be decided that is it unethical to have a placebo arm, and the trial design will be changed to only measure safety and not the gold-standard efficacy of a placebo-controlled study. This could happen if the trial has enrolled sufficient subjects and already reached their primary endpoint of 50% reduction in coronavirus cases. I’m sure we will hear soon about this.

The Challenges of a Vaccine Challenge Study
The following information came from a webinar by the group 1DaySooner.org.
I refer you to that website for more details.

The argument for performing viral challenge studies is that you can save lives today by accelerating clinical trials, especially if a challenge design can be devised ethically and minimize the risk to participants.

A challenge study involves deliberately infecting a volunteer with SARS-CoV-2 virus following the standard protocol that is being used in the vaccine trials. It would be an “add-on arm” to an existing trial. In this study, the participant would be exposed to a measured dose of coronavirus approximately 3 weeks following the vaccine booster step. The ultimate goal is to accelerate our knowledge about the efficacy of vaccines.

Who would volunteer to be deliberately infected with COVID-19? Already 2,300 people in multiple countries have offered to participate. In general, they are in the age group of 22-40 years old with no underlying health conditions. This age group has shown a lower rate of serious complications or hospitalizations from coronavirus infections. They often have jobs where they are more likely to become infected (e.g. caring for COVID-19 patients) and want to support the acceleration of vaccine development. They would be well-informed on the risks. After receiving vaccination, they would be isolated into a controlled environment and virus drops would be placed in their nose. They would stay under quarantine should they become infectious or shed viral particles. Rescue medicines such as monoclonal antibodies or Remdesivir would be made available, should they become sick.

From a scientific perspective, this makes sense. Not only will it prove quickly if a vaccine is working, but it can be used to evaluate which vaccines (of the 175 in development) are most effective. The viral challenge could be done in a dose response manner. What level of virus dose (MOI – measure of infectivity) or number of infectious particles is required to get a response? Maybe a vaccinated participant is protected from all viral levels to be tested. The most elegant study would require a placebo control, but who would volunteer for that?

From a human perspective, I would recommend that these studies be performed in a primate surrogate such as Rhesus monkeys. I am not sure we fully understand the medical complications of COVID-19 infections and the potential of longer term, lingering disease. A participant may have disease complications for years to come. This is the real challenge of performing challenge studies. We just don’t know what we don’t know about this virus.