Posted on April 10, 2020 at 9:00 AM
by Ariadne A. Nichol, B.A.
Development of experimental vaccines to combat the COVID-19 pandemic has been rapidly progressing. In the United States, several Phase I clinical trial participants already received an injection of mRNA-1273, the experimental vaccine developed by the National Institutes of Health (NIH) and a biotechnology firm called Moderna. The chief medical officer at Moderna, Dr. Tal Zaks, lauded the speed with which his company has provided a potential COVID-19 vaccine: “I think we’ve set a new record here.” However, the usual Food and Drug Administration (FDA) standard for proving safety and efficacy in animal models before moving onto testing in humans, has not been followed. Instead, safety and efficacy studies in animals will run concurrently with the Phase I clinical trial in humans. This article highlights the potential implications of this new manner of testing, while placing it in the context of the current pandemic.
The platform itself is different than the live-attenuated, inactivated, or subunit vaccines normally tested. The proposed vaccine is mRNA based, meaning the injection given is comprised of mRNA that can enter human cells and cause the production of the viral surface antigens; and production of these antigens then leads to the production of antibodies that are potentially protective against SARS-CoV-2. Moderna has been working on this platform to specifically target SARS-CoV-2 since January 2020 when it received major funding from Coalition for Epidemic Preparedness Innovations (CEPI) to manufacture the first clinical batch. Many scientists believe this new kind of vaccine platform holds the potential to “transform areas of medicine, including the prophylaxis of infectious diseases.” However, Moderna has yet to bring any viable mRNA-based vaccines to market. The novel mRNA-based platform and use of concurrent animal modeling leaves many questions unanswered.
For instance, how will preclinical findings be communicated to clinical researchers if testing in animals and humans is simultaneous? This normally occurs via publication when animal modeling and Phase I human safety trials are completed in a sequential manner. Both the Institutional Animal Care and Use Committee (IACUC) and the Data Safety and Monitoring Board (DSMB) have stopping rules to terminate a trial early due to safety concerns. Hypothetically, if the IACUC found mRNA-1273 to be harmful, how would researchers conducting the Phase I clinical trial become aware of these preclinical findings? A new data sharing mechanism and monitoring would be beneficial to make sure dissemination of results is timely.
There is also the question of whether the potential benefit of concurrent preclinical and clinical testing outweighs the risks. Currently, the justification of conducting concurrent animal modeling with the Phase I clinical trial is the need for rapid progress due to the ongoing COVID-19 pandemic. With an emerging infectious disease threat at hand, the potential ramifications of developing vaccines at the usual pace, which takes 10-15 years, are serious. Many would die in the meantime. Moreover, other researchers have previously demonstrated safety and efficacy in animal modes with mRNA vaccine technology for other emerging infectious diseases. Therefore, potential human harm would be predicted to be minimal since one mRNA sequence is simply being swapped for another one.
However, we must also consider the potential risks posed to the research participants when no animal modeling specifically for mRNA-1273 has been done previously to provide an indication of this particular vaccine’s safety profile. Participants enrolled in the Phase I clinical trial for mRNA-1273 signed a lengthy, 45-page long informed consent document. Preclinical safety results are normally required in order to justify the potential risk to human subjects, since risk is only justified by potential benefit. Without proven benefit from preclinical work, it appears questionable to subject human trial participants to risks, even if those risks are minimal.
In addition, the current context of the pandemic, while illuminating a significant need for increased research and development of vaccines, might cloud rational judgment with the seductive promise of hope. Even if all went exactly as planned, the experimental vaccine would still not be available for at least another 12–18 months. Rushing through regulatory approvals with this new manner of concurrent testing of animal modeling and Phase I human safety trials should be carefully scrutinized. Perhaps the risk is in fact justified due to the large amount of potential cases we may still have as the disease continues to hit more and more countries and as the death count continues to rise at an alarming rate. Yet, there has been no proven benefit that mRNA-1273 will be safe and efficacious in people.
A final and important implication of this manner of concurrent testing for an experimental vaccine during a pandemic is setting new precedent for all mRNA-based vaccines. One recommendation is that data sharing mechanisms should be established prior to start of concurrent testing. Another recommendation would be to create a monitoring board to provide oversight of the concurrent processes. Emerging infectious disease pandemics will begin to occur with more frequency, so whatever we do now will have an impact on how we respond in the future. Overall, a cautious approach should be adopted in implementation of concurrent testing of mRNA-based experimental vaccines that are rapidly developed as a response to emerging infectious disease outbreaks.