The WHO Monkeypox Research: What are the knowledge gaps and priority research questions webinar was held on Thursday 2 and Friday 3 June 2022. The WHO Monkeypox research consultation, held over two days, saw professionals working in the fields of medicine, research, pharmaceuticals, and regulation come together to discuss the emergence of Monkeypox outside of traditional endemic locations.
Monkeypox is a rare, albeit endemic viral disease not often detected outside of Africa. Previous infections outside of Africa have been associated with travel to Africa and importation of infected animals. Based on discussions during the WHO consultation, it may be possible that other animals could be ‘reservoir hosts’ for monkeypox. Monkeypox is related to smallpox, and is currently treated with a range of medications, including smallpox treatments.
The two-day consultation discussed a range of topics, including current and emerging drugs for use against monkeypox, research methodologies and research outcome measures. As recently discussed in the media, talks during the consultation also included discussion around the possible renaming of monkeypox to reduce stigmatization of those infected with the virus. Attendees at the consultation explained that “we have learned a lot from covid about names and stigma”. Alongside possible name changes, it appears the attendees also gained other learnings from the covid saga.
Research methodologies were a particular focus of day two, with experts discussing the need for strong research design, data collection and analysis.
Ira Longini from the University of Florida suggested that a randomized control trial and multi-centre placebo trial (that is trials conducted throughout the globe)–‘as has been done during covid’, would be beneficial to better understand the efficacy of vaccines. He further stated that the randomization for populations at risk could assess how transmission occurs. For example, whether monkeypox is transmitted through rings (close contacts), households or sexual contact networks.
A randomized control trial (RCT) is often regarded as the gold standard of research. This is when participants are randomly assigned to receive a treatment, a placebo or no intervention (comparator). This way, researchers can better understand cause and effect. The idea of the RCT is that no one actually knows which participant receives what treatment -thus reducing any bias that might result. When discussing how to treat monkeypox, Ira Longini explained that an RCT would be beneficial, but would also take a long time to accumulate the required data. He went on to say that it would be possible to conduct a randomized trial in the middle of this (monkeypox outbreak). This could be done by providing vaccines or a comparator to individuals in high-risk areas–such as health care workers or randomized to clusters of individuals, such as households.
Ira Longini noted that vaccines deemed to be less than 30% effective would be removed from the trial. One attendee asked why vaccine efficacy was so low when compared to other cases. This is a great question. In non-medical studies, anything equal to 50% is no better than chance and would be discounted. It would be interesting to understand why the threshold for this monkeypox study would be so much lower. The presentation also discussed the expected study duration required to accumulate data and the number of participants required.
Other presenters examined the effectiveness of current drugs approved by the FDA and other authorities. Dr. Marco Calaveri discussed various vaccines, including Brincidofovir. This drug has been approved for use in the USA under the FDA’s Animal Rule treatment of human smallpox disease caused by variola virus in humans. It has also been approved for use in Canada. Although approved by the FDA, this drug is not approved for use in the European Union.
When explaining Brincidofovir further, Dr. Calaveri explained that the drug had been approved for children from 13kg and upwards. He also noted that efficacy data was from animal model studies using rabbits and mice. Dr. Calaveri noted that this drug could not be used in monkeys because of metabolism issues and clear side effects. This drug was not able to be used in pregnancy.
Another drug, Tecovirimat was authorised for use in the EU in January 2022 for the treatment of various infections such as monkeypox, smallpox, cowpox and vaccinia virus. Approval was only granted for use under ‘exceptional circumstances.’ Tecovirimat has been authorised for use in the US since July 2018 for the treatment of smallpox disease under the FDA’s Animal Rule. This drug is also approved for use in Canada. To date, evidence for the effect to humans comes from nonclinical studies, with no data available on the efficacy of the vaccine for pregnant women.
Dr. Calaveri explained that since no clinical efficacy data was part of the approval process for regulatory approval, it was important that further clinical efficacy and safety data be collected. He suggested that ‘this outbreak represent[s] a case for which further clinical evidence should be collected’. As with Ira Longini, Dr. Calaveri saw the newest ‘disease outbreak’ as an opportunity to conduct randomised controlled studies – especially in low-risk individuals with mild-moderate disease. He also noted that pregnant women and young people should be included in clinical trials.
Clinician’s attending the consultation called for greater consideration of patients when conducting trials. As mentioned by Dr. Lindsey Baden, when effective therapies are lacking, clinical care and research are both important. This includes the importance of observational data to compliment any data obtained through an RCT. Dr. Baden also noted the lack of correlational efficacy data that is critical for helping patients.
It was refreshing to hear caution from Dr. Baden, something that was lacking during covid. Dr. Baden acknowledged that controlled studies were required to properly understand what is being treated, what is being prevented and how treatments affect different populations.