Even if everything goes to plan, it will take at least 12-18 months for a novel coronavirus (SARS-CoV-2) vaccine to be tested if conventional clinical trial procedures are adopted. Meanwhile, thousands are getting infected and hundreds are dying every few days. As a result, the healthcare system is getting stretched and strained, and doctors are forced to remove ventilators from older or sicker patients to make them available for younger people who have better chances of survival, as seen in Italy.
A preprint, which has not been peer-reviewed and published in a journal, posted in the Harvard University repository, has proposed an alternative approach to test the candidate vaccine and make it available earlier.
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Is there a way to hasten the vaccine development process so that a vaccine becomes available earlier?
Yes, there is an option to accelerate the process and possibly make the vaccine rollout possible several months earlier. The process is called the “Controlled human infection model (CHIM) or simply human challenge studies. The human challenge study does not involve the conventional Phase-3 trial where thousands of healthy volunteers receive either a vaccine or a placebo and followed up for a long time to assess the safety and efficacy of the vaccine. Instead, about a hundred healthy volunteers are first vaccinated and then intentionally exposed to the novel coronavirus to test the ability of the vaccine to protect the individuals from getting infected. This will sharply cut the time taken to complete the trial.
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In the case of the conventional Phase-3 trial, vaccine safety and efficacy are tested on high-risk volunteers who would get naturally infected. In this, all volunteers are mandatorily advised to reduce the risk of getting infected by following risk-reduction measures such as hand hygiene. Recruiting thousands of volunteers and waiting for a sizeable number of them to get infected to study the efficacy of the vaccine is what takes a long time.
But in the case of the human challenge study, previously uninfected volunteers will be first vaccinated and then deliberately exposed to the virus in a controlled environment and monitored on a regular basis. This drastically cuts down the time to study the safety and efficacy of the vaccine.
Has the CHIM model been used earlier in vaccine trials?
According to 2016 World Health Organization regulatory guidelines, human challenge studies have been conducted over hundreds of years. The yellow fever experiments conducted in the early 1900s helped prove that mosquitoes transmit the virus causing yellow fever. The human challenge studies have generally been used for testing “less deadly diseases” such as influenza, dengue, typhoid, cholera and malaria.
At what stage will the human challenge study be undertaken?
According to the corresponding author Prof. Nir Eyal from the Center for Population-Level Bioethics and Department of Philosophy, Rutgers University, New Jersey, human challenge study will come into the picture only after initial safety, vaccine dosage, number of doses required and immune responses have been verified through conventional Phase-1 and Phase-2 human clinical trials.
Who will be the ideal individuals recruited for the CHIM study?
While the coronavirus has been found to infect all age groups — children to older people — young adults in the age group 20-45 generally do not exhibit severe symptoms requiring hospitalisation and ventilator support. According to the authors, young adults who do not have any chronic conditions and who have not been already infected with the novel coronavirus will be the ideal candidates. These people should be residing in areas with high transmission rate and hence are at substantial risk of getting naturally infected with the coronavirus.
How will the vaccine be tested on the volunteers?
The safety and immune responses are tested through the conventional Phase-1 and Phase-2 trials. As part of the human challenge trial, the volunteers would be first exposed to the virus to cause an infection. “This is done to know the dosage required to produce an infection in about two-thirds of the participants,” explains Prof. Gagandeep Kang, executive director of the Translational Health Science and Technology Institute (THSTI), Faridabad. She is not an author of the preprint.
“The symptoms caused by the infection will be milder than what people would get if naturally infected. To ensure that the virus causes only mild symptoms, a particular strain has to be selected or the virus should be weakened,” Prof. Kang explains. In the case of dengue, the symptom caused is just a rash and viraemia (presence of virus in the blood) and no fever, she says.
According to her, unlike in the case of Zika, the novel coronavirus does not seem to persist for a long time, thus making it ethically easier to undertake a human challenge route to test a vaccine.
The final step will involve volunteers randomly chosen to receive either the vaccine or a placebo. After a predetermined time, during which the body develops immune response to the vaccine, the volunteers will challenged with the virus. According to the authors, the participants will be carefully followed to monitor how they respond to the viral challenge. The participants will remain isolated during the course of the study.
What will be the outcomes that will be monitored?
The authors say the primary endpoint of the trial will include measures of viral load, time taken for first symptoms to show up, and proportion of people who get infected despite being vaccinated. The immune responses in the vaccinated participants will be studied post viral challenge.
How soon will a vaccine be ready if human challenge model is adopted?
“We should have the vaccine by the end of the year if the human challenge model is adopted,” says Prof. Kang. “But licensing agencies will ask for efficacy studies to be carried out in large numbers of people post-licensing.”
However, the authors say they would conduct an expanded placebo-control study in the field on at least 3,000 people for evidence on immune responses and short-term adverse effects prior to applying for a licence.
Is carrying out a human challenge trial ethical?
“We let people, for example, volunteer to be emergency medical services during this period. That significantly elevates their risk of getting infected. But it’s also very important. In clinical trials in general, we don’t focus only on reducing risks to participants; we focus on achieving a reasonable balance between the added risks that they take and the importance for the community,” Prof. Eyal tells Nature .