Issue #58: Confronting the virus: human challenge studies and Phase II trials

Written by Nobel Laureate Professor Peter Doherty

Over (#53 - #57) the past weeks we’ve looked at basic issues, including ethical approvals, that determine the conduct of Observational (#54) and double blind, randomised, Interventional clinical trials (#56, #57). Earlier discussion of Phase I safety trials mentioned the current absence of background SARS-CoV-2 infection in the Australian community, plus advantages conferred by our comprehensive, tax-payer-funded Medicare scheme. A further strength when it comes to Phase I clinical trials is the ethnic diversity of our population. Regulatory authorities in different Nation States are increasingly mandating that clinical trial data must be available for their predominant ethnic and cultural groups, not just for Caucasians, especially Caucasian males.

Once a vaccine has been shown to be safe and to be capable of stimulating immunity in both animals (pre-clinical trial) and humans (Phase 1 trial), the next step is, of course, to see if it will limit (hopefully prevent) infection with the SARS-CoV-2 virus. Apart from animal studies, the ‘gold standard’ antibody assay (#23) for any vaccinologist is the virus neutralisation test where mixing in, say, graded dilutions of the serum fraction of blood taken from someone’s arm will block the virus from infecting susceptible cells, likely Vero cells (‘immortalised’ from the kidney of an African Green Monkey), that are growing on the surface of a plastic tissue culture well. The next step is then to move to a Phase II clinical trial where several hundred, to maybe a 1,000 or more susceptible people who are living in a country where the virus is actively infecting people and causing clinical disease are enrolled to receive either the vaccine or a placebo (typically saline).

Phase II trials are typically ‘underpowered’ (not enough people) when it comes to getting a clear picture of vaccine efficacy so, apart from being a further check on vaccine safety, why do them? The point is that, unlike the situation for a drug, once a vaccine has been given the procedure cannot be reversed (#1). Depending on its half-life, any passively administered drug (or monoclonal antibody) will eventually ‘wash out’ of our body. Vaccines stimulate our own immune response. From the moment the product is injected into someone’s arm, the die is set. Why worry, you might ask, you’ve already checked that it is safe in animals and in people in a Phase I trial? But the information we lack re safety is what happens when vaccine-induced antibodies and T cells (#21, #34) meet the infection in the human body. Might there be some untoward effect like, for instance, the development of ‘enhancing antibodies’ (#57) that could make the disease process more severe? Even for haemorrhagic dengue, where enhancing antibodies are thought to be a major problem (#20), we’ve never succeeded in developing an animal model to test for this!

Apart from waiting for Phase II trial participants to be randomly infected in the community, there is another approach that could potentially be used to check whether the confrontation in us between vaccine-induced immunity and a virus like SARS-CoV-2 is safe.  With influenza at least, human virus challenge studies conducted under rigorously monitored and controlled conditions are now an accepted practice. Australia has infectious disease specialists with expertise in this area and there are facilities available where such work can be done.

Earlier on in the course of the COVID-19 pandemic, there was active discussion of the possibility that young people – who seemed at that time to be relatively spared when it came to severe COVID-19 disease – might be challenged with SARS-CoV-2 then monitored for virus-production and the development of immunity. Many (especially in the UK) were prepared to volunteer. In those dark and desperate early days, that led to an intense discussion in the medical ethics community, with professionals coming out on both sides of the debate. Any perception that this is a justifiable risk may, however, have fallen off with the progressive identification of the chronically debilitating ‘long-COVID’ syndrome that can emerge at any age. Also, by the time the discussion re the novel possibility of human virus challenge studies had been adequately explored, conventional Phase III clinical trials had already shown that the most advanced COVID-19 vaccines were proving to be extraordinarily effective (#49).

One of the reasons the vaccines moved forward so quickly was that, reflecting the urgency of the COVID-19 pandemic situation, regulators were willing to combine some steps in the normal trial progression to speed up the evaluation process. The following Phase I/II design for the AstraZeneca (AZ) vaccine – conducted in southeast England where the virus was actively spreading – illustrates how investigators were continuing through the Phase II stage to probe different parameters as they sought to develop an optimal vaccination regime that would work across all age groups. The trial design for the initial 560 participants included 160 aged 18–55, 160 aged 56–69, and 240 aged 70 or over. Participants were split where they received a high or low dose of the AZ vaccine, or a meningococcal vaccine as a placebo. Some were given a single shot, while others had two doses 28 days apart. No safety flags were raised, and the AZ vaccine progressed rapidly to Phase III studies in the UK, South Africa and Brazil. Next week we’ll focus on vaccine efficacy and Phase III trials.