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Manufacture Clinical Trials, Vaccines

The Human Challenge

Vaccines have played a huge role in improving human health, but there is still a great need for new and improved vaccines. Despite decades of innovation, vaccine development remains challenging. Immunological responses are frequently difficult to measure and the mechanisms underlying how an immunological response confers protection remain poorly understood.

Traditionally, vaccines are tested in late-stage trials against naturally circulating viruses in the community. Many thousands of people are inoculated with the developmental vaccine in the hope that a sufficient number will encounter the virus for its protective index to be calculated. This approach can be hit and miss. For example, if the incidence of infection at the time is low, there may be insufficient responses to provide statistically significant results. Other circulating viruses can also interfere with the observation of symptoms, making for “noisy” data. In addition, trials of this type are expensive – and often fail when early evaluations of efficacy or safety in small numbers of healthy volunteers don’t translate into larger, more heterogeneous populations. Indeed, a key question for vaccine development is, how can predictions of a vaccine’s real-world effectiveness be improved?

In my view, it’s time for more developers to consider the human challenge model. Human challenge trials involve deliberately infecting healthy volunteers with a target organism, such as influenza, in order to test the effectiveness of a vaccine at preventing illness. By challenging people with a live, disease-causing pathogen post-vaccination, it is possible to assess responses in vivo, and to compare the course of disease to that in unvaccinated subjects. Does it give a muted infection, or completely block the entry of the pathogen? Does it reduce the symptoms, or shorten the duration of the illness?

Regulatory authorities have (understandably) been wary of embracing the concept of a human challenge trial – after all, it uses live infectious agents and makes people ill. There are, of course, a number of considerations, including ethics, but more human challenge trials are gaining approval – and both the EMA and FDA say they are open to discussions with companies wishing to conduct such trials. Important prerequisites for approval are units with effective containment and a challenge agent that is an effective surrogate for the wild type infection – but usually with a milder pathogenicity.

The study is performed in small groups of healthy volunteers. Firstly, the subjects are tested to ensure they are not suffering from any other infection and to check their immunity status regarding the challenge agent (they must be susceptible to infection). If the study is for a vaccine, vaccinations will be administered three or four weeks ahead of the trial. The challenge virus is usually administered via an intranasal spray. With an influenza infection, the virus will start replicating rapidly after 12 hours. Symptoms tend to lag behind viral load and are usually reached in 72 hours. During the period of infection, many signs and symptoms will be monitored, such as body temperature, pulse rate, lung function and the amount of mucus produced, as well as viral shedding and antibody levels. Subjects also fill out a symptom scorecard. All of this serves to give a good indication of how effective the vaccine was at preventing disease – and the early efficacy and safety data is immensely valuable to vaccine developers.

There are, of course, still challenges associated with human challenge trials. The biggest is finding the right volunteers. Any center equipped to run a human challenge study will have a database of potential volunteers, but the size of the volunteer pool will depend on the infection rate in the population. For example, about 95 percent of potential volunteers have already developed immunity to the 2009 pandemic H1N1 strain, so cannot be included in trials using H1N1 as a challenge agent. In contrast, a much smaller percentage of the population (usually around 25-50 percent) will have immunity to a recently developed challenge virus that has not circulated for long in the general population.

It should be noted, of course, that not all diseases are suitable for human challenge studies. At this moment, challenge trials are largely limited to upper respiratory tract infections – notably RSV, influenza and the common cold. We desperately need new innovations in vaccines and human challenge trials offer many benefits in terms of delivering efficacy and safety data. They also tend to be faster and cheaper than community-run trials, which may require hundreds or even thousands of subjects, recruited across several flu seasons, and in both northern and southern hemispheres. A challenge trial can be completed in around three months.

In my view, challenge trials will become more commonplace and rolled out in other disease areas. We are already seeing human challenge trials being used for other attenuated organisms, such as dengue and malaria, and discussions are taking place about human challenge trials for Zika. In the future, we may even envisage the use of replicatory deficient agents being used to model chronic infections, such as HIV or hepatitis.

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About the Author
Adrian Wildfire

Adrian Wildfire is Project Director of the SGS Clinical Research Human Challenge Unit.

Adrian Wildfire has worked as an infectious disease specialist for over 30 years, having trained and worked within the fields of bacteriology, virology, parasitology and mycology after obtaining his Fellowship in Medical Microbiology in 1990, and a Masters in Parasitology in 1998. He has specialised in Human Challenge Models for nearly 10 years and is currently leading a multidisciplinary team manufacturing challenge agents for use in clinical trials. He is the author of numerous published papers and articles relating to HIV, ethics and viral challenge amongst others.

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