It is estimated that more than 115 million animals are used for research purposes worldwide every year. Animal disease models have historically played a critical role in drug development, clinical trials, pathophysiology and many other disciplines of biology and medicine.

Animal models aim to resemble human conditions in terms of individual characteristics or response to treatment, and can exist naturally or be induced artificially. Out of 106 Nobel Prizes in Physiology or Medicine, 94 were awarded for research on animal models. While animals have played their role in making the world a better place, the current pace of scientific progress means there is an increasing urge to make things more precise, accurate and translatable.

Increasingly, however, animal studies across medical fields fail to replicate the conditions of the human body with necessary complexity. Despite large investments in drug development reaching into the billions, only very few drugs make it out of the clinical trials. One prominent explanation is that animal models are simply imprecise in studying human disease.

mice obesity human challenge models

Mice are often animal models in the study of obesity – Mouse on the right is bearing a homozygous mutation of the Lep gene, and its normal sibling (left).

On the way to a solution

In 1948, the UK Medical Research Council (MRC) founded a research facility at Porton Down to test the new treatments for the “common cold”. At the unit, brave volunteers became human subjects – they were “challenged” with rhinoviruses, the chief agents responsible for colds. This research led to the discovery of over 100 new rhinoviruses.

However unethical the study may seem today, it inspired a whole cohort of scientists to emulate Human Challenge Modules (HCM) in researching a wide spectrum of diseases. This practice has a long and checkered past, but Human Challenge Models have only received the appreciation they deserve in the last decade. Nowadays, stricter ethical and safety procedures are in place, and new technology is capable of weakening pathogens. This has all led to increased research implementing HCM.

David Tyrrell, a clinical virologist and a Head of the Common Cold Unit at Salisbury. He contributed to the discovery of over 100 rhinoviruses and coronaviruses causing common cold. He also proved that a search for a single, effective anti-viral treatment for the common cold is futile.

 

Human Challenge Model (HCM): is it safe?

HCMs are usually clinical trials in which participants are intentionally “challenged” with an infectious disease such as malaria, influenza, dengue,  or norovirus. Participants may or may not be vaccinated against the infectious agent, which may be pathogenic, adapted or attenuated to pose less or no pathogenicity, or be genetically modified in some way. Sound scary?

In reality, any research using HCM must go thorough very extensive ethical and regulatory reviews. As a result, the risk of being getting sick is extremely low. The benefits from such studies reach beyond any studies conducted on animals and speed up the development of new, safer drugs and more effective vaccines.

However, HCM also has its own limitations. In many cases even with an attenuated pathogen, studies on humans would not be safe, and therefore rendered unethical. This would include pathogens with high case fatality rate and in a case where no known treatments exist.

Human Challenge models are proven to be successful in a number of applications and have shown their scientific utility, for instance, The Experimental Human Pneumococcal Carriage (EHPC) at the Liverpool School of Tropical Medicine. In a world first, the research team has developed a method for inoculating humans safely with live Streptococcus Pneumoniae in order to establish carriage. They have now tested over 500 volunteers without any adverse effects. This programme can test new vaccines more quickly and cheaper than clinical studies and furthermore, several vaccines can be tested at the same time. This all raises exciting questions about the future of medical research.