Saturday 25^th April 2026 was World Malaria Day, and each year it falls with World Immunisation Week. This is particularly fitting since vaccines are at the very forefront of the fight against malaria, which continues to cause more than 600,000 childhood deaths every year. It gives us a chance to highlight a particular method of infection research that has a long history and yet continues to play an important role in the development of the latest malaria vaccines. We are talking about human challenge studies.

The deliberate infection of humans by exposure to infectious agents has been performed for over 300 years. Perhaps the most famous early example is that of Edward Jenner who used the infectious material of cowpox lesions to protect against the more lethal disease smallpox, essentially forming the basis of vaccination.¹ Early examples of human challenge studies confirmed much of the emerging infection theory, but were often conducted without proper ethical consideration and at the exploitation of vulnerable groups.² However, over the course of the 20^th Century, the utility of human challenge studies as a valid research tool started to be increasingly recognised, and, crucially, it was demonstrated that these studies could be conducted within the remit of ethical principles and regulations.

Malaria has its own fascinating history with regards to human challenge. In the late 1890s - early 1900s, experiments involving the deliberate malaria infection of humans (often self-infection of the experimentalists themselves) provided insights into this complex pathogen in its formative years of discovery. The transmission of malaria from mosquitoes to a human volunteer was first demonstrated by Grassi and Bignami in 1898 in Italy.^3-5 In 1900, Sir Patrick Manson felt compelled to repeat this experiment in a non-endemic setting to address the “endless objections” raised by “the amateur biologist and sanitarian” concerning the mosquito-malaria theory.⁶ Infected mosquitoes provided by Bignami and Bastianelli were shipped from Italy to London, arriving within 48 hours, and fed on two healthy volunteers, namely his 23 year old son Dr Patrick Thurburn Manson and Mr George Warren. Both developed malaria symptoms and evidence of peripheral parasitaemia within few days.

Another remarkable period of medical history subsequently followed in the form of malariotherapy for the treatment of neurosyphilis, or, as it was called at the time, general paralysis of the insane.⁷ Driven by the observation that “not rarely psychoses were healed through intercurrent infectious diseases”, the Austrian physician Julius Wagner-Jauregg explored induced fever as a treatment for general paralysis of the insane.⁸ Encouraged by initial attempts with tuberculin, he pursued more effective methods of inducing fever and ultimately settled on using malaria as the treatment of choice. In 1917, he inoculated (subcutaneously) a selection of neurosyphilis patients with blood from a soldier with benign tertiary malaria. Of the 200 patients initially treated by Wagner-Jauregg, 50 patients demonstrated complete remission and returned to work, most at the occupation of their “former calling”.⁸ The practice of malariotherapy for the treatment of neurosyphilis quickly became widespread with many tens of thousands of patients treated across the world. At the time, malariotherapy offered the “best, perhaps the only, chance of recovery” for patients with neurosyphillis.⁹ An estimated 17,000 patients underwent malariotherapy treatment at Horton hospital in Sussex alone over a 40 year period before the practice was ultimately discontinued with the advent of antibiotics.⁷ Wagner-Jauregg was awarded the Nobel Prize for medicine or physiology in 1927.

Human challenge studies provide an opportunity to study host-pathogen interaction in exquisite detail, with sampling able to be performed before, during and after infection, at a level of control unachievable in a natural infection.^2,10  They have come to occupy a niche in the vaccine development pipeline, aiding with the rapid down selection of vaccine candidates.¹¹ However, the design of human challenge studies requires considerable thought.¹⁰ Participants require careful selection and rigorous screening. The method of administration and follow-up procedures need to prioritise safety and consider the natural route and incubation period of the specific infection. The endpoints, whether clinical features (such as fever or diarrhoea) or microbiological criteria, need to well-defined, safe and comparable. There needs to be careful consideration of the ethics underpinning the basis for and conduct of the study.^2,10 This includes a careful assessment of risk of harm, the risk of discomfort, consideration of alternative methods and appropriate consent.^12-14 In addition, it is also vital that members of the public are protected from the risk of onward transmission of infection. Inpatient quarantine or home isolation of participants may be required, particularly for gastrointestinal and respiratory infections.^2,10

Malaria infection can be administered by mosquito-bite, direct inoculation of cryopreserved sporozoites, or intravenous administration of infected red blood cells. In a controlled research setting, malaria can be diagnosed early (often prior to symptoms) and treated with effective oral medication. Malaria challenge studies, or Controlled Human Malaria Infection (CHMI) studies, have become a well-established research practice. The currently licensed malaria vaccines RTS,S/AS01 and R21/Matrix-M were both assessed by malaria challenge.^15,16 These demonstrated protective efficacy against malaria infection administered to healthy volunteers by mosquito bite. By doing so, in a small number of participants in a short amount of time, these studies helped generate confidence before scaling up vaccine development to larger phase 2/3 studies that rely on natural infections to occur to demonstrate protective efficacy.

Human challenge studies continue to play an important role malaria research and the search for more effective and durable vaccines. Blood-stage malaria vaccine candidates (such as RH5.1 and R78C in Matrix-M) and transmission-blocking interventions continue to be assessed by human challenge.¹⁷ We are also using malaria challenge studies to improve our understanding of naturally acquired immunity to repeated malaria infections and develop new research tools and vaccines for Plasmodium vivax, the second most common cause of malaria after Plasmodium falciparum.

So there you have it – human challenge studies, in some ways a historic method of experimentation, continue to play an important role in malaria infection research.

Andrew Duncan
BIA ECRC Secretary
Clinical Research Fellow, Controlled Human Malaria Infection studies, University of Oxford

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