By Robert Read, Director of the NIHR Southampton Biomedical Research Centre, and Professor of Infectious Diseases at the University of Southampton

Professor Rob Read

In my work as a physician I spend much of my time trying either to prevent, or treat infectious disease; however my dark secret is that much of my research work paradoxically involves controlled human infection.

This technique that has come a long way since Edward Jenner deliberately infected children with vesicle fluid from pox lesions in the 1700s, and Walter Reed deliberately exposed soldiers to mosquitoes captured in the Yellow Fever tents in the early 1900s.

Southampton is considered one of the world’s leading centres for controlled human infections because of our unique studies with the agent that causes Whooping cough – Bordetella pertussis, and our work on Neisseria lactamica – a commensal bacterium that is closely related to Neisseria meningitidis  – the cause of meningitis.

Controlled human challenge trials have two particular advantages over conventional clinical trials. Firstly, whilst infectious disease events subject to clinical trial  may occur sporadically, episodically and heterogenously, in controlled infection the investigator is able to plan the infection and the intervention a priori.  Secondly, when an investigator needs to demonstrate whether a new vaccine is superior to an established vaccine in the schedule, it may be unethical to withdraw the existing vaccine in the trial to enable the comparison – controlled infection studies are able to circumvent this particularly in studies of booster vaccines. 

Southampton’s expertise

Last week our work was showcased at the International Bordetella Society in Vancouver, Canada.

We began work with Bordetella pertussis in 2016 and the first volunteers who took part agreed to be in-patients in the Clinical Research Facility at University Hospital Southampton, and were infected intra-nasally with live bacteria at very low doses.

The first volunteers did not subsequently become infected, so we increased the dose incrementally until we were able to reliably ‘colonise’ more than 70% of volunteers.

Since then, we have deliberately infected over 80 people with Bordetella pertussis and they carry the organism in their noses without any symptoms for at least two weeks until we give an antibiotic to stop the infection.

Volunteers generate a specific immune response following infection which we are able to interrogate. Currently my colleagues Dr Diane Gbesemete, Dr Alison Hill, Muktar Ibrahim, Jonathan Guy and Lucy Raud are investigating which immune parameters provide relative protection against infection. This is done by measuring immunity before infection and identifying those immune events that are under or over represented in people who do not subsequently become infected.

We can also test new vaccines with this technology. In fact, this September we will start the world’s first vaccine challenge study for Whooping cough in which we will inoculate people an attenuated strain of Bordetella pertussis in a nasal spray. Forty-four people will be immunised in this way and then we will  infect them with the wild type organism three months after vaccination to determine whether it prevents infection.

Fighting meningitis

Neisseria spp. are a lifelong interest of mine. We began infecting people with N.lactamica over 12 years ago and since then, over 500 people have been deliberately infected with this organism.  

Dr Adam Dale used his Wellcome Training Fellowship and subsequently a NIHR clinical lectureship to  determine why commensal organisms can confer immunity to pathogens with a focus on cellular immunity.

Dr Jay Laver has worked on a method to genetically transform Neisseria lactamica so that it expresses surface proteins usually expressed by Neisseria meningitidis. Jay published his work recently in the journal Science Translational Medicine and results of controlled human infection suggest this strategy can generate a cross-protective immune response to N.meningitidis that could be harnessed in future generations of vaccines for meningitis. He is now developing new potential vaccine strains with the help of Dr Muhammad Ahmed.  Dr Anastasia Theodosiou, an MRC research training fellow, is working with Dr Chrissie Jones and inoculating pregnant women with Neisseria lactamica to measure transmission to their babies. This is more reasonable than it sounds because in nature, N.lactamica is more commonly carried in the noses of toddlers than in adults, and seems to confer natural protection against meningitis.

Our volunteers

We admire greatly and thank all those volunteers who take part in our studies. We could not do it without them. The Whooping Cough vaccine study is currently underway and anyone wants to take part, they should visit https://champion1.co.uk. The safety of our volunteers is one of our highest priorities and people are adequately compensated for their time.

Deliberate infection of human volunteers for research

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