Successful development of viral infection models

‘We have been working towards this for years, and now our efforts are starting to bear fruit,’ says Dr Ingrid de Visser-Kamerling, Research Director Infectious Diseases. The three studies that were conducted involved controlled human infection models (CHIMs), in which healthy participants are exposed to specific pathogens. After a relatively simple study with attenuated chikungunya virus, an outpatient study was conducted with RS virus and a study with influenza in which the participants were quarantined in special rooms at the CRU. The latter two studies were conducted within European consortia: the RSV study within Inno4Vac and the influenza study within FLUniversal. These were validation studies that examined whether the CHIMs led to demonstrable infection.

Even with the respiratory syncytial virus (RSV), which is harmless to healthy adults, setting up a CHIM requires considerable effort. De Visser: 'It's understandable that there are strict rules for multiplying and administering pathogens, but it surely is quite a challenge to deal with all the regulations. Luckily, we could use the results of a study from Utrecht showing that an RSV study can also be conducted safely on an outpatient basis, provided that the participants are given clear instructions. In their study, the infection was not transmitted to the participants' housemates. The few cases of colds that did occur turned out to be caused by a different virus.' Thanks to this earlier research, the CHDR team was also allowed to conduct their RSV study on an outpatient basis.

De Visser is impressed by the commitment of the study participants, who proved willing to adhere to strict rules once they were carefully instructed. Participants were not allowed to visit children under the age of two or vulnerable elderly people during the study period and had to comply with strict hygiene measures. At the CHDR reception area, face masks and hand hygiene were in place when participants reported for check-ups.

The virus used in the CHIM was isolated from a young patient and was multiplied under GMP conditions. De Visser: ‘The production was more than enough for our initial study and several other studies. So, we now have a freezer full of virus samples ready to be used for CHIM studies.’

In compliance with strict regulatory requirements, the researchers started with a low dose of the virus. Nasal swabs showed that this already resulted in a certain degree of virus shedding. With the next dose, the effects of infection were clearly visible. In three-quarters of the participants, viral shedding in the nose could be demonstrated and more than two-thirds of them also showed symptoms of a respiratory viral infection.

‘We deliberately chose not to determine background immunity in advance,’ says De Visser. ‘With RSV, the correlation between antibody titre and the likelihood of infection is not so straightforward, and we felt confident enough not to exclude anyone on the basis of possible immunity. And that worked out well, with an infection rate of around 75%.’

Setting up a CHIM for influenza was even more complex. Here, the researchers used a reconstructed virus from the National Institutes of Health in the USA. ‘According to European regulations, this is a genetically modified organism, even though it is molecularly identical to an influenza virus isolated from an American patient. That made it quite challenging to obtain permission.’ Environmental rules and ethical requirements proved to be difficult to align. According to the environmental authorities it was prohibited that the virus could be released into the environment, while according to the ethical principle of informed consent, participants are allowed to withdraw their consent at any time.

Ultimately, a solution was found for all these issues and De Visser was granted permission. The study proceeded smoothly. Study participants generally become ill from the virus – in this study, participants were selected on the basis of background immunity, which increased the likelihood of this happening. ‘We had to exclude more than half of potential participants because of their immunity,’ says De Visser. ‘But we knew in advance that the background immunity would be high. Every year we test around 100 subjects to determine their antibody titres against a number of variants of influenza and other viruses.’

With the growing number of working infection models, De Visser expects to be able to conduct various studies in the coming years, in close collaboration with her colleagues from the Immunology and Inflammation Cluster at CHDR. Meanwhile, collaboration has been strengthened within the Dutch Infect-NL consortium and its clinical research company INFECTA. In addition to her work at CHDR, De Visser is Chief Operations Officer at INFECTA: ‘Preparations for the construction of the INFECTA facility with a BSL-3 laboratory and isolation rooms entered a new phase in 2025, and we expect to be operational in 2028. We also concluded a Master Service Agreement between INFECTA and CHDR, so that INFECTA already will be able to conduct clinical studies in the coming years, in CHDR's dedicated infection rooms. In short, we have made enormous progress in many areas this year, thanks to the synergy between our team and many others.’