Experimental Human Rhinovirus Infection, a randomized placebo-controlled pilot study

The importance of the common cold derives primarily from its frequency and from
its enormous socioeconomic impact. Human Rhinoviruses (HRVs) are the major
cause of the common cold, being responsible for 30-50% of all acute respiratory
illnesses with no causal remedies for hand. A model to investigate the
pathophysiology of HRV infection and to test compounds that could treat or
protect one from infection or developing symptoms would therefore be very
valuable. With this HRV model it is also possible to investigate crosstalk
between bacteria and viruses. This is very relevant because, following a viral
infection, bacterial superinfections are common in clinical practice, and
underlying mechanisms and subsequent possible therapies that could prevent this
remain to be discovered.

Our primary objective is to set up the Human Rhinovirus (HRV)-model in our
centre, using HRV serotype 16 (HRV-16).

Secondary objectives:
1. To determine the incubation period of HRV-16 infection.

2. To determine the effects of HRV-16 infection on cold symptoms, temperature,
and spirometry.

3. To determine suitable inflammatory parameters (and their kinetics) that play
a role in the HRV-16-induced local inflammatory response by measuring
leukocyte counts and differentiation as well as cytokine levels in nasal washes.

4. To determine whether HRV-16 infection can induce a systemic immune response
and its kinetics by measuring leukocyte counts and differentiation. and
circulating plasma cytokines.

5. To determine the effect of HRV-16 seropositivity on the clinical and
immunological response to re-infection with HRV-16.

6. To determine if a subject is protected against re-infection with HRV-16
within one week (tolerance formation to HRV), and if so which mechanisms play a
role (local immune response parameters, systemic immune response parameters).

7. To determine whether HRV-16 infection modulates the immune response of
circulating leukocytes by measuring the cytokine response, of leukocytes ex
vivo stimulated with different inflammatory stimuli.

8. To determine the effects of HRV-16 (re-)infection on the nasal, oral and
faecal microbiota

9. To determine the effects of HRV-16 (re)infection on the host transcriptome

10. To determine the effects of HRV-16 (re)infection on the host metabolome

A parallel, randomized placebo-controlled pilot study in healthy male and
female volunteers. The subjects will be randomized to become either inoculated
with HRV-16 (n=20; 10 male + 10 female) or with placebo (NaCl 0.9%, n=20, 10
male + 10 female). After one week a second inoculation with HRV-16 will be
performed in both groups.

Human rhinovirus 16 (HRV-16)

Subjects have to visit the hospital on a total of 13 occasions (about 10
minutes each visit). Upon screening, a medical interview is conducted. Subjects
have to keep a symptoms diary. In total, approximately 500 ml of blood will be
drawn (on 13 occasions via venapuncture). This is not associated with side
effects (500 mL is also drawn at the blood bank without any side effects).
Furthermore, 13 nasal washes will be performed, which can lead to slight
irritation of the nasal mucosa but is not associated with riskss. HRV infection
is associated with short-term symptoms of a cold. Worldwide, thousands of
subjects have been exposed to experimental rhinovirus infection, of which more
than 600 to HRV-16. Serious adverse events related to rhinovirus infection have
never beendocumented. Therefore, this model can be considered a safe and highly
reproducible model. Moreover, 52 volunteers have already been exposed to the
HRV-16 virus from the batch that we want to use in this study.