Experimental Human Rhinovirus Infection
Condition: Common Cold
MeSH terms: Common Cold
Study type: Interventional
Phase: Phase 1

Summary: 
      Our primary objective is to set up the Human Rhinovirus (HRV)-model in our centre. In
      addition, to facilitate future clinical trials, we want to determine optimal read-out
      parameters and read-out time points for experimental HRV infection in healthy volunteers.
      Furthermore, we want to analyze to what extent HRV can cause systemic immune effects, and we
      want to test if subjects with antibodies against HRV can be re-infected with the same virus,
      and if the presence of HRV antibodies influences the local clinical and immunological
      response upon infection. Additionally, to gain insight in the immune modulating properties of
      HRV, we want to investigate the immunological response to a HRV re-infection within one week
      to determine if there are mechanisms that provide immediate protection against re-infection.
      This facilitates a cross-over design of future pharmacological intervention-trials.
      Furthermore, we want to investigate the capacity of HRV infection to modulate the systemic
      immune response by analyzing the response of leukocytes ex vivo stimulated with different
      stimuli. Moreover, we want to evaluate the effects of HRV-16 infection on the host
      transcriptome and metabolome. Finally, The influence of HRV-16 infection on nasal and gut
      microbiota will be assessed.
    

Detailed description: 
      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 at 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. 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 been documented.
      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.

      Healthy volunteers who meet all inclusion criteria and none of the exclusion criteria that
      have given informed consent to participate in the study will be randomized to become either
      inoculated with HRV-16 (n=20; 10 male+10 female) or with placebo (saline 0.9%, n=20, 10 male+
      10 female). After one week a second inoculation with HRV-16 will be performed in both groups.
      In both groups, 50% of the subjects will be sero-negative and 50% sero-positive to HRV-16.
      One hundred TCID50 units of HRV-16 (by spraying 0.5 mL into each nostril in supine position
      in a randomized manner) will be administered.

      The main study parameter is the rate of infection (defined by a positive viral culture, qPCR
      and/or a four-fold rise in antibody titre) caused by HRV-16 inoculation. Secondary endpoints
      include the duration of the incubation period, the effects of HRV-16 (re-)infection on cold
      symptoms and spirometry, kinetics of HRV-16-induced local inflammation parameters in nasal
      washes (including immune cells and cytokine production), kinetics of the HRV-16-induced
      systemic immune response (including circulating cytokines), the ability of HRV to modulate
      the systemic immune response (as reflected by the ex vivo production of inflammatory
      mediators by stimulated leukocytes), the effects of seropositivity on clinical and
      immunological responses, and the effects of HRV-16 infection on faecal and nasal-pharyngeal
      microbiota and host transcriptome and metabolome.
    

Intervention name(s): placebo; Human Rhinovirus strain 16 (HRV-16)
Intervention type(s): Other; Other
Intervention description(s): 100 TCID50 dosis of HRV-16 will be inoculated on day 7 and / or day 0
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Basic Science
Keywords: HRV; Pharmacodynamics / kinetics; Resistance