A controlled human pneumococcal infection model

In most cases infection with Streptococcus pneumoniae (the pneumococcus) occurs
in the absence of clinical symptoms. However, infection can also lead to mild
disease such as otitis media, or to invasive pneumococcal disease such as
pneumonia, bacterial meningitis and sepsis. Invasive pneumococcal disease is a
leading global cause of morbidity and mortality, particularly in children and
the elderly. Although vaccines exist that protect against invasive pneumococcal
disease, these vaccines do not cover all circulating pneumococcal serotypes and
are less effective in preventing infection. New strategies to reduce
pneumococcal infection are therefore urgently needed. An Experimental Human
Pneumococcal Carriage (EHPC) model has previously been developed at the
Liverpool School of Tropical Medicine (LSTM). This model has been used to
assess new strategies to treat or prevent pneumococcal infection and to answer
questions about host-pathogen interaction and immunity. Investigating these
aspects in a different population could provide new insights due to e.g.
differences in circulating pneumococcal strains and infection-induced immunity.
Moreover, this could increase the capacity of vaccine testing. Therefore, we
aim to implement this model at the Radboudumc, combining world leading
expertise regarding controlled human infection studies and pneumococcal
research. This will assure maximum scientific output in a volunteer safe
setting. The current study aims to establish this model in healthy adults
living in the Netherlands using the inoculation dose currently used at LSTM.

Primary objective:
- To establish a controlled human infection model in which healthy Dutch adult
volunteers are inoculated with a wild-type Streptococcus pneumoniae bacterium
with strict safety reviews.

Secondary objectives:
- To assess the frequency and nature of (severe) adverse events of a controlled
human infection model in which healthy Dutch adult volunteers are inoculated
with a wild-type Streptococcus pneumoniae bacterium
- To evaluate the duration and density of S. pneumoniae in volunteers following
inoculation with S. pneumoniae
- To investigate the S. pneumoniae-specific IgM, IgA and IgG antibody responses
in serum and in nasal lining fluid in healthy adult volunteers who have been
inoculated with S. pneumoniae

Intervention study

Participants will be inoculated intranasally with strain BHN418, a penicillin
sensitive serotype 6B strain of S. pneumoniae that was previously isolated from
a healthy carrier and characterized by Birgitta Henriques-Normark and
colleagues. This strain has been used as the challenge agent in >1100
participants at LSTM without safety concerns. Following inoculation,
participants will be closely monitored and blood and nasal samples will be
collected over a period of 28 days. Participants will receive a course of
pheneticillin to eradicate infection on day 28±3, unless no S. pneumoniae is
detected on both day 14 and 28±3 post-inoculation.

Although the vast majority of cases, nasopharyngeal infection with S.
pneumoniae occur in the absence of clinical symptoms, participants remain at
risk of developing pneumococcal disease. However, there have been no reported
cases of severe pneumococcal disease in the more than 1100 volunteers who have
been inoculated with the same challenge strain used in this study at the LSTM.
We therefore expect the risk of developing (invasive) pneumococcal disease in
participants to be minimal. To further minimize risks, a healthy adult study
population is selected and participants will be monitored closely to detect
possible adverse events if they occur. Dosage and strain to be tested in this
study has previously been tested and proven to be safe at the LSTM. In case
participants develop symptoms or disease potentially caused by S. pneumoniae,
this can be treated effectively with antibiotics. Participants may experience
discomfort during the collection of blood and nasal samples. The study involves
7 visits in the hospital in total, including 1 nasal inoculation, 6 blood
drawings, 6 nasal washes, 6 mucosal lining fluid samples and 4 nasal swabs.
Additionally, participants are asked to complete a short questionaire at
several moments during the study and are asked to collect nasal lining fluid 5
times at home. Depending on the infection outcome, a volunteeer may need to
take an antibiotics course to clear infection ±four weeks after inoculation.
Potential benefits for participants such as developing protective antibodies
are uncertain, and as such, it must be assumed that volunteers will not
experience any benefit from their participation in the study.