Safety, Diagnostics, and Serotype Expansion in a Human Pneumococcal Challenge Model Involving Healthy Participants

Robinson, Ryan (2024) Safety, Diagnostics, and Serotype Expansion in a Human Pneumococcal Challenge Model Involving Healthy Participants, Thesis (Doctoral), Liverpool School of Tropical Medicine.

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Abstract

Introduction
Streptococcus pneumoniae (Spn) remains a significant problem worldwide, leading to community acquire pneumonia and invasive pneumococcal disease, despite widespread vaccination programmes. To address this ongoing global issue, both improved pneumococcal vaccines and improved diagnostic methods are required.
Experimental Human Pneumococcal Challenge involves the controlled exposure of adults to a specific Spn serotype, with the aim of inducing nasopharyngeal colonisation, to enable accelerated vaccine research and testing of new diagnostic methods. The aims of this thesis are 1) to assess overall safety of the EHPC model, and 2) expand it to a higher risk pneumococcal serotype, Spn3 and investigate the specific mucosal immune response. In addition, the model will be used to 3) investigate novel breath-based pneumococcal diagnostic techniques.

Methods
Safety review included all available pneumococcal challenge studies at our centre and data were compiled into a database. Frequency of serious adverse events and medical review was assessed and associations tested using an unblinded individual patient data meta-analysis methodology. EHPC involving three well characterized and
antibiotic sensitive isolates of Spn3 was developed and nasal inoculum doses were escalated (10,000- 160,000 cfu) until maximal colonisation rates (established using microbiological and molecular methods) with concurrent acceptable safety were achieved. IgG antibodies recognising Spn3 capsular polysaccharide were measured at baseline and day 14 post-challenge in nasal wash and salivary samples. Two breath-based pneumococcal diagnostic methods, gas capillary- ion mobility spectrometry (BreathSpec) and exhaled detection facemasks, were utilised pre- and post- experimental human pneumococcal challenge using Spn6b.

Results
Safety review identified 1416 individuals (median age 21, IQR 20–25), with a total of 1663 experimental pneumococcal inoculations performed. No pneumococcal-related serious adverse events were identified. 96 healthy participants (median age 21, interquartile range 19-25) were inoculated with Spn3, with colonisation rates 30.0-70.0%, based on dose/isolate. Spn3 specific salivary IgG antibody levels were identified and increased from baseline to day 14 in colonised participants (P=0.005) with a median IgG fold change of 1.458 [IQR 0.613-4.281], but not in uncolonised participants (P=0.193). No signature volatile organic compound peak was identified following Spn6B pneumococcal inoculation (n=41), despite colonisation being achieved in 70.7% [29/41] of study participants. Exhaled detection facemasks were able to identify pneumococcus, however only in a small number of individuals and timepoints overall (1.42%).

Conclusions
Safety review for symptoms in keeping with pneumococcal disease post-pneumococcal challenge was infrequent but occurred more in colonised participants. We have successfully demonstrated that an Spn3 human challenge model is feasible, safe and generates an identifiable salivary, but not nasal, immune response by day 14 in colonised individuals. This model will allow the development of future vaccine studies against this clinically relevant serotype. BreathSpec was not able to detect pneumococcal colonisation but, while infrequent, shedding pneumococcus was evident using exhaled detection facemasks and further comparison of shedding rates between serotypes is recommended.

Item Type:	Thesis (Doctoral)
Subjects:	WC Communicable Diseases > WC 20 Research (General) WC Communicable Diseases > Infection. Bacterial Infections > Bacterial Infections > WC 217 Pneumococcal infections
Repository link:	Item title Item URI Comprehensive review of safety in an Experimental Human Pneumococcal Challenge https://archive.lstmed.ac.uk/22443/ Human Infection Challenge with Serotype 3 Pneumococcus https://archive.lstmed.ac.uk/20856/
Faculty: Department:	Clinical Sciences & International Health > Clinical Sciences Department
Depositing User:	Lynn Roberts-Maloney
Date Deposited:	05 Mar 2025 10:57
Last Modified:	05 Mar 2025 11:45
URI:	https://archive.lstmed.ac.uk/id/eprint/26276

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