A feasibility study of controlled human infection with Streptococcus pneumoniae in Malawi

Abstract

Background Persistent carriage of pneumococcal vaccine serotypes has occurred after introduction of PCV13 vaccination in Africa but the mechanisms are unclear. We tested the feasibility of using a human pneumococcal challenge model in Malawi to understand immune correlates of protection against carriage and to trial alternative vaccine candidates. We aimed to identify a dose of Streptococcus pneumoniae serotype 6B sufficient to establish nasopharyngeal carriage in 40% of those nasally inoculated and evaluate nasal mucosal immunity before and after experimental inoculation. Methods Healthy student volunteers were recruited and inoculated with saline, 20,000 CFU/naris or 80,000 CFU/naris of Streptococcus pneumoniae serotype 6B Post inoculation carriage was determined by nasal sampling for bacterial culture and lytA PCR. Immunological responses were measured in serum and nasal mucosal biopsies before and after bacterial inoculation. Findings Twenty-four subjects completed the feasibility protocol with minimal side effects. pneumococcal carriage was established in 0/6, 3/9 and 4/9 subjects in the saline, 20,000 CFU/naris and 80,000 CFU/naris groups, respectively. Incidental (natural) serotype carriage was common (7/24 participants carried non-6B strains, 29.2%. Experimentally induced type 6B pneumococcal carriage was associated with pro-inflammatory nasal mucosal responses prior to inoculation and altered mucosal recruitment of immune cells post bacterial challenge. There was no association with serum anti-capsular antibody. Interpretation The serotype 6B experimental human pneumococcal carriage model is feasible in Malawi and can now be used to determine the immunological correlates of protection against carriage and vaccine efficacy in this population.

The influence of pneumococcal conjugate vaccine-13 on nasal colonisation in a controlled human infection model of pneumococcal carriage in Malawi: a double-blinded randomised controlled trial protocol

“…The 4/9 carriage rate at 80,000 CFUs met our predefined study stopping criteria 4 to confirm CHIM feasibility. This confirms that the 80,000 CFU pneumococcal dose used by LSTM to test vaccines in the UK is relevant to populations within Malawi 8 . Based on successful transfer of procedures, we are confident that our clinical and laboratory procedures are sufficiently robust to test vaccine efficacy.…”

“…Our feasibility study of pneumococcal controlled human infection in Malawi 7 has demonstrated no SAEs or AEs and minimal symptoms for participants who completed the programme 8 . We have confirmed LSTM procedures and successfully adapted standard operating procedures for in-country use.…”

“…Based on the pneumococcal dose of 80,000 cfu/naris and using data from our feasibility study 7 , 8 and Liverpool-based studies 6 , we estimate that 60% of the control (normal saline) group will be colonised with pneumococci following inoculation and 36% of the PCV-13 group, this equates to a 40% reduction in colonisation. We observed a 78% reduction in the UK based study 6 .…”

Innovative vaccine approaches—a Keystone Symposia report

“…137 The group is moving forward with conducting human challenge studies in Malawi. A feasibility study was recently completed, 138 and techniques to study saliva, nasal fluid, nasal microbiopsies, and nasal biopsies have been transferred to Malawi. The studies will address which vaccines can prevent pneumococcal carriage, how effective they are in vulnerable populations, and the mechanisms of respiratory tract defense needed for an effective mucosal vaccine.…”

Human infection studies: Key considerations for challenge agent development and production

“…However, since the turn of the century the number of human infection studies conducted has risen dramatically 4 , facilitated in part by significant technological advances that have increased the scientific value of this research. In the last decade there has also been an increase in their geographical spread, with Plasmodium falciparum , and more recently Plasmodium vivax 5 and Pneumococcus 6 challenge studies being conducted in Africa and Asia.…”