Understanding the interaction of upper respiratory tract infection with respiratory syncytial virus and Streptococcus pneumoniae using a human challenge model: a multicenter, randomized controlled study protocol

Abstract

Background: Streptococcus pneumoniae (pneumococcus) and respiratory syncytial virus (RSV) are major causes of respiratory infections globally. Viral and bacterial co-infections are commonly observed in respiratory infections and there is evidence that these pathogens interact synergistically to evade host responses and lead to more severe disease. Notably, RSV seasonal outbreaks are associated with increased hospitalization and a subsequent peak in invasive pneumococcal disease cases, particularly in pediatric populations. Here, we summarize a protocol for a controlled human infection model aiming to evaluate pathogen interaction dynamics and immune responses in a combined pneumococcus and RSV model. The primary objective is to determine whether primary RSV challenge increases the risk of secondary pneumococcal colonization.

Methods: This is an open-label, multi-center, randomized controlled human co-infection study, inclusive of a pilot phase. Individuals will be randomized to primary inoculation with either pneumococcus (serotype 6B) or RSV (subtype RSV-A) intra-nasally on day 0 followed by a reciprocal challenge on day 7. During pilot phase A up to 10 participants will be monitored in an in-patient facility for 7-10 days following RSV-A challenge. If there are no safety concerns, we will then progress to an outpatient phase where participants will self-isolate at home. Clinical samples to be taken from participants include nasal swabs and washes for pathogen detection; and nasal cells, nasal lining fluid, and blood samples to examine mucosal and systemic immune responses.

Discussion: This work will lead to important scientific knowledge on the interaction and dynamics between pneumococcus and RSV. This knowledge could help inform pneumococcal and RSV vaccination strategies, particularly for groups at risk of developing severe pneumococcal and RSV disease.

Trial registration: The study is registered on ISRCTN (The UKs Clinical Study Registry). DOI https://doi.org/10.1186/ISRCTN12036902.

Fig 1. SPIRIT schedule of enrolment, interventions and assessments.

(A) V9–V12 for participants consenting to the optional nasal biopsy; (B) Eligibility assessment includes assessing temporary exclusion prior to inoculation and nasal biopsy. (C) Randomization occurs before inoculation to allow participant preparation for self-isolation. (D) Blood-borne virus screen will only be done at screening and includes human immunodeficiency virus and hepatitis B and C. Clotting is only for participants undergoing nose biopsy. Abbreviations: BBV, blood-borne virus; CRP, C-reactive protein; FBC, full blood count; PBMCs, peripheral blood mononuclear cells; RNA, ribonucleic acid; RSV-A, respiratory syncytial virus A; Spn6B, Streptococcus pneumoniae 6B; U&Es, urea and electrolytes.

Fig 2. RESPECCT study phases.

(A) If fewer than 2 participants are infected with RSV-A in phase A, then phase C will be conducted instead of phase B. Abbreviations: DSMC, data safety monitoring committee; RSV-A, respiratory syncytial virus; SAEs, serious adverse events.