Human Nasal Challenge with Streptococcus pneumoniae Is Immunising in the Absence of Carriage

Abstract

Infectious challenge of the human nasal mucosa elicits immune responses that determine the fate of the host-bacterial interaction; leading either to clearance, colonisation and/or disease. Persistent antigenic exposure from pneumococcal colonisation can induce both humoral and cellular defences that are protective against carriage and disease. We challenged healthy adults intra-nasally with live 23F or 6B Streptococcus pneumoniae in two sequential cohorts and collected nasal wash, bronchoalveolar lavage (BAL) and blood before and 6 weeks after challenge. We hypothesised that both cohorts would successfully become colonised but this did not occur except for one volunteer. The effect of bacterial challenge without colonisation in healthy adults has not been previously assessed. We measured the antigen-specific humoral and cellular immune responses in challenged but not colonised volunteers by ELISA and Flow Cytometry. Antigen-specific responses were seen in each compartment both before and after bacterial challenge for both cohorts. Antigen-specific IgG and IgA levels were significantly elevated in nasal wash 6 weeks after challenge compared to baseline. Immunoglobulin responses to pneumococci were directed towards various protein targets but not capsular polysaccharide. 23F but not 6B challenge elevated IgG anti-PspA in BAL. Serum immunoglobulins did not increase in response to challenge. In neither challenge cohort was there any alteration in the frequencies of TNF, IL-17 or IFNγ producing CD4 T cells before or after challenge in BAL or blood. We show that simple, low dose mucosal exposure with pneumococci may immunise mucosal surfaces by augmenting anti-protein immunoglobulin responses; but not capsular or cellular responses. We hypothesise that mucosal exposure alone may not replicate the systemic immunising effect of experimental or natural carriage in humans.

Author Summary

Exposure to respiratory pathogens such as Streptococcus pneumoniae (pneumococcus) is a frequent event that can result in immediate clearance, nasal colonisation or disease for the host. Human and mouse studies have shown that natural colonisation is an immunising event. Colonisation is prevalent in children but rare in human adults (<10%), suggesting that despite high pneumococcal exposure adult mucosal defences are sufficient to prevent colonisation. We exposed healthy adults to pneumococci in the nose in order to achieve colonisation and mimic a natural colonisation event. In most volunteers, however, we were not able to obtain colonisation using this protocol. In exposed but not colonised volunteers we measured antibody and cellular responses in nose, lung and blood samples. The mucosal defences elicited during acute pneumococcal exposure are poorly described but these data will shed light on the mechanisms that prevent colonisation in healthy adults and inform future vaccine design. Live bacterial exposure increases specific antibody and innate responses at mucosal surfaces such as the nose and lung. Systemic responses were not increased. These data suggest that acute bacterial exposure per se augments mucosal but not systemic defences. Natural or experimental colonisation may be required for systemic immunisation.