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.

Polysaccharide-Specific Memory B Cells Predict Protection against Experimental Human Pneumococcal Carriage

“…Although these immunologic responses are well described in murine models, the immunologic responses that mediate protection in humans have not been identified. We have previously observed that pneumococcal colonization increases the level and functional capacity of pneumococcal-specific IgG and IgA in serum and nasal wash, and that colonization also increases the number of pneumococcal-specific IL-17-secreting CD4 1 T cells in the lung (3,6,7). Epidemiologic data support the role of polysaccharide (PS)-mediated immunity in protection against carriage.…”

Staphylococcus aureusandStreptococcus pneumoniaeinteraction and response to pneumococcal vaccination: Myth or reality?

“…[52][53][54] Moreover, »20% of healthy adult individuals are persistent carriers of a single strain for many years, 55,56 while young healthy adults are typically carriers of S pneumoniae only for very short durations, even following experimental exposures. 57 Shak et al showed that when S. aureus carriers were artificially inoculated with S. pneumoniae, successful colonization resulted in a decrease in S. aureus carriage, but only 14 d later. The authors suggested that this delayed response may point to an immune mediated interaction.…”

The new first-line defense: the potential of nasopharyngeal colonization in vaccine strategies

“…15,16,18,19 Importantly, intranasal administration of the 6B strain without successful colonization also augmented local mucosal serological responses, 82 showing that exposure of the nasopharynx to the organism can stimulate an immunological response even if colonization was not detected.…”

“…114 A potentially significant problem is that mouse and human data indicate that a reduced duration of nasopharyngeal colonization by S. pneumoniae significantly weakens the induced adaptive immune response. 82,111,115 In mice, attenuated strains often have a reduced duration of colonization compared to wild-type bacteria, 107,111,115 and this may therefore affect the efficacy of using attenuated mutants for preventing S. pneumoniae infections. For example, the pabB deletion strain is very rapidly cleared from the mouse nasopharynx and was only weakly immunogenic after nasopharyngeal administration.…”

“…112 Repeated dosing of poorly colonizing strains may overcome this issue. 82,107,110,115 Another potential problem is the surprising lack of cross-protection induced by attenuated strains in some of these studies. For example, although the protein antigens targeted by protective responses are largely conserved between S. pneumoniae strains, adaptive responses to one episode of colonization or systemic vaccination with a live attenuated vaccine either were not or only weakly cross-protective against heterologous strains in mouse models.…”