Controlled Human Infection and Rechallenge with Streptococcus pneumoniae Reveals the Protective Efficacy of Carriage in Healthy Adults

Abstract

Rationale: The immunological and protective role of pneumococcal carriage in healthy adults is not known, but high rates of disease and death in the elderly are associated with low carriage prevalence. Objectives: We employed an experimental human pneumococcal carriage model to investigate the immunizing effect of a single carriage episode. Methods: Seventy healthy adults were challenged, and of those with carriage, 10 were rechallenged intranasally with live 6B Streptococcus pneumoniae up to 11 months after clearance of the first carriage episode. Serum and nasal wash antibody responses were measured before and after each challenge. Measurements and Main Results: A total of 29 subjects were experimentally colonized. No subjects were colonized by experimental rechallenge, demonstrating the protective effect of initial carriage against subsequent infection. Carriage increased both mucosal and serum IgG levels to pneumococcal proteins and polysaccharide, resulting in a fourfold increase in opsonophagocytic activity. Importantly, passive transfer of postcarriage sera from colonized subjects conferred 70% protection against lethal challenge by a heterologous strain in a murine model of invasive pneumococcal pneumonia. These levels were significantly higher than the protection conferred by either precarriage sera (30%) or saline (10%). Conclusions: Experimental human carriage resulted in mucosal and systemic immunological responses that conferred protection against recolonization and invasive pneumococcal disease. These data suggest that mucosal pneumococcal vaccination strategies may be important for vulnerable patient groups, particularly the elderly, who do not sustain carriage.

Review: Current and new generation pneumococcal vaccines

“…184 Interestingly, passive transfer of post-colonisation serum to mice was associated with serotype-independent protection against experimentally-induced invasive disease, consistent with the involvement of antibodies reactive with pneumococcal proteins. 184 While highlighting the potential of viable, whole cell mucosal vaccines, the safety of these in high-risk, immunosuppressed groups is of potential concern. 185 The various types of protein-based pneumococcal vaccine which have reached phase I/II development, as well as currently licensed and pipeline PCV vaccines are shown in Table 3.…”

“…183 Recent studies using a model of experimental pneumococcal carriage in healthy adult human volunteers based on intranasal infection with live, encapsulated serotype 6B of the pneumococcus have demonstrated the potential for mucosal immunisation with whole cell vaccines. 184 Experimental colonisation with the pneumococcus was associated with production of protective mucosal and systemic IgA and IgG antibodies reactive with both capsular and protein antigens which promoted both eradication and prevention of re-colonisation on subsequent re-challenge. 184 Interestingly, passive transfer of post-colonisation serum to mice was associated with serotype-independent protection against experimentally-induced invasive disease, consistent with the involvement of antibodies reactive with pneumococcal proteins.…”

“…184 Experimental colonisation with the pneumococcus was associated with production of protective mucosal and systemic IgA and IgG antibodies reactive with both capsular and protein antigens which promoted both eradication and prevention of re-colonisation on subsequent re-challenge. 184 Interestingly, passive transfer of post-colonisation serum to mice was associated with serotype-independent protection against experimentally-induced invasive disease, consistent with the involvement of antibodies reactive with pneumococcal proteins. 184 While highlighting the potential of viable, whole cell mucosal vaccines, the safety of these in high-risk, immunosuppressed groups is of potential concern.…”

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

“…[15][16][17][18][19][20][21] These observations suggest that novel vaccine strategies could harness the immunizing effects of nasopharyngeal colonization to prevent serious infections, and this is the subject addressed in this review with a particular focus on the potential of nasopharyngeal colonization for the prevention of S. pneumoniae and N. meningitidis infections, which are used as case studies that illustrate the benefits and potential drawbacks of this approach.…”

“…Rechallenge failed to result in a second carriage event by the same strain, with protection persisting for up to 1 year. 21 In these challenge studies, colonization resulted in cellular and humoral immune responses to S pneumoniae. Data from mouse colonization models indicate that nasopharyngeal colonization leads to Th17-cell responses 16,18,19 that enhance phagocyte recruitment to the nasopharynx, 18,78 and are critical for both the initial clearance of the colonizing strain and subsequent protection against recolonization.…”