Intestinal helminth co-infection is an unrecognised risk factor for increased pneumococcal carriage density and invasive disease.

Infection with Streptococcus pneumoniae is the leading cause of death in children and burden of disease is greatest where helminth infections are also common. We investigated the impact of intestinal helminth co-infection on pneumococcal carriage; a risk factor for invasive disease. We used a mouse co-infection model and clinical data to assess the impact of co-infection on carriage density. Co-infection in mice was associated with increased pneumococcal carriage density and dissemination into lungs. Helminth-infected children also exhibited increased carriage density as compared to uninfected children. Anthelmintic treatment may be a cost-effective method of reducing pneumococcal disease burden in lower-income countries.

The global distribution and diversity of protein vaccine candidate antigens in the highly virulent Streptococcus pnuemoniae serotype 1.

Serotype 1 is one of the most common causes of pneumococcal disease worldwide. Pneumococcal protein vaccines are currently being developed as an alternate intervention strategy to pneumococcal conjugate vaccines. Pre-requisites for an efficacious pneumococcal protein vaccine are universal presence and minimal variation of the target antigen in the pneumococcal population, and the capability to induce a robust human immune response. We used in silico analysis to assess the prevalence of seven protein vaccine candidates (CbpA, PcpA, PhtD, PspA, SP0148, SP1912, SP2108) among 445 serotype 1 pneumococci from 26 different countries, across four continents. CbpA (76%), PspA (68%), PhtD (28%), PcpA (11%) were not universally encoded in the study population, and would not provide full coverage against serotype 1. PcpA was widely present in the European (82%), but not in the African (2%) population. A multi-valent vaccine incorporating CbpA, PcpA, PhtD and PspA was predicted to provide coverage against 86% of the global population. SP0148, SP1912 and SP2108 were universally encoded and we further assessed their predicted amino acid, antigenic and structural variation. Multiple allelic variants of these proteins were identified, different allelic variants dominated in different continents; the observed variation was predicted to impact the antigenicity and structure of two SP0148 variants, one SP1912 variant and four SP2108 variants, however these variants were each only present in a small fraction of the global population (<2%). The vast majority of the observed variation was predicted to have no impact on the efficaciousness of a protein vaccine incorporating a single variant of SP0148, SP1912 and/or SP2108 from S. pneumoniae TIGR4. Our findings emphasise the importance of taking geographic differences into account when designing global vaccine interventions and support the continued development of SP0148, SP1912 and SP2108 as protein vaccine candidates against this important pneumococcal serotype.

The immunising effect of pneumococcal nasopharyngeal colonisation; protection against future colonisation and fatal invasive disease

The human nasopharynx is an important ecological niche for Streptococcus pneumoniae, and asymptomatic nasopharyngeal carriage is a common precursor to invasive disease. However, knowledge of the immunological events, which occur during carriage, both on a cellular and humoral level, remains limited. Here, we present a long-term stable model of asymptomatic nasopharyngeal carriage using outbred naïve mice, in which we have investigated the effect of previous nasopharyngeal exposure to pneumococci, in the prevention of subsequent carriage and invasive disease. Carriage of D39 wildtype pneumococci restricted to the nasopharynx could be detected for at least 28 days post-infection, whereas nasopharyngeal carriage of a pneumolysin negative isogenic mutant (PLN-A) was cleared in 7–14 days. Both carriage events induced total and capsule specific IgA mucosal antibodies and increased levels of systemic antibodies (IgG against pneumococcal surface protein A (PspA) and IgM capsular polysaccharide), which increased over time and correlated to reduced nasopharyngeal pneumococcal numbers. Prior nasopharyngeal colonisation with PLN-A significantly reduced the duration of subsequent D39 wildtype carriage, and significantly increased survival following invasive pneumococcal challenge. In this case systemic anti-PspA and anti-capsular antibody IgM concentrations showed a strong correlation with reduced bacterial numbers in the lungs and nasopharynx, respectively and also with increased levels of IL17A and CD4+ T cells in lungs of pre-colonised mice. Prior nasopharyngeal colonisation with PLN-A also resulted in significant cross-serotype protection with mice protected from invasive disease with serotype 3 strain (A66) after pre-colonisation with a serotype 2 strain (D39). Our results suggest that both mucosal and systemic antibody as well as cellular host factors have a role in long-term protection against both colonisation and invasive pneumococcal challenge.