Preclinical Evaluation of the Pht Proteins as Potential Cross-Protective Pneumococcal Vaccine Antigens

Abstract

Current pneumococcal vaccines are composed of capsular polysaccharides (PS) of various serotypes, either as free PS or as protein-PS conjugates. The use of pneumococcus protein antigens that are able to afford protection across the majority of serotypes is envisaged as a relevant alternative and/or complement to the polysaccharides. In this context, based on several studies, the Pht protein family emerged as relevant vaccine candidates. The purpose of the present study was to evaluate the Pht protein family in several preclinical mouse models. Immunization with these antigens was compared with immunization with other pneumococcal antigens, such as CbpA, PspA, and PsaA. In a nasopharyngeal colonization model and in a lung colonization model, the Phts were found to be superior to the other candidates in terms of efficacy of protection and serotype coverage. Likewise, vaccination with PhtD allowed higher animal survival rates after lethal intranasal challenge. Finally, a passive transfer model in which natural anti-PhtD human antibodies were transferred into mice demonstrated significant protection against lethal intranasal challenge. This indicates that natural anti-PhtD human antibodies are able to protect against pneumococcal infection. Our findings, together with the serotype-independent occurrence of the Phts, designate this protein family as valid candidate antigens to be incorporated in protein-based pneumococcal vaccines.

Human Antibodies to PhtD, PcpA, and Ply Reduce Adherence to Human Lung Epithelial Cells and Murine Nasopharyngeal Colonization by Streptococcus pneumoniae

“…The decrease in murine NP bacterial load with human anti-PhtD antibodies indicates that naturally raised human antibodies can be functional to reduce the number of colonizing S. pneumoniae and therefore relevant to developing a PhtDbased vaccine. Godfroid et al also showed a role for anti-PhtD human antibody in protection against lethal intranasal challenge in a mouse model (49); however, they did not use Fabs. Vaccination of rhesus macaques with PhtD has been shown to elicit protection against pneumonia (50) and is currently in human clinical trials (51).…”

Transcriptional regulation, occurrence and putative role of the Pht family of Streptococcus pneumoniae

“…Consequently, our results confirm the Pht proteins as genuine vaccine candidates against pneumococcal infections. The different members of the Pht family have already been evaluated for their potential as pneumococcal vaccine antigens Godfroid et al, 2011;Hamel et al, 2004;Ogunniyi et al, 2007;Wizemann et al, 2001;Zhang et al, 2001). PhtA, PhtB and PhtD were examined for their ability to protect mice against a subset of pneumococcal isolates .…”

“…PhtE is a longer protein, the only one with six repeats of the histidine triad motif. In mouse immunization studies, all members of the Pht family have been shown to afford a high level of protection to subsequent pneumococcal challenge with a number of different strains/serotypes Godfroid et al, 2011;Hamel et al, 2004;Ogunniyi et al, 2007;Wizemann et al, 2001;Zhang et al, 2001).…”

Protection against Streptococcus pneumoniae Invasive Pathogenesis by a Protein-Based Vaccine Is Achieved by Suppression of Nasopharyngeal Bacterial Density during Influenza A Virus Coinfection

“…As a vaccine, we used S. pneumoniae histidine triad protein D (PhtD), a highly conserved, surface-exposed adhesin protein that facilitates attachment to the NP and lung epithelium cells (10)(11)(12). PhtD as a vaccine component has been shown to be protective in a number of mouse S. pneumoniae infection models (11,13,14) and is included in vaccines currently in human trials (15)(16)(17). In our current mouse study, the outcome of PhtD vaccinemediated prevention of invasive S. pneumoniae pathogenesis proved comparable to that achieved with PCV13 vaccination.…”