Immunity to pneumococcal surface proteins in children with community-acquired pneumonia: a distinct pattern of responses to pneumococcal choline-binding protein A

Abstract

The aetiological diagnosis of community-acquired pneumonia (CAP) is challenging in children, and serological markers would be useful surrogates for epidemiological studies of pneumococcal CAP. We compared the use of anti-pneumolysin (Ply) antibody alone or with four additional pneumococcal surface proteins (PSPs) (pneumococcal histidine triad D (PhtD), pneumococcal histidine triad E (PhtE), LytB, and pneumococcal choline-binding protein A (PcpA)) as serological probes in children hospitalized with CAP. Recent pneumococcal exposure (positive blood culture for Streptococcus pneumoniae, Ply(+) blood PCR finding, and PSP seroresponse) was predefined as supporting the diagnosis of presumed pneumococcal CAP (P-CAP). Twenty-three of 75 (31%) children with CAP (mean age 33.7 months) had a Ply(+) PCR finding and/or a ≥ 2-fold increase of antibodies. Adding seroresponses to four PSPs identified 12 additional patients (35/75, 45%), increasing the sensitivity of the diagnosis of P-CAP from 0.44 (Ply alone) to 0.94. Convalescent anti-Ply and anti-PhtD antibody titres were significantly higher in P-CAP than in non P-CAP patients (446 vs. 169 ELISA Units (EU)/mL, p 0.031, and 189 vs. 66 EU/mL, p 0.044), confirming recent exposure. Acute anti-PcpA titres were three-fold lower (71 vs. 286 EU/mL, p <0.001) in P-CAP children. Regression analyses confirmed a low level of acute PcpA antibodies as the only independent predictor (p 0.002) of P-CAP. Novel PSPs facilitate the demonstration of recent pneumococcal exposure in CAP children. Low anti-PcpA antibody titres at admission distinguished children with P-CAP from those with CAP with a non-pneumococcal origin.

Contributions to Protection from Streptococcus pneumoniae Infection Using the Monovalent Recombinant Protein Vaccine Candidates PcpA, PhtD, and PlyD1 in an Infant Murine Model during Challenge

“…Second, antibodies to PcpA and PhtD prevent binding of S. pneumoniae to airway epithelium, and here, we observed prevention of binding to primary epithelial cells for the first time. Previous studies have demonstrated a correlation between the levels of antibodies to PcpA (in conjunction with Ply) and reduction in pneumonia (23). Antibodies directed to PcpA and PhtD also appear to correlate with a reduction in bacteremia (11).…”

“…PcpA is not required for colonization of the murine nasopharynx (21,22). Human antibodies to PcpA have been detected in infants and children with pneumococcal bacteremia or pneumonia (23). In monovalent vaccines containing PcpA, some level of protection from pneumonia was found, and a delay in morbidity after sepsis challenge was detected in an adult mouse model (21).…”

PspA Family Distribution, unlike Capsular Serotype, Remains Unaltered following Introduction of the Heptavalent Pneumococcal Conjugate Vaccine

“…Other promising proteins that could be used in combination with PspA for a protein vaccine to protect against strains not covered by conjugate vaccines include pneumolysoid, PspC (CbpA), PcpA, and PhtD (9,17,19,22). Regardless of how new vaccines are constructed, it is likely that continued surveillance of pneumococcal serotypes associated with invasive disease will be critical to determine the effectiveness of PCV13 in reducing IPD and to help identify the best vaccine strategy for further improvement in the control of pneumococcal disease.…”

A Pneumococcal Protein Array as a Platform to Discover Serodiagnostic Antigens Against Infection

“…Some epidemiological studies have been conducted, based on reduced sets of proteins showing unclear patterns of antibody response when applied to heterogeneous cohorts of patients (6,13,62). Serological diagnosis of pneumococcal disease is challenging because it should discriminate between infected patients and nonsymptomatic carriers (63), and because of difficulties in obtaining acute and convalescent sera from pediatric patients (1).…”

“…The detection of antibody serological markers by any immunoassay is widely used for early diagnosis, epidemiological surveillance, or evaluation of vaccine immunogenicity against many pathogens, including the pneumococcus (6,12,13). Serological diagnosis of pneumococcal disease based on a single antigen is often challenging, because of the interference of natural antibodies elicited by previous colonization events.…”