Maternal Antibodies to Pneumolysin but Not to Pneumococcal Surface Protein A Delay Early Pneumococcal Carriage in High-Risk Papua New Guinean Infants

Immunization of pregnant women can be an efficient strategy to induce early protection in infants in developing countries. Pneumococcal protein-based vaccines may have the capacity to induce pneumococcal serotype-independent protection. To understand the potential of maternal pneumococcal protein-specific antibodies in infants in high-risk areas, we studied the placental transfer of naturally acquired antibodies to pneumolysin (Ply) and pneumococcal surface protein A family 1 and 2 (PspA1 and PspA2) in relation to onset of pneumococcal nasopharyngeal carriage in infants in Papua New Guinea (PNG). In this study, 76% of the infants carried Streptococcus pneumoniae in the upper respiratory tract within the first month of life, at a median age of 19 days. Maternal and cord blood antibody titers to Ply (ρ = 0.824, P < 0.001), PspA1 (ρ = 0.746, P < 0.001), and PspA2 (ρ = 0.631, P < 0.001) were strongly correlated. Maternal pneumococcal carriage (hazard ratio [HR], 2.60; 95% confidence interval [CI], 1.25 to 5.39) and younger maternal age (HR, 0.74; 95% CI, 0.54 to 1.00) were independent risk factors for early carriage, while higher cord Ply-specific antibody titers predicted a significantly delayed onset (HR, 0.71; 95% CI, 0.52 to 1.00) and cord PspA1-specific antibodies a significantly younger onset of carriage in PNG infants (HR, 1.57; 95% CI, 1.03 to 2.40). Maternal vaccination with a pneumococcal protein-based vaccine should be considered as a strategy to protect high-risk infants against pneumococcal disease by reducing carriage risks in both mothers and infants.Every year approximately 1 million children under 5 years of age die of pneumococcal pneumonia, meningitis, or sepsis, mostly in developing countries (4). Despite the efficacy of pneumococcal conjugate vaccines, Streptococcus pneumoniae remains an important cause of serious morbidity and mortality in young infants in developing countries (5, 8, 44), where the age of onset of disease is often younger than the recommended vaccination age of 6 weeks old and many of the serotypes causing serious disease are not included in currently available conjugate vaccines. Alternative vaccines and vaccine strategies are therefore needed to induce the earliest protection possible in high-risk infants.Early onset of pneumococcal colonization and prolonged carriage in the upper respiratory tract are believed to play important roles in the high incidence and early onset of pneumococcal diseases in children in developing countries (10, 25). In the highlands of Papua New Guinea (PNG), where this study was performed, all infants carry pneumococci in the upper respiratory tract by the age of 3 months old, and 60% of them are already carriers during the neonatal period at a median age of 17 days old (14). This is in contrast to high-income countries, where less than half of the children experience pneumococcal colonization within the first year of life (3, 10, 43). Besides children, pneumococcal carriage rates remain higher in adulthood in developing countries, including PNG, where approximately half of the adults carry pneumococci in the upper respiratory tract (17, 39), compared to 1 to 13% of adults in low-risk countries (12, 15, 20). Consequently, maternal pneumococcal carriage may be an important risk factor for early colonization in infants in high-risk areas, in particular considering the frequent and close contact between mother and child in the critical early period of life when infants are highly susceptible.In the first few months of life, when the human immune system is still highly immature (27), infants largely depend on passively acquired maternal immunoglobulin G (IgG) antibodies to protect themselves against invading pathogens. Immunization of pregnant women is a strategy that has been proven to reduce infection risks in both mothers and infants (9, 13, 45). This includes the potential to reduce acute lower respiratory illnesses in infants in high-risk areas, as shown with maternal immunization with the 23-valent pneumococcal polysaccharide vaccine (36, 37). However, the efficacy of pneumococcal polysaccharide vaccines on reducing nasopharyngeal colonization is limited, whereas the protective effect of pneumococcal conjugate vaccines is restricted by the number of pneumococcal serotypes that can be included. On the other hand, novel vaccines based on conserved pneumococcal proteins may offer better, serotype-independent protection against pneumococcal carriage and disease. This may include maternal immunization strategies, as supported by findings in mice (21).Pneumolysin (Ply) and pneumococcal surface protein A (PspA) are two conserved proteins that are expressed by virtually all S. pneumoniae isolates and that are being considered as vaccine candidates. Pneumolysin is the thiol-activated cytolysin produced by S. pneumoniae that enables the bacterium to penetrate the host''s physical defenses through its cytotoxic effect on epithelial cells, thus facilitating carriage and disease (28). PspA is a cell wall-associated protein that plays a role in inhibiting complement-mediated opsonization (7, 33) and can prevent lactoferrin-mediated clearance (19). In contrast to Ply, PspA shows structural diversity between pneumococcal strains and has been classified into three families based on the sequence variability of the most C-terminal 100 amino acids of the N-terminal domain of PspA. Although S. pneumoniae strains expressing family 1 or 2 PspA proteins account for 98% of clinical isolates, protective PspA-specific IgG antibodies binding to this highly variable region are family dependent (7).Both Ply and PspA have been shown to be highly immunogenic and to protect mice against disease and colonization following pneumococcal challenge (2, 6, 7, 11, 34). There is evidence that in humans naturally acquired IgA and IgG antibodies to PspA and Ply can mediate protection against subsequent pneumococcal carriage and disease (22, 24, 30, 31, 38, 46). Moreover, naturally acquired antibodies to Ply and PspA have been shown to be transferred from mother to child and to protect against early pneumococcal carriage and infection, at least in populations in low-risk areas (18, 38). It is not known whether these findings hold true for areas of high endemicity, where infants are at a considerably higher risk for early carriage and disease.In order to understand the role of maternal antibodies to Ply and PspA in protecting high-risk infants against early carriage, we studied antibody titers in paired maternal and cord blood samples in relation to the infant''s age of first pneumococcal nasopharyngeal carriage. We hypothesized that, compared to lower-risk settings, maternal Ply- and PspA-specific antibody titers would be higher and would be associated with a delay in the age of first pneumococcal carriage in the offspring.