Differences in Pneumococcal and Haemophilus influenzae Natural Antibody Development in Papua New Guinean Children in the First Year of Life

Abstract

Background: Development of vaccines to prevent disease and death from Streptococcus pneumoniae, and nontypeable Haemophilus influenzae (NTHi), the main pathogens that cause otitis media, pneumonia, meningitis and sepsis, are a global priority. Children living in low and lower-middle income settings are at the highest risk of contracting and dying from these diseases. Improved vaccines with broader coverage are required. Data on the natural development of antibodies to putative vaccine antigens, especially in high-risk settings, can inform the rational selection of the best antigens for vaccine development.

Methods: Serum IgG titres to four pneumococcal proteins (PspA1, PspA2, CbpA, and Ply) and five NTHi antigens (P4, P6, OMP26, rsPilA and ChimV4) were measured in sera collected from 101 Papua New Guinean children at 1, 4, 9, 10, 23 and 24 months of age using multiplexed bead-based immunoassays. Carriage density of S. pneumoniae and H. influenzae were assessed by quantitative PCR on genomic DNA extracted from nasopharyngeal swabs using species-specific primers and probes. All data were log-transformed for analysis using Student's unpaired t-tests with geometric mean titre (GMT) or density (GMD) calculated with 95% confidence intervals (CI).

Results: Serum -pneumococcal protein-specific IgG titres followed a "U" shaped pattern, with a decrease in presumably maternally-derived IgG titres between 1 and 4 months of age and returning to similar levels as those measured at 1 month of age by 24 months of age. In contrast, NTHi protein-specific IgG titres steadily increased with age. There was no correlation between antibody titres and carriage density for either pathogen.

Conclusion: This longitudinal study indicates that the waning of maternally- derived antibodies that is usually observed in infants, after infants does not occur for NTHi antigens in Papua New Guinean infants. Whether NTHi antigen IgG can be transferred maternally remains to be determined. Vaccines that are designed to specifically increase the presence of protective NTHi antibodies in the first few months of life may be most effective in reducing NTHi disease.

Clinical trial registration: https://ichgcp.net/clinical-trials-registry/NCT01619462" title="See in ClinicalTrials.gov">NCT01619462.

Keywords: Papua New Guinea; natural antibody; nontypeable Haemophilus influenzae (NTHi); pneumococcus; protein IgG; vaccines.

Conflict of interest statement

WP has received funding from Pfizer Australia to attend a conference. AB conducts part-time consultancy work for vaccine companies on projects not related to this study. L-AK has received investigator-initiated research grants, educational grants and travel support from Pfizer, GlaxoSmithKline and Merck, Sharp & Dohme, and is an inventor on patents for a pneumococcal protein vaccine antigen. DL is an investigator on an investigator-initiated research grant that was funded by Pfizer Australia. PR has received nonfinancial support from Pfizer, grants from GlaxoSmithKline and Pfizer, and nonfinancial support from GlaxoSmithKline for work outside the submitted work. The Papua New Guinea Institute of Medical Research received sponsorship from Pfizer Australia to host a national Medical Symposium in 2014. AC is a member of the Seqirus Australia Pneumococcal Advisory Board and the Merck & Co Global Pneumococcal Advisory Board. LB has received grants from GlaxoSmithKline to develop NTHi type IV pilus-derived vaccine antigens. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Copyright © 2021 Martinovich, Rahman, de Gier, Seppanen, Orami, Granland, Francis, Yoannes, Corscadden, Ford, Jacoby, van den Biggelaar, Bakaletz, Cripps, Lehmann, Richmond, Pomat, Kirkham and Thornton.

Figures

Figure 1

Serum IgG antibodies against pneumococcal proteins waned in the first months of life and returned close to baseline by 2 years of age. Each point represents the serum IgG titres against pneumococcal proteins for a child in AU/mL (A) PspA1, (B) PspA2, (C) CbpA and (D) Ply in children from PNG at different ages. The horizontal bars depict the geometric mean titre (GMT) of IgG at each time-point +/- 95% CI. PspA1, pneumococcal surface protein A family 1; PspA2, pneumococcal surface protein A family 2; CbpA, choline-binding protein A; Ply, pneumolysin. *p-value <0.05, statistical analyses were conducted on the logarithmically transformed data. All children had measurable antibody titres.

Figure 2

Serum IgG antibodies against NTHi antigens increase gradually over the first 2 years of life. Each point represents the serum IgG titre against NTHi antigens for a child in AU/mL (A) P4, (B) P6, (C) OMP26 and (D) rsPilA (E) ChimV4. The horizontal bars depict the geometric mean titre (GMT) of IgG at each time-point +/- 95% CI. PD, Protein D; P4, Protein 4; P6, outer membrane protein 6, OMP26, outer membrane protein 26; rsPilA, recombinant soluble pilus A protein; ChimV4, chimeric vaccine antigen 4 (rsPilA and P5). *p-value <0.05, Statistical analyses were conducted logarithmically transformed data. All children had measurable antibody titres.