Evidence of maternal transfer of antigen-specific antibodies in serum and breast milk to infants at high-risk of S. pneumoniae and H. influenzae disease

Kelly M Martinovich, Elke J Seppanen, Amy S Bleakley, Sharon L Clark, Ross M Andrews, Peter C Richmond, Michael J Binks, Ruth B Thornton, Lea-Ann S Kirkham, Kelly M Martinovich, Elke J Seppanen, Amy S Bleakley, Sharon L Clark, Ross M Andrews, Peter C Richmond, Michael J Binks, Ruth B Thornton, Lea-Ann S Kirkham

Abstract

Introduction: Children in low-mid income countries, and First Nations children in high-income countries, experience disproportionately high rates of Streptococcus pneumoniae and Haemophilus influenzae infections and diseases including pneumonia and otitis media. We previously observed that infants from Papua New Guinea had no evidence of waning maternal immunity for H. influenzae-specific antibodies. In this study, we assessed S. pneumoniae and H. influenzae antibody titres in Australian First Nation mothers and infants to determine antigen-specific antibody ontogenies and whether H. influenzae antibody titres in infants were due to low maternal antibody titres or lack of placental transfer.

Methods: Breast milk, infant nasopharyngeal swabs and ear assessment data were collected 1-, 2-, 7-months post-birth as well as maternal, cord and 7-month-old infant sera, from 85 Australian Aboriginal and Torres Strait Islander mother-infant pairs. Serum IgG and breast milk IgG and IgA antibody titres to S. pneumoniae antigens (PspA1, PspA2, CbpA, Ply) and H. influenzae antigens (PD, ChimV4, OMP26, rsPilA) were measured.

Results: IgG titres in maternal and cord sera were similar for all antigens, except Ply (higher in cord; p=0.004). Sera IgG titres at 7-months of age were lower than cord sera IgG titres for all S. pneumoniae antigens (p<0.001). Infant sera IgG titres were higher than cord sera for H. influenzae PD (p=0.029), similar for OMP26 (p=0.817) and rsPilA (p=0.290), and lower for ChimV4 (p=0.004). Breast milk titres were similar for all antigens at 1, 2 and 7-months except OMP26 IgA (lower at 7-months than 1-month; p=0.035), PspA2 IgG (p=0.012) and Ply IgG that increased by 7-months (p=0.032). One third of infants carried nontypeable Haemophilus influenzae (NTHi), 45% carried S. pneumoniae and 52% had otitis media (OM) observed at least once over the 7-months. 73% of infants who carried either S. pneumoniae or NTHi, also had otitis media observed.

Conclusions: Similarities between maternal and cord IgG titres, and absence of waning, support a lack of maternal H. influenzae IgG antibodies available for cross-placental transfer. Increased maternal anti-PD IgG could offer some protection from early carriage with NTHi, and maternal immunisation strategies should be considered for passive-active immunisation of infants to protect against S. pneumoniae and H. influenzae diseases.

Trial registration: ClinicalTrials.gov NCT00714064 and NCT00310349.

Keywords: Haemophilus influenzae; IgA; IgG; Streptococcus pneumoniae; breast milk; maternal.

Conflict of interest statement

The 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 © 2022 Martinovich, Seppanen, Bleakley, Clark, Andrews, Richmond, Binks, Thornton and Kirkham.

Figures

Figure 1
Figure 1
Participant flow chart and sample numbers. Of the 85 mother:infant pairs in this study 1 maternal serum sample was not collected (n=84); 5 mothers had no cord blood sera collected (n=80), and infant sera was not collected from 58 of the 85 infants (n=27).
Figure 2
Figure 2
IgG titres against Streptococcus pneumoniae and Haemophilus influenzae antigens in maternal, cord and infant sera. Each point represents sera IgG titres against S. pneumoniae antigens (A) PspA1, (B) PspA2, (C) CbpA, (D) Ply and H. influenzae antigens (E) PD, (F) OMP26, (G) rsPilA and (H) ChimV4. PspA1, pneumococcal surface protein A family 1; PspA2, pneumococcal surface protein A family 2; CbpA, choline-binding protein A; Ply, pneumolysin. PD, Protein D; OMP26, outer membrane protein 26; rsPilA, recombinant soluble pilus A protein; ChimV4, chimeric vaccine antigen 4 (rsPilA and P5). * p-value <0.05, Paired t-tests were conducted on the logarithmically transformed data. All samples had measurable antibody titres.
Figure 3
Figure 3
Sera IgG titres against Streptococcus pneumoniae or Haemophilus influenzae separated based on any NPS positive to S. pneumoniae or NTHi in the first 7-months of life, in maternal venous sera, cord sera and infant venous sera from matched mother-infant pairs. Each point represents the sera IgG titres against S. pneumoniae antigens (A) PspA1, (B) PspA2, (C) CbpA, (D) Ply and H. influenzae antigens (E) PD, (F) OMP26, (G) rsPilA and (H) ChimV4. PspA1, pneumococcal surface protein A family 1; PspA2, pneumococcal surface protein A family 2; CbpA, choline-binding protein A; Ply, pneumolysin. PD, Protein D; OMP26, outer membrane protein 26; rsPilA, recombinant soluble pilus A protein; ChimV4, chimeric vaccine antigen 4 (rsPilA and P5). *p-value <0.05, Unpaired t-tests were conducted on logarithmically transformed data. Positive NPS = open squares.
Figure 4
Figure 4
IgG antibodies against Streptococcus pneumoniae and Haemophilus influenzae antigens in maternal, cord and infant sera from matched mother-infant pairs, separated based on otitis media diagnosis in the first 7-months of life or not. Each point represents sera IgG titres against S. pneumoniae antigens (A) PspA1, (B) PspA2, (C) CbpA, (D) Ply and H. influenzae antigens (E) PD, (F) OMP26, (G) rsPilA and (H) ChimV4. PspA1, pneumococcal surface protein A family 1; PspA2, pneumococcal surface protein A family 2; CbpA, choline-binding protein A; Ply, pneumolysin. Protein D; OMP26, outer membrane protein 26; rsPilA, recombinant soluble pilus A protein; ChimV4, chimeric vaccine antigen 4 (rsPilA and P5). *p-value <0.05, Unpaired t-tests were conducted on the logarithmically transformed data. With otitis media diagnosis = open circles.
Figure 5
Figure 5
Breast milk IgG and IgA titres against Streptococcus pneumoniae and Haemophilus influenzae antigens. Each point represents the breast milk IgG and IgA titres against S. pneumoniae antigens (A) PspA1, (B) PspA2, (C) Ply and H. influenzae antigens (D) PD, (E) OMP26, (F) rsPilA and (G) ChimV4. PspA1, pneumococcal surface protein A family 1; PspA2, pneumococcal surface protein A family 2; Ply, pneumolysin. PD, Protein D; OMP26, outer membrane protein 26; rsPilA, recombinant soluble pilus A protein; ChimV4, chimeric vaccine antigen 4 (rsPilA and P5). * p-value <0.05, paired t-tested were conducted on the logarithmically transformed data. 1-month n=55, 2-months n=51, 7-months n=38. All samples had measurable antibody titres except for rsPilA, for which 6 samples were below the limit of detection for anti-rsPilA IgA. The assay reference breast milk had minimal rsPilA IgG therefore anti-rsPilA IgG titres could not be quantified.
Figure 6
Figure 6
Breast milk IgG and IgA titres against Streptococcus pneumoniae and Haemophilus influenzae separated based on any NPS positive to S. pneumoniae or NTHi in the first 7-months of life. Each point represents the breast milk IgG or IgA titres against S. pneumoniae antigens (A) PspA1, (B) PspA2, (C) Ply and H. influenzae antigens (D) PD, (E) OMP26, (F) rsPilA, (G) ChimV4. PspA1, pneumococcal surface protein A family 1; PspA2, pneumococcal surface protein A family 2; Ply, pneumolysin. PD, Protein D; OMP26, outer membrane protein 26; rsPilA, recombinant soluble pilus A protein; ChimV4, chimeric vaccine antigen 4 (rsPilA and P5). Unpaired t-tests were conducted on logarithmically transformed data with * p<0.05. For the 1-month visit n=55, 2-months visit n=51, 7-months visit n=38. Positive NPS = open squares.
Figure 7
Figure 7
Breast milk IgG and IgA antibodies against Streptococcus pneumoniae and Haemophilus influenzae antigens separated based on otitis media diagnosis in the first 7-months of life or not. Each point represents breast milk IgG or IgA titres against S. pneumoniae antigens (A) PspA1, (B) PspA2, (C) Ply and H. influenzae antigens (D) PD, (E) OMP26, (F) rsPilA, (G) ChimV4. PspA1, pneumococcal surface protein A family 1; PspA2, pneumococcal surface protein A family 2; Ply, pneumolysin. PD, Protein D; OMP26, outer membrane protein 26; rsPilA, recombinant soluble pilus A protein; ChimV4, chimeric vaccine antigen 4 (rsPilA and P5). Unpaired t-tests were conducted on logarithmically transformed data with * p<0.05. 1-month n=55, 2-months n=51, 7-months n=38. With otitis media= open circles.

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