HIV-related immune activation attenuates polyfunctional IgG and memory B-cell responses to Tdap immunization during pregnancy

Abstract

Background: Maternal pertussis vaccination with Tdap vaccine is recommended to protect newborns from severe postnatal infection. HIV-exposed uninfected (HEU) infants have a higher incidence of pertussis infection and may particularly benefit from maternal immunization. The impact of HIV infection on the quality of IgG and memory B cell (MBC) responses to Tdap vaccination in pregnant women (PW) living with HIV (PWH) is unknown.

Methods: In this observational study, humoral immune responses to Tdap vaccination, including IgG levels, Fc-dependent effector functions, and MBC frequencies, were measured before and after vaccination in 40 PWH and 42 HIV-uninfected PW. Placental transfer of IgG and avidity were assessed in cord blood (CB). Soluble and cellular immune activation markers were quantified at baseline.

Findings: One month after vaccination, PWH had lower frequencies of MBC compared with HIV-uninfected PW. At delivery, PWH had attenuated pertussis-specific IgG levels and Fc-dependent effector functions. Reduced levels of maternal vaccine polyfunctional IgG and IgG avidity were transferred to HEU as compared to HIV-unexposed newborns. After adjustment with ethnicity, maternal antibody levels and gestational age at vaccination, HIV infection was independently associated with decreased levels of PT specific-IgG in CB. Both maternal and neonatal pertussis-specific IgG responses as well as PT-specific IgG avidity were inversely correlated with maternal sCD14 levels before vaccination among PWH.

Interpretation: Maternal HIV infection is associated with attenuated humoral immune responses to Tdap vaccination that correlate with sCD14. Suboptimal transfer of maternal immunity may further increase the risk of severe pertussis infection in HEU infants.

Funding: This work was supported by IRIS Fund managed by the Foundation Roi Baudouin [2017J1820690206902], Association Vésale pour la Recherche Médicale and the Medical Council of CHU Saint-Pierre and has been funded in part with Federal funds from the National Institute of Allergy and Infectious Diseases, National Institutes of Health, US Department of Health and Human Services, under Award No. U19AI145825. N.D. is a clinical researcher and A.M. is Research Director at the Fonds de la Recherche Scientifique (F.R.S.-FNRS), Belgium. M.E.A. was partially supported by NIHNIAID1U19AI14825. This article is published with the support of the Fondation Universitaire of Belgium.

Keywords: HIV; Memory B cells; Pertussis; Polyfunctional IgG; Pregnancy; Vaccination.

Fig. 1

Levels of inflammatory markers in pregnant women living with HIV and HIV-uninfected pregnant women before vaccination. Serum levels of sCD14, sCD163, sCD25, IP-10, IFN-γ, IL-6, IL-10, and TNF-α were measured by multiplex assay in 39 pregnant women living with HIV (PWH, red) and 40 HIV-uninfected pregnant women (PW, blue) before (Pre) Tdap vaccination. Results are expressed in ng/mL or pg/mL. Violin plots represent the distribution of the data with median and quartiles. Statistical significance between groups was assessed using Mann–Whitney U test.

Fig. 2

Peripheral T cell subsets and expression of immune activation markers in pregnant women living with HIV and HIV-uninfected pregnant women before Tdap vaccination. (A) Peripheral blood T cell subsets were analyzed by flow cytometry in 33 pregnant women living with HIV (PWH, red) and 20 HIV-uninfected pregnant women (PW, blue) before (Pre) Tdap vaccination using the markers and the gating strategy depicted in the panel. Frequencies (%) of cells positive for indicated markers among (B) CD8+, (C) CD4+ and (D) HLADR + CD38+ T cells, observed in individual subjects. (E) Percentage of CD4 T cell subsets. (F) Expression of activation markers on pTfh cells. Violin plots represent the distribution of the data with median and quartiles. Lines represent the medians with 95% confidence interval (CI). T cell effector (Teff), effector memory (TEM), central memory (TCM), transitional memory (TTM), peripheral T follicular helper (pTfh). Statistical significances between groups were assessed using Mann–Whitney U test.

Fig. 3

Levels of antigen-specific IgG in pregnant women living with HIV and HIV-uninfected pregnant women before and after Tdap vaccination. Serum levels of PT (A), FHA (B), PRN (C) and TT (D)-specific IgG (IU/mL) were measured by ELISA in 40 pregnant women living with HIV (PWH, red) and 42 HIV-uninfected pregnant women (PW, blue) before (Pre), one week (+1 wk.) and one month (+1 mo.) after Tdap immunization and, at delivery (D). Lines represent the medians with 95% confidence interval (CI) (Log₁₀). Statistical significances between groups were assessed using Mann–Whitney U test.

Fig. 4

IgG Fc-dependent effector functions in pregnant women living with HIV and HIV-uninfected pregnant women before and after Tdap vaccination. Vaccine-specific IgG Fc-dependent effector functions were measured in 40 pregnant women living with HIV (PWH, red) and 42 HIV-uninfected pregnant women (PW, blue) before (Pre), one week (+1 wk.) and one month (+1 mo.) after Tdap immunization, and at delivery (D). Antibody-dependent complement deposition (ADCD) was measured by multiplex bead array assay and is expressed as median fluorescence intensity (MFI) with 95% confidence interval (CI). (B) Antibody-dependent cellular phagocytosis (ADCP) and (C) Antibody-dependent neutrophil phagocytosis (ADNP) were measured by flow cytometry and are expressed as phagocytic score (PS) with 95% confidence interval (CI). Lines represent the medians with 95% confidence interval (CI). Statistical significances between groups were assessed using Mann–Whitney U test. p values are presented in Supplementary Table S2.

Fig. 5

Placental transfer of antigen-specific IgG in mother:cord pairs following maternal Tdap immunization. Serum levels of PT (A), FHA (B), PRN (C), and TT (D)-specific total IgG (IU/mL) were measured by ELISA in both 37 pregnant women living with HIV (PWH, red) and HIV-uninfected pregnant women (PW, blue) at delivery (D), as well as in the cord blood (CB) of 35 HIV-exposed uninfected (HEU) infants and 30 HIV-unexposed uninfected (HUU) after maternal Tdap immunization. Lines represent the medians with 95% confidence interval (CI) (Log₁₀). The box and whisker plots (min to max, median, quartiles) represent placental transfer ratios of antigen-specific IgG calculated as percentages of cord blood to maternal blood ratios from 34 PWH:HEU and 30 PW:HUU pairs. Dashed lines show a 100% transfer efficiency. Statistical significances between groups were assessed using Mann–Whitney test.

Fig. 6

Placental transfer of antigen-specific IgG Fc-dependent effector functions in mother:cord pairs following maternal Tdap immunization. PT, FHA, PRN, and TT-specific IgG Fc-dependent effector functions were analyzed in both 37 pregnant women living with HIV (PWH, red) and HIV-uninfected pregnant women (PW, blue) at delivery (D) and in the cord blood (CB) of 35 HIV-exposed uninfected (HEU) infants and 30 HIV-unexposed uninfected (HUU) infants after maternal Tdap immunization. (A) Antibody-dependent complement deposition (ADCD) was measured by multiplex bead array assay and is expressed as median fluorescence intensity (MFI) with 95% confidence interval (CI). (B) Antibody-dependent cellular phagocytosis (ADCP) and (C) Antibody-dependent neutrophil phagocytosis (ADNP) were measured by flow cytometry and are expressed as phagocytic score (PS) with 95% confidence interval (CI). The box and whisker plots (min to max, median, quartiles) represent placental transfer ratios of antigen-specific IgG Fc-dependent effector functions calculated as percentages of cord blood to maternal blood ratios from 34 PWH:HEU and 30 PW:HUU pairs. Dashed lines show a 100% transfer efficiency. Statistical significances between groups were assessed using Mann–Whitney U test.

Fig. 7

Placental transfer of PT-specific IgG avidity in mother:cord pairs after maternal Tdap immunization. PT-specific IgG avidity (K_off [s⁻¹]) was measured by BLI (Bio-layer interferometry) in both 37 pregnant women living with HIV (PWH, red) and HIV-uninfected pregnant women (PW, blue) at delivery (D), as well as in the cord blood (CB) of 35 HIV-exposed uninfected (HEU) infants and 30 HIV-unexposed uninfected (HUU) after maternal Tdap immunization. Lines represent the medians with 95% confidence interval (CI). The box and whisker plots (min to max, median, quartiles) represent placental transfer ratios of antigen-specific IgG avidity calculated as percentages of cord blood to maternal blood ratios from 34 PWH:HEU and 30 PW:HUU pairs. Dashed lines show a 100% transfer efficiency. Statistical significances between groups were assessed using Mann–Whitney U test.

Fig. 8

Frequencies of antigen-specific memory B cells in pregnant women living with HIV and HIV-uninfected pregnant women before and after Tdap vaccination. (A) PT (B) FHA (C) PRN and (D) TT-specific IgG producing memory B cells (MBCs) were measured by ELISPOT in 38 women living with HIV (PWH, red) and 35 HIV-uninfected pregnant women (PW, blue) before (Pre) and after (+1 mo.) Tdap vaccination. Off-scale values (i.e., 0) are represented on the axe. Data are expressed as medians with 95% confidence interval (CI) of the numbers of MBCs per million PBMCs (Log₁₀). Statistical significances between groups were assessed using Mann–Whitney U test.

Fig. 9

Association between serum levels of sCD14 in pregnant women living with HIV and pertussis-specific IgG levels in HIV-exposed uninfected infants. Simple linear regression comparing serum sCD14 levels in 35 pregnant women living with HIV (PWH) before vaccination with pertussis-specific IgG titers in the cord blood of their 35 HIV-exposed uninfected (HEU) infants after maternal Tdap immunization. sCD14 levels were measured by multiplex bead array assay and are expressed as ng/mL. Serum levels of PT, FHA and PRN-specific IgG (IU/mL) were measured by ELISA. Correlations were determined using the Spearman non-parametric correlation test.