Reduced Transplacental Transfer of Antimalarial Antibodies in Kenyan HIV-Exposed Uninfected Infants

Abstract

Background: Altered neonatal immune responses may contribute to the increased morbidity observed in HIV-exposed but uninfected (HEU) infants compared with HIV-unexposed uninfected (HUU) infants. We sought to examine the effects of prenatal HIV and malaria exposure on maternal and neonatal plasma cytokine profiles and transplacental antibody transfer.

Methods: Forty-nine HIV+ and 50 HIV- women and their HIV-uninfected neonate pairs from Kenya were assessed. All HIV+ mothers received combination antiretroviral therapy. Maternal plasma and cord blood plasma samples at delivery were tested for 12 cytokines, total IgG, and IgG specific to 4 vaccine antigens and 14 Plasmodium falciparum antigens.

Results: HIV+ mothers had lower levels of all 12 plasma cytokines at delivery compared with HIV- mothers, but there were no differences between HEU and HUU neonates. There were no differences in the cord-to-maternal ratios (CMRs) of vaccine-specific IgG between HIV+/HEU and HIV-/HUU maternal-neonate pairs. HIV+/HEU maternal-neonate pairs had significantly lower CMRs for 3 antimalarial IgGs-merozoite surface protein 9, circumsporozoite protein, and erythrocyte binding antigen 181-which remained statistically significant after adjustment for malaria in pregnancy.

Conclusions: In a cohort of optimally treated HIV-infected pregnant women, maternal HIV infection was associated with reduced transplacental transfer of antimalarial antibodies.

Keywords: HIV-exposed uninfected neonate; antimalarial antibodies; inflammation; malaria; transplacental antibody transfer; vaccines.

Figure 1.

Lower plasma cytokine levels in HIV+ mothers compared with HIV- mothers. Maternal cytokines in plasma at delivery. Cytokines measured in 43 HIV- mothers (blue) and 44 HIV+ mothers (red). Cytokines to the left of the dotted line are associated with the left y-axis (ng/mL), and cytokines to the right of dotted line are associated with the right y-axis (pg/mL). All raw data points are plotted, with mean and SEM superimposed. The means of the 2 groups were compared using unpaired the Student t test. P values are presented for all statistically significant differences between the 2 groups.

Figure 2.

Lower plasma cytokines in HIV+ mothers with and without malaria in pregnancy. Maternal interleukin (IL)-10, IL-21, IL-6, and tumor necrosis factor in plasma at the time of delivery, measured in 9 HIV-/malaria- mothers (green), 34 HIV-/malaria+ mothers (blue), 30 HIV+/malaria- mothers (orange), and 12 HIV+/malaria+ mothers (maroon). All data points are plotted, and medians with interquartile ranges are superimposed. The Kruskal-Wallis test was used to compare medians across the 4 groups. P values are presented for all statistically significant differences among the groups.

Figure 3.

Vaccine-specific antibody levels in HIV- vs HIV+ mothers and HIV-unexposed uninfected (HUU) vs HIV-exposed but uninfected (HEU) neonates. A, Maternal antibody concentrations (circles) in HIV- (blue) and HIV+ (red) mothers. B, Corresponding neonatal antibody concentrations (squares) in HUU (navy blue) and HEU (pink) neonates. From left to right: diphtheria (n = 34 HIV-/HUU, n = 35 HIV+/HEU), tetanus (n = 24 HIV-/HUU, n = 25 HIV+/HEU), hepatitis B (n = 41 HIV-/HUU, n = 43 HIV+/HEU), and measles (n = 41 HIV-/HUU, n = 43 HIV+/HEU). Horizontal dotted lines represent antibody concentrations considered to be protective against infection (diphtheria, 0.1 IU/mL; tetanus, 0.1 IU/mL; hepatitis B, 10 IU/L; and measles, 0.25 IU/mL) All data points are plotted, and medians with interquartile ranges are superimposed. Medians were compared for each antibody using the Mann-Whitney test. P values are presented for statistically significant differences.

Figure 4.

Lower antimalarial antibody levels in HIV+ vs HIV- mothers and in HIV-exposed but uninfected (HEU) vs HIV-unexposed uninfected (HUU) neonates. Antibodies to 14 Pf-specific antigens measured in maternal plasma at the time of delivery and in cord blood plasma. A, 48 HIV- mothers (blue) and 46 HIV+ mothers (red) and (B) 48 HUU neonates (navy blue) and 46 HEU neonates (pink) included. All data points are plotted, and means with SEMs are superimposed. All antigen-specific antibodies to the left of the dotted line are plotted against the left y-axis; all antigen-specific antibodies to the right of the dotted line are plotted against the right y-axis. An unpaired Student t test was used to compare the means of values for HIV- vs HIV+ mothers and for HUU vs HEU neonates. P values for all statistically significant differences are shown.

Figure 5.

Lower cord-to-maternal ratios of MSP9, CSP, and EBA181 in HIV+/ HIV-exposed but uninfected (HEU) maternal–neonate pairs. Cord-to-maternal ratios (CMRs) of antibodies to 14 Pf antigens. Forty-eight HIV-/ HIV-unexposed uninfected (HUU) CMRs (blue) and 46 HIV+/HEU CMRs (red) are presented. Each data point represents a maternal–neonate pair; means with SEMs are superimposed. An unpaired Student t test was used to compare ratio means of HIV-/HUU and HIV+/HEU. P values for all statistically significant differences are shown.