Reduced transplacental transfer of antimalarial antibodies in Kenyan HIV-exposed uninfected infants

Open Forum Infectious Diseases, Volume 6, No. 6, Year 2019

Interpretação

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. Informed consent was obtained from all participants in the appropriate local language. Ethical approval was obtained from the Institutional Review Board of University Hospitals Cleveland Medical Center (08-07-09), Cleveland, Ohio, the Colorado Multiple Institution Review Board (15–1277), and the Kenya Medical Research Institute Scientific and Ethical Review Unit (NON SSC 089). The study was conducted at Chulaimbo County Hospital in Kisumu County, Kenya, between 2013 and 2015. Malaria transmission in this area is perennially high, with peaks coinciding with seasonal rains [28]. Chulaimbo Hospital serves a primarily rural catchment area outside of Kisumu and is an Academic Model Providing Access to Healthcare (AMPATH) site where clinical services and medications for HIV+ patients and their families are supported by USAID and the Indiana University–Kenya partnership. Participants included HIV- and HIV+ pregnant women who were enrolled at their first prenatal visit (typically during the second trimester) and followed throughout pregnancy (up to 4 prenatal visits). All HIV+ women received ART therapy. Fifty HIV- mothers/HUU neonates and 49 HIV+ mothers/HEU neonatal pairs with complete maternal and neonatal clinical data and samples at the time of delivery were included in this study. Data collected during prenatal visits included clinical history, physical exam, and concurrent diagnoses (eg, urinary tract infection, malaria). HIV- women received sulfadoxine-pyrimethamine (SP) beginning in the second trimester (for a total of 3 doses at intervals of 1 month or more). However, from January 2015 to November 2016, there was a shortage of SP at the clinic. HIV+ women did not receive SP, but they received cotrimoxazole as a part of their HIV treatment, which has antimalarial activity. Women were tested at their first prenatal visit for intestinal parasites including hookworm, Trichuris trichiura, Ascaris lumbricoides, Entamoeba histolytica, Giardia lamblia, Strongyloides, and Schistosoma mansoni, and, if positive, they were treated per Kenyan Ministry of Health guidelines. Neonatal data collected at delivery included APGAR scores, birth weight, length, and head circumference. Gestational age was calculated by the date of the last menstrual period. At delivery, cord blood and maternal venous blood samples were collected in heparinized syringes or vacutainers, and plasma was separated and stored at –80°C. All sample processing occurred within 1–5 hours of collection at the laboratory facilities at the Center for Global Health Research of KEMRI, located approximately 10 kilometers from Chulaimbo Hospital. All assays were conducted at the KEMRI laboratories. From all time points available (up to 4 prenatal visits and delivery), DNA was extracted from up to 200 μL whole blood using Qiagen QIAmp DNA Mini Kits, as per the manufacturer’s instructions. Pf polymerase chain reaction (PCR) was performed as previously described [29]. Malaria in pregnancy was defined as infection detected by blood smear or by Pf PCR at any time. Previous studies of malaria in pregnancy have used blood smear, PCR, and/or placental histopathology at delivery to define malaria in pregnancy rather than detection of infection at any time during pregnancy. Of those women who were Pf PCR+, 52% had 1 time point that was positive, whereas 27% had 2 positive time points, 15% had 3 positive time points, 4% had 4 positive time points, and 2% had all 5 time points Pf PCR+. We measured levels of 12 cytokines in plasma samples from 43 HIV-/HUU and 44 HIV+/HEU maternal–neonate pairs at the time of delivery. All plasma samples were assayed immediately after initial thawing. Some maternal/neonatal pairs were not included, as plasma had been previously thawed, which could compromise results. A multiplexed bead-based immunoassay was used to simultaneously measure plasma concentrations of interleukin (IL)-17F, interferon (IFN)-γ, IL-10, IL-12P70, IL-17A, IL-22, IL-1β, IL-21, IL-23, IL-6, IL-17E, and tumor necrosis factor alpha (TNFα) according to manufacturer instructions (Human Th17 Magnetic Bead Panel, EMD Millipore, Burlington, MA). We measured total IgG in plasma samples from 41 HIV-/HUU and 40 HIV+/HEU maternal–neonate pairs at delivery using enzyme-linked immunosorbent assay (ELISA) (Human Total IgG ELISA Kits, AbCam, Cambridge, MA) following the manufacturer’s instructions, with these exceptions: (1) A 15-point standard curve was constructed using 1:2 serial dilutions, and (2) all cord blood and maternal samples were diluted 1:500 000 in assay buffer. Maternal and neonate pairs were run on the same plate to eliminate interplate variability. Plasma samples from some pairs were missing as they were consumed in other assays. We measured IgG antibodies to diphtheria, tetanus, hepatitis B, and measles in plasma from maternal–neonate pairs at delivery by ELISA, as previously described [30, 31]. Multiple dilutions of samples were compared with 5-point standard curves made with serial dilutions from World Health Organization–approved antigen-specific reference sera; diphtheria Ig, human (NIBSC 10/262, 2 IU/mL), tetanus Ig, human (NIBSC TE-3, 120 IU/mL), hepatitis B Ig, human (NIBSC 07/164, 100 IU/mL), and measles Ig, human (NIBSC 97/648, 3 IU/mL). We measured IgG antibodies to 14 recombinant Pf proteins in plasma samples from 48 HIV-/HUU and 46 HIV+/HEU maternal–neonate pairs at delivery using Luminex MagPix assays. Supplementary Table 1 contains Pf protein concentrations used in conjugation to magnetic microspheres. Pf proteins were conjugated to MagPix magnetic microspheres (MagPlex, Luminex, Austin, TX) according to the manufacturer’s instructions. For each assay, plasma was incubated with a master mix of Pf protein conjugated beads at a 1:1 ratio, for final plasma dilutions of 1:100 and 1:1000. R-Phycoerythrin-conjugated AffiniPure F(ab’) Fragment Goat Anti-Human IgG Fcγ Fragment Specific (Jackson ImmunoReaserch, West Grove, PA) was used as a secondary antibody. Seven malaria-naïve North American adult plasma samples were tested on all plates as negative controls. Mean fluorescent intensity (MFI) values were divided by the average MFIs of the negative controls. Final results are expressed as the fold-increase of the sample MFI relative to the negative control MFI (reported as fold over North American), as previously described [32]. For continuous numerical variables with normal distribution or n > 30, Student t tests were used. For continuous numerical variables with non-normal distribution or n < 30, Mann-Whitney tests or Kruskal-Wallis tests were performed. All basic statistical analyses were performed using Prism (GraphPad, La Jolla, CA) and JMP (SAS, Cary, NC) software. Multiple linear regression was performed to investigate the relationships between (1) maternal HIV status and maternal plasma cytokine levels, adjusting for effects of malaria and intestinal parasite infection in pregnancy, as well as age and gravidity; (2) maternal HIV status and maternal antimalarial IgG levels, adjusting for effect of malaria in pregnancy, age, and gravidity; and (3) maternal HIV status and CMR of antimalarial IgG, adjusting for effect of malaria in pregnancy, age, and gravidity. Variance inflation factor (VIF) values were calculated for each coefficient and were ≤6.1 in all models. Statistical significance was set at P < .05. All regression analyses were performed using base R [33].

AI Digest

Study Justification:

The study aimed to investigate the effects of prenatal HIV and malaria exposure on maternal and neonatal plasma cytokine profiles and transplacental antibody transfer. This is important because 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.

Highlights:

– The study included 49 HIV+ and 50 HIV- women and their HIV-uninfected neonate pairs from Kenya.
– Maternal HIV infection was associated with reduced transplacental transfer of antimalarial antibodies.
– HIV+ mothers had lower levels of plasma cytokines at delivery compared with HIV- mothers.
– There were no differences in the cord-to-maternal ratios (CMRs) of vaccine-specific IgG between HIV+/HEU and HIV-/HUU maternal-neonate pairs.

Recommendations:

Based on the findings of the study, the following recommendations can be made:

1. Improve transplacental transfer of antimalarial antibodies in HIV+ mothers by exploring interventions to enhance antibody transfer during pregnancy.
2. Further investigate the impact of altered neonatal immune responses on the increased morbidity observed in HEU infants.
3. Conduct larger studies to confirm the findings and explore potential factors influencing transplacental antibody transfer.

Key Role Players:

To address the recommendations, the following key role players are needed:

1. Researchers and scientists to conduct further studies and explore interventions.
2. Healthcare providers to implement interventions and monitor the health of HIV-exposed uninfected infants.
3. Policy makers to support and fund research, as well as implement policies to improve maternal and neonatal health.

Cost Items:

In planning the recommendations, the following cost items should be considered (not actual cost but budget items):

1. Research funding for conducting larger studies and exploring interventions.
2. Healthcare resources for implementing interventions and monitoring the health of HIV-exposed uninfected infants.
3. Training and education programs for healthcare providers to ensure proper implementation of interventions and monitoring protocols.
4. Policy development and implementation costs, including awareness campaigns and monitoring systems.
Please note that the actual cost will depend on various factors and should be determined through detailed budget planning.

Força da prova

The strength of evidence for this abstract is 7 out of 10.
The evidence in the abstract is moderately strong. The study design includes a comparison between HIV+ and HIV- women and their neonates, and the researchers measured various cytokines and antibodies in maternal and neonatal plasma samples. The findings indicate that HIV+ mothers had lower levels of plasma cytokines compared to HIV- mothers, but there were no differences in cytokine levels between HIV-exposed uninfected (HEU) and HIV-unexposed uninfected (HUU) neonates. Additionally, the study found that HIV+ mothers had reduced transplacental transfer of antimalarial antibodies. The study was conducted in Kenya and involved a cohort of optimally treated HIV-infected pregnant women. To improve the evidence, future studies could consider increasing the sample size and including a control group of HIV+ mothers who did not receive antiretroviral therapy.

Resumo

Informed consent was obtained from all participants in the appropriate local language. Ethical approval was obtained from the Institutional Review Board of University Hospitals Cleveland Medical Center (08-07-09), Cleveland, Ohio, the Colorado Multiple Institution Review Board (15–1277), and the Kenya Medical Research Institute Scientific and Ethical Review Unit (NON SSC 089). The study was conducted at Chulaimbo County Hospital in Kisumu County, Kenya, between 2013 and 2015. Malaria transmission in this area is perennially high, with peaks coinciding with seasonal rains [28]. Chulaimbo Hospital serves a primarily rural catchment area outside of Kisumu and is an Academic Model Providing Access to Healthcare (AMPATH) site where clinical services and medications for HIV+ patients and their families are supported by USAID and the Indiana University–Kenya partnership. Participants included HIV- and HIV+ pregnant women who were enrolled at their first prenatal visit (typically during the second trimester) and followed throughout pregnancy (up to 4 prenatal visits). All HIV+ women received ART therapy. Fifty HIV- mothers/HUU neonates and 49 HIV+ mothers/HEU neonatal pairs with complete maternal and neonatal clinical data and samples at the time of delivery were included in this study. Data collected during prenatal visits included clinical history, physical exam, and concurrent diagnoses (eg, urinary tract infection, malaria). HIV- women received sulfadoxine-pyrimethamine (SP) beginning in the second trimester (for a total of 3 doses at intervals of 1 month or more). However, from January 2015 to November 2016, there was a shortage of SP at the clinic. HIV+ women did not receive SP, but they received cotrimoxazole as a part of their HIV treatment, which has antimalarial activity. Women were tested at their first prenatal visit for intestinal parasites including hookworm, Trichuris trichiura, Ascaris lumbricoides, Entamoeba histolytica, Giardia lamblia, Strongyloides, and Schistosoma mansoni, and, if positive, they were treated per Kenyan Ministry of Health guidelines. Neonatal data collected at delivery included APGAR scores, birth weight, length, and head circumference. Gestational age was calculated by the date of the last menstrual period. At delivery, cord blood and maternal venous blood samples were collected in heparinized syringes or vacutainers, and plasma was separated and stored at –80°C. All sample processing occurred within 1–5 hours of collection at the laboratory facilities at the Center for Global Health Research of KEMRI, located approximately 10 kilometers from Chulaimbo Hospital. All assays were conducted at the KEMRI laboratories. From all time points available (up to 4 prenatal visits and delivery), DNA was extracted from up to 200 μL whole blood using Qiagen QIAmp DNA Mini Kits, as per the manufacturer’s instructions. Pf polymerase chain reaction (PCR) was performed as previously described [29]. Malaria in pregnancy was defined as infection detected by blood smear or by Pf PCR at any time. Previous studies of malaria in pregnancy have used blood smear, PCR, and/or placental histopathology at delivery to define malaria in pregnancy rather than detection of infection at any time during pregnancy. Of those women who were Pf PCR+, 52% had 1 time point that was positive, whereas 27% had 2 positive time points, 15% had 3 positive time points, 4% had 4 positive time points, and 2% had all 5 time points Pf PCR+. We measured levels of 12 cytokines in plasma samples from 43 HIV-/HUU and 44 HIV+/HEU maternal–neonate pairs at the time of delivery. All plasma samples were assayed immediately after initial thawing. Some maternal/neonatal pairs were not included, as plasma had been previously thawed, which could compromise results. A multiplexed bead-based immunoassay was used to simultaneously measure plasma concentrations of interleukin (IL)-17F, interferon (IFN)-γ, IL-10, IL-12P70, IL-17A, IL-22, IL-1β, IL-21, IL-23, IL-6, IL-17E, and tumor necrosis factor alpha (TNFα) according to manufacturer instructions (Human Th17 Magnetic Bead Panel, EMD Millipore, Burlington, MA). We measured total IgG in plasma samples from 41 HIV-/HUU and 40 HIV+/HEU maternal–neonate pairs at delivery using enzyme-linked immunosorbent assay (ELISA) (Human Total IgG ELISA Kits, AbCam, Cambridge, MA) following the manufacturer’s instructions, with these exceptions: (1) A 15-point standard curve was constructed using 1:2 serial dilutions, and (2) all cord blood and maternal samples were diluted 1:500 000 in assay buffer. Maternal and neonate pairs were run on the same plate to eliminate interplate variability. Plasma samples from some pairs were missing as they were consumed in other assays. We measured IgG antibodies to diphtheria, tetanus, hepatitis B, and measles in plasma from maternal–neonate pairs at delivery by ELISA, as previously described [30, 31]. Multiple dilutions of samples were compared with 5-point standard curves made with serial dilutions from World Health Organization–approved antigen-specific reference sera; diphtheria Ig, human (NIBSC 10/262, 2 IU/mL), tetanus Ig, human (NIBSC TE-3, 120 IU/mL), hepatitis B Ig, human (NIBSC 07/164, 100 IU/mL), and measles Ig, human (NIBSC 97/648, 3 IU/mL). We measured IgG antibodies to 14 recombinant Pf proteins in plasma samples from 48 HIV-/HUU and 46 HIV+/HEU maternal–neonate pairs at delivery using Luminex MagPix assays. Supplementary Table 1 contains Pf protein concentrations used in conjugation to magnetic microspheres. Pf proteins were conjugated to MagPix magnetic microspheres (MagPlex, Luminex, Austin, TX) according to the manufacturer’s instructions. For each assay, plasma was incubated with a master mix of Pf protein conjugated beads at a 1:1 ratio, for final plasma dilutions of 1:100 and 1:1000. R-Phycoerythrin-conjugated AffiniPure F(ab’) Fragment Goat Anti-Human IgG Fcγ Fragment Specific (Jackson ImmunoReaserch, West Grove, PA) was used as a secondary antibody. Seven malaria-naïve North American adult plasma samples were tested on all plates as negative controls. Mean fluorescent intensity (MFI) values were divided by the average MFIs of the negative controls. Final results are expressed as the fold-increase of the sample MFI relative to the negative control MFI (reported as fold over North American), as previously described [32]. For continuous numerical variables with normal distribution or n > 30, Student t tests were used. For continuous numerical variables with non-normal distribution or n < 30, Mann-Whitney tests or Kruskal-Wallis tests were performed. All basic statistical analyses were performed using Prism (GraphPad, La Jolla, CA) and JMP (SAS, Cary, NC) software. Multiple linear regression was performed to investigate the relationships between (1) maternal HIV status and maternal plasma cytokine levels, adjusting for effects of malaria and intestinal parasite infection in pregnancy, as well as age and gravidity; (2) maternal HIV status and maternal antimalarial IgG levels, adjusting for effect of malaria in pregnancy, age, and gravidity; and (3) maternal HIV status and CMR of antimalarial IgG, adjusting for effect of malaria in pregnancy, age, and gravidity. Variance inflation factor (VIF) values were calculated for each coefficient and were ≤6.1 in all models. Statistical significance was set at P < .05. All regression analyses were performed using base R [33].

Materiais

Inovações

Based on the provided information, it is difficult to determine specific innovations for improving access to maternal health. The description provided focuses on a study examining the effects of prenatal HIV and malaria exposure on maternal and neonatal plasma cytokine profiles and transplacental antibody transfer. It does not provide information on potential innovations or recommendations for improving access to maternal health.

AI Innovations Description

Based on the provided information, the recommendation to improve access to maternal health is to focus on enhancing the transplacental transfer of antimalarial antibodies in HIV-exposed uninfected infants. This can be achieved through the following innovation:

1. Strengthening Prenatal Care: Implement comprehensive prenatal care programs that specifically address the needs of HIV-positive pregnant women. This includes regular monitoring of maternal health, early detection and treatment of malaria, and provision of antiretroviral therapy to prevent mother-to-child transmission of HIV.

2. Enhancing Maternal Immune Response: Develop interventions to boost the immune response of HIV-positive pregnant women, such as targeted vaccination campaigns and supplementation with immune-boosting nutrients. This can help improve the production and transfer of antimalarial antibodies to the fetus.

3. Improving Antenatal Education: Provide education and counseling to HIV-positive pregnant women about the importance of malaria prevention and the potential impact of HIV on the transfer of antibodies to their infants. This can empower women to take proactive measures to protect themselves and their babies.

4. Collaboration and Integration: Foster collaboration between HIV and malaria control programs to ensure integrated and coordinated care for pregnant women. This includes joint training of healthcare providers, sharing of resources and data, and alignment of policies and guidelines.

5. Research and Development: Invest in research to further understand the mechanisms behind reduced transplacental transfer of antimalarial antibodies in HIV-exposed uninfected infants. This can lead to the development of targeted interventions and strategies to overcome this challenge.

By implementing these recommendations, access to maternal health can be improved, leading to better health outcomes for both HIV-positive mothers and their infants in terms of reduced malaria-related morbidity and mortality.

AI Innovations Methodology

Based on the provided description, here are some potential recommendations for improving access to maternal health:

1. Strengthening Antenatal Care: Implementing comprehensive antenatal care programs that include regular check-ups, screenings, and education on maternal health issues can help identify and address potential complications early on.

2. Mobile Health (mHealth) Solutions: Utilizing mobile technology to provide remote access to healthcare services, such as telemedicine consultations and appointment reminders, can improve access to maternal health services, especially in remote or underserved areas.

3. Community Health Workers: Training and deploying community health workers who can provide basic maternal healthcare services, education, and referrals in their communities can help bridge the gap in access to healthcare, particularly in rural areas.

4. Transportation Support: Providing transportation support, such as ambulances or vouchers for transportation services, can ensure that pregnant women have access to timely and safe transportation to healthcare facilities during emergencies or for routine check-ups.

To simulate the impact of these recommendations on improving access to maternal health, a methodology could include the following steps:

1. Define the indicators: Identify specific indicators that measure access to maternal health, such as the number of antenatal care visits, percentage of pregnant women receiving skilled birth attendance, or distance to the nearest healthcare facility.

2. Collect baseline data: Gather data on the current status of the indicators in the target population. This can be done through surveys, interviews, or existing data sources.

3. Develop a simulation model: Create a mathematical or computational model that represents the target population and simulates the impact of the recommendations. The model should consider factors such as population demographics, healthcare infrastructure, and the implementation of the proposed interventions.

4. Input intervention parameters: Define the parameters of the interventions, such as the number of community health workers deployed, the coverage of mobile health services, or the availability of transportation support. These parameters should be based on evidence and expert input.

5. Run simulations: Use the simulation model to run multiple scenarios, varying the intervention parameters to assess their impact on the selected indicators. This can help identify the most effective combination of interventions and estimate the potential improvements in access to maternal health.

6. Analyze results: Analyze the simulation results to determine the potential impact of the recommendations on improving access to maternal health. This can include comparing the indicators between different scenarios and assessing the cost-effectiveness of the interventions.

7. Validate and refine the model: Validate the simulation model by comparing its predictions with real-world data, and refine the model based on feedback and additional data sources.

By following this methodology, policymakers and healthcare providers can gain insights into the potential impact of different interventions and make informed decisions to improve access to maternal health.

Autor

Dima Health

Statistics:

Citations: 6

Identifiers:

DOI: 10.1093/ofid/ofz237

Research Areas:

Cancer, Disparities, Genetics and Genomics, Health System and Policy, Infectious Diseases, Maternal Access, Maternal and Child Health, Quality of Care, Sexual and Reproductive Health, Social Determinants

Study Countries:

Kenya

Study Design:

Cohort Study

Participants Gender:

Female

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