Disturbances in the IgG Antibody Profile in HIV-Exposed Uninfected Infants Associated with Maternal Factors.

Over the last 20 years, the incidence of vertical HIV transmission has decreased from 25%-42% to less than 1%. Although there are no signs of infection, the health of HIV-exposed uninfected (HEU) infants is notoriously affected during the first months of life, with opportunistic infections being the most common disease. Some studies have reported effects on the vertical transfer of antibodies, but little is known about the subclass distribution of these antibodies. We proposed to evaluate the total IgG concentration and its subclasses in HIV+ mothers and HEU pairs and to determine which maternal factors condition their levels. In this study, plasma from 69 HEU newborns, their mothers, and 71 control pairs was quantified via immunoassays for each IgG isotype. Furthermore, we followed the antibody profile of HEUs throughout the first year of life. We showed that mothers present an antibody profile characterized by high concentrations of IgG1 and IgG3 but reduced IgG2, and HEU infants are born with an IgG subclass profile similar to that of their maternal pair. Interestingly, this passively transferred profile could remain influenced even during their own antibody production in HEU infants, depending on maternal conditions such as CD4+ T-cell counts and maternal antiretroviral treatment. Our findings indicate that HEU infants exhibit an altered IgG subclass profile influenced by maternal factors, potentially contributing to their increased susceptibility to infections.

Camacho-Pacheco RT ，Hernández-Pineda J ，Brito-Pérez Y ，Plazola-Camacho N ，Coronado-Zarco IA ，Arreola-Ramírez G ，Bermejo-Haro MY ，Najera-Hernández MA ，González-Pérez G ，Herrera-Salazar A ，Olmos-Ortiz A ，Soriano-Becerril D ，Sandoval-Montes C ，Figueroa-Damian R ，Rodríguez-Martínez S ，Mancilla-Herrera I ... -  《-》

Immunoglobulin G passive transfer from mothers to infants: total IgG, IgG subclasses and specific antipneumococcal IgG in 6-week Malawian infants exposed or unexposed to HIV.

The impaired transplacental passage of IgG from mothers living with HIV to their infants could be one of the causes of the high vulnerability to infections of HIV-exposed uninfected (HEU) infants, but controversial results have been obtained in different settings. The aim of this study was to assess in 6-week old HEU and HIV-unexposed, uninfected (HUU) Malawian infants the total IgG levels, the subclasses profile and the concentrations of global anti-pneumococcal capsular polysaccharide (anti-PCP) IgG and IgG2. Dried blood spots were collected from 80 infants (40 HEU, 40 HUU) and antibodies concentrations determined by nephelometric method (total IgG and subclasses), or using ELISA (anti-PCP total IgG and IgG2). Results are expressed as median levels with IQR, while the proportions of each subclass out of the total IgG are used to describe the subclasses profile. At 6 weeks HEU infants had higher median levels of total IgG and IgG1 and a significantly lower level of IgG2 [0.376 (0.344-0.523) g/l vs 0.485 (0.374-0.781) g/l, p = 0.037] compared to the HUU counterparts. The IgG subclasses distribution confirmed the underrepresentation of IgG2 (IgG2 represented 5.82% of total IgG in HEU and 8.87% in HUU). The anti-PCP IgG and IgG2 levels were significantly lower in HEU infants [8.9 (5.4-15.1) mg/l vs 16.2 (9.61-25.8) mg/l in HUU, p < 0.001, and 2.69 (1.90-4.29) mg/l vs 4.47 (2.96-5.71) mg/l in HUU, p = 0.001, respectively]. Compared to HUU infants, HEU infants have IgG abnormalities mainly represented by low IgG2 levels, suggesting that despite maternal antiretroviral therapy, the mechanisms of IgG transplacental passage continue to be impaired in women living with HIV. HEU infants also showed a significantly lower level of specific anti-PCP IgG, possibly favouring a high vulnerability to S. pneumoniae infection at an age when protection is mostly depending on maternal IgG.

Baroncelli S ，Galluzzo CM ，Orlando S ，Mphwere R ，Kavalo T ，Luhanga R ，Amici R ，Floridia M ，Andreotti M ，Ciccacci F ，Marazzi MC ，Giuliano M ... -  《BMC INFECTIOUS DISEASES》

Dynamics of immunoglobulin G subclasses during the first two years of life in Malawian infants born to HIV-positive mothers.

Baroncelli S ，Galluzzo CM ，Liotta G ，Andreotti M ，Orlando S ，Ciccacci F ，Jere H ，Luhanga R ，Sagno JB ，Amici R ，Marazzi MC ，Giuliano M ... -  《BMC Pediatrics》

Infectious morbidity of breastfed, HIV-exposed uninfected infants under conditions of universal antiretroviral therapy in South Africa: a prospective cohort study.

Without breastfeeding and maternal antiretroviral therapy (ART), HIV-exposed uninfected (HEU) infants have greater infectious morbidity than HIV-unexposed (HU) infants. We hypothesised that with the introduction of universal maternal ART, breastfed HEU and HU infants would have similar morbidity. We prospectively studied a cohort of HIV-infected pregnant women initiating ART, and a parallel group of HIV-uninfected pregnant women, starting from their first antenatal care visit at the Gugulethu Midwife Obstetrics Unit in Cape Town, South Africa. All pregnant women attending their first antenatal care visit were eligible for enrolment if aged 18 years or older and planning to deliver in Cape Town, without gestational age restrictions. HIV-infected women were participants of the Maternal Child Health ART (MCH-ART) study, and HIV-uninfected women were participants of the HIV-Unexposed Uninfected (HU2) study. All enrolled women were followed up during pregnancy and through delivery. At the early neonatal visit (scheduled for the first week after birth), mother-infant pairs who practiced any breastfeeding in the first 7 days of life were eligible for further postnatal follow-up for at least 12 months post partum. HIV infection was excluded among HEU infants at ages 6 weeks and 12 months by PCR. We evaluated the effect of HIV exposure on two primary outcomes: hospitalisation (all-cause and infection-related admission to hospital) and longitudinal prevalence of child infectious illness (diarrhoea and presumed lower respiratory tract infection [LRTI]). Hospitalisation data were abstracted from routine health records. Crude and adjusted incidence rate ratios (aIRRs; with adjustment for maternal HIV disease severity, timing of ART initiation, breastfeeding, timely vaccination, and birth outcomes [gestational size and age]) for infection-related hospitalisations were calculated from Poisson regression models (with variance corrected for clustering). Prevalence of infant infectious illness was based on maternal self-report for the preceding 2 weeks of each visit, with questions based on Demographic and Health Survey (DHS) questionnaires. Infants who acquired HIV infection during follow-up were excluded from this analysis. MCH-ART is registered on ClinicalTrials.gov, NCT01933477. Pregnant women were recruited between March 20, 2013, and Aug 19, 2015. Mother-infant pairs (HEU, n=459; HU, n=410) were followed up for a median of 12 months until March 24, 2017. Compared with HU infants, HEU infants had more infection-related hospitalisations between the age of 8 days and 3 months (HEU, 34·2 admissions per 100 child-years [24·4-47·9] vs 9·8 per 100 child-years [95% CI 5·1-18·8]; IRR 3·50 [95% CI 1·68-7·30]), but rates were similar at other ages. In infants aged 8 days to 3 months, infection-related hospitalisations for HEU infants with healthier mothers (n=84; ART initiation at <24 weeks' gestation, CD4 count >350 cells per μL, HIV viral load <4·0 log10 copies per mL: 15·88 admissions per 100 child-years [5·12-49·23]) approximated those of HU infants (9·77 per 100 child-years [5·08-18·78]; aIRR 1·28 [0·27-6·05]). HEU infants of mothers with late ART initiation (at ≥24 weeks' gestation) and advanced disease (CD4 count ≤350 cells per μL and HIV viral load ≥4·0 log10 copies per mL; n=44) had the highest admission rate (40·44 per 100 child-years [15·18-107·74]; aIRR 5·01 [1·50-16·71]). In this age group, reduced admissions were seen in HEU infants with optimal breastfeeding (initiated within 1 h of birth and exclusive through age 3 months) and timely vaccination (required doses received within 2 weeks of indicated age; n=90; 9·63 admissions per 100 child-years [2·41-38·49]). Between birth and age 6 months, HEU infants had an almost five times greater prevalence of LRTIs than HU infants (aPR 4·69 [2·40-9·17]), and a three-times greater prevalence of diarrhoeal illness (aPR 2·93 [1·70-5·07]). After age 6 months, these associations were ameliorated. Despite ART in pregnancy, breastfed HEU infants versus breastfed HU infants had transiently increased infectious morbidity risks in early infancy. However, differences were driven by factors potentially amenable to intervention, including delayed diagnosis and ART initiation in HIV-positive mothers, and suboptimal breastfeeding and vaccination of their infants. US National Institute of Child Health and Human Development, Elizabeth Glaser Pediatric AIDS Foundation, South African Medical Research Council, Fogarty Foundation and the Office of AIDS Research.

le Roux SM ，Abrams EJ ，Donald KA ，Brittain K ，Phillips TK ，Zerbe A ，le Roux DM ，Kroon M ，Myer L ... -  《-》

Impaired haemophilus influenzae type b transplacental antibody transmission and declining antibody avidity through the first year of life represent potential vulnerabilities for HIV-exposed but -uninfected infants.

To determine whether immune function is impaired among HIV-exposed but -uninfected (HEU) infants born to HIV-infected mothers and to identify potential vulnerabilities to vaccine-preventable infection, we characterized the mother-to-infant placental transfer of Haemophilus influenzae type b-specific IgG (Hib-IgG) and its levels and avidity after vaccination in Ugandan HEU infants and in HIV-unexposed U.S. infants. Hib-IgG was measured by enzyme-linked immunosorbent assay in 57 Ugandan HIV-infected mothers prenatally and in their vaccinated HEU infants and 14 HIV-unexposed U.S. infants at birth and 12, 24, and 48 weeks of age. Antibody avidity at birth and 48 weeks of age was determined with 1 M ammonium thiocyanate. A median of 43% of maternal Hib-IgG was transferred to HEU infants. Although its level was lower in HEU infants than in U.S. infants at birth (P < 0.001), Hib-IgG was present at protective levels (>1.0 μg/ml) at birth in 90% of HEU infants and all U.S. infants. HEU infants had robust Hib-IgG responses to a primary vaccination. Although Hib-IgG levels declined from 24 to 48 weeks of age in HEU infants, they were higher than those in U.S. infants (P = 0.002). Antibody avidity, comparable at birth, declined by 48 weeks of age in both populations. Early vaccination of HEU infants may limit an initial vulnerability to Hib disease resulting from impaired transplacental antibody transfer. While initial Hib vaccine responses appeared adequate, the confluence of lower antibody avidity and declining Hib-IgG levels in HEU infants by 12 months support Hib booster vaccination at 1 year. Potential immunologic impairments of HEU infants should be considered in the development of vaccine platforms for populations with high maternal HIV prevalence.

Gaensbauer JT ，Rakhola JT ，Onyango-Makumbi C ，Mubiru M ，Westcott JE ，Krebs NF ，Asturias EJ ，Fowler MG ，McFarland E ，Janoff EN ... -  《-》