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AIDS:
doi: 10.1097/QAD.0000000000000127
Clinical Science

Effect of HIV-1 exposure and antiretroviral treatment strategies in HIV-infected children on immunogenicity of vaccines during infancy

Simani, Omphile E.a; Izu, Alanea; Violari, Avyc; Cotton, Mark F.d; van Niekerk, Nadiaa; Adrian, Peter V.a,b; Madhi, Shabir A.a,b,e

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Author Information

aDepartment of Science and Technology/National Research Foundation: Vaccine Preventable Diseases; Johannesburg

bMedical Research Council, Respiratory and Meningeal Pathogens Research Unit, Faculty Health Sciences; University of the Witwatersrand, Faculty of Health Sciences, Johannesburg;

cPerinatal HIV Research Unit, University of the Witwatersrand, Faculty of Health Sciences

dStellenbosch University, Children's Infectious Diseases Clinical Research Unit, Tygerberg

eDivision of National Health Laboratory Service, National Institute for Communicable Diseases, Centre for Vaccines and Immunology, Sandringham, South Africa.

Correspondence to Shabir A. Madhi, National Institute for Communicable Diseases, 1 Modderfontein Road, Sandringham, Gauteng, 2131, South Africa. Tel: +27 11 3866137; fax: +27 11 8821872; e-mail: shabirm@nicd.ac.za

Received 31 July, 2013

Revised 23 October, 2013

Accepted 23 October, 2013

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's Website (http://www.AIDSonline.com).

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Abstract

Introduction: We studied the effect of maternal HIV-exposure and timing of antiretroviral treatment (ART) in HIV-infected infants on antibody responses to combined diphtheria-toxoid–tetanus-toxoid–whole cell pertussis and Haemophilus influenzae type b conjugate vaccine (HibCV) and monovalent hepatitis B vaccine (HBV).

Methods: HIV-uninfected infants born to HIV-infected (HEU) or HIV-uninfected (HUU) mothers were enrolled in parallel with HIV-infected children with CD4+ ≥25%, who were randomized to initiate ART immediately upon confirmation of HIV-infection (ART-Immed) or when clinically and/or immunologically indicated (ART-Def). Infants received three doses of diphtheria-toxoid–tetanus-toxoid -wP-HibC/HBV at 7.3, 11.4 and 15.4 weeks of age. Antibody to diphtheria-toxoid, tetanus-toxoid, pertussis toxin, filamentous hemagglutinin (FHA) and hepatitis B surface antigen (HBsAg) were measured by Luminex multiplex-immunoassay and polyribosyl-ribitol phosphate (PRP) antibodies by standard ELISA and bactericidal assay.

Results: Prevaccination antibody geometric mean concentrations (GMCs) were higher in HUU than HEU infants for tetanus-toxoid, but lower for HBsAg, diphtheria-toxoid and FHA. Postvaccination GMCs and proportion with seroprotective antibody levels or sero-conversion rates were similar between HUU and HEU infants for all vaccines. Postvaccination GMCs were higher in HUU for tetanus-toxoid, diphtheria-toxoid, HBsAg and FHA than ART-Immed infants; and for tetanus-toxoid, HBsAg and pertussis-toxoid than ART-Def infants. Nevertheless, there was no difference in proportion of HUU and HIV-infected infants who developed sero-protective vaccine-specific antibody levels postvaccination. The timing of ART initiation generally did not affect immune responses to vaccines between HIV-infected groups.

Conclusion: Vaccination with DTwP-HibCV/HBV of HEU and HIV-infected infants initiated on early-ART confers similar immunity compared with HUU children.

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Introduction

HIV-infection impairs humoral and cell-mediated immune functions early in infancy [1,2]. Immune dysfunction in HIV-infected individuals include loss of T-lymphocytic proliferative responses and hyper-activation of T-lymphocytes leading to accelerated apoptosis [2–4], decline in B-lymphocyte number and function [5,6], and impaired priming for immunological memory and/or loss of anamnestic responses [7,8]. Early initiation of combination antiretroviral treatment (ART) in HIV-infected infants prior to immunological or clinical deterioration is associated with improved survival [9]. Control of HIV replication limits and reverses immunosuppression in HIV-infected individuals [1,10,11], improving immune responses to vaccines [12–14].

Due to effective ART regimens for preventing mother-to-child HIV-transmission, the majority (>97%) of infants born to HIV-infected women are HIV-uninfected (HEU) [15–18]. HEU children may, however, have increased risk of morbidity and mortality than infants born to HIV-uninfected mothers (i.e. HUU) [19,20]. This may be due to perturbations of the immune systems of HEU infants due to in-utero HIV virion particle exposure and/or ART-exposure [21–26], affecting lymphocyte differentiation and function [21–24,27,28]. There are conflicting data on vaccine-related immune responses of HEU compared with HUU children. These include variable responses to BCG vaccine [29,30], tetanus toxoid, pertussis, Haemophilus influenzae type b-conjugate (HibCV), hepatitis B vaccine (HBV) and pneumococcal conjugate vaccines (PCV) [13,31,32]. Differences in immune responses to some vaccines in HEU compared with HUU children is attributed to lower maternal-derived vaccine-epitope-specific antibody in HEU children, possibly reducing interference in immune responses to the homotypic vaccines [31,32].

The aim of this study was to evaluate the effect of HIV exposure in HIV-uninfected and timing of ART initiation in HIV-infected children on the kinetics of antibodies to epitopes of diphtheria-toxoid, tetanus-toxoid, whole cell pertussis-HibCV (i.e. DTwP-HibCV) and monovalent HBV prior to and 1-month following the primary three-dose series of vaccines. The HUU group was the referent group for comparison of immune responses in relation to other groups.

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Methods

Study population

The study was conducted on archived serum samples from a study investigating the effects of HIV exposure and timing of ART initiation in HIV-infected infants on immune responses to seven-valent PCV [13,14]. Briefly, four groups of infants aged 6–12 weeks were enrolled at two South African Centers (Chris Hani-Baragwanath Hospital in Soweto, Johannesburg and Tygerberg Children's Hospital, Stellenbosch) from April 2005 to June 2006 (See on-line supplementary material for Study participant selection criteria, http://links.lww.com/QAD/A443). HUU infants born to HIV-uninfected mothers (confirmed by a nonreactive HIV ELISA at enrolment); and HEU infants in whom HIV-PCR was nonreactive at enrolment. HIV-infected infants participating in the ‘Children with HIV Early Antiretroviral (CHER)’ study were co-enrolled [9]. The latter were aged less than 12 weeks with CD4% ≥25% and randomized to deferred ART until immunological and/or clinically indicated (ART-Def) or immediately started on ART upon confirmation of their HIV-infection status (ART-Immed). Additionally, a convenience sample of HIV-infected infants from CHER with CD4+ <25% (ART-CD4<25%) was recruited. The first-line ART regimen in CHER included zidovudine, lamivudine and lopinavir-ritonavir. Following an interim analysis of the CHER study in which HIV-disease progression to AIDS or death was greater in ART-Def compared with ART-Immed infants, the Data Safety and Monitoring Board recommended halting recruitment to the ART-Def group and that all infants in this group be evaluated whether they required ART to be initiated [9].

Participants were scheduled to receive three doses of combined DTwP-HibCV (CombAct-Hib, Sanofi Pastuer, France) and monovalent recombinant HBV (HerberBiotec S.A., Cuba) at approximately 6, 10 and 14 weeks of age with a 4–6 week interval between doses. Both, DTPw-HibCV and HBV were administered at separate sites in the left arm, PCV (Prevnar-7; Wyeth Vaccines and Pediatrics, Philadelphia, Pennsylvania, USA) in the right arm and trivalent oral polio vaccine (POLIORAL-trivalEnt, Novartis Vaccines and Diagnostics, Srl, Italy) orally.

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Sample collection

Clotted blood samples were collected immediately prior to the first DTwP-Hib/HBV dose and 1-month following the third dose. Blood samples were stored in a cooler box and transported within 4 h to the site laboratory. This included the Respiratory and Meningeal Pathogens Research Unit (RMPRU), which is based at Chris Hani-Baragwanath Hospital for the Johannesburg site. The blood samples were then centrifuged and aliquots of serum were stored at −70°C. Samples from Stellenbosch were subsequently couriered on dry ice to RMPRU, where it was also archived at −70°C until testing was done at RMPRU. Antibody to diphtheria-toxoid, tetanus-toxoid, pertussis toxoid, filamentous hemagglutinin (FHA) and hepatitis B surface antigen (HBsAg) were measured by an in-house Luminex-multiplex immunoassay and polyribosyl-ribitol phosphate (PRP for HibCV) antibodies by standard ELISA and bactericidal assay. (See on-line as supplementary material for Luminex assay methods and validation results, http://links.lww.com/QAD/A443).

Data were acquired in real-time using Bio-plex Manager 5.0 (Bio-Rad Laboratories, Hemel Hempstead, UK) software. Values for unknown test sera were generated from a standard curve of median fluorescent intensity (MFI) against expected IgG concentration for the in-house reference sera and converted to either IU/ml or mIU/ml. The limits of quantification (LOQ) were 0.001 IU/ml for anti-diphtheria-toxoid and anti-tetanus-toxoid, 20 IU/ml for anti-pertussis toxoid, 2 IU/ml for anti-FHA and 10 mIU/ml for anti-HBsAg, these values were regarded as sero-positive thresholds. Samples with a titer below the LOQ were assigned a titer of half the LOQ when calculating geometric mean concentrations (GMC). The specificity of the assay was more than 92% for all tested antibodies and the coefficient of variation for intra-assay and inter-assay ranged between 5 and 22% for individual assays.

Polyribosyl-ribitol phosphate IgG antibodies were measured by standardized in-house enzyme immunoassay [33], with samples below detection limit assigned a concentration half the detection limit (i.e. 0.06 μg/ml) when calculating GMCs. Polyribosyl-ribitol phosphate conjugated to human serum albumin (HbO-HA) was purchased from the National Institute for Biological Standards and Control (NIBSC, London, UK). Antibody activity was measured by bactericidal assay as described previously [34,35]. Titers were given as the reciprocal serum dilution for 50% killing activity. The lower limit of detection for the assay was a titer of 8, with samples below the threshold assigned an arbitrary value of 4.

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Serological correlates of protection

The antibody thresholds used as serological correlates for protection were defined as antibody concentrations greater or equal to 0.01 and 0.1 IU/ml for diphtheria-toxoid, 0.1 IU/ml for tetanus-toxoid, 10 mIU/ml for HBsAg and 0.15 μg/ml for PRP (i.e. Hib epitope) [36]. The surrogate for measuring immune responsiveness to pertussis was defined as at least four-fold increase in antibody titer from prevaccination to postvaccination for pertussis toxoid and FHA [36]. Alternate antibody threshold levels evaluated included ≥100 mIU/ml for HBsAg and ≥1.0 μg/ml for PRP, which may be a predictor for long-term protection [36].

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Statistical analyses

Descriptive statistics were reported for demographic and baseline features of participants included in this study. Paired t-tests were used in the comparison of pre and postvaccination CD4+ percentages. Prevaccination and postvaccination GMCs and proportions with sero-protective levels or surrogates of antibody responses were compared using analysis of covariance and multivariate logistic regression, respectively, considering sex, age, race (black African or mixed ancestry), CD4+ lymphocyte percentage, study center, birth weight, mother-to-child HIV-prevention antiretroviral regimen and prevaccination antibody concentrations. To minimize additional confounders, the analysis was limited to children who received all three-vaccine doses and had both prevaccination and postvaccination bloods for immunogenicity assays collected within protocol-specified window periods. For all the tests, a two-sided P-value ≤0.05 was considered statistically significant.

Statistical analyses were performed using GraphPad Prism 5a (GraphPad Software Inc, La Jolla, California, USA), R (R Foundation for Statistical Computing, Vienna, Austria) and STATA statistical package (STATA Corporation, College Station, Texas, USA).

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Ethics

This sub-study was approved by the Human Research Ethics Committee (HREC) of the University of the Witwatersrand (M080966). The study from which samples were obtained was approved by HREC, the Ethics Committee of Stellenbosch University, Medicine Control Council (South Africa) and the Division of AIDS of the National Institute for Health (NIH) and was registered under Clinical Trials number (NCT00099658).

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Results

Samples from 493 (85.3%) of 578 children in the parent-study were available as shown in Table 1. The main reasons for unavailability of samples postvaccination were the high mortality rate in ART-Def infants as reported [9] and visits undertaken beyond the protocol-defined window-period; Fig. 1. The mean age at prevaccination (±SD) was 7.3 (SD 1.3) weeks and 19.5 (SD 1.3) weeks at postvaccination being similar between groups; Table 1. Forty six % were male and 90.7% were of black-African descent; Table 1. All infants in the ART-Immed and ART-CD4<25% groups were initiated on ART within 4 days prior to the first DTwP-HibC/HBV dose. Thirteen (16.9%) ART-Def infants were initiated on ART at a median of 40 days following the first vaccine-doses [13]. The mean CD4+-lymphocyte percentages were 35.1% in ART-Immed, 37.5% in ART-Def and 22.0% in ART-CD4<25% group prevaccination; and 40.7% (P < 0.001), 30.1% (P < 0.001) and 27.5% (P = 0.06) 1-month post third-dose in the respective groups; Table 1.

Table 1
Table 1
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Fig. 1
Fig. 1
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Antibody responses in HUU compared to HIV-infected infants
Prevaccination

Compared to HUU, ART-Immed and ART-Def infants had lower antibody GMCs to tetanus-toxoid (P < 0.001 for both), HBsAg (P = 0.01 for ART-Immed; P = 0.002 for ART-Def) and pertussis toxoid (P < 0.001 for both); Table 2. The proportion of infants with antibodies above the sero-protective threshold were generally similar between HUU and the HIV-infected groups, except for HBV which was lower in ART-Def (39.5% vs. 49.6% in HUU, P = 0.03); Table 2.

Table 2
Table 2
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Postvaccination

Compared to HUU, lower postvaccination GMCs were observed in the ART-Immed and ART-Def groups for tetanus-toxoid (P < 0.001 for both) and HBsAg (P < 0.001 for both); Table 3. Also, lower GMCs were observed in ART-Immed infants to diphtheria-toxoid (P = 0.001) and FHA (P < 0.001), as well as for pertussis toxoid in ART-Def children (P < 0.001) compared to HUU infants, Table 3.

Table 3
Table 3
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In HUU, despite higher postvaccination antibody GMCs to some epitopes, the proportion with sero-protective levels of antibody were similar for tetanus-toxoid (82.7% to 100%), diphtheria-toxoid at ≥0.01IU/ml (100%), PRP (>96%) and HBsAg (>84%) compared to ART-Immed and ART-Def infants; Table 3. Also, a similar proportion in each group had antibody above ≥1.0 μg/ml for PRP (>88%), HBsAg ≥100mIU/ml (>84%) and diphtheria-toxoid ≥0.1IU/ml (76.9 to 100%); Table 3. Sero-conversion rates associated with pertussis vaccination, however, were higher in HUU (38.2%) for FHA compared to ART-Immed infants (20.6%, P = 0.008), and lower for pertussis toxoid in HUU (39.1%) compared with ART-Def (51.4%, P = 0.02) infants, Table 3.

Despite no differences in PRP antibody concentrations, the SBA geometric mean titers (GMTs) were higher for HUU than ART-Def infants (P < 0.001) and more HUU infants had SBA titers ≥8 (90.3 vs. 71.1%; P < 0.001). There was no difference in SBA GMTs or proportion with titers ≥8 in HUU compared with ART-Immed infants; Table 3.

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Antibody responses in HUU compared with HEU infants
Prevaccination

Prior to vaccination, HEU only had lower antibody GMCs to tetanus-toxoid (P = 0.001) than HUU infants; but higher GMCs for diphtheria-toxoid, HBsAg and FHA (P < 0.001 for all); Table 2. HEU were also more likely than HUU infants to have sero-protective diphtheria-toxoid (61.0 vs. 29.2%, P < 0.001) and HBsAg (80.5 vs. 49.6%, P < 0.001) antibody concentrations at prevaccination; Table 2.

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Postvaccination

Antibody GMCs were similar postvaccination between HUU and HEU for tetanus-toxoid, diphtheria-toxoid, PRP and FHA. Antibody GMCs in HUU were, however, slightly higher for HBsAg (2521.0 vs. 2019.3 mIU/ml; P = 0.041) and lower for pertussis-toxoid (134.3 vs. 261.3 IU/ml, P < 0.001) than in HEU; Table 3.

A high proportion (>99%) of HEU and HUU children developed sero-protective levels to tetanus-toxoid, diphtheria-toxoid, HBV and PRP postvaccination, which did not differ by group. Similarly, more than 99% of HUU and HEU infants had antibody levels ≥100 mIU/ml to HBsAg and more than 88% had ≥1.0 μg/ml to PRP postvaccination. The proportion of HUU compared with HEU children with sero-conversion (i.e. at least four-fold increase between prevaccination and postvaccination) to pertussis antigens was similar for FHA (38.2 vs. 21.6%; P = 0.53), however, against pertussis toxoid this proportion was lower in HUU infants (39.1 vs. 76.7%; P > 0.001). There was no difference in SBA GMTs or proportion with SBA titers ≥8 between HUU (90.3%) and HEU (94.1%) infants; Table 3.

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Antibody responses in HEU compared to HIV-infected infants
Prevaccination

Prevaccination antibody GMCs were lower in ART-Immed and ART-Def children than HEU infants for all epitopes (P < 0.001 for all comparisons), except for PRP; Table 2. HEU infants were also more likely to have sero-protective antibody concentrations against diphtheria-toxoid (61.0%) and HBV (80.5%) compared with ART-Immed (39.9, and 45.8%, respectively) and ART-Def (34.2, and 39.5%, respectively); P < 0.001 for all comparisons, Table 2.

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Postvaccination

Postvaccination antibody GMCs were higher in HEU than ART-Immed or ART-Def infants to tetanus-toxoid, diphtheria-toxoid, PRP, HBsAg and PT; Table 3. The proportion of children with sero-protective antibody levels were similar in HEU and ART-Immed infants, although the latter were less likely to have anti-diphtheria-toxoid antibody ≥0.1 IU/ml for diphtheria-toxoid (99.2 vs. 76.9%; P < 0.001). In contrast, lower proportions of ART-Immed infants had sero-protective antibody levels postvaccination compared to HEU infants to tetanus-toxoid (82.7 vs. 98.3%; P = 0.02), diphtheria-toxoid at the ≥0.1 IU/ml threshold (80.0 vs. 99.2%; P = 0.001), HBV at ≥100 mIU/ml threshold (84.0 vs. 99.2%; P = 0.02) and were also less likely to demonstrate sero-conversion to pertussis toxin (51.4 vs. 76.7%; P < 0.001); Table 3. HEU also had higher SBA GMTs compared with either ART-Immed (P = 0.03) or ART-Def (P < 0.001) groups and were also more likely (94.1%) to have SBA titers ≥8 compared with ART-Immed (87.8%, P = 0.06) and ART-Def infants (71.1%, P = 0.02).

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Antibody responses in antiretroviral treatment-Immed compared to antiretroviral treatment-Def infants
Prevaccination

There were no differences between ART-Immed and ART-Def groups prior to vaccination in either GMCs or the proportion of children with sero-protective antibody levels for any vaccine; Table 2

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Postvaccination

Postimmunization immune GMCs against most epitopes were similar, but higher in ART-Immed for HBV (P = 0.017) and lower for FHA (P = 0.02) than ART-Def infants; Table 3. A similar proportion of ART-Immed and ART-Def infants developed antibody concentrations above the sero-protective threshold for most vaccines, except for more ART-Immed infants with tetanus-toxoid antibody ≥0.1 IU/ml (92.3 vs. 82.7%; P = 0.03) and HBsAg antibody ≥100 mIU/ml (97.0 vs. 84.0%; P = 0.02). Serum bactericidal assay GMTs trended to be higher in ART-Immed children, among whom it was more likely to be ≥8 (87.8%) compared with ART-Def group (71.1%; P = 0.02; Table 3).

The proportion of ART-CD4 < 25% group with sero-protective levels of antibody and/or with sero-conversion to pertussis-toxoid and FHA was similar to ART-Immed infants.

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Sensitivity analysis

Because of the imbalance of race in the population among the different groups, a sensitivity analysis was performed restricting the analysis to black African participants. P-values were similar to those when including mixed race participants suggesting that any differences can be attributed to HIV exposure and not race (data not shown).

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Discussion

This is the first and most-comprehensive study evaluating immune responses to routine vaccines in HIV-infected infants receiving early ART, irrespective of CD4+ count/percentage according to current WHO recommendations [37]. Our findings show that early ART in HIV-infected infants, is associated with similar quantitative and qualitative immune responses to vaccines as in HUU infants. Although the immune responses in infants among whom ART was deferred was generally similar to the ART-Immed group, the ART-Def infants had lower proportion with anti-HBsAg antibody ≥100 mIU/ml and was also associated with lower levels of functional antibody to HibCV. A similar observation was observed on opsonophagocytic activity assay following PCV vaccination in ART-Def compared to ART-Immed groups [13]. Therefore, only measuring quantitative antibody responses could over-estimate protection induced by some vaccines among HIV-infected infants not yet on ART.

Differences observed between ART-Immed and ART-Def infants may have been masked by survivor bias in the ART-Def group especially in the postvaccination comparison. It is plausible that vaccine immune responses were even poorer among ART-Def infants who died compared to surviving children. A recent review on the association of ART on vaccine immune responses in HIV-infected children, included studies in older children re-vaccinated between 28 weeks and 5.3 years after ART initiation [38]. We report a higher proportion of children with sero-protective antibody concentrations than in previous studies, undertaken prior to early ART initiation in infants becoming policy, where the proportion of HIV-infected children without severe immunosuppression developing sero-protective antibody levels varied between 37 and 86% with GMCs generally much lower than in HIV-uninfected infants [39–41].

Our data on the relative immune responses to DTwP-HibCV/HBV in HEU compared with HUU infants differed from other reports. In-utero HIV-exposure was not consistently associated with lower GMCs prior to immunization in HEU compared with HUU infants as proposed by others [31,32,42–44]. Although we also identified lower GMCs to tetanus-toxoid in HEU infants prevaccination, the converse was true for antibody GMCs to diphtheria-toxoid, HBsAg and FHA. This could be due to regional differences in maternal antibody concentrations to different vaccine-epitopes and variations in factors which may influence transplacental antibody transfer, including differences in maternal HIV-viral load, total IgG antibody concentrations and placental function sufficiency in different populations [31,32,42–44]. These factors may influence HEU infants’ susceptibility to vaccine-preventable diseases during early infancy and prior to vaccination.

Comparing HEU and HUU infants, HEU had a trend toward lower prevaccination anti-pertussis toxoid GMCs but higher postvaccination levels, and conversely had higher prevaccination HBsAg antibody GMCs, but lower postvaccination levels to HBsAg. This corroborates that higher epitope-specific antibody levels prevaccination may interfere with the immunogenicity to homotypic epitopes. The higher preimmunization HBsAg antibody GMCs in HEU in our study has been attributed to higher hepatitis B virus infection prevalence in HIV-infected than HIV-uninfected women [45]. However, we also observed higher antibody levels to HBsAg and other vaccine-epitope GMCs (except PRP) in HEU compared with both ART-Immed and ART-Def infants. Our study did not determine HIV-infection status at birth and since only 10% of HIV-exposed infants were breast-fed, it is likely that the majority of HIV-infection in infants of our cohort occurred either in utero or the immediate peri-partum period. Therefore, differences in prevaccination GMCs to most epitopes between HEU and either ART-Immed or ART-Def infants, suggests an association between factors related to acquiring maternal-derived vaccine-related antibodies and the risk of the infant being HIV-infected. Placental abnormalities can affect transplacental antibody transfer. For example, placentas from HIV-infected women from the Tygerberg site showed a higher percentage of villitis and infarcts than from HIV-uninfected controls, especially in women with CD4+ cell counts below 200 cells/μl [46].

Our study has some limitations, including that we were unable to distinguish in utero from intra-partum infection and placentas were not collected in our study. Also, we recruited only a small number of HIV-infected infants in whom with baseline CD4+ lymphocyte <25%. Data from CHER showed that by 7 weeks of age, 20% of HIV-infected infants already have severe CD4+-lymphocyte depletion. The trends in immune responses in the ART-CD4<25% group included in our study was, however, similar to that of ART-Immed infants. Also, despite having used whole cell pertussis vaccine, we elected to measure antibody to pertussis toxoid and FHA rather than using the whole-cell pertussis ELISA assay, as this was more practical for inclusion in the multiplex Luminex assay. The pertussis toxoid and FHA antibody responses, although providing a relative measure of immunogenicity of the whole cell pertussis vaccine between groups in our study, is not recommended as a measure of immunogenicity of whole cell pertussis vaccine.

In conclusion, HEU infants were not at increased susceptibility to most of the studied vaccine-preventable diseases by 6-weeks of age, suggesting similar acquisition of antibody from their mothers in our study. Furthermore, the immune responses in HEU were similar to HUU infants postvaccination. Although HIV-infected children had lower GMCs postvaccination, including to tetanus-toxoid and HBsAg irrespective of timing of ART initiation, the proportion with sero-protective antibody concentrations postvaccination were similar and timing of ART initiation generally did not affect immune responses between the HIV-infected groups. Our study indicates that vaccination of HEU and HIV-infected infants initiated on early-ART confers with DTwP-HibCV/HBV would provide similar immunity to the targeted vaccine-preventable disease compared with HUU infants. The persistence of sero-protective antibody concentrations and anamnestic responses to the studied vaccines among HEU and HIV-infected children initiated on early ART needs to be investigated.

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Acknowledgements

Collaborators and Centers for study: South Africa: Avy Violari, James McIntyre, Wilma Pelser, Ravindre Panchia, Kennedy Otwombe, Afaaf Liberty, Nastassja Choolinal (Perinatal HIV Research Unit); Mark F Cotton, Helena Rabie, Anita Janse van Rensburg, Els Dobbels, George Fourie, Marietjie Bester, Wilma Orange, Ronelle Arendze, Catherine Andrea, Marlize Smuts, Kurt Smith, Theresa Louw, Alec Abrahams, Kenny Kelly, Amelia Bohle, Irene Mong, Jodie Howard, Tanya Cyster, Genevieve Solomon, Galroy Benjamin, Jennifer Mkhalipi, Edward Barnes (Children's Infectious Diseases Clinical Research Unit); Peter Adrian; Shabir A Madhi; Nadia van Niekerk (Respiratory and Meningeal Pathogens Research Unit). United States of America: Karen Reese, Patrick Jean-Philippe (HJF-DAIDS). United Kingdom: Diana M Gibb, Abdel Babiker (Medical Research Council Clinical Trials Unit, London). We acknowledge the assistance of Dr Marta Nunes in the editing of this article.

Author contributions: O.E.S., P.V.A. and S.A.M. were involved in study design. O.E.S. and P.V.A. were involved in setting up the assays and testing of samples. NvN assisted in processing of the samples. O.E.S. and A.I. undertook the data analysis. O.E.S. and S.A.M. were the primary authors of the article. A.V. and M.F.C. were involved in patient enrolment. All authors critically reviewed the article and approved the final submission.

This study was funded through the Department of Science and Technology/National Research Foundation: South African Research Chair Initiative in Vaccine Preventable Diseases. The parent study was funded by National Institute of Allergy and Infectious Diseases (NIAID) of the US National Institutes for Health (NIH), through the Comprehensive International Program of Research on AIDS (CIPRA) network, grant number U19 AI53217. Additional support for this work was provided with Federal funds from the National Institute of Allergies & Infectious Diseases, National Institutes of Health, Department of Health and Human Services, under Contract No. HHSN272200800014C.

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Conflicts of interest

There are no conflicts of interest.

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References

1. Resino S, Galan I, Perez A, Leon JA, Seoane E, Gurbindo D, et al. HIV infected children with moderate/severe immune-suppression: changes in the immune system after highly active antiretroviral therapy. Clin Exp Immunol 2004; 137:570–577.

2. Letvin NL, Walker BD. Immunopathogenesis and immunotherapy in AIDS virus infection. Nat Med 2003; 9:861–866.

3. Palumbo P, Hoyt L, Demasio K, Oleske J, Connor E. Population based study on measles and measles immunization in human immunodeficiency virus infected children. Pediat Infect Dis J 1992; 11:1008–1014.

4. Borkowsky W, Rigaud M, Krasinski K, Moore T, Lawrence R, Pollack H. Cell mediated and humoral immune responses in children infected with human immunodeficiency virus during the first four years of life. J Pediat 1992; 120:371–375.

5. Lane HC, Masur H, Edgar LC, Whalen G, Rook AH, Fauci AS. Abnormalities of B-cell activation and immunoregulation in patients with acquired immunodeficiency syndrome. N Engl J Med 1983; 309:453–458.

6. Shearer WT, Easley KA, Goldfarb J, Rosenblatt HM, Jenson HB, Kovacs A, et al. Prospective 5-year study of peripheral blood CD4, CD8, and CD19/CD20 lymphocytes and serum Igs in children born to HIV-1 mothers. J Allerg Clin Immunol 2000; 106:559–566.

7. Pensieroso S, Cagigi A, Palma P, Nilsson A, Capponi C, Freda E, et al. Timing of HAART defines the integrity of memory B cells and the longevity of humoral responses in HIV-1 vertically-infected children. Proc Natl Acad Sci 2009; 106:7939–7944.

8. al-Attar I, Reisman J, Muehlmann M, McIntosh K. Decline of measles antibody titers after immunization in human immunodeficiency virus-infected children. Pediatr Infect Dis J 1995; 14:149–151.

9. Violari A, Cotton MF, Gibb DM, Babiker AG, Steyn J, Madhi SA, et al. Early antiretroviral therapy and mortality among HIV-infected infants. N Engl J Med 2008; 359:2233–2244.

10. Melvin AJ, Mohan KM. Response to immunization with measles, tetanus and Haemophilus influenzae type b vaccines in children who have human immunodeficiency virus type 1 and are treated with highly active antiretroviral therapy. Pediatrics 2003; 111:641–644.

11. Valdez H. Immune restoration after treatment of HIV-1 infection with highly active antiretroviral therapy (HAART). AIDS Rev 2002; 4:157–164.

12. Obaro SK, Pungatch D, Luzuruago K. Immunogenicity and efficacy of childhood vaccines in HIV-1 infected children. Lancet 2004; 4:510–518.

13. Madhi SA, Adrian P, Cotton MF, McIntyre JA, Jean-Philippe P, Meadows S, et al. Effect of HIV infection status and antiretroviral treatment on quantitative and qualitative antibody responses to pneumococcal conjugate vaccine in infants. J Infect Dis 2010; 202:355–361.

14. Simani OE, Adrian PV, Violari A, Kuwanda L, Otwembe K, Nunes M, et al. Effect of in-utero HIV exposure and antiretroviral treatment strategies on measles susceptibility and immunogenicity of measles-vaccine. AIDS 2013; 27:1583–1591.

15. Chuachoowong R, Shaffer N, Siriwasin W, Chaisilwattana P, Young NL, Mock PA, et al. Short course antenatal zidovudine reduces both cervicovaginal human immunodeficiency virus type 1 RNA levels and risk of perinatal transmission. J Infect Dis 2000; 181:99–106.

16. Connor EM, Sperling RS, Gelber R, Kiselev P, Scott G, O'Sullivan MJ, et al. Reduction of maternal-infant transmission of human immunodeficiency virus type 1 with zidovudine treatment. N Engl J Med 1994; 331:1173–1180.

17. Kind C, Rudin C, Siegrist C, Wyler CA, Biedermann K, Lauper U, et al. Prevention of vertical HIV infection: additive protective effect of elective cesarean section and zidovudine prophalaxis. AIDS 1998; 12:205–210.

18. Simonds RJ, Steketee R, Nesheim P, Matheson P, Palumbo P, Algeret L, et al. Impact of zidovudine use on risk and risk factors for perinatal transmission of HIV. AIDS 1998; 12:301–308.

19. Newell ML, Coovadia H, Cortina-Borja M, Rollins N, Gaillard P, Dabis F, et al. Mortality of infected and uninfected infants born to HIV-infected mothers in Africa: a pooled analysis. Lancet 2004; 364:1236–1243.

20. Koyanagi A, Humphrey JH, Ntozini R, Nathoo K, Moulton LH, Iliff P, et al. Morbidity among human immunodeficiency virus-exposed but uninfected, human immunodeficiency virus-infected, and human immunodeficiency virus-unexposed infants in Zimbabwe before availability of highly active antiretroviral therapy. Pediatr Infect Dis J 2011; 30:45–51.

21. Hygino J, Lima PG, Filho RGS, Silva AAL, Saramago CSM, Andrade RGM, et al. Altered immunological reactivity in HIV-1-exposed uninfected neonates. Clin Immunol 2008; 127:340–347.

22. Faye A, Pornprasert S, Mary JY, Dolcini G, Derrien M, Barré-Sinoussi F, et al. Characterization of the main placental cytokine profiles from HIV-1-infected pregnant women treated with antiretroviral drugs in France. Clin Exp Immunol 2007; 149:430–439.

23. Bunders M, Thorne C, Newell ML. Maternal and infant factors and lymphocyte, CD4 and CD8 cell counts in uninfected children of HIV-1-infected mothers. AIDS 2005; 19:1071–1079.

24. Clerici M, Saresella M, Colombo F, Fossati S, Sala N, Bricalli D, et al. T-lymphocyte maturation abnormalities in uninfected newborns and children with vertical exposure to HIV. Blood 2000; 96:3866–3871.

25. Gesner M, Papaevangelou V, Kim M, Chen S, Moore T, Krasinski K, et al. Alteration in the proportion of CD4 T lymphocytes in a subgroup of human immunodefiency virus-exposed-uninfected children. Pediatrics 1994; 93:624–630.

26. Neilsen SD, Jeppesen DL, Kolte L, Clark DR, Sorensen TU, Dreves A, et al. Impaired progenator cell function in HIV-negative infants of HIV-positive mothers results in decreased thymic output and low CD4 counts. Blood 2001; 98:398–404.

27. Feiterna-Sperling C, Weizsaecker K, Bührer C, Casteleyn S, Loui A, Schmitz T, et al. Hematologic effects of maternal antiretroviral therapy and transmission prophylaxis in HIV-1-exposed uninfected newborn infants. JAIDS 2007; 45:43–51.

28. Borges-Almeida E, Milanez HMBM, Vilela MMS, Cunha FGP, Abramczuk BM, Reis-Alves SC, et al. The impact of maternal HIV infection on cord blood lymphocyte subsets and cytokine profile in exposed noninfected newborns. BMC Infect Dis 2011; 11:38–48.

29. Van Rie A, Madhi SA, Heera JR, Meddows-Taylor S, Wendelboe AM, Anthony F, et al. Gamma inteferon production in response to Mycobacterium bovis BCG and Mycobacterium tuberculosis antigens in infants born to human immunodeficiency virus-infected mothers. Clin Vaccine Immunol 2006; 13:246–252.

30. Mahomed H, Kibel M, Hawkridge T, Schaaf HS, Hanekom WA, Iloni K, et al. The impact of a change in Bacille Calmette-Guérin vaccine policy on tuberculosis incidence in children in Cape Town, South Africa. Pediatr Infect Dis J 2006; 25:1167–1172.

31. Jones CE, Naidoo S, De Beer C, Esser M, Kampmann B, Hesseling AC. Maternal HIV infection and antibody responses against vaccine-preventable diseases in uninfected infants. JAMA 2011; 305:576–584.

32. Abramczuk BM, Mazzola TN, Moreno YM, Zorzeto TQ, Quintilio W, Wolf PS, et al. Impaired humoral response to vaccines among HIV-exposed uninfected infants. Clin Vaccine Immunol 2011; 18:1406–1409.

33. Kurikka S, Kayhty H, Saarrinen L, Ronnberg PR, Eskola J, Makela PH. Immunologic priming by one dose of Haemophilus influenzae type b conjugate vaccine in infancy. J Infect Dis 1995; 172:1268–1272.

34. Romero-Steiner S, XXX FJ, Biltoft C, Wohl ME, Sanchez J, Feris J, et al. Functional antibody activity elicited by fractional doses of Haemophilus influenzae type b conjugate vaccine (polyribosylribitol phosphate-tetanus toxoid conjugate). Clin Diag Lab Immunol 2001; 8:1115–1119.

35. Schlesinger Y, Granoff DM. Avidity and bactericidal activity of antibody elicited by different Haemophilus influenzae type b conjugate vaccine. JAMA 1992; 267:1489–1494.

36. Plotkin SA. Correlates of protection induced by vaccination. Clin Vacc Immunol 2010; 17:1055–1065.

37. WHOAntiretroviral therapy for HIV infection in infants and children: Towards universal access: Recommendations for a Public Health approach: 2010 Revision. Geneva:World Health Organization; 2010.

38. Sutcliffe CG, Moss WJ. Do children infected with HIV receiving HAART need to be re-vaccinated?. Lancet Infect Dis 2010; 10:630–642.

39. Madhi SA, Peterson K, Khoosal M, Huebner RE, Mbelle N, Mothupi R, et al. Reduced effectiveness of Haemophilus influenzae type b conjugate vaccine in children with high prevalence of human immunodeficiency virus type 1 infection. Pediatr Infect Dis 2002; 21:315–321.

40. Peters VB, Sood SK. Immunity to Haemophilus influenzae type b after reimmunization with oligosaccharide CRM197 conjugate vaccine in children with human immunodeficiency virus infection. Pediatr Infect Dis J 1997; 16:711–713.

41. Rustein RM, Rudy BJ, Cnaan A. Response of human immunodeficiency virus-exposed and infected infants to Haemophilus influenzae type b conjugate vaccine. Arch Pediatr Adolesc Med 1996; 150:838–841.

42. Scott S, Moss WJ, Cousens S, Beeler JA, Audet SA, Mugala N, et al. The influence of HIV-1 exposure and infection on levels of passively acquired antibodies to measles virus in Zambian infants. Clin Infect Dis 2007; 45:1417–1424.

43. Montoya CJ, Toro MF, Aguirre C, Bustamante A, Hernandez M, Aranggo LP, et al. Abnormal humoral immune response to influenza vaccination in pediatric type-1 human immunodeficiency virus infected patients receiving highly active antiretroviral therapy. Mem Inst Oswaldo Cruz 2007; 102:501–508.

44. Miyamoto M, Pessoa SD, Ono E, Machado DM, Salomao R, Succi RC, et al. Low CD4+ T-cell levels and B-cell apoptosis in vertically exposed noninfected children and adolescents. J Trop Pediat 2010; 56:427–432.

45. Rieke BA, Naidoo S, Ruck CE, Slogrove AL, de Beer C, la Grange L, et al. Antibody responses to vaccination among South African HIV-exposed and uninfected infants during the first 2 years of life. Clin Vaccine Immunol 2013; 20:33–38.

46. Vermaak A, Theron GB, Schubert PT, Kidd M, Rabie U, Adjiba BM, et al. Morphologic changes in the placentas of HIV-positive women and their association with degree of immune suppression. Int J Gynecol Obst 2012; 119:239–243.

Keywords:

diphtheria vaccine; Haemophilus influenzae type b conjugate vaccine; hepatitis B vaccine; HIV-exposed uninfected; HIV-infected; pertussis vaccine; tetanus vaccine

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