Establishing communication challenges and preferences among clinical trial participants in an under-resourced setting to improve adherence to study visits and participant retention.

BACKGROUND: Ensuring protocol visit compliance and maintaining high participant retention remain critical elements of clinical trials. In the HVTN 702 HIV vaccine trial, Setshaba Research Centre in Soshanguve, Tshwane, South Africa, experienced challenges in communicating with participants to remind them about their study visits. In order to improve participants adhering to their study visits, and study retention, we aimed to identify challenges in mobile communication, and to establish preferences in communication methods and interest in receiving study information via cellphones. METHODS: We conducted a paper-based survey among HVTN 702 HIV vaccine trial participants at Setshaba Research Centre. The survey comprised of dichotomous and scale questions and was completed voluntarily and anonymously. The questions included those on their primary form of communication (calling, SMS and WhatsApp), the best time of day for the site to communicate with them, whether they were interested in receiving regular general study information updates via their cellular phone, how often they changed their cellular phones and/or network, whether they experienced any challenges with their cellular phones and what these challenges were, if any. All participants scheduled to visit the clinic from February to May 2019 were invited to participate. Thus, 90 of 380 (24%) participants enrolled by May 2019 were surveyed. RESULTS: The majority (68%) of participants were 26-35 years old and almost three-quarters (73%) were female. Almost all participants (99%) had a personal cellphone. Half of the participants experienced some challenge related to cellphones, these being poor network signal at home (12%), battery running flat frequently (11%), sharing their phone (9%), lack of data (9%), challenges with use of applications (6%) and their cellphones being unreliable (3%). Annually, 20% of participants made a single or multiple network changes. Communication preferences were calls by site staff (80%), SMS (16%) and WhatsApp (3%). Most preferred to be contacted in the morning (49%) or afternoon (31%). Site contact was rated as 'very helpful' (87%), and 97% were interested in receiving regular general study information updates via their cellphone. CONCLUSION: Despite participants owning cellphones, there are still technical challenges, for example, network signals, battery-charging and applications. The majority of participants preferred being called rather than communicating by text messages or WhatsApp. Future studies need to include addressing participant challenges in maintaining contact and training of participants on use of cellphone applications to optimise communication. Noting the preferred time of day for participants to be called might improve the likelihood of making contact with them. The willingness to receive updates will aid in keeping participant interest high and enhance retention.

Bacterial nasopharyngeal carriage following infant immunization with pneumococcal conjugate vaccines according to a 2+1 schedule in children in South Africa: an exploratory analysis of two clinical trials.

Background: We evaluated bacterial nasopharyngeal carriage (NPC) prevalence and cumulative acquisition following 7-valent pneumococcal conjugate vaccine (PCV7) or pneumococcal non-typeable Haemophilus influenzae protein D conjugate vaccine (PHiD-CV) administration. Methods: Participants were children from two clinical trials in a South African center who received PCV7 (n = 250) or PHiD-CV (n = 100) at ~6 weeks, ~14 weeks, and ~9-10 months of age, and were enrolled between Dec2009-Apr2010 and Mar2009-May2010 in the PCV7 and PHiD-CV studies, respectively. Sample collection, most microbiological assessments, and data re-analysis methods were identical. Results: NPC prevalence of any pneumococcal serotype was 18.5% and 17.0% at pre-vaccination, and 63.1% and 67.3% in 24-27 month-old children among PCV7 and PHiD-CV recipients, respectively. In 24-27 month-old children, 96.1% and 99.0% of PCV7 and PHiD-CV recipients had acquired ≥1 pneumococcal serotype, 53.7% and 62.9% ≥1 PCV7 serotype, 1.5%, and 3.1% ≥1 of serotypes 1, 5 or 7F, 23.2% and 19.6% serotype 6A, 23.2% and 21.7% serotype 19A, 88.7%, and 91.0% H. influenzae, and 50.3% and 62.9% Staphylococcus aureus, respectively. Conclusions: This analysis of two concurrent clinical trials did not reveal differences in bacterial NPC prevalence or acquisition in PCV7- and PHiD-CV-vaccinated children. Trial registration: South African National Clinical Trial Register (NHREC DOH-27-0511-299); ClinicalTrials.gov (NCT00829010).

Residual colonization by vaccine serotypes in rural South Africa four years following initiation of pneumococcal conjugate vaccine immunization.

BACKGROUND: We evaluated pneumococcal colonization in children and adults between the time of 7-valent pneumococcal conjugate vaccine (PCV) introduction in the immunization program in 2009 to two years after transitioning to PCV13 in 2011. METHODS: Community-based carriage surveillance was undertaken between May-November 2013 (Period-3), with similar surveys in 2009 (Period-1) and 2011 (Period-2). Households with children below two years had a similar probability of being sampled in all surveys. Nasopharyngeal swabs were processed using standard methods and serotyped by Quellung. RESULTS: In children>9-59 months old, overall pneumococcal colonization prevalence declined from 81.8% in Period-1 to 65.0% in Period-3 (p<0.001). Reductions of 70% (41.2% vs. 13.6%) in PCV7-serotypes colonization and 66% (15.3% vs. 4.4%) for the six additional PCV13-serotypes (PCV13-add6VT) were observed. There was, however, high residual colonization by PCV7-serotypes 19F (14.9% vs. 6.3%) and 23F (8.5% vs. 4.1%), despite reduction of 57% and 52%, respectively. Among individuals>12 years of age, there was 61% reduction in PCV7-serotype colonization (3.1% vs. 1.3%) and 75% decrease for PCV13-add6VT (2.1% vs. 0.6%) between Period-1 and Period-3. CONCLUSIONS: The residual prevalence of serotypes 19F and 23F, four years after introducing PCV in the South Africa, suggests ongoing community transmission and transient vaccine effects.

Streptococcus pneumoniae colonization in pneumococcal vaccine-naïve human immunodeficiency virus-exposed infected and -uninfected South African children.

Pneumococcal nasopharyngeal colonization is a pre-requisite for pneumococcal disease; the risk for pneumococcal disease is high in children born to women living with human immunodeficiency virus (HIV). We investigated pneumococcal colonization, serotype distribution and antibiotic susceptibility of Streptococcus pneumoniae isolates carried by perinatal HIV-infected and HIV-exposed-uninfected (HEU) children.Serial nasopharyngeal swabs were collected from 331 HIV-infected and 491 HEU children, at up to 6 scheduled timepoints, between median ages of 25 to 181 weeks. Pneumococcus was identified by culture; serotyping and antibiotic susceptibility testing were done by conventional methods. No pneumococcal vaccine was given.HIV-infected children were less likely to be colonized with 7-valent pneumococcal conjugate vaccine 7 serotypes than HEU at a median of 25 weeks of age (23% vs 36%; P < .001); however, no differences in colonization between the 2 groups were observed at subsequent study-visits. Over the 36-months study-period pneumococcal colonization increased in both HIV-infected (from 45% to 77%) and HEU (from 57% to 61%) children. Over the study-period, pneumococcal isolates non-susceptible to cotrimoxazole decreased from 92% to 57% and had a similar trend to penicillin (from 65% to 42%) in HIV-infected children. Similarly, pneumococcal nonsusceptible to cotrimoxazole decreased from 93% to 57% and to penicillin from 69% to 37% in HEU children.Vaccine serotype colonization was common in this population and similar rates were observed in HIV-infected and HEU children. The prevalence of pneumococcal isolates non-susceptible to cotrimoxazole and penicillin decreased with age.

Impact of HIV status and vaccination schedule on bacterial nasopharyngeal carriage following infant immunisation with the pneumococcal non-typeable Haemophilus influenzae protein D conjugate vaccine in South Africa.

BACKGROUND: Nasopharyngeal carriage (NPC) of Streptococcus pneumoniae is a precondition for pneumococcal disease and a source of transmission. This trial evaluated NPC of S. pneumoniae and other pathogens post-vaccination with the pneumococcal non-typeable Haemophilus influenzae (NTHi) protein D conjugate vaccine (PHiD-CV) in human immunodeficiency virus (HIV)-infected (HIV+), HIV-exposed-uninfected (HEU), and HIV-unexposed-uninfected (HUU) South African children. METHODS: In this phase III, open, single-centre, controlled study (ClinicalTrials.gov: NCT00829010), 484 children were stratified by HIV status: 83 HIV+, 101 HEU, and 300 HUU. HIV+ and HEU children received a 3 + 1 PHiD-CV vaccination schedule: primary vaccination, age 6/10/14 weeks, and booster dose, age 9-10 months. HUU infants were randomised (1:1:1) to 3-dose priming and booster (HUU/3+1); 3-dose priming without booster (HUU/3+0); or 2-dose priming and booster (HUU/2+1). Bacterial NPC was assessed 8 times up to 24-27 months of age. RESULTS: Overall pneumococcal carriage rates were similar across 3+1 groups irrespective of HIV status; trends towards higher carriage rates in the HIV+ than HEU and HUU/3+1 groups were observed at 24-27 months of age. In HUU children, carriage of any pneumococcal serotype was similar for the three different dosing schedules at all timepoints; carriage of vaccine-type pneumococci tended to be lower at 16-19 months and 24-27 months of age in children who had received a booster dose (HUU/2+1 and HUU/3+1 groups) than in the HUU/3+0 group. Carriage rates of NTHi, Staphylococcus aureus and Moraxella catarrhalis were comparable between all groups. CONCLUSIONS: HIV infection or exposure did not seem to alter the effect of PHiD-CV on pneumococcal NPC in children during their first 2 years of life. NPC prevalence of vaccine-type pneumococci following vaccination series tended to be lower in children who had received a booster dose in comparison to those who had not.

Effect of HIV exposure and timing of antiretroviral therapy initiation on immune memory responses to diphtheria, tetanus, whole cell pertussis and hepatitis B vaccines.

OBJECTIVES: We evaluated memory responses and antibody persistence to diphtheria-toxoid, tetanus-toxoid, whole-cell-pertussis (DTwP), and Hepatitis-B vaccines in HIV-unexposed, HIV-exposed-uninfected and HIV-infected children previously randomized to initiate time-limited ART at 6-10 weeks (ART-Immed) or when clinically/immunologically indicated (ART-Def). METHODS: All children received DTwP booster at 15-18 months. Antibodies were measured for pertussis-toxoid, filamentous haemagglutinin (FHA), diphtheria-toxoid, tetanus-toxoid, and hepatitis-B prior to booster, 1-2 weeks post-booster and at 24 months of age. RESULTS: Pre-booster antibody GMC were lower in HIV-infected groups than HIV-unexposed children for all epitopes. Post-booster and at 24 months of age, the ART-Def group had lower GMCs and antibody proportion ≥0.1 IU/ml for tetanus-toxoid and diphtheria-toxoid compared to HIV-unexposed children. At 24 months of age, the ART-Immed group had higher GMCs, and more likely to maintain antibody titres ≥1.0 IU/ml to tetanus-toxoid and diphtheria-toxoid compared to HIV-unexposed children. Compared to HIV-unexposed children, at 15 and 24 months of age, persistence of antibody to HBsAg of ≥10 mIU/ml was similar in the ART-Immed group but lower among the ART-Def group. Antibody kinetics indicated more robust memory responses in HIV-exposed-uninfected than HIV-unexposed children to diphtheria-toxoid and wP. CONCLUSION: HIV-infected children not on ART at primary vaccination had poorer memory responses, whereas HIV-exposed-uninfected children mounted robust memory responses.

Burden of Respiratory Syncytial Virus Infection in South African Human Immunodeficiency Virus (HIV)-Infected and HIV-Uninfected Pregnant and Postpartum Women: A Longitudinal Cohort Study.

Background: Limited data exist on the burden of respiratory syncytial virus (RSV) illness among pregnant women, to determine their potential benefit from RSV vaccination. We evaluated the incidence of RSV illness from midpregnancy until 24 weeks postpartum in human immunodeficiency virus (HIV)-uninfected and HIV-infected women and their infants. Methods: Mother-infant dyads were enrolled in maternal influenza vaccine efficacy trials. These included 1060 and 1056 HIV-uninfected pregnant women in 2011 and 2012, respectively, 194 HIV-infected pregnant women in 2011, and their infants. Upper respiratory tract samples obtained at illness visits were tested for RSV. Results: The incidence (per 1000 person-months) of RSV illness (n = 43 overall) among HIV-uninfected women was lower in 2011 (1.2; 95% confidence interval [CI], .6-2.2) than in 2012 (4.0; 95% CI, 2.8-5.6). The incidence of RSV illness (n = 5) in HIV-infected women was 3.4 (95% CI, 1.4-8.1). Maternal RSV infection was associated with respiratory symptoms including cough (72.1%), rhinorrhea (39.5%), sore throat (37.2%), and headache (42%), but fever was absent. RSV infection during pregnancy was not associated with adverse pregnancy outcomes. Postpartum, RSV infection in mothers (n = 27) was associated with concurrent infection among 51.9% of their infants and, conversely, 29.8% of mothers investigated within 7 days of their infants having an RSV illness also tested positive for RSV. Conclusions: RSV infection is associated with respiratory illness during pregnancy and postpartum. Vaccination of pregnant women against RSV could benefit the mother, albeit primarily against nonfebrile illness, and her infant. Clinical Trial Registration: NCT01306669 and NCT01306682.

Immunization with 10-valent pneumococcal non-typeable Haemophilus influenzae protein D conjugate vaccine (PHiD-CV) according to different schedules in infants in South Africa: a phase III trial.

BACKGROUND: Limited clinical data exists to assess differences between various infant pneumococcal conjugate vaccine schedules. In this trial, we evaluated immunogenicity of the 10-valent pneumococcal non-typeable Haemophilus influenzae protein D conjugate vaccine (PHiD-CV) administered using 3 different immunization schedules in HIV unexposed-uninfected infants in South Africa. METHODS: In this phase III, open, single-center, controlled study (clinicaltrials.gov: NCT00829010), 300 infants were randomized (1:1:1) to 1 of 3 PHiD-CV schedules: 3-dose priming and booster (3 + 1); 3-dose priming without booster (3 + 0); or 2-dose priming and booster (2 + 1). The booster was administered at 9-10 months of age. immune responses were assessed up to 21 months after primary vaccination. RESULTS: Post-priming antibody levels tended to be lower in the 2 + 1 group. At 6 months post-priming, antibody concentrations and opsonophagocytic activity titers were within similar ranges after 2- or 3-dose priming. Robust increases were observed pre- to post-booster in the 3 + 1 and 2 + 1 groups. CONCLUSIONS: PHiD-CV was immunogenic when administered in different schedules. Post-booster responses suggest effective immunological priming with both 2- and 3-dose primary series and support administration of the booster dose at 9-10 months of age.

Contribution of Serologic Assays in the Evaluation of Influenza Virus Infection Rates and Vaccine Efficacy in Pregnant Women: Report From Randomized Controlled Trials.

BACKGROUND.: The utility of serologic testing to evaluate vaccine efficacy of seasonal inactivated influenza vaccine (IIV) is controversial. We aimed to evaluate the efficacy of IIV against serologically diagnosed influenza infection (SDI) and reverse-transcription polymerase chain reaction-confirmed influenza illness (PCR-CI) in women vaccinated during pregnancy. METHODS.: We undertook a post hoc analysis of 2 randomized clinical trials evaluating IIV efficacy among human immunodeficiency virus (HIV)-uninfected and HIV-infected pregnant women. SDI was defined as ≥4-fold increase in paired hemagglutinin antibody inhibition titers from 1 month postvaccination until end-of-study participation. PCR-CI was defined as molecular diagnostic evidence of influenza virus in pharyngeal specimens collected during clinical illness. RESULTS.: Among placebo recipients, the respective incidence of PCR-CI and SDI was 5.6% and 35.0% in HIV-uninfected women and 20.5% and 43.6% among HIV-infected women. Vaccine efficacy in HIV-uninfected women was similar for PCR-CI (66.9%; 95% confidence interval [CI], -20.1% to 90.9%) and SDI (59.2%; 95% CI, 37.0%-73.5%); however, fewer women required vaccination to prevent 1 episode of SDI (5; 95% CI, 3-9) than PCR-CI (27; 95% CI, 12-∞). Also, vaccine efficacy was similar for PCR-CI (61.2%; 95% CI, 10.7%-83.2%) and SDI (60.9%; 95% CI, 33.9%-76.9%) in HIV-infected women, with 2-fold fewer women needing to be vaccinated to prevent SDI (4; 95% CI, 3-8) than PCR-CI (8; 95% CI, 4-52). CONCLUSIONS.: Although vaccine efficacy was similar when measured for PCR-CI or SDI, IIV vaccination prevented a greater number of SDI than PCR-CI; the clinical relevance of the former warrants interrogation.Clinical Trials Registration. NCT01306669 and NCT01306682.

Vaccination with 10-valent pneumococcal conjugate vaccine in infants according to HIV status.

BACKGROUND: Phase III, open-label, single-center, controlled study in South Africa (ClinicalTrials.gov: NCT00829010) to evaluate immunogenicity, reactogenicity, and safety of the 10-valent pneumococcal non-typeable Haemophilus influenzae protein D conjugate vaccine (PHiD-CV) in human immunodeficiency virus (HIV)-infected (HIV+), HIV-exposed-uninfected (HEU), and HIV-unexposed-uninfected (HUU) children. METHODS: Children stratified by HIV status received PHiD-CV primary vaccination (age 6/10/14 weeks; coadministered with routine childhood vaccines) and booster dose (age 9-10 months). Immune responses, assessed using enzyme-linked immunosorbent and functional assays, and safety were evaluated up to 14 months post-booster. RESULTS: Of 83, 101, and 100 children enrolled in HIV+, HEU, and HUU groups, 70, 91, and 93 were included in according-to-protocol immunogenicity cohort. For each vaccine-serotype, percentages of children with antibody concentrations ≥0.2 µg/mL were ≥97% 1 month post-primary vaccination and ≥98.5% 1 month post-booster (except for 6B and 23F at both timepoints). Post-primary vaccination, functional antibody responses were lower in HIV+ children: for each vaccine-serotype, percentages of children with opsonophagocytic activity (OPA) titres ≥8 were ≥72%, ≥81%, and ≥79% for HIV+, HEU, and HUU children. Post-booster, ≥87% of children in each group had OPA titres ≥8. Reactogenicity was similar across groups. Thirty one (37%) HIV+, 25 (25%) HEU, and 20 (20%) HUU children reported ≥1 serious adverse event. Five HIV+ and 4 HEU children died. One death (sudden infant death syndrome; HEU group; 3 days post-dose 1) was considered potentially vaccine-related. CONCLUSION: PHiD-CV was immunogenic and well-tolerated in HIV+, HEU, and HUU children, and has the potential to provide substantial benefit irrespective of HIV infection status.

Multiplex Urinary Antigen Detection for 13 Streptococcus pneumoniae Serotypes Improves Diagnosis of Pneumococcal Pneumonia in South African HIV-Infected Adults.

A serotype-specific urinary antigen detection (UAD) assay for 13 serotypes included in the pneumococcal conjugate vaccine (PCV13) was recently reported as a useful diagnostic tool for pneumococcal pneumonia. We aimed to assess the diagnostic accuracy of the UAD in HIV-infected South African adults. Urine specimens from a well-defined cohort of HIV-infected South African adults with pneumonia were evaluated retrospectively in the UAD assay. Pneumonia was considered pneumococcal if either sputum Gram stain, sputum culture, blood culture, or the immunochromatographic (ICT) BinaxNow S. pneumoniae test (composite diagnostic) was positive. Among 235 enrolled pneumonia patients, the UAD assay was more frequently positive (104 [44.3%]) than the composite diagnostic (71 [30.2%]; P < 0.001) and increased the pneumococcal etiology from 30.2% by an additional 22.6% to 52.8%. The UAD assay detected more pneumococcal etiologies (45.0%) than the serotype-independent ICT (23.4%, P < 0.001). UAD identified 6/7 patients with PCV13 serotype bacteremia without misclassification of bacteremia episodes due to non-PCV13 serotypes. UAD was positive for 5.1% of asymptomatic HIV-infected persons, with higher rates among those with nasopharyngeal carriage. Concordance between serotypes identified by UAD and by Quellung reaction and PCR serotyping was 70/86 (81.4%). UAD identified the dominant serotype in multiple serotype carriage. This study confirms the utility of the UAD assay for HIV-infected adults comparing favorably with other diagnostic tests. A highly valent UAD may become a new standard for detection of pneumococcal pneumonia in adults. Prior to PCV introduction, at least 53% of pneumonia cases were due to pneumococci in HIV-infected South African adults.

The Burden of Pertussis Hospitalization in HIV-Exposed and HIV-Unexposed South African Infants.

BACKGROUND: There are limited data on pertussis in African children, including among human immunodeficiency virus (HIV)-exposed infants. We conducted population-based hospital surveillance to determine the incidence and clinical presentation of Bordetella pertussis-associated hospitalization in perinatal HIV-exposed and -unexposed infants. METHODS: Children <12 months of age hospitalized with any sign or symptom of respiratory illness (including suspected sepsis or apnea in neonates) were enrolled from 1 January 2015 to 31 December 2015. Detailed clinical and demographic information was recorded and respiratory samples were tested by polymerase chain reaction (PCR). RESULTS: The overall B. pertussis PCR positivity was 2.3% (42/1839), of which 86% (n = 36) occurred in infants <3 months of age. Bordetella pertussis was detected in 2.1% (n = 26/1257) of HIV-unexposed and 2.7% (n = 16/599) of HIV-exposed infants. The incidence (per 1000) of B. pertussis-associated hospitalization was 2.9 (95% confidence interval [CI], 1.8-4.5) and 1.9 (95% CI, 1.3-2.6) in HIV-exposed and HIV-unexposed infants, respectively (P = .09). The overall in-hospital case fatality ratio among the cases was 4.8% (2/42), both deaths of which occurred in HIV-exposed infants <3 months of age. Among cases, presence of cough ≥14 days (20.5%) and paroxysmal coughing spells (33.3%) at diagnosis were uncommon. Only 16 (38%) B. pertussis-associated hospitalizations fulfilled the Centers for Diseases Control and Prevention case definition of "definite" pertussis. CONCLUSIONS: Bordetella pertussis contributed to a modest proportion of all-cause respiratory illness hospitalization among black-African children, with a trend for higher incidence among HIV-exposed than HIV-unexposed infants. Maternal vaccination of pregnant women should be considered to reduce the burden of pertussis hospitalization in this population.

Bordetella pertussis Infection in South African HIV-Infected and HIV-Uninfected Mother-Infant Dyads: A Longitudinal Cohort Study.

BACKGROUND: There is a paucity of data regarding the burden of Bordetella pertussis in African women and young infants, and particularly the impact of maternal human immunodeficiency virus (HIV) infection thereon. We performed a retrospective analysis of respiratory illness samples from longitudinal cohorts of HIV-uninfected and HIV-infected women and their infants to evaluate the burden of pertussis illness in a black-African community. METHODS: The women were followed up for respiratory illness from midpregnancy and together with their infants until 24 weeks postpartum. Respiratory samples obtained at the time of illness visits were tested for B. pertussis by polymerase chain reaction (PCR). RESULTS: The study included 194 HIV-infected and 1060 HIV-uninfected women, and 188 and 1028 infant offspring, respectively. There were 7 PCR-confirmed pertussis cases in the HIV-exposed infants and 30 in HIV-unexposed infants (7.4 vs 5.5 episodes per 1000 infant-months; P = .47), at a mean age of 70.9 days. All infant pertussis cases had a history of cough (mean duration, 6.3 days). Six of 17 (35.3%) pertussis-confirmed cases in infants <2 months of age were admitted to hospital within 21 days of B. pertussis detection, whereas none of the 20 cases ≥2 months of age required hospitalization. Ten PCR-positive pertussis-associated illnesses were detected in HIV-infected women compared with 32 in the HIV-uninfected women (6.8 vs 3.9 episodes per 1000 person-months; P = .12). CONCLUSIONS: Bordetella pertussis identification was common among young infants with respiratory illness, most of whom were too young to be fully protected through direct vaccination. Vaccination of pregnant women might be a valuable strategy in a setting such us ours to prevent B. pertussis-associated illness in women and their young infants.

Prevaccination Rotavirus Serum IgG and IgA Are Associated With Lower Immunogenicity of Live, Oral Human Rotavirus Vaccine in South African Infants.

BACKGROUND: Live oral rotavirus (RV) vaccines have shown modest efficacy among children in African countries for reasons that are not completely understood. We examined the possible inhibitory effect of preexisting antirotavirus antibodies on immunogenicity of monovalent RV vaccine (RV1). METHODS: Mother-infant pairs were enrolled at presentation for their routine immunization visit in Soweto, South Africa, when infants were aged 5-8 weeks. Infant serum samples were obtained before the first and second doses of RV1 and 1 month after the second dose. Maternal serum and breast milk samples were obtained prior to administration of each dose of RV1 to infants. RV-specific immunoglobulin G (IgG), IgA, and neutralizing activity in sera of infants and serum or breast milk samples of mothers were measured using enzyme-linked immunosorbent assays or a microneutralization test. RESULTS: Of the 107 serum pairs from infants who were seronegative for RV IgA at enrollment, we observed a strong positive association between IgG titers in pre-dose 1 sera of infants and mothers and significant negative associations between IgG titers in pre-dose 1 sera of infants and seroconversion to RV1 post-dose 1. Similarly, mothers whose infants' IgA seroconverted after RV1 had significantly lower pre-dose 1 IgG titers in sera than those whose infants did not seroconvert. CONCLUSIONS: High levels of preexisting serum IgG, including transplacentally acquired maternal IgG, appeared to have an inhibitory effect on the immunogenicity of RV1 among infants and may, in part, contribute to lower efficacy of RV vaccines in this and other low-income settings.

Kinetics of Hemagglutination-Inhibiting Antibodies Following Maternal Influenza Vaccination Among Mothers With and Those Without HIV Infection and Their Infants.

BACKGROUND: We evaluated the immunogenicity of trivalent inactivated influenza vaccine (IIV3) in pregnant women with and those without human immunodeficiency virus (HIV) infection and the persistence of hemagglutination-inhibiting antibodies in mothers and infants. METHODS: Antibodies were measured before vaccination, 1 month after vaccination, at delivery, and at postpartum week 24 in mothers and within 1 week of birth and at 8, 16, and 24 weeks of age in infants. RESULTS: We enrolled 98 HIV-uninfected and 100 HIV-infected pregnant women, including 93% with a CD4(+) T-cell count of ≥ 200 cells/µL. Compared with HIV-uninfected women, HIV-infected women had lower seroconversion rates (ranging from 63%-92% vs 36%-40%), lower antibody titers through postpartum week 24, and overlapping antibody half-lives (ranging from 106-121 vs 87-153 days). Infant titers were lower than the maternal titers within 1 week of delivery, regardless of vaccine strain and HIV exposure status. Compared with HIV-unexposed infants, HIV-exposed infants had a similar transplacental influenza virus antibody transfer ratio, lower titers, and a lower frequency of titers ≥ 1:40 (ranging from 82%-95% vs 43%-79%) at birth and higher antibody half-lives (ranging from 43-45 vs 56-65 days). CONCLUSIONS: Compared with HIV-uninfected pregnant women, HIV-infected pregnant women had lower antibody responses and persistence. Compared with HIV-unexposed infants, HIV-exposed infants had lower antibody levels at birth but similar antibody levels after 8 weeks of life. Early IIV3 administration during pregnancy did not decrease antibody titers among infants at birth.

Bacterial and Respiratory Viral Interactions in the Etiology of Acute Otitis Media in HIV-infected and HIV-uninfected South African Children.

BACKGROUND: Bacteria and respiratory viruses are implicated in the pathogenesis of acute otitis media (AOM); however, data from low-middle income countries are sparse. We investigated the etiology of AOM in HIV-infected (HIV+), HIV-uninfected (HIV-) and HIV-exposed clinically asymptomatic for HIV-infection (HEU) South African children. METHODS: Children ≥3 months to <5 years of age with AOM were enrolled between May 2009 and April 2010 (NCT01031082). Middle ear fluid samples were cultured for bacteria; antibacterial susceptibility was done and serotyping undertaken for Streptococcus pneumoniae and Haemophilus influenzae. Nasopharyngeal aspirates were analyzed for respiratory viruses using immunofluorescence assay and polymerase chain reaction. RESULTS: Of 260 AOM episodes (HIV+:15; HIV-:182; HEU:63), bacteria were found in 54.6%, including Haemophilus influenzae (30.8%), 98.8% of which were nontypeable, and Streptococcus pneumoniae (20.4%), Staphylococcus aureus (15.8%), Moraxella catarrhalis (5.0%) and Streptococcus pyogenes (1.5%). Nonsusceptibility of Streptococcus pneumoniae to penicillin was 64.2%. Respiratory viruses were detected in 74.2% of cases. Human rhinovirus was most frequently detected (37.7%), followed by adenovirus (14.2%) and human bocavirus (11.5%) overall and irrespective of HIV status. Respiratory viruses were identified concurrently with S. pneumoniae, H. influenzae, M. catarrhalis (76.9-78.8%) and Staphylococcus aureus (63.4%) cultured from middle ear fluid, as well as in 72.0% of episodes negative for any bacteria. CONCLUSION: The study suggests that respiratory viruses and pathogenic bacteria play an important role in the development of AOM in children. A similar spectrum of pathogens was observed independently of HIV status. Vaccines targeting both nontypeable Haemophilus influenzae and S. pneumoniae may have a broad impact on AOM in South Africa.

Longitudinal study on Streptococcus pneumoniae, Haemophilus influenzae and Staphylococcus aureus nasopharyngeal colonization in HIV-infected and -uninfected infants vaccinated with pneumococcal conjugate vaccine.

BACKGROUND: Streptococcus pneumoniae, Haemophilus influenzae and Staphylococcus aureus are all potentially pathogenic, which frequently colonize the nasopharynx (NP) prior to causing disease. We studied bacterial NP-colonization in 321 HIV-infected and 243 HIV-uninfected children vaccinated with 7-valent pneumococcal conjugate vaccine (PCV7) at 6, 10 and 14 weeks of age. METHODS: HIV-uninfected infants included those born to HIV-uninfected (HUU) and HIV-infected women (HEU); HIV-infected children with CD4+ lymphocyte ≥25% were randomized to initiate antiretroviral therapy immediately (ART-Immed) or when clinically indicated (ART-Def). Nasopharyngeal swabs for bacterial culture were taken prior to each PCV7 dose (Visits 1-3) and at 20, 39, 47 and 67 weeks of age (Visits 4-7). Swabs were cultured by standard methods and pneumococcal serotyping done by the Quellung method. RESULTS: Colonization patterns for pneumococcus, H. influenzae and S. aureus did not differ between HUU and HEU children; and were also generally similar between ART-Def and ART-Immed children. Prevalence of PCV7-serotype colonization was similar between HIV-infected and HIV-uninfected children, however, overall pneumococcal and specifically non-vaccine serotype colonization tended to be lower in HIV-infected children. HIV-infected children also had a 44% lower prevalence of S. aureus colonization at Visit-1 (p=0.010); and H. influenzae colonization was also lower among HIV-infected than HIV-uninfected children at Visit-2, Visit-3, Visit-6 and Visit-7. CONCLUSION: Vaccine-serotype colonization is similar in PCV-immunized HIV-infected and HIV-uninfected children. We, however, identified a lower prevalence of overall-pneumococcal and H. influenzae colonization in HIV-infected children post-PCV vaccination, the clinical-relevance of which warrants further study.

Temporal Changes in Pneumococcal Colonization in HIV-infected and HIV-uninfected Mother-Child Pairs Following Transitioning From 7-valent to 13-valent Pneumococcal Conjugate Vaccine, Soweto, South Africa.

BACKGROUND: We investigated the impact of infant pneumococcal conjugate vaccine (PCV) immunization on pneumococcal colonization among human immunodeficiency virus (HIV)-infected and HIV-uninfected mother-child pairs. METHODS: Pneumococcal colonization was assessed in May 2010-February 2011 (period 1; 7-valent PCV era) and May 2012-April 2013 (period 2; 13-valent PCV era). Standard microbiological methods were used for pneumococcus isolation and serotyping. RESULTS: In children 0-12 years, PCV13-serotype colonization decreased from period 1 to period 2 among HIV-uninfected (adjusted odds ratio [OR], 0.32; 95% confidence interval [CI], .25-.40) and HIV-infected children (adjusted OR, 0.37; 95% CI, .28-.49), while there was an increase in nonvaccine serotype colonization. Decreases in PCV13-serotype colonization were observed in HIV-uninfected women (adjusted OR, 0.44; 95% CI, .23-.81), with a similar trend in HIV-infected women. HIV-infected compared to -uninfected women had higher prevalence of overall (20.5% vs 9.7% in period 1; 13.8% vs 9.7% in period 2) and PCV13-serotype colonization (8.7% vs 5.4% in period 1; 4.8% vs 2.0% in period 2), P < .04 for all observations. CONCLUSIONS: Targeted PCV vaccination of African infants in a setting with high HIV prevalence was associated with PCV13-serotype colonization reduction, including among unvaccinated HIV-infected women.

HIV-1 Is Associated With Lower Group B Streptococcus Capsular and Surface-Protein IgG Antibody Levels and Reduced Transplacental Antibody Transfer in Pregnant Women.

BACKGROUND: Human immunodeficiency virus (HIV)-exposed infants are at increased risk of invasive Group B Streptococcus (GBS) disease; however, the reason for this increased susceptibility has not been characterized. METHODS: We compared GBS capsular and surface-protein maternal immunoglobin G antibody concentrations and cord-maternal ratios between HIV-infected and HIV-uninfected mother-newborn dyads. RESULTS: Median capsular antibody concentrations (µg/mL) were lower in HIV-infected than HIV-uninfected women for serotypes Ib (P = .033) and V (P = .040); and for pilus island (PI)-1 (P = .016), PI-2a (P = .015), PI-2b (P = .015), and fibrinogen-binding protein A (P < .001). For serotypes Ia and III, cord-maternal ratios were 37.4% (P < .001) and 32.5% (P = .027) lower in HIV-infected compared to HIV-uninfected mother-newborn dyads. The adjusted odds of having capsular antibody concentration ≥2 µg/mL when comparing HIV-infected to -uninfected women were 0.33 (95% confidence interval [CI], .15-.75) and 0.34 (95% CI, .12-1.00) for serotypes Ia and III, respectively. Antibody levels and cord-maternal ratios were independent of CD4(+) lymphocyte counts or HIV-1 viral load. CONCLUSIONS: The lower GBS antibody concentrations and reduced transplacental antibody transfer in HIV-infected women, which likely contribute to their infants being at heightened susceptibility for invasive GBS disease, could possibly be mitigated by vaccination with a GBS conjugate vaccine currently under clinical development.

Acquisition of Streptococcus pneumoniae in South African children vaccinated with 7-valent pneumococcal conjugate vaccine at 6, 14 and 40 weeks of age.

BACKGROUND: Seven-valent pneumococcal conjugate vaccine (PCV7) was introduced into the South African immunization program using 6, 14 and 40 weeks dosing schedule (2+1), with no catch-up in older children since April 2009. We investigated pneumococcal colonization acquisition in children who received this schedule and also compared it to historical cohorts of PCV-naïve children (n=123 in 2007) and children who received a 3+1 PCV7 schedule (n=124 in 2005/06). METHODS: Two hundred and fifty children aged 6-12 weeks were enrolled from December 2009 to April 2010. Participants had nasopharyngeal swabs collected on eight occasions between enrolment and 2-years of age. Standard methods were undertaken for bacterial culture and Streptococcus pneumoniae were serotyped using the Quellung method. Pneumococcal and Staphylococcus aureus colonization in the present study was compared to colonization in two historical longitudinal cohorts. RESULTS: S. pneumoniae was identified in 1081 (61.4%) of 1761 swabs collected in the current cohort. Pneumococcal colonization peaked at 41-weeks of age (76.8%) and decreased to 62.8% by 2-years of age (p=0.002); PCV7-serotype colonization decreased during the same period from 28.6% to 15.6% (p=0.001). Children from the current cohort compared to PCV-naïve children were less likely to be colonized by PCV7-serotypes from 40-weeks to 2-years of age and acquired PCV7-serotypes less frequently. No differences in overall pneumococcal, PCV7-serotype and non-PCV7-serotype colonization or new serotype acquisitions were detected comparing the current cohort to the historical cohort who received the 3+1 PCV7 schedule. Staphylococcus aureus colonization was similar in all three cohorts. CONCLUSION: A 2+1 PCV7 schedule implemented in South Africa was temporally associated with reduced risk of vaccine-serotype colonization compared to historically unvaccinated children. Also, vaccine-serotype acquisition rate using the 2+1 schedule was similar to that in the 3+1 dosing cohort, suggesting that similar indirect protection against pneumococcal disease could be derived from either schedule in South Africa.