Anthonet Koen

Trivalent Inactivated Influenza Vaccine in African Adults Infected With Human Immunodeficient Virus: Double Blind, Randomized Clinical Trial of Efficacy, Immunogenicity, and Safety

BACKGROUND Data on the efficacy of trivalent, inactivated influenza vaccine (TIV) in HIV-infected adults, particularly in Africa, are limited. This study evaluated the safety, immunogenicity, and efficacy of TIV in HIV-infected adults. METHODS In Johannesburg, South Africa, we undertook a randomized, double-blind, placebo-controlled trial involving 506 HIV-infected adults. Subjects included 157 individuals who were antiretroviral treatment (ART) naive and 349 on stable-ART. Participants were randomly assigned to receive TIV or normal saline intramuscularly. Oropharyngeal swabs were obtained at illness visits during the influenza season and tested by shell vial culture and RT PCR assay for influenza virus. Immune response was evaluated by hemagglutinin antibody inhibition assay (HAI) in a nested cohort. The primary study outcome involved vaccine efficacy against influenza confirmed illness. This trial is registered with ClinicalTrials.gov, number NCT00757900. RESULTS The efficacy of TIV against confirmed influenza illness was 75.5% (95% CI: 9.2%-95.6%); with a risk difference of 0.18 per 100 person-weeks in TIV recipients. Among TIV recipients, seroconversion, measured by HAI titers, was evident in 52.6% for H1N1, 60.8% for H3N2, and 53.6% for influenza B virus. This compared with 2.2%, 2.2%, and 4.4% of placebo recipients (P < .0001). The frequency of local and systemic adverse events post-immunization was similar between study groups. CONCLUSIONS TIV immunization is safe and efficacious in African HIV-infected adults without underlying co-morbidities. Further evaluation of effectiveness is warranted in severely immunocompromized HIV-infected adults and those with co-morbidities such as tuberculosis.

Burden of Invasive Group B Streptococcus Disease and Early Neurological Sequelae in South African Infants

Introduction Group B Streptococcus (GBS) is a leading cause of neonatal sepsis and meningitis. We aimed to evaluate the burden of invasive early-onset (0–6 days of life, EOD) and late-onset (7–89 days, LOD) GBS disease and subsequent neurological sequelae in infants from a setting with a high prevalence (29.5%) of HIV among pregnant women. Methods A case-control study was undertaken at three secondary-tertiary care public hospitals in Johannesburg. Invasive cases in infants <3 months age were identified by surveillance of laboratories from November 2012 to February 2014. Neurodevelopmental screening was done in surviving cases and controls at 3 and 6 months of age. Results We identified 122 cases of invasive GBS disease over a 12 month period. Although the incidence (per 1,000 live births) of EOD was similar between HIV-exposed and HIV-unexposed infants (1.13 vs. 1.46; p = 0.487), there was a 4.67-fold (95%CI: 2.24–9.74) greater risk for LOD in HIV-exposed infants (2.27 vs. 0.49; p<0.001). Overall, serotypes Ia, Ib and III constituted 75.8% and 92.5% of EOD and LOD, respectively. Risk factors for EOD included offensive draining liquor (adjusted Odds Ratio: 27.37; 95%CI: 1.94–386.50) and maternal GBS bacteriuria (aOR: 8.41; 95%CI: 1.44–49.15), which was also a risk-factor for LOD (aOR: 3.49; 95%CI: 1.17–10.40). The overall case fatality rate among cases was 18.0%. The adjusted odds for neurological sequelae at 6 months age was 13.18-fold (95%CI: 1.44–120.95) greater in cases (13.2%) than controls (0.4%). Discussion The high burden of invasive GBS disease in South Africa, which is also associated with high case fatality rates and significant neurological sequelae among survivors, is partly due to the heightened risk for LOD in infants born to HIV-infected women. An effective trivalent GBS conjugate vaccine targeted at pregnant women could prevent invasive GBS disease in this setting.

Acquisition of streptococcus pneumoniae in Pneumococcal Conjugate Vaccine-naïve South African Children and Their Mothers

Background: Pneumococcal nasopharyngeal colonization is a prerequisite to developing pneumococcal disease. We investigated the dynamics of pneumococcal colonization in perinatal HIV-unexposed and HIV-exposed children and their mothers and risk factors associated with new serotypes acquisition. Methods: Two hundred forty-three mother–child pairs (120 HIV-infected, 123 HIV-uninfected mothers) were studied at 4.4, 7.2, 9.4, 12.3 and 16.0 months of the child’s age. Demographic data, nasopharyngeal swabs, as well as oropharyngeal swabs, from mothers were collected for pneumococcal conventional culture and serotyping by the Quellung method. Results: The rate of new serotype acquisition during the 16 months did not differ between HIV-exposed (49.1%) and HIV-unexposed (52.0%) children, or between HIV-infected (18.9%) and HIV-uninfected (19.5%) mothers. Serotypes included in the 7-valent pneumococcal conjugate vaccine (PCV7) were acquired more often by HIV-infected (10.0%) compared with HIV-uninfected mothers (6.4%; P = 0.03). On multivariate analysis, day-care attendance (adjusted odds ratio [AOR], = 1.80, P = 0.02) and maternal pneumococcal colonization (AOR = 1.54, P = 0.01) were positively associated with pneumococcal acquisition in the child, whereas breast-feeding had a protective effect on PCV7-serotype acquisition in HIV-uninfected children. New acquisition of PCV7 and PCV13 serotypes in the mother was positively associated with colonization in the child (AOR = 2.01, P = 0.006 and AOR = 2.04, P = 0.002, respectively). Conclusions: There is an association of acquisition of PCV7 and PCV13 serotypes between young children and their mothers. The higher prevalence of PCV7 serotype in HIV-infected mothers suggests that they may be a reservoir for transmission of these serotypes, which could delay indirect effects of PCV in settings with a high HIV burden.

Immunogenicity of seven-valent pneumococcal conjugate vaccine administered at 6, 14 and 40 weeks of age in South African infants.

Background The high cost of pneumococcal conjugate vaccine (PCV) and local epidemiological factors contributed to evaluating different PCV dosing-schedules. This study evaluated the immunogenicity of seven-valent PCV (PCV7) administered at 6-weeks; 14-weeks and 9-months of age. Methods 250 healthy, HIV-unexposed infants were immunized with PCV7 concurrently with other childhood vaccines. Serotype-specific anti-capsular IgG concentrations were measured one-month following the 1st and 2nd PCV-doses, prior to and two-weeks following the 3rd dose. Opsonophagocytic killing assay (OPA) was measured for three serotypes following the 2nd and 3rd PCV7-doses. Immunogenicity of the current schedule was compared to a historical cohort of infants who received PCV7 at 6, 10 and 14 weeks of age. Results The proportion of infants with serotype-specific antibody ≥0.35 µg/ml following the 2nd PCV7-dose ranged from 84% for 6B to ≥89% for other serotypes. Robust antibody responses were observed following the 3rd dose. The proportion of children with OPA ≥8 for serotypes 9V, 19F and 23F increased significantly following the 3rd PCV7-dose to 93.6%; 86.0% and 89.7% respectively. The quantitative antibody concentrations following the 2nd PCV7-dose were comparable to that after the 3rd -dose in the 6-10-14 week schedule. Geometric mean concentrations (GMCs) following the 3rd PCV7-dose were higher for all serotypes in this study compared to the historical cohort. Conclusions The studied PCV7 dosing schedule induced good immune responses, including higher GMCs following the 3rd-dose at 9-months compared to when given at 14-weeks of age. This may confer longer persistence of antibodies and duration of protection against pneumococcal disease.

Antibody persistence and booster vaccination of a fully liquid hexavalent vaccine coadministered with measles/mumps/rubella and varicella vaccines at 15-18 months of age in healthy South African infants.

Objective: To assess antibody persistence and booster immunogenicity and safety of a new, fully liquid, hexavalent DTaP-IPV-Hep B-PRP-T vaccine. Methods: Phase III, open-label, 2-center trial. Infants previously primed at 6, 10, 14 weeks of age with DTaP-IPV-Hep B-PRP-T either without (group 1: N = 218) or with hepatitis B at birth (group 3: N = 130) or control DTwP-Hib, hepatitis B and oral poliovirus vaccine vaccines (group 2: N = 219) received the same vaccine(s) as booster (except hepatitis B for group 2) at 15–18 months of age, coadministered with measles/mumps/rubella and varicella vaccines (MMR+V). All participants had received measles vaccine at 9 months of age. Antibodies were measured prebooster and 1 month postbooster vaccination. Safety was evaluated from parental reports. Analyses were descriptive. Results: Antibody persistence (seroprotection and concentration) at 15–18 months of age was high for each valence and similar in each group, except for Hep B (highest in group 3 [extra dose of hepatitis B]) and PRP (highest in group 2). Postbooster seroprotection (D, T, IPV, Hep B, PRP) and seroconversion (pertussis toxin and filamentous hemagglutinin) rates were high and similar in each group (excluding Hep B in group 2 [no booster]); geometric mean antibody levels increased markedly in all groups. The response to MMR+V was similar in each group. All vaccines were well tolerated. Conclusions: A booster dose of the new DTaP-IPV-Hep B-PRP-T vaccine at 15–18 months of age is highly immunogenic and safe compared with licensed comparators, following primary series administration in the Expanded Program on Immunization schedule, with or without a hepatitis B vaccine at birth and coadministered with MMR+V.

Antibody Kinetics and Response to Routine Vaccinations in Infants Born to Women Who Received an Investigational Trivalent Group B Streptococcus Polysaccharide CRM197-Conjugate Vaccine During Pregnancy

Group B Streptococcus (GBS)–specific antibodies were detectable in 3-month-old infants of mothers having received an investigational trivalent GBS vaccine during pregnancy. Maternal GBS vaccination did not have a clinically meaningful impact on immune responses to diphtheria or pneumococcal pediatric vaccination.

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 &mgr;g/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.

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

ABSTRACT 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.