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Wolter N.,South African National Institute for Communicable Diseases | Wolter N.,Medical Research Council Respiratory and Meningeal Pathogens Research Unit | Tempia S.,National Science Foundation | Cohen C.,University of Witwatersrand | And 15 more authors.
Journal of Infectious Diseases | Year: 2014

Background.We identified factors associated with pneumococcal colonization, high colonization density, and invasive pneumococcal pneumonia among patients hospitalized with acute lower respiratory tract infections (ALRTIs).Methods.In 2010, 4025 cases were enrolled in surveillance in South Africa. A total of 969 of 4025 systematically selected nasopharyngeal-oropharyngeal specimens (24%) were tested for respiratory viruses and Streptococcus pneumoniae by real-time polymerase chain reaction. Of these, 749 (77%) had blood tested for S. pneumoniae.Results.Pneumococcal colonization was detected in 55% of cases (534 of 969). On multivariable analysis that controlled for age and tuberculosis treatment, infection with influenza virus (adjusted odds ratio [OR], 2.2; 95% confidence interval [CI], 1.1-4.5), adenovirus (adjusted OR, 1.7; 95% CI, 1.1-2.7), rhinovirus (adjusted OR, 1.6; 95% CI, 1.1-2.3), and human immunodeficiency virus (HIV; adjusted OR, 1.6; 95% CI, 1.1-2.4) were associated with pneumococcal colonization. High colonization density was associated with respiratory virus coinfection (adjusted OR, 1.7; 95% CI, 1.1-2.6) and invasive pneumococcal pneumonia (adjusted OR, 2.3; 95% CI, 1.3-4.0), after adjustment for age and sex. Seven percent (52 of 749) had pneumococci detected in blood. On multivariable analysis among colonized cases, invasive pneumococcal pneumonia was associated with HIV (adjusted OR, 3.2; 95% CI, 1.4-7.5), influenza virus (adjusted OR, 8.2; 95% CI, 2.7-25.0), high colonization density (adjusted OR, 18.7; 95% CI, 2.3-155.1), and =5 days of hospitalization (adjusted OR, 3.7; 95% CI, 1.7-8.2).Conclusions.Respiratory virus infection was associated with elevated colonization density and, in turn, invasive pneumococcal pneumonia. © 2014 © The Author 2014.


Madhi S.A.,University of Witwatersrand | Madhi S.A.,Medical Research Council Respiratory and Meningeal Pathogens Research Unit | Madhi S.A.,South African National Institute for Communicable Diseases | Koen A.,University of Witwatersrand | And 5 more authors.
Pediatric Infectious Disease Journal | Year: 2013

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. Copyright © 2013 Lippincott Williams &Wilkins.


Pathirana J.,Medical Research Council Respiratory and Meningeal Pathogens Research Unit | Pathirana J.,National Science Foundation | Pathirana J.,University of Witwatersrand | Munoz F.M.,Baylor College of Medicine | And 14 more authors.
Vaccine | Year: 2016

More than 40% of all deaths in children under 5 years of age occur during the neonatal period: the first month of life. Immunization of pregnant women has proven beneficial to both mother and infant by decreasing morbidity and mortality. With an increasing number of immunization trials being conducted in pregnant women, as well as roll-out of recommended vaccines to pregnant women, there is a need to clarify details of a neonatal death. This manuscript defines levels of certainty of a neonatal death, related to the viability of the neonate, who confirmed the death, and the timing of the death during the neonatal period and in relation to immunization of the mother. © 2016.


Madhi S.A.,South African National Institute for Communicable Diseases | Madhi S.A.,University of Witwatersrand | Madhi S.A.,Medical Research Council Respiratory and Meningeal Pathogens Research Unit | Dangor Z.,University of Witwatersrand | And 7 more authors.
Vaccine | Year: 2013

In 2010, an estimated 393,000 infection-related neonatal deaths occurred worldwide with Group B streptococcus (GBS) being a leading cause. Prevention of early-onset disease (0-6 days; EOD) is currently focused on intra-partum antibiotic prophylaxis to mothers identified as being at risk; such strategies reduce EOD by 75-80% but are resource-intensive and logistically-difficult to implement in developing countries. Vaccination of pregnant women is an alternate strategy for preventing both EOD and late-onset disease (7-89 days; LOD). A trivalent GBS polysaccharide-protein conjugate vaccine (GBS-CV) composed of capsular epitopes from serotypes Ia, Ib and III is undergoing phase-II evaluation among pregnant women in Europe, North America and Africa. These serotypes cause 70-80% of all invasive GBS disease in early-infancy. Maternal anti-GBS antibodies are associated with protection from EOD, however, since a correlate of efficacy has not been defined, a phase III efficacy trial may be required for licensure. Criteria for selecting appropriate sites include sufficiently high GBS incidence in large birth cohorts, as well as adequate clinical and microbiological diagnostic skills and capacities. Alternate pathways to licensure should be explored, e.g. identification of serological correlates of protection with subsequent phase IV studies establishing vaccine-effectiveness against invasive GBS disease. Conducting a randomized, placebo-controlled efficacy trial, however, has the additional advantage of also being able to evaluate the role of GBS contributing to neonatal culture-negative sepsis, stillbirths, prematurity and low-birth weight. © 2013 Elsevier Ltd.


Cutland C.L.,Medical Research Council Respiratory and Meningeal Pathogens Research Unit | Cutland C.L.,National Science Foundation | Cutland C.L.,University of Witwatersrand | Cunnington M.,Glaxosmithkline | And 15 more authors.
Vaccine | Year: 2015

Introduction: Infectious causes are a significant contributor to morbidity and mortality in neonates and young infants. Immunization of pregnant women to protect the mother and/or her infant is gaining momentum due to the benefits of this strategy demonstrated in numerous implemented strategies (Maternal and Neonatal Tetanus Elimination Initiative) and clinical trials.Reluctance by regulators, participants and healthcare providers to include pregnant women in clinical trials is considerable, but reducing. Infectious disease burden, and therefore need for interventions to reduce morbidity and mortality in mothers and infants, is highest in low-middle income countries (LMIC), however, reliable background data on adverse pregnancy outcomes and lack of experience in clinical trials and community opinions on immunization during pregnancy are not well documented. Methods: We used our experiences in conducting two clinical studies in pregnant women in South Africa to illustrate the challenges experienced and lessons learnt which may benefit others working in the maternal immunization field. Results: Accurate gestational age assessment, which is essential for clinical trials, is challenging in LMIC due to limited access to early ultrasound examinations, and unreliable assessment by history (last menstrual period date) and physical examination (symphyseal-fundal height).Concomitant administration of recommended vaccines has previously been avoided in clinical trials; however, this limitation could impact the potentially beneficial interventions that participants can access during antenatal care.Women in LMIC have a higher burden of concomitant illnesses (e.g. HIV infection, malaria and anaemia) and adverse pregnancy outcomes (e.g. stillbirth) than pregnant women in higher income countries. Availability of local data is essential for safety monitoring committees to identify vaccine-related adverse event triggers. Conclusion: Immunization of pregnant women to reduce disease burden in them and their infants is promising, and women in high-risk settings should be included in trials (Clinical trial registry number: 'Study A': NCT01193920, 'Study B': NCT01888471). © 2015 The Authors.

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