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Biomedical subjects

Shabir A Madhi

Publications and source records attributed to Shabir A Madhi.

At least 19 recordsLinked to original sources
PubMed2007

HIV and pneumococcal disease.

PURPOSE OF REVIEW: To describe the impact of highly active antiretroviral therapy on the burden of pneumococcal disease and advances in our understanding of the impact of HIV on this disease. RECENT FINDINGS: Although highly active antiretroviral therapy has reduced the burden of pneumococcal disease among HIV-infected adults, these infections remain far more common than in HIV uninfected adults. HIV-infected adults who smoke or have comorbidities are at particular risk. In the absence of highly active antiretroviral therapy, pneumococcal meningitis has emerged in Africa as a major disease burden with a high mortality among HIV-infected children and adults. Conjugate pneumococcal vaccine protects HIV-infected infants from pneumococcal pneumonia. In the United States, where conjugate vaccine is given to children, herd immunity has reduced the burden of invasive pneumococcal disease among HIV-infected adults. SUMMARY: The pneumococcus remains a significant cause of morbidity and mortality among HIV-infected children and adults, both in developed and in developing countries.

Anti-Retroviral Agents↗
PubMed2006

Long-term immunogenicity and efficacy of a 9-valent conjugate pneumococcal vaccine in human immunodeficient virus infected and non-infected children in the absence of a booster dose of vaccine.

The long-term immunogenicity and vaccine efficacy (VE) of a 9-valent conjugate pneumococcal vaccine was studied in HIV infected and HIV non-infected children. VE against vaccine-serotype invasive pneumococcal disease following 6.16 years of follow-up persisted in HIV non-infected children (77.8%; 95% CI 34.4-92.5 compared to 83% after 2.3 years of follow-up), and declined from 65% to 38.8% (95% CI -7.8 to 65.2) in HIV infected children. HIV non-infected vaccinees had equal (serotypes 4, 6B, 14, 19F) or greater (serotypes 9V, 18C, 23F) proportions of serotype-specific antibody concentrations of > or =0.2microg/ml to vaccine-serotypes analyzed compared to HIV infected vaccinees at 5.3 years of age.

Antibody Formation↗
PubMed2006

World Health Organisation definition of "radiologically-confirmed pneumonia" may under-estimate the true public health value of conjugate pneumococcal vaccines.

The public health benefit of conjugate pneumococcal vaccine (PCV) in preventing pneumonia would only be appreciated if the tool used for measuring "pneumococcal pneumonia" had good sensitivity. Exploratory studies in South Africa indicate that the sensitivity of "radiologically-confirmed pneumonia" (CXR-AC) underestimates the burden of pneumococcal pneumonia prevented by PCV by as much as 63%. The use of alternate markers such as C-reactive protein enhance the ability of measuring the burden of pneumonia preventable by PCV. A broadened definition of "pneumococcal pneumonia" which includes episodes of pneumonia associated with CXR-AC and those associated with an abnormal chest radiograph other than CXR-AC associated with a CRP of > or =40mg/l should be considered an a priori outcome in future PCV efficacy trials.

Humans↗
PubMed2006

Five-year cohort study of hospitalization for respiratory syncytial virus associated lower respiratory tract infection in African children.

OBJECTIVES: To describe the epidemiology of respiratory syncytial virus (RSV) associated lower respiratory tract infection (RSV-LRTI) hospitalizations in South African children over a 5-year period, and determine the impact of gestational age (GA) on the incidence of RSV-LRTI hospitalization. STUDY DESIGN: A cohort of 39,836 children, 6.47% of whom were HIV infected, enrolled into a phase 3 trial were prospectively studied for respiratory viruses when hospitalized for LRTI. RESULTS: The incidence of hospitalization for RSV-LRTI was 19.4 per 1000 in HIV uninfected children and 2.5-fold (95% CI 2.04-3.03) greater in HIV infected children (45.0 per 1000). The incidence of RSV-LRTI was 4.9-fold greater (95% CI 3.9-6.8) in children born at <36 weeks of gestational age (GA) and repeat hospitalizations for RSV-LRTI was 3.7-fold (95% CI 1.4-9.4) more likely in these children (7.3%) than children born at > or =36 weeks of GA (1.9%). The burden of RSV-LRTI was greater in children born at <32 weeks of GA than those born at 32-35 weeks of GA between 6-12 months (P=0.008) and 12-24 months of age (P=0.001). The RSV epidemic occurred at the end of the rainy season and peaked when the monthly temperatures were at its lowest each year.

Cohort Studies↗
PubMed2006

Pneumococcal coinfection with human metapneumovirus.

BACKGROUND: Infection with the newly discovered human metapneumovirus (hMPV) may lead to hospitalization of children with lower respiratory tract infection (LRTI), although the pathogenesis thereof remains to be elucidated. METHODS: This hypothesis-generating study involved a cohort of children randomized to receive 9-valent conjugate pneumococcal vaccine or placebo and who were tested for hMPV infection when hospitalized for LRTI. By use of a nested reverse-transcription polymerase chain reaction assay targeted at amplifying a fragment of the hMPV fusion (F) protein gene, 202 such infections were identified among 2715 episodes of LRTI in children. RESULTS: Among human immunodeficiency virus (HIV)-uninfected children who had received 3 doses of conjugate pneumococcal vaccine, the incidence of hMPV-associated LRTI was reduced by 45% (95% confidence interval [CI], 19%-62%; P = .002), and the incidence of clinical pneumonia was reduced by 55% (95% CI, 22%-74%; P = .003). Similarly, in fully vaccinated HIV-infected children, the incidence of hMPV-associated LRTI was reduced by 53% (95% CI, 3%-77%; P = .035), and that of clinical pneumonia was reduced by 65% (95% CI, 19%-85%; P = .020). CONCLUSIONS: The pathogenesis of hMPV-associated LRTI that results in hospitalization of both HIV-infected and -uninfected children involves bacterial coinfection with pneumococcus, and a significant proportion of these hospitalizations may be prevented by vaccination with pneumococcal conjugate vaccine.

Child↗
PubMed2006

The interferon antagonist NS2 protein of respiratory syncytial virus is an important virulence determinant for humans.

BACKGROUND: Respiratory syncytial virus (RSV) is targeted for vaccine development, because it causes severe respiratory tract illness in the elderly, young children, and infants. A primary strategy has been to derive live attenuated viruses for use in intranasally administered vaccines that will induce a protective immune response. In the present study, the NS2 gene, whose encoded protein antagonizes the host's interferon- alpha / beta response, was deleted from RSV vaccine candidates by use of reverse genetics. METHODS: Three NS2 gene-deleted RSV vaccine candidates were studied: rA2cp Delta NS2, rA2cp248/404 Delta NS2, and rA2cp530/1009 Delta NS2. rA2cp Delta NS2, which had the fewest attenuating mutations, was evaluated in adults and RSV-seropositive children. rA2cp248/404 Delta NS2 and rA2cp530/1009 Delta NS2 were evaluated in adults and RSV-seropositive and RSV-seronegative children. RESULTS: At a high dose (10(7.0) pfu), rA2cp Delta NS2 was not shed by adults, and only 13% of them had an immune response. The other vaccine candidates, rA2cp248/404 Delta NS2 and rA2cp530/1009 Delta NS2, had greatly decreased infectivity in RSV-seronegative children, compared with that of their immediate parent strains, which possess an intact NS2 gene. CONCLUSIONS: Deletion of the NS2 gene attenuates RSV in subjects of all ages studied. This validates the strategy of developing live respiratory tract virus vaccines in which the virus's ability to inhibit the human innate immune system is blocked. rA2cp248/404 Delta NS2 should be studied in children at a higher input titer, because it was more infectious and immunogenic than was rA2cp530/1009 Delta NS2.

Adult↗
PubMed2006

Bacterial pneumonia vaccines and childhood pneumonia: are we winning, refining, or redefining?

Bacterial pneumonia is a substantial cause of childhood morbidity and mortality worldwide, but determination of pathogen-specific burden remains a challenge. In less developed settings, the WHO recommended guidelines are useful for initiating care, but are non-specific. Blood culture has low sensitivity, while radiological findings are non-specific and do not discriminate between viral and bacterial causes of pneumonia. In vaccine probe studies, efficacy is dependent on the specificity of the study outcome to detect pneumonia and the impact of the vaccine on the selected outcome, and may underestimate the true burden of bacterial pneumonia. The rising incidence of antibiotic resistance, emerging respiratory pathogens, potential replacement pneumococcal disease following widespread introduction of pneumococcal polysaccharide-protein conjugate vaccine, the limited specificity of chest radiography, and the poor sensitivity of blood culture are substantial obstacles to accurate surveillance. We provide an overview of the diagnostic challenges of bacterial pneumonia and highlight the need for refining the current diagnostic approach to ensure adequate epidemiological surveillance of childhood pneumonia and the success, or otherwise, of any immunisation strategies.

Bacterial Vaccines↗
PubMed2006

Usefulness of C-reactive protein to define pneumococcal conjugate vaccine efficacy in the prevention of pneumonia.

OBJECTIVES AND METHODS: This study explored whether C-reactive protein (CRP) and/or procalcitonin levels were useful to measure vaccine efficacy (VE) and impact against the burden of pneumonia of a 9-valent pneumococcal conjugate vaccine (PCV), compared with chest radiograph-confirmed alveolar consolidation (CXR-AC) as an outcome. Sera obtained from children participating in a phase 3 PCV efficacy trial who were hospitalized for treatment of clinically diagnosed lower respiratory tract infection (C-LRTI) were retrospectively analyzed for CRP and procalcitonin measurements. RESULTS: For non-human immunodeficiency virus (HIV)-infected children, the VE estimates for C-LRTI with CRP levels of > or =40 mg/dL (VE 26.3%; P = 0.003) or CRP levels of > or =120 mg/dL (VE 41.0%; P = 0.003) were 1.7-fold (P = 0.002) and 2.7-fold (P < 0.0001) greater, respectively, than that for CXR-AC (VE 15.1%; P= 0.15). The sensitivity of CXR-AC as an outcome to detect the burden of pneumonia prevented by PCV was 44% (95% confidence interval, 36-55%) in comparison with C-LRTI with CRP levels of > or =40 mg/dL and 73% (95% confidence interval, 58-92%) in comparison with C-LRTI with CRP levels of > or =120 mg/dL. CRP also helped to measure the PCV efficacy for children with C-LRTI but the absence of CXR-AC, for whom the outcome of C-LRTI with CRP levels of > or =40 mg/dL (VE 31.5%; P = 0.007) increased the VE estimate 19.8-fold (P < 0.0001) in comparison with C-LRTI alone (VE 1.6%; P = 0.78) and 3.2-fold (P = 0.005) in comparison with WHO-defined severe pneumonia (VE 10.0%; P = 0.17). Although there was a significant correlation between CRP and procalcitonin levels (Spearman's rho = 0.45; P < 0.0001), the use of procalcitonin levels did not improve either the specificity or sensitivity of measuring the effect of PCV against pneumonia for non-HIV-infected children. The observations were similar for HIV-infected children. CONCLUSIONS: CRP levels of > or =40 mg/dL provide a better measure than chest radiographs to assess the effect of PCV in preventing pneumonia.

C-Reactive Protein↗
PubMed2006

Gamma interferon production in response to Mycobacterium bovis BCG and Mycobacterium tuberculosis antigens in infants born to human immunodeficiency virus-infected mothers.

In utero sensitization to infectious pathogens can establish immunological memory and may influence the immune response to unrelated antigens. Little is known about the influence of intrauterine human immunodeficiency virus (HIV) exposure on the cellular immune response to mycobacterial antigens. Whole-blood culture gamma interferon (IFN-gamma) production in response to mycobacterial antigens was measured at birth and 6 weeks of age to determine the characteristics of the IFN-gamma response in HIV-exposed infants to Mycobacterium bovis BCG and mycobacterial antigens. At birth, we observed an increased immune activation in response to phytohemagglutinin among HIV-exposed, uninfected infants. In a proportion of these infants, we also observed an increased immune activation in response to purified protein derivative, BCG, and early secreted antigen target 6. Increases in the IFN-gamma response to the four antigens between birth and 6 weeks of age, observed in all HIV-unexposed infants, was absent in a substantial proportion of HIV-exposed, uninfected infants. The immunological differences persisted at 6 weeks of age, suggesting a sustained impact of in utero immune priming by HIV. Intrauterine exposure to HIV affects the infants' cellular immune response to mycobacterial antigens, either specifically or as a consequence of nonspecific, broadly reactive immune activation. Further studies will be important to help determine optimal vaccination and disease prevention strategies for this vulnerable population group.

Antigens, Bacterial↗
PubMed2006

Childhood pneumonia--progress and challenges.

UNLABELLED: Remarkable progress has been made in the development of antimicrobial therapy, effective vaccines and pneumonia management guidelines in the past 50 years. However, pneumonia is currently the leading cause of death in children younger than 5 years in developing countries, accounting for approximately 20% of childhood deaths. This article reviews changes in the epidemiology, management and prevention of childhood pneumonia in developing countries, specifically in Africa and South Africa, and addresses future challenges. MAIN FINDINGS: The HIV epidemic has sharply increased the incidence, severity of, and mortality due to, childhood pneumonia. Bacterial infection remains a major cause of pneumonia mortality. Additional pathogens such as Pneumocystis jirovecii and Gram-negative bacteria are found in HIV-infected children, associated with a high mortality. Mycobacterium tuberculosis is an important cause of acute pneumonia in both HIV-infected and uninfected children. Use of case management guidelines can substantially reduce neonatal, infant and under-5 mortality and pneumonia-specific mortality. General preventive interventions including micronutrient supplementation with zinc and vitamin A, and immunisations can substantially reduce the burden of childhood pneumonia. Despite a lower efficacy in HIV-infected children, vaccination protects against disease in a significant proportion of children. In South Africa, new advances over the past 50 years have included greater access to primary health care for children, the use of Integrated Management of Childhood Illness guidelines in primary care, development of guidelines for diagnosis and management of childhood pneumonia and adoption of an expanded immunisation programme that includes coverage for Haemophilus influenzae type b. The pneumococcal conjugate vaccine recently licensed in South Africa also has the potential to significantly reduce the burden of childhood pneumonia. Recent roll-out of the national antiretroviral programme can reduce the incidence and severity of HIV-associated pneumonia through the prevention of HIV infection, use of cotrimoxazole prophylaxis and treatment with antiretrovirals. CONCLUSION: Available, effective interventions for prevention and treatment of childhood pneumonia exist; the challenge is to achieve widespread implementation and high coverage rates in developing countries. Greater access to newer vaccines and to antiretroviral therapy and co-trimoxazole prophylaxis in HIV-infected children is necessary to further reduce the burden of childhood pneumonia and the discrepancies in global child lung health.

Child↗
PubMed2005

Transmissibility, infectivity and immunogenicity of a live human parainfluenza type 3 virus vaccine (HPIV3cp45) among susceptible infants and toddlers.

BACKGROUND: This study examined the transmissibility between young children of an intranasally administered live attenuated human parainfluenza virus type 3 (HPIV3)-cp45 vaccine candidate. METHODS: Eighty subjects were enrolled in playgroups among whom there was at least one infected vaccinee in close contact with a seronegative placebo recipient over 21 days without a confounding infection with wtHPIV3. Following vaccination viral cultures were obtained on nine occasions to detect shedding and transmission of HPIV3cp45. Serum antibody titers were measured before and 7 weeks after vaccination. RESULTS: No child fulfilled the criteria for transmission of HPIV3cp45 giving a risk of transmission of 0.04 (95% CI 0.01-0.19), hence establishing that HPIV3cp45 is less infectious than wtHPIV3 and risk of transmission is not a limitation to further clinical development of this vaccine candidate.

Antibodies, Viral↗
PubMed2005

Immunogenicity and effectiveness of Haemophilus influenzae type b conjugate vaccine in HIV infected and uninfected African children.

The quantitative (anti-Hib capsular polysaccharide antibody concentrations; anti-HibPS) and qualitative (bactericidal activity and avidity) aspects in immune responses to Haemophilus influenzae type b polyribosyl ribitol phospshate-CRM(197) conjugate vaccine (HibCV; HibTiter) were evaluated in 66 HIV infected children not receiving anti-retroviral therapy and 127 HIV uninfected children. Surveillance was conducted for invasive Hib disease in a cohort of 39,865 (approximately 6.4% of whom were HIV infected) children from March 1998 to June 2004. HIV infected children had lower anti-HibPS geometric mean antibody concentrations 1 month post-immunisation than HIV uninfected children (P<0.00001) and were less likely to have anti-HibPS antibody concentrations of >or=1.0 microg/ml (RR 0.54; 95% CI 0.43-0.69). A lower proportion of HIV infected children than HIV uninfected children (RR 0.78; 95% CI 0.66-0.93) had measurable anti-Hib serum bactericidal activity (SBA) and the HibPS antibody concentration required for 50% killing of Hib bacteria was greater among HIV infected than HIV uninfected children (P=0.001). The estimated risk of HibCV failure was 35.1-fold greater (95% CI 14.6-84.6) amongst HIV infected than HIV uninfected children.

Africa↗
PubMed2005

Standardized interpretation of paediatric chest radiographs for the diagnosis of pneumonia in epidemiological studies.

BACKGROUND: Although radiological pneumonia is used as an outcome measure in epidemiological studies, there is considerable variability in the interpretation of chest radiographs. A standardized method for identifying radiological pneumonia would facilitate comparison of the results of vaccine trials and epidemiological studies of pneumonia. METHODS: A WHO working group developed definitions for radiological pneumonia. Inter-observer variability in categorizing a set of 222 chest radiographic images was measured by comparing the readings made by 20 radiologists and clinicians with a reference reading. Intra-observer variability was measured by comparing the initial readings of a randomly chosen subset of 100 radiographs with repeat readings made 8-30 days later. FINDINGS: Of the 222 images, 208 were considered interpretable. The reference reading categorized 43% of these images as showing alveolar consolidation or pleural effusion (primary end-point pneumonia); the proportion thus categorized by each of the 20 readers ranged from 8% to 61%. Using the reference reading as the gold standard, 14 of the 20 readers had sensitivity and specificity of > 0.70 in identifying primary end-point pneumonia; 13 out of 20 readers had a kappa index of > 0.6 compared with the reference reading. For the 92 radiographs deemed to be interpretable among the 100 images used for intra-observer variability, 19 out of 20 readers had a kappa index of > 0.6. CONCLUSION: Using standardized definitions and training, it is possible to achieve agreement in identifying radiological pneumonia, thus facilitating the comparison of results of epidemiological studies that use radiological pneumonia as an outcome.

Child, Preschool↗
PubMed2005

The impact of a 9-valent pneumococcal conjugate vaccine on the public health burden of pneumonia in HIV-infected and -uninfected children.

INTRODUCTION: Pneumococcal conjugate vaccine (PnCV) may be used as a probe to define the burden of pneumococcal disease and better characterize the clinical presentation of pneumococcal pneumonia. METHODS: This study used a 9-valent PnCV to define different end points of vaccine efficacy and the preventable burden of pneumococcal pneumonia in 39,836 children who were randomized in a double-blind, placebo-controlled trial in South Africa. RESULTS: Whereas the point-estimate of vaccine efficacy was greatest when measured against the outcome of vaccine-serotype specific pneumococcal bacteremic pneumonia (61%; P = .01), the sensitivity of blood culture to measure the burden of pneumococcal pneumonia prevented by vaccination was only 2.6% in human immunodeficiency virus (HIV)-uninfected children and 18.8% in HIV-infected children. Only 37.8% of cases of pneumococcal pneumonia prevented by PnCV were detected by means of chest radiographs showing alveolar consolidation. A clinical diagnosis of pneumonia provided the best estimate of the burden of pneumococcal pneumonia prevented through vaccination in HIV-uninfected children (267 cases prevented per 100,000 child-years) and HIV-infected children (2573 cases prevented per 100,000 child-years). CONCLUSION: Although outcome measures with high specificity, such as bacteremic pneumococcal pneumonia, provide a better estimate as to vaccine efficacy, the burden of disease prevented by vaccination is best evaluated using outcome measures with high sensitivity, such as a clinical diagnosis of pneumonia.

Double-Blind Method↗
PubMed2005

Use of procalcitonin and C-reactive protein to evaluate vaccine efficacy against pneumonia.

BACKGROUND: Pneumonia remains the leading cause of death in young children. The poor specificity of chest radiographs (CXRs) to diagnose pneumococcal pneumonia may underestimate the efficacy of pneumococcal conjugate vaccine in preventing pneumococcal pneumonia. METHODS AND FINDINGS: The efficacy of nine-valent pneumococcal conjugate vaccine among children not infected with HIV (21%; 95% confidence interval, 1%-37%) increased when CXR-confirmed pneumonia was associated with serum C-reactive protein of 120 mg/l (12 mg/dl) or more and procalcitonin of 5.0 ng/ml or more (64%; 95% confidence interval, 23%-83%). Similar results were observed in children infected with HIV. CONCLUSION: C-reactive protein and procalcitonin improve the specificity of CXR to diagnose pneumococcal pneumonia and may be useful for the future evaluation of the effectiveness of pneumococcal conjugate vaccine in preventing pneumococcal pneumonia.

Biomarkers↗
PubMed2005

Quantitative and qualitative antibody response to pneumococcal conjugate vaccine among African human immunodeficiency virus-infected and uninfected children.

OBJECTIVE: To determine the quantitative and qualitative antibody responses to a pneumococcal conjugate vaccine (PnCV) in human immunodeficiency virus (HIV)-exposed infected and uninfected children. METHODS: Children were randomized to receive either a PnCV or placebo at 6, 10 and 14 weeks of age. PnCV serotype-specific antibody concentrations were measured by a standard enzyme immunoassay (EIA) and a 22F modified EIA (22F EIA) on single serum samples drawn at 21-42 days post-dose 3. Functional activities of the serotype-specific antibody to serotypes 6B, 19F and 23F were measured with an opsonophagocytic assay (OPA). RESULTS: The geometric mean antibody concentrations (GMC) were similar in HIV-infected and HIV-uninfected PnCV recipients for 7 of the 9 vaccine serotypes. In placebo recipients, the GMCs were significantly higher in HIV-infected than in uninfected children for 7 of the serotypes. In HIV-infected PnCV recipients, the GMCs were lower for 5 of the serotypes in children with severe acquired immunodeficiency syndrome than in children who were asymptomatic or mildly symptomatic with acquired immunodeficiency syndrome. HIV-infected PnCV recipients were less likely to have measurable functional antibody (OPA titer > or =1/8) to all 3 studied serotypes (6B, 19F and 23F) than in HIV-uninfected children. HIV-infected children required a higher concentration of anticapsular antibody to achieve 50% of the maximum uptake of labeled Streptococcus pneumoniae in the OPA assay than HIV-uninfected children for 2 of the 3 serotypes, although this was significant only for serotype 6B (P = 0.0005). CONCLUSION: HIV-infected children have similar quantitative antibody responses but poorer qualitative antibody responses to the PnCV.

AIDS-Related Opportunistic Infections↗
PubMed2005

Human metapneumovirus genetic variability, South Africa.

The molecular epidemiology and genetic diversity of the human metapneumovirus (hMPV) were characterized for a 3-year period (2000-2002) from viruses that were identified in South Africa. Two major genetic groups (A and B) and 2 subgroups (1 and 2) of hMPV were identified, as well as 2-6 possible genotypes within the subgroups. A shift in the predominant group was documented in successive seasons. Whereas the F gene was relatively conserved between subgroups, a high degree of variation was observed in the extracellular domain of the G gene of the virus. The G protein identities between groups A and B were 45.1%-53.1% at the nucleotide level and 22.4%-27.6% at the amino acid level. These results provide evidence for the diversity of both surface glycoproteins of hMPV in Africa, which may be a prerequisite to understanding protective immunity against hMPV.

Genetic Variation↗