Shabir A Madhi

• MBBCh, FCPaeds, MMEd, PhD
• Dean and Professor of Vaccinology at University of the Witwatersrand

Respiratory syncytial virus (RSV) is the commonest cause of lower respiratory tract infection (LRTI) in children, particularly those aged <1 year. In South Africa (SA), increased hospitalisation rates during the RSV season, including access to intensive care facilities, place a huge burden on the healthcare system. Furthermore, RSV-LRTI during earl...

Importance The emergence of acute neurological symptoms in children necessitates immediate intervention. Although low- and middle-income countries (LMICs) bear the highest burden of neurological diseases, there is a scarcity of diagnostic and therapeutic resources. Therefore, current understanding of the etiology of neurological emergencies in LMIC...

Brand serves as the foundation for the entire experience an organisation can deliver across communications, products and services, environments and people. Establishing a strong brand identity is crucial for research institutions to stand out and fulfill their missions effectively. Wits VIDA (previously RMPRU) leadership understood the importance...

SARS-CoV-2 cell-mediated immunity remains understudied during pregnancy in unvaccinated Black African women living with HIV (WLWH) from low- and middle-income countries. We investigated SARS-CoV-2-specific T-cell responses 1 month following infection in 24 HIV-uninfected women and 15 WLWH at any stage during pregnancy or postpartum. The full-length...

Background Rectovaginal group B Streptococcus (GBS) colonisation in pregnant individuals at the time of labour is a major risk factor for invasive GBS disease by age 7 days (early-onset disease). We aimed to investigate the prevalence of rectovaginal GBS colonisation at the time of labour among pregnant women and vertical transmission to their newb...

Streptococcus pneumoniae remains a leading cause of morbidity and mortality in children <5-years-old in sub-Saharan Africa. Monitoring serotype-specific nasopharyngeal colonisation can serve as a proxy to evaluate the effect of vaccination against vaccine-serotype (VT) disease. We evaluated the impact of 13-valent pneumococcal conjugate vaccine (PC...

Background Hypoxemia predicts mortality at all levels of care, and appropriate management can reduce preventable deaths. However, pulse oximetry and oxygen therapy remain inaccessible in many primary care health facilities. We aimed to develop and validate a simple risk score comprising commonly evaluated clinical features to predict hypoxemia in 2...

Background: Group B streptococcus (GBS) surface protein epitopes are potential targets for development of vaccines that could confer protection against invasive GBS disease (IGbsD) irrespective of the capsular serotype. The aim of this study was to determine the association of natural acquired mother-newborn GBS surface proteins specific serum IgG...

Introduction Determining aetiology of severe illness can be difficult, especially in settings with limited diagnostic resources, yet critical for providing life-saving care. Our objective was to describe the accuracy of antemortem clinical diagnoses in young children in high-mortality settings, compared with results of specific postmortem diagnoses...

Streptococcus pneumoniae is a leading cause of pneumonia and meningitis worldwide. Many different serotypes co-circulate endemically in any one location 1,2 . The extent and mechanisms of spread and vaccine-driven changes in fitness and antimicrobial resistance remain largely unquantified. Here using geolocated genome sequences from South Africa (...

Background There is limited evidence regarding the proportion of wheeze in young children attributable to respiratory syncytial virus lower respiratory tract infections (RSV-LRTI) occurring early in life. This cohort study prospectively determined the population attributable risk (PAR) and risk percent (PAR%) of wheeze in 2–<6-year-old children pre...

Background Vaccination of infants with pneumococcal conjugate vaccines is recommended by the World Health Organization. Evidence is mixed regarding the differences in immunogenicity and efficacy of the different pneumococcal vaccines. Objectives The primary objective was to compare the immunogenicity of pneumococcal conjugate vaccine-10 versus pne...

Introduction Chronic lung disease is a major cause of morbidity in African children with HIV infection; however, the microbial determinants of HIV-associated chronic lung disease (HCLD) remain poorly understood. We conducted a case–control study to investigate the prevalence and densities of respiratory microbes among pneumococcal conjugate vaccine...

Title: Factors affecting antenatal care attendance in Soweto, Johannesburg: The three-delay model Authors: Nellie Myburgh, Thabisile Qwabi, Lunghile Shivambo, Lerato Ntsie, Andile Sokani, Maria Maixenchs, Isaac Choge, Sana Mahtab, Ziyaad Dangor, Shabir Madhi Background: Antenatal care remains critical for identifying and managing complications co...

Background Identifying risk factors for respiratory syncytial virus (RSV)–associated severe acute respiratory illness (SARI) will assist with targeting vaccine interventions. Methods Using surveillance data from South Africa (2012-2018). We compared the characteristics of individuals with RSV-associated ILI (reference group) to those with RSV-assoc...

Background Several influenza vaccine candidates aim to elicit antibodies against the conserved hemagglutinin stalk domain. Understanding the protective mechanism of these antibodies, which mediate broad neutralization and Fc-mediated functions, following seasonal vaccination is critical. Methods Plasma samples were obtained from a subset of pregna...

How human genetic variation contributes to vaccine effectiveness in infants is unclear, and data are limited on these relationships in populations with African ancestries. We undertook genetic analyses of vaccine antibody responses in infants from Uganda (n = 1391), Burkina Faso (n = 353) and South Africa (n = 755), identifying associations between...

Measurement of IgG antibodies against group B streptococcus (GBS) capsular polysaccharide (CPS) by use of a standardized and internationally accepted multiplex immunoassay is important for the evaluation of candidate maternal GBS vaccines in order to compare results across studies. A standardized assay is also required if serocorrelates of protecti...

The essence of a vaccine lies in its ability to elicit a set of immune responses specifically directed at a particular pathogen. Accordingly, vaccines were historically designed, developed, registered, recommended, procured, and administered as monopathogen formulations. Nonetheless, the control and elimination of an astonishing number of diseases...

Introduction In 2012, the World Health Organization revised treatment guidelines for childhood pneumonia with lower chest wall indrawing (LCWI) but no ‘danger signs’, to recommend home-based treatment. We analysed data from children hospitalized with LCWI pneumonia in the Pneumonia Etiology Research for Child Health (PERCH) study to identify sub-gr...

Health care workers (HCWs) are primary health providers therefore ensuring their protection and recovery from Covid-19 is of high interest. We investigated post-acute sequelae of SARS-CoV-2 infection (PASC) in HCWs who had previously been infected with SARS-CoV-2. Overall, 68 HCWs were classified as PASC according to duration in days of persisting...

In the aftermath of the COVID-19 pandemic, the evolution of the SARS-CoV-2 into a seasonal pathogen along with the emergence of new variants, underscores the need for dynamic and adaptable responses, emphasizing the importance of sustained vaccination strategies. This observer-blind, double-dummy, randomized immunobridging phase 2 study (NCT0517574...

Background: Seroepidemiology studies are useful for quantifying the magnitude of past infections and estimating the extent of population-based immunity to inform risk mitigation strategies for the future. We report on the only national population-based survey of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) immunoglobulin G (IgG) ser...

Determining the death burden for prioritising public health interventions necessitates detailed data on the causal pathways to death. Postmortem minimally invasive tissue sampling (MITS), incorporating histology, molecular and microbial culture diagnostics, enhances cause-of-death attribution, particularly for infectious deaths. MITS proves a valid...

Delays in illness recognition, healthcare seeking, and in the provision of appropriate clinical care are common in resource-limited settings. Our objective was to determine the frequency of delays in the “Three Delays-in-Healthcare”, and factors associated with delays, among deceased infants and children in seven countries with high childhood morta...

HIV-exposed uninfected infants (HEU) have higher infectious morbidity than HIV-unexposed infants (HUU). HEU have multiple immune defects of unknown origin. We hypothesized that HEU have higher regulatory T cells (Treg) than HUU, which may dampen their immune defenses against pathogens. We compared 25 Treg subsets between HEU and HUU and sought the...

Background The Child Health and Mortality Prevention Surveillance (CHAMPS) Network programme undertakes post-mortem minimally invasive tissue sampling (MITS), together with collection of ante-mortem clinical information, to investigate causes of childhood deaths across multiple countries. We aimed to evaluate the overall contribution of pneumonia i...

Rationale: In the upper respiratory tract replicating (culturable) SARS-CoV-2 is recoverable for ~ 4 to 8 days after symptom onset, however, there is paucity of data about the frequency or duration of replicating virus in the lower respiratory tract (i.e. the human lung). Objectives: We undertook lung tissue sampling (needle biopsy), shortly aft...

To characterize nirsevimab in the prevention of RSV, children from the Phase 3 MELODY trial were followed through their second RSV season. No increase in medically attended RSV lower respiratory tract infections or evidence of antibody-dependent enhancement of infection or disease severity was found for nirsevimab vs placebo recipients. Clinical Tr...

Background Klebsiella pneumoniae is an important cause of nosocomial and community-acquired pneumonia and sepsis in children, and antibiotic-resistant K pneumoniae is a growing public health threat. We aimed to characterise child mortality associated with this pathogen in seven high-mortality settings. Methods We analysed Child Health and Mortalit...

Pertussis remains a public health concern in South Africa, with an increase in reported cases and outbreaks in recent years. Whole genome sequencing was performed on 32 Bordetella pertussis isolates sourced from three different surveillance programmes in South Africa between 2015 and 2019. Genome sequences were characterized using multilocus sequen...

SARS-CoV-2 cell-mediated immunity remains understudied during pregnancy in unvaccinated black African women living with HIV (WLWH) from low- and middle-income countries. We investigated SARS-CoV-2-specific T-cell responses one-month post infection in 24 HIV-uninfected women and 15 WLWH at any stage during pregnancy or postpartum. The full-length sp...

Background COVID-19, first reported in Wuhan, China in December 2019, was declared a pandemic in March 2020, causing restrictions of movement of people and goods worldwide. This affected every aspect of life, including the conduct of clinical trials. We highlight the challenges faced by the PediCAP consortium and how we navigated them. Methods The...

Background In 2020, updated South African guidance on management of children with community-acquired pneumonia were published by the South African Thoracic Society. These guidelines recommend intravenous co-amoxiclav as first-line therapy for children hospitalised with World Health Organisation (WHO) defined severe pneumonia. We evaluated how this...

Acinetobacter baumannii is a Gram-negative multidrug-resistant bacterial pathogen primarily associated with nosocomial infections resulting in increased morbidity and mortality in adults and infants, especially in sub-Saharan Africa where the clinical burden is high. New therapeutics are needed to treat multidrug-resistant Acinetobacter baumannii i...

Pneumonia is a major cause of death among adults living with HIV in South Africa, but the etiology of many cases remains unknown. This study evaluated the utility of a nanofluidic qPCR assay to detect and serotype Streptococcus pneumoniae in urine samples from patients hospitalized with community-acquired pneumonia (CAP). The nanofluidic qPCR assay...

Background Deployment of non-pharmaceutical interventions such as face masking and physical distancing during the COVID-19 pandemic could have altered the transmission dynamics and carriage of respiratory organisms. We evaluated colonisation with Streptococcus pneumoniae and other upper respiratory tract bacterial colonisers before and during the C...

BACKGROUND. In children, hypernatraemia occurs most commonly in infants (younger than 1 year). Although hypernatraemia is associated with high mortality and morbidity rates, it is variably defined in the paediatric literature as either serum sodium >150 mmol/L or serum sodium >145 mmol/L. In hospitalised adults, a serum sodium level >145 mmol/L but...

Respiratory syncytial virus (RSV) is the most common cause of lower respiratory tract infection (LRTI) in children, and is associated with long-term pulmonary sequelae for up to 30 years after infection. The mainstay of RSV management is supportive therapy such as supplemental oxygen. Palivizumab (Synagis™–AstraZeneca), a monoclonal antibody target...

Background Neonatal colonization with multidrug-resistant (MDR) Enterobacter spp., Staphylococcus aureus , Klebsiella pneumoniae , Acinetobacter baumannii , Pseudomonas aeruginosa and Enterococcus faecium (ESKAPE) and Candida spp. often precedes invasive hospital-acquired infections. We investigated the prevalence and dynamics of neonatal ESKAPE an...

Objectives To assess postmortem vitamin A (VA) concentrations in children under 5 years of age and evaluate the association between VA deficiency (VAD) and infectious causes of death (CoD). Study design In this cross-sectional study from the Child Health and Mortality Prevention Surveillance (CHAMPS) Network, liver biopsies collected within 72 hou...

Vaccination during pregnancy with tetanus-diphtheria-acellular pertussis (Tdap) vaccine is recommended to protect the young infants against pertussis. There is a paucity of data on immune responses to Tdap in pregnant women living with HIV (PWLWH), and its impact on the protection of their infants has not been described. In an open label phase IV c...

Background Neural tube defects are common birth defects resulting in severe morbidity and mortality; they can largely be prevented with periconceptional maternal intake of folic acid. Understanding the occurrence of neural tube defects and their contribution to mortality in settings where their burden is highest could inform prevention and health-c...

Postmortem minimally invasive tissue sampling together with the detailed review of clinical records has been shown to be highly successful in determining the cause of neonatal deaths. However, conventional tests including traditional culture methods and nucleic acid amplification tests have periodically proven to be insufficient to detect the causa...

A matched case-control evaluated infectious etiologies in children <3 years in post-rotavirus vaccine intussusception surveillance. Adenovirus and adenovirus types C, A, and B were detected more frequently in cases versus controls at statistically significant values. Wild-type rotavirus, rotavirus vaccine strains, and human herpesvirus were not ass...

Background: Most childhood deaths globally are considered preventable through high-quality clinical care, which includes adherence to clinical care recommendations. Our objective was to describe adherence to World Health Organization recommendations for the management of leading causes of death among children. Methods: We conducted a retrospective,...

The pathogenesis of coronavirus disease 2019 (COVID-19) pneumonia remains poorly understood. The urine proteome of hospitalized patients with severe COVID-19 pneumonia, compared with severe non-COVID-19 pneumonia controls, was distinct and associated with lower abundance of several host proteins. Protein-specific machine learning analysis outlined...

The kinetics of Fc-mediated functions following SARS-CoV-2 infection or vaccination in people living with HIV (PLWH) are not known. We compared SARS-CoV-2 spike-specific Fc functions, binding, and neutralization in PLWH and people without HIV (PWOH) during acute infection (without prior vaccination) with either the D614G or Beta variants of SARS-Co...

BACKGROUND: P1041 was a randomised, placebo-controlled isoniazid prophylaxis trial in South Africa. We studied predictors for TB in HIV-exposed children participating in the P1041 trial.METHODS: We included data from entry until Week 108. Predictors considered were type of housing, overcrowding, age, sex, ethnicity, tobacco exposure, weight-for-age...

Background: Natural history studies have correlated serotype-specific anti-capsular polysaccharide (CPS) IgG in newborns with a reduced risk of group B streptococcal disease. A hexavalent CPS-cross-reactive material 197 glycoconjugate vaccine (GBS6) is being developed as a maternal vaccine to prevent invasive group B streptococcus in young infants...

Nirsevimab is a monoclonal antibody that binds to the respiratory syncytial virus (RSV) fusion protein. During the Phase 2b (NCT02878330) and MELODY (NCT03979313) clinical trials, infants received one dose of nirsevimab or placebo before their first RSV season. In this pre-specified analysis, isolates from RSV infections were subtyped, sequenced an...

Background Invasive Group B Streptococcus (GBS) is a common cause of early-onset neonatal sepsis and is also associated with stillbirth. This study aimed to determine the proportion of stillborn infants and infants who died between 0 and 90 days attributable to GBS using postmortem minimally invasive tissue sampling (MITS) in 7 low- and middle-inco...

Importance: The number of deaths of children younger than 5 years has been steadily decreasing worldwide, from more than 17 million annual deaths in the 1970s to an estimated 5.3 million in 2019 (with 2.8 million deaths occurring in those aged 1-59 months [53% of all deaths in children aged <5 years]). More detailed characterization of childhood d...

Background: Vaccination of infants with pneumococcal conjugate vaccines (PCV) is recommended by the World Health Organization. Evidence is mixed regarding the differences in immunogenicity and efficacy of the different pneumococcal vaccines. Methods: In this systematic-review and network meta-analysis, we searched the Cochrane Library, Embase, G...

Immunization of pregnant women with Group B Streptococcus (GBS) capsular polysaccharide (CPS) conjugate vaccine (CV) could protect young infants against invasive GBS disease. We evaluated the immunogenicity of investigational five GBS monovalent (serotypes Ia, Ib, II, III, and V) CPS-tetanus toxoid (TT)-CV with adjuvant and GBS pentavalent CPS-TT-C...

The burden of cervical cancer is disproportionately distributed globally, with the vast majority of cases occurring in low- and middle-income countries. Women with human immunodeficiency virus (HIV) (WWH) are at increased risk of human papillomavirus (HPV) infection and cervical cancer as compared to HIV-negative individuals. HPV vaccination remain...

Hepatitis B virus (HBV) vaccine escape mutants (VEM) are increasingly described, threatening progress in control of this virus worldwide. Here we studied the relationship between host genetic variation, vaccine immunogenicity and viral sequences implicating VEM emergence. In a cohort of 1,096 Bangladeshi children, we identified human leukocyte anti...

Despite the success of COVID-19 vaccines, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern have emerged that can cause breakthrough infections. Although protection against severe disease has been largely preserved, the immunological mediators of protection in humans remain undefined. We performed a substudy on the Ch...

[This corrects the article DOI: 10.3389/fimmu.2023.1130539.].

Introduction The coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has resulted in significant morbidity and mortality worldwide. As SARS-CoV-2 moves into endemic status, vaccination remains a key element in protecting the health of individuals, societies, and economies worldwide....

The COVID-19 pandemic heralded unprecedented resource mobilisation and global scientific collaboration to rapidly develop effective vaccines. Regrettably, vaccine distribution has been inequitable, particularly in Africa where manufacturing capacity remains nominal. To address this, several initiatives are underway to develop and manufacture COVID-...

Background Neural tube defects are common birth defects resulting in severe morbidity and mortality; they can largely be prevented with periconceptionally maternal intake of folic acid. Understanding the occurrence of neural tube defects and their contribution to mortality in settings where their burden is highest could inform prevention and health...

The highly transmissible Omicron (B.1.1.529) variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was first detected in late 2021. Initial Omicron waves were primarily made up of sub-lineages BA.1 and/or BA.2, BA.4, and BA.5 subsequently became dominant in mid-2022, and several descendants of these sub-lineages have since emerged...

Background Respiratory syncytial virus (RSV) is the most common cause of hospitalisation for lower respiratory tract infection (LRTI) in children. RSV LRTI during early childhood may increase susceptibility to recurrent wheezing and asthma. Research question The aim of this study was to describe the pulmonary sequelae at 1 and 2 years of age follo...

Citation: Muthoni, J.; Otwombe, K.; Thaele, D.; Choge, I.; Steenberg, B.; Cutland, C.; Madhi, S.A.; Sokani, A.; Myburgh, N. COVID-19 Vaccination Hesitancy among Youths in Soweto, South Africa. Vaccines 2023, 11, 960. Abstract: In combatting COronaVIrus Disease 2019 (COVID-19), immunization is the most prominent strategy. However, vaccination hesita...

Background Various case definitions of respiratory syncytial virus lower respiratory tract infection (RSV-LRTI) are currently proposed. We assessed the performance of three clinical case definitions against the World Health Organization definition recommended in 2015 (WHO 2015). Methods In this prospective cohort study conducted in eight countries...

Background: Non-pharmaceutical interventions affected the circulation of and illness due to endemic respiratory pathogens during the COVID-19 pandemic. We investigated the incidence of admissions to hospital for overall and specific pathogen-associated lower respiratory tract infection (LRTI) during the COVID-19 pandemic compared with incidence in...

Background: Pneumococcal Conjugate Vaccines (PCVs) reduce pneumococcal-associated disease by reducing vaccine-serotype (VT) acquisition in vaccinated children, thereby interrupting VT transmission. The 7-valent-PCV was introduced in the South African immunisation program since 2009 (13-valent-PCV since 2011) using a 2+1 schedule (6-, 14- and 40-we...

Introduction: The detection of respiratory syncytial virus (RSV) in upper airway samples does not necessarily infer causality of illness. Calculating the attributable fraction (AF) of RSV in clinical syndromes could refine disease burden estimates. Method: Using unconditional logistic regression models, we estimated the AF of RSV-associated infl...

The development of new antimicrobial drugs is needed to combat multi-drug resistant and novel hypervirulent strains of Klebsiella pneumoniae (KPN) that are associated with increased morbidity and mortality globally. The FabI protein plays a crucial role in fatty acid biosynthesis and has been identified as an important target for in-silico, in-vitr...

Respiratory syncytial virus (RSV) is the most common cause of lower respiratory tract infection (LRTI) in children, causing approximately 3.6 million hospitalizations per year, and has been associated with long-term pulmonary sequelae for up to 30 years after infection, yet preventative strategies and active treatment options remain elusive. The as...

Background: Whether vaccination during pregnancy could reduce the burden of respiratory syncytial virus (RSV)-associated lower respiratory tract illness in newborns and infants is uncertain. Methods: In this phase 3, double-blind trial conducted in 18 countries, we randomly assigned, in a 1:1 ratio, pregnant women at 24 through 36 weeks' gestati...

Objectives: We investigated whether patients with cryptococcal meningitis (CM) or fungaemia detected through South Africa's laboratory cryptococcal antigen (CrAg) screening programme had better outcomes than those presenting directly to hospital. Methods: We compared 14-day in-hospital case-fatality ratios (CFR) of HIV-seropositive individuals w...

COVID-19 vaccine efficacy (VE) has been observed to vary against antigenically distinct SARS-CoV-2 variants of concern (VoC). Here we report the final analysis of VE and safety from COV005: a phase 1b/2, multicenter, double-blind, randomized, placebo-controlled study of primary series AZD1222 (ChAdOx1 nCoV-19) vaccination in South African adults ag...

Citation: Myburgh, N.; Mulaudzi, M.; Tshabalala, G.; Beta, N.; Gutu, K.; Vermaak, S.; Lau, C.; Hill, C.; Stanberry, L.; James, W.; et al. A Qualitative Study Exploring Motivators and Barriers to COVID-19 Vaccine Uptake among Adults in South Africa and Zimbabwe. Vaccines 2023, 11, 729. https://doi. Abstract: While vaccines are a well-established met...

Sensitive tools for detecting concurrent colonizing pneumococcal serotypes are needed for detailed evaluation of the direct and indirect impact of routine pneumococcal conjugate vaccine (PCV) immunization. A high-throughput quantitative nanofluidic real-time PCR (Standard BioTools ‘Fluidigm’) reaction-set was developed to detect and quantify 92 pne...

Objectives: To evaluate the safety and immunogenicity of V114 (15-valent pneumococcal conjugate vaccine [PCV] containing serotypes 1, 3, 4, 5, 6A, 6B, 7F, 9 V, 14, 18C, 19A, 19F, 22F, 23F, 33F), followed by 23-valent pneumococcal polysaccharide vaccine (PPSV23) 8 weeks later, in children living with HIV. Design: This phase 3 study (NCT03921424)...

Each year, 2.4 million children die within their first month of life. Child Health and Mortality Prevention Surveillance (CHAMPS) established in 7 countries aims to generate accurate data on why such deaths occur and inform prevention strategies. Neonatal deaths that occurred between December 2016 and December 2021 were investigated with MITS withi...