Richard Guy White

London School of Hygiene and Tropical Medicine | LSHTM

Background Tuberculosis remains a major public health problem in South Africa, with an estimated 300,000 cases and 55,000 deaths in 2021. New tuberculosis vaccines could play an important role in reducing this burden. Phase IIb trials have suggested efficacy of the M72/AS01E vaccine candidate and BCG-revaccination. The potential population impact o...

Background India has the largest tuberculosis burden globally, but this burden varies nationwide. All-age tuberculosis prevalence in 2021 ranged from 747/100,000 in Delhi to 137/100,000 in Gujarat. Previous modelling has demonstrated the benefits and costs of introducing novel tuberculosis vaccines in India overall. However, no studies have compare...

A new tuberculosis (TB) vaccine is a high priority. However, the classical development pathway is a major deterrent. Most TB cases arise within two years after M. tuberculosis exposure, suggesting a three-year trial period should be possible if sample size is large to maximise the number of early exposures. Increased sample size could be facilitate...

Background Mathematical modelling has been used extensively to estimate the potential impact of new tuberculosis vaccines, with the majority of existing models assuming that individuals with Mycobacterium tuberculosis (Mtb) infection remain at lifelong risk of tuberculosis disease. Recent research provides evidence that self-clearance of Mtb infect...

Background India had an estimated 2.9 million tuberculosis cases and 506 thousand deaths in 2021. Novel vaccines effective in adolescents and adults could reduce this burden. M72/AS01E and BCG-revaccination have recently completed phase IIb trials and estimates of their population-level impact are needed. We estimated the potential health and econo...

Introduction One in two patients developing tuberculosis (TB) in low-income and middle-income countries (LMICs) faces catastrophic household costs. We assessed the potential financial risk protection from introducing novel TB vaccines, and how health and economic benefits would be distributed across income quintiles. Methods We modelled the impact...

Background: Most individuals developing tuberculosis (TB) are working age adults living in low- and middle-income countries (LMICs). The resulting disability and death impact economic productivity and burden health systems. New TB vaccine products may reduce this burden. In this study, we estimated the impact of introducing novel TB vaccines on gr...

Tuberculosis is the leading bacterial cause of death globally. In 2021, 10·6 million people developed symptomatic tuberculosis and 1·6 million died. Seven promising vaccine candidates that aim to prevent tuberculosis disease in adolescents and adults are currently in late-stage clinical trials. Conventional phase 3 trials provide information on the...

Background. Mathematical modelling has been used extensively to estimate the potential impact of new tuberculosis vaccines, with the majority of existing models assuming that individuals with Mycobacterium tuberculosis (Mtb) infection remain at lifelong risk of tuberculosis disease. Recent research provides evidence that self-clearance of Mtb infec...

Background: Tuberculosis is a leading infectious cause of death worldwide. Novel vaccines will be required to reach global targets and reverse setbacks resulting from the COVID-19 pandemic. We estimated the impact of novel tuberculosis vaccines in low-income and middle-income countries (LMICs) in several delivery scenarios. Methods: We calibrate...

Infectious disease models are widely used by epidemiologists to improve the understanding of transmission dynamics and disease natural history, and to predict the possible effects of interventions. As the complexity of such models increases, however, it becomes increasingly challenging to robustly calibrate them to empirical data. History matching...

Approximately 10·6 million people worldwide develop tuberculosis each year, representing a failure in epidemic control that is accentuated by the absence of effective vaccines to prevent infection or disease in adolescents and adults. Without effective vaccines, tuberculosis prevention has relied on testing for Mycobacterium tuberculosis infection...

Background India had an estimated 2.9 million tuberculosis cases and 506 thousand deaths in 2021. Novel vaccines effective in adolescents and adults could reduce this burden. M72/AS01 E and BCG-revaccination have recently completed Phase IIb trials and estimates of their population-level impact are needed. We estimated the potential health and econ...

Introduction Nosocomial Mycobacterium tuberculosis ( Mtb ) transmission substantially impacts health workers, patients and communities. Guidelines for tuberculosis infection prevention and control (TB IPC) exist but implementation in many settings remains suboptimal. Evidence is needed on cost-effective investments to prevent Mtb transmission that...

Background Tuberculosis (TB) is preventable and curable but eliminating it has proven challenging. Safe and effective TB vaccines that can rapidly reduce disease burden are essential for achieving TB elimination. We assessed future costs, cost-savings, and cost-effectiveness of introducing novel TB vaccines in low- and middle-income countries (LMIC...

Most individuals who develop tuberculosis (TB) are working-age adults living in low- and middle-income countries (LMICs). The resulting disability and death impacts economic productivity and burdens health systems. New TB vaccine candidates may reduce this burden. In this study, we estimated the impact of introducing novel TB vaccines on GDP growth...

Mathematical models are widely used to provide evidence to inform policies for tuberculosis (TB) control. These models contain many sources of input uncertainty including the choice of model structure, parameter values and input data. Quantifying the role of these different sources of input uncertainty on the model outputs is important for understa...

Early trials of novel vaccines against tuberculosis (TB) in adults have suggested substantial protection against TB. However, little is known about the feasibility and affordability of rolling out such vaccines in practice. We conducted expert interviews to identify plausible vaccination implementation strategies for the novel M72/AS01 E vaccine ca...

Objectives Disease transmission models are used in impact assessment and economic evaluations of infectious disease prevention and treatment strategies, prominently so in the COVID-19 response. These models rarely consider dimensions of equity relating to the differential health burden between individuals and groups. We describe concepts and approa...

Mathematical modelling methods and adaptive trial design are likely to be effective for optimising vaccine dose but are not yet commonly used. This may be due to uncertainty with regard to the correct choice of parametric model for dose-efficacy or dose-toxicity. Non-parametric models have previously been suggested to be potentially useful in this...

Background: One in two patients developing tuberculosis (TB) in low- and middle-income countries (LMICs) faces catastrophic household costs. We assessed the potential financial risk protection from introducing novel TB vaccines, and how health and economic benefits would be distributed across income quintiles. Methods: We modelled the impact of int...

New tuberculosis vaccine candidates that are in the development pipeline need to be studied in people with HIV, who are at high risk of acquiring Mycobacterium tuberculosis infection and tuberculosis disease and tend to develop less robust vaccine-induced immune responses. To address the gaps in developing tuberculosis vaccines for people with HIV,...

Modelling complex real-world situations such as infectious diseases, geological phenomena, and biological processes can present a dilemma: the computer model (referred to as a simulator) needs to be complex enough to capture the dynamics of the system, but each increase in complexity increases the evaluation time of such a simulation, making it dif...

Data on social contact patterns are widely used to parameterize age-mixing matrices in mathematical models of infectious diseases. Most studies focus on close contacts only (i.e., persons spoken with to face-to-face). This focus may be appropriate for studies of droplet and short-range aerosol transmission but neglects casual or shared air contacts...

High prevalence of infectious tuberculosis among men suggests potential population-wide benefits from addressing programmatic and social determinants of gender disparities. Utilising a sex-stratified compartmental transmission model calibrated to tuberculosis burden estimates for Viet Nam, we modelled interventions to increase active case finding,...

Tuberculosis (TB) remains a leading infectious cause of death worldwide and the coronavirus disease 2019 pandemic has negatively impacted the global TB burden of disease indicators. If the targets of TB mortality and incidence reduction set by the international community are to be met, new more effective adult and adolescent TB vaccines are urgentl...

Background Individuals with bacteriologically confirmed pulmonary tuberculosis disease (TB) that do not report symptoms (subclinical TB) represent around half of all prevalent cases of TB, yet their contribution to Mycobacterium tuberculosis ( Mtb ) transmission is unknown, especially compared to individuals who report symptoms at time of diagnosis...

Infectious disease models are widely used by epidemiologists to improve the understanding of transmission dynamics and disease natural history, and to predict the possible effects of interventions. As the complexity of such models increases, however, it becomes increasingly challenging to robustly calibrate them to empirical data. History matching...

Vaccination is a key tool to reduce global disease burden. Vaccine dose can affect vaccine efficacy and toxicity. Given the expense of developing vaccines, optimising vaccine dose is essential. Mathematical modelling has been suggested as an approach for optimising vaccine dose by quantitatively establishing the relationships between dose and effic...

Background Tuberculosis (TB) is preventable and curable but eliminating it has proven challenging. Safe and effective TB vaccines that can rapidly reduce disease burden are essential for achieving TB elimination. We assessed future costs, cost-savings, and cost-effectiveness of introducing novel TB vaccines in low- and middle-income countries (LMIC...

Recently, two Phase 2B tuberculosis vaccine trials reported positive efficacy results in adolescents and adults. However, experience in vaccinating these age groups is limited. We identified potential implementation strategies for the M72/AS01 E vaccination and BCG-revaccination-like candidates and explored their acceptability and feasibility. We c...

We investigated the effects of updating age-specific social contact matrices to match evolving demography on vaccine impact estimates. We used a dynamic transmission model of tuberculosis in India as a case study. We modelled four incremental methods to update contact matrices over time, where each method incorporated its predecessor: fixed contact...

Background Tuberculosis is a leading infectious cause of death worldwide. Novel vaccines will be required to reach global targets and reverse setbacks from the COVID-19 pandemic. We estimated the impact of novel tuberculosis vaccines in low- and middle-income countries (LMICs), under alternative delivery scenarios. Methods We calibrated a tubercul...

Background There is a high risk of Mycobacterium tuberculosis ( Mtb ) transmission in healthcare facilities in high burden settings. WHO guidelines on tuberculosis (TB) infection prevention and control (IPC) recommend a range of measures to reduce transmission in healthcare settings. These were evaluated primarily based on evidence for their effect...

Background Data on social contact patterns are widely used to parameterise age-mixing matrices in mathematical models of infectious diseases designed to help understand transmission patterns or estimate intervention impacts. Despite this, little attention is given to how social contact data are collected and analysed, or how the types of contact mo...

Currently, no formal mechanisms or systematic approaches exist to inform developers of new vaccines of the evidence anticipated to facilitate global policy recommendations, before a vaccine candidate approaches regulatory approval at the end of pre-licensure efficacy studies. Consequently, significant delays may result in vaccine introduction and u...

BACKGROUND: Tests that identify individuals at greatest risk of TB will allow more efficient targeting of preventive therapy. The WHO target product profile for such tests defines optimal sensitivity of 90% and minimum sensitivity of 75% for predicting incident TB. The CORTIS (Correlate of Risk Targeted Intervention Study) evaluated a blood transcr...

Objectives Selected Zambian communities formed part of a cluster randomised trial: the Zambia and South Africa TB and AIDS Reduction study (ZAMSTAR). There was wide variability in the prevalence of Mycobacterium tuberculosis infection and tuberculosis (TB) disease across these communities. We sought to clarify whether specific communities could hav...

Background Tuberculosis (TB) preventive therapy is recommended for all people living with HIV (PLHIV). Despite the elevated risk of TB amongst PLHIV, most of those eligible for preventive therapy would never develop TB. Tests which can identify individuals at greatest risk of disease would allow more efficient targeting of preventive therapy. Meth...

The impact of COVID-19 disruptions on global Bacillus Calmette-Guérin (BCG) coverage and paediatric tuberculosis (TB) mortality is still unknown. To fill this evidence-gap and guide mitigation measures, we estimated the impact of COVID-19 disruptions on global BCG coverage and paediatric TB mortality. First, we used data from multiple sources to es...

Background Elevated rates of tuberculosis in healthcare workers demonstrate the high rate of Mycobacterium tuberculosis (Mtb ) transmission in health facilities in high-burden settings. In the context of a project taking a whole systems approach to tuberculosis infection prevention and control (IPC), we aimed to evaluate the potential impact of con...

Background South Africa implemented rapid and strict physical distancing regulations to minimize SARS-CoV-2 epidemic spread. Evidence on the impact of such measures on interpersonal contact in rural and lower-income settings is limited. Methods We compared population-representative social contact surveys conducted in the same rural KwaZulu-Natal l...

Background There is a high risk of Mycobacterium tuberculosis (Mtb) transmission in healthcare facilities in high burden settings. Recent World Health Organization guidelines on tuberculosis infection prevention and control (IPC) recommend a range of measures to reduce transmission in healthcare and institutional settings. These were evaluated prim...

Mathematical modelling is increasingly used to inform budgeting and strategic decision-making by national TB programmes. Despite the importance of these decisions, there is currently no mechanism to review and confirm the appropriateness of modelling analyses. We have developed a benchmarking, reporting, and review (BRR) approach and accompanying t...

Background Elevated rates of tuberculosis in health care workers demonstrate the high rate of Mycobacterium tuberculosis (Mtb) transmission in health facilities in high burden settings. In the context of a project taking a whole systems approach to tuberculosis infection prevention and control (IPC), we aimed to evaluate the potential impact of con...

Background In light of the role that airborne transmission plays in the spread of SARS-CoV-2, as well as the ongoing high global mortality from well-known airborne diseases such as tuberculosis and measles, there is an urgent need for practical ways of identifying congregate spaces where low ventilation levels contribute to high transmission risk....

Background A rapid, blood-based triage test that allows targeted investigation for tuberculosis at the point of care could shorten the time to tuberculosis treatment and reduce mortality. We aimed to test the performance of a host blood transcriptomic signature (RISK11) in diagnosing tuberculosis and predicting progression to active pulmonary disea...

New tuberculosis vaccines have made substantial progress in the development pipeline. Previous modelling suggests that adolescent/adult mass vaccination may cost-effectively contribute towards achieving global tuberculosis control goals. These analyses have not considered the budgetary feasibility of vaccine programmes. We estimate the maximum tota...

Background Despite recent advances through the development pipeline, how novel tuberculosis (TB) vaccines might affect rifampicin-resistant and multidrug-resistant tuberculosis (RR/MDR-TB) is unknown. We investigated the epidemiologic impact, cost-effectiveness, and budget impact of hypothetical novel prophylactic prevention of disease TB vaccines...

Background Targeted preventive therapy for individuals at highest risk of incident tuberculosis might impact the epidemic by interrupting transmission. We tested performance of a transcriptomic signature of tuberculosis (RISK11) and efficacy of signature-guided preventive therapy in parallel, using a hybrid three-group study design. Methods Adult...

Background: We tested diagnostic and prognostic performance of a host blood transcriptomic signature of tuberculosis (RISK11) for screening of people living with HIV (PLHIV) in a prospective, community-based cohort. Methods: Ambulant adult volunteers living with HIV were enrolled at five South African sites. RISK11 status was assessed at baseline...

Developing a vaccine against the global pandemic SARS-CoV-2 is a critical area of active research. Modelling can be used to identify optimal vaccine dosing; maximising vaccine efficacy and safety and minimising cost. We calibrated statistical models to published dose-dependent seroconversion and adverse event data of a recombinant adenovirus type-5...

Background : it is widely assumed that individuals with Mycobacterium tuberculosis ( Mtb ) infection remain at lifelong risk of tuberculosis (TB) disease. However, there is substantial evidence that self-clearance of Mtb infection can occur. We infer a curve of self-clearance by time since infection and explore its implications for TB epidemiology....

Background South Africa implemented rapid and strict physical distancing regulations to minimize SARS-CoV-2 epidemic spread. Evidence on the impact of such measures on interpersonal contact in rural and lower-income settings is limited. Methods We compared population-representative social contact surveys conducted in the same rural KwaZulu-Natal l...

Background: South Africa implemented rapid and strict physical distancing regulations to minimize SARS-CoV-2 epidemic spread. Evidence on the impact of such measures on interpersonal contact in rural and lower-income settings is limited. Methods: We compared population-representative social contact surveys conducted in the same rural KwaZulu-Natal...

Background Following infection with Mycobacterium tuberculosis (M.tb), individuals may rapidly develop tuberculosis (TB) disease or enter a “latent” infection state with a low risk of progression to disease. Mathematical models use a variety of structures and parameterisations to represent this process. The effect of these different assumptions on...

More effective tuberculosis vaccines are needed to help reach World Health Organization tuberculosis elimination goals. Insufficient evidence exists on the potential impact of future tuberculosis vaccines with varying characteristics and in different epidemiological settings. To inform vaccine development decision making, we modeled the impact of h...

Previous analyses suggest children with tuberculosis (TB) are no more or no less likely to have multidrug- or rifampicin-resistant TB (MDR/RR-TB) than adults. However, the availability of new data, particularly for high MDR/RR-TB burden countries, suggest updates of country-specific estimates are warranted. We used data from population-representati...

Men are at an increased risk of Tuberculosis disease compared to women. Several risk factors for multidrug-resistant (MDR) or rifampicin-resistant (RR) TB disease are also more common in men, hence male TB patients may have a higher relative risk of MDR/RR-TB than female TB patients. We used sex-disaggregated data of TB patients reported to the Wor...

Social contact patterns might contribute to excess burden of tuberculosis in men. We conducted a study of social contact surveys to evaluate contact patterns relevant to tuberculosis transmission. Available data describe 21 surveys in 17 countries and show profound differences in sex-based and age-based patterns of contact. Adults reported more adu...

BACKGROUND: In South Africa, it is generally estimated that only 0.5–0.6% of people's contacts occur in clinics. Both people with infectious tuberculosis and people with increased susceptibility to disease progression may spend more time in clinics, however, increasing the importance of clinic-based transmission to overall disease incidence. METHOD...

Mycobacterium tuberculosis (Mtb) kills more people worldwide than any single infectious pathogen, yet the only vaccine licensed against tuberculosis, Bacille Calmette Guerin (BCG) is approaching its centenary. Two recent advances in clinical tuberculosis vaccine development have invigorated the field. BCG revaccination of interferon-gamma release a...

Background: BCG has been recommended at birth in countries with a high tuberculosis burden for decades, yet delayed vaccination is widespread. To support a WHO guidance review, we estimated the potential global tuberculosis mortality benefit of administering BCG on time and consequences of later administration. Methods: We estimated age-specific...