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Luabeya AKK, Rozot V, Imbratta C, Ratangee F, Shenje J, Tameris M, Mendelsohn SC, Geldenhuys H, Fisher M, Musvosvi M, Young C, Mulenga H, Bilek N, Mabwe S, Jelsbak IM, Rodríguez E, Puentes E, Doce J, Aguilo N, Martin C, Pillay C, Tait D, Russell M, Van Der Merve A, Rutkowski K, Hunt D, Ginsberg A, Scriba TJ, Hatherill M. Live-attenuated Mycobacterium tuberculosis vaccine, MTBVAC, in adults with or without M tuberculosis sensitisation: a single-centre, phase 1b-2a, double-blind, dose-escalation, randomised controlled trial. Lancet Glob Health 2025:S2214-109X(25)00046-4. [PMID: 40250461 DOI: 10.1016/s2214-109x(25)00046-4] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2023] [Revised: 12/18/2024] [Accepted: 01/23/2025] [Indexed: 04/20/2025]
Abstract
BACKGROUND An effective adult vaccine is needed to control tuberculosis. We evaluated the safety and immunogenicity of a live-attenuated Mycobacterium tuberculosis vaccine (MTBVAC). METHODS This single-centre, phase 1b-2a, double-blind, dose-escalation, randomised controlled trial (NCT02933281) enrolled South African adults previously vaccinated with BCG, who were HIV negative and aged 18-50 years, with or without M tuberculosis sensitisation assessed by QuantiFERON-tuberculosis Gold-Plus assay (QFT). Participants were recruited from the local community and randomly allocated (2:1) to receive MTBVAC (5 × 103, 5 × 104, 5 × 105, or 5 × 106 colony-forming unit [CFU] doses) or BCG revaccination (5 × 105 CFU dose). The primary outcomes were the occurrence of systemic solicited adverse events within 7 days and unsolicited adverse events within 28 days after vaccination, the occurrence of solicited and unsolicited injection-site reactions within 84 days after vaccination, and the occurrence of serious adverse events (SAEs) until the end of study, 365 days after vaccination. Data were analysed per modified intention to treat. The trial is now complete and closed. FINDINGS Between Jan 15, 2019, and Sept 7, 2020, 485 participants provided consent and were screened. 144 participants were enrolled and 143 (99%) were vaccinated. BCG was administrated to 47 (33%) of 143 and MTBVAC to 96 (67%) of 143. 12 participants with QFT-negative results and 12 with QFT-positive results were randomly allocated to receive each dose of MTBVAC and 24 participants with QFT-negative results and 24 with QFT-positive results were randomly allocated to receive BCG revaccination. Injection-site pain, discharge, erythema, and swelling increased with MTBVAC dose level. MTBVAC 5 × 105 CFU recipients reported a similar proportion of related adverse events (23 [96%] of 24) as BCG recipients (45 [96%] of 47). MTBVAC recipients who were QFT positive reported more injection-site reactions (46 [96%] of 48; 95% CI 85·7-99·5) than MTBVAC recipients who were QFT negative (32 [67%] of 48; 51·6-79·6). No vaccine-related SAEs were reported. All doses of MTBVAC were immunogenic; vaccine-induced antigen-specific CD4 T-cell responses peaked 28 days after vaccination. The MTBVAC 5 × 105 and 5 × 106 CFU doses induced T-helper-cell-1 cytokine-expressing CD4 T-cell responses that exceeded BCG-induced responses in participants who were QFT negative and QFT positive. INTERPRETATION MTBVAC at the 5 × 105 dose showed similar safety and reactogenicity and greater immunogenicity when compared to BCG. These results suggest that the 5 × 105 dose of MTBVAC could be selected for a subsequent efficacy evaluation. FUNDING Congressionally Directed Medical Research Programmes and US National Institutes of Health.
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Affiliation(s)
- Angelique Kany Kany Luabeya
- South African Tuberculosis Vaccine Initiative, Institute of Infectious Disease and Molecular Medicine and Department of Pathology, University of Cape Town, Cape Town, South Africa
| | - Virginie Rozot
- South African Tuberculosis Vaccine Initiative, Institute of Infectious Disease and Molecular Medicine and Department of Pathology, University of Cape Town, Cape Town, South Africa
| | - Claire Imbratta
- South African Tuberculosis Vaccine Initiative, Institute of Infectious Disease and Molecular Medicine and Department of Pathology, University of Cape Town, Cape Town, South Africa
| | - Frances Ratangee
- South African Tuberculosis Vaccine Initiative, Institute of Infectious Disease and Molecular Medicine and Department of Pathology, University of Cape Town, Cape Town, South Africa
| | - Justin Shenje
- South African Tuberculosis Vaccine Initiative, Institute of Infectious Disease and Molecular Medicine and Department of Pathology, University of Cape Town, Cape Town, South Africa
| | - Michele Tameris
- South African Tuberculosis Vaccine Initiative, Institute of Infectious Disease and Molecular Medicine and Department of Pathology, University of Cape Town, Cape Town, South Africa
| | - Simon C Mendelsohn
- South African Tuberculosis Vaccine Initiative, Institute of Infectious Disease and Molecular Medicine and Department of Pathology, University of Cape Town, Cape Town, South Africa
| | - Hennie Geldenhuys
- South African Tuberculosis Vaccine Initiative, Institute of Infectious Disease and Molecular Medicine and Department of Pathology, University of Cape Town, Cape Town, South Africa
| | - Michelle Fisher
- South African Tuberculosis Vaccine Initiative, Institute of Infectious Disease and Molecular Medicine and Department of Pathology, University of Cape Town, Cape Town, South Africa
| | - Munyaradzi Musvosvi
- South African Tuberculosis Vaccine Initiative, Institute of Infectious Disease and Molecular Medicine and Department of Pathology, University of Cape Town, Cape Town, South Africa
| | - Carly Young
- South African Tuberculosis Vaccine Initiative, Institute of Infectious Disease and Molecular Medicine and Department of Pathology, University of Cape Town, Cape Town, South Africa
| | - Humphrey Mulenga
- South African Tuberculosis Vaccine Initiative, Institute of Infectious Disease and Molecular Medicine and Department of Pathology, University of Cape Town, Cape Town, South Africa
| | - Nicole Bilek
- South African Tuberculosis Vaccine Initiative, Institute of Infectious Disease and Molecular Medicine and Department of Pathology, University of Cape Town, Cape Town, South Africa
| | - Simbarashe Mabwe
- South African Tuberculosis Vaccine Initiative, Institute of Infectious Disease and Molecular Medicine and Department of Pathology, University of Cape Town, Cape Town, South Africa
| | | | | | | | | | - Nacho Aguilo
- Department of Microbiology Pediatrics, Radiology, and Public Health, Faculty of Medicine, University of Zaragoza, CIBERES, Instituto Salud Carlos III, Madrid, Spain
| | - Carlos Martin
- Department of Microbiology Pediatrics, Radiology, and Public Health, Faculty of Medicine, University of Zaragoza, CIBERES, Instituto Salud Carlos III, Madrid, Spain
| | | | - Dereck Tait
- IAVI, New York, NY, USA; IAVI, Cape Town, South Africa
| | | | | | | | - Devin Hunt
- IAVI, New York, NY, USA; IAVI, Cape Town, South Africa
| | - Ann Ginsberg
- IAVI, New York, NY, USA; IAVI, Cape Town, South Africa; Bill & Melinda Gates Foundation, Seattle, WA, USA
| | - Thomas J Scriba
- South African Tuberculosis Vaccine Initiative, Institute of Infectious Disease and Molecular Medicine and Department of Pathology, University of Cape Town, Cape Town, South Africa
| | - Mark Hatherill
- South African Tuberculosis Vaccine Initiative, Institute of Infectious Disease and Molecular Medicine and Department of Pathology, University of Cape Town, Cape Town, South Africa.
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Sumner T, Clark RA, Prys-Jones TO, Bakker R, Churchyard G, White RG. The potential impact of new tuberculosis vaccines on the burden of tuberculosis in people with HIV in South Africa. AIDS 2025; 39:175-183. [PMID: 39411889 PMCID: PMC11676631 DOI: 10.1097/qad.0000000000004038] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2024] [Revised: 09/25/2024] [Accepted: 10/03/2024] [Indexed: 01/11/2025]
Abstract
BACKGROUND People with HIV (PWH) are at an increased risk of tuberculosis (TB). New TB vaccines may help reduce this burden. New TB vaccine candidates are well tolerated and immunogenic in PWH. There are currently limited data on vaccine efficacy in this population. METHODS Using mathematical modeling, we explored the potential impact of a novel TB vaccine on TB burden in PWH in South Africa between 2030 and 2050. We compared the impact of a vaccine delivered irrespective of HIV status to vaccination of either PWH or people without HIV. We explored the impact of reduced vaccine efficacy and duration of protection in PWH relative to people without HIV on our model predictions. RESULTS Vaccination irrespective of HIV status, with a vaccine with equal efficacy and duration in PWH, could avert up to 1.01 (95% range: 0.96-1.22) million TB cases in PWH. Restricting vaccination to PWH or people without HIV would achieve 65% (60-70) and 48% (46-53) of the total impact, respectively. These results are strongly dependent on the assumed efficacy and duration of protection in PWH. Further information on these characteristics is important to identify the most efficient use of new vaccines to reduce TB burden in PWH. CONCLUSION Our results suggest that new vaccines could play an important role in reducing the TB burden in PWH. Vaccines targeted at people without HIV could provide significant indirect benefit to PWH, but vaccines which are well tolerated and effective in PWH will be critical to maximizing the impact in this population.
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Affiliation(s)
- Tom Sumner
- TB Modelling Group and TB Centre, London School of Hygiene and Tropical Medicine
- Centre for the Mathematical Modelling of Infectious Diseases
- Department of Infectious Disease Epidemiology, London School of Hygiene and Tropical Medicine, London, UK
| | - Rebecca A. Clark
- TB Modelling Group and TB Centre, London School of Hygiene and Tropical Medicine
- Centre for the Mathematical Modelling of Infectious Diseases
- Department of Infectious Disease Epidemiology, London School of Hygiene and Tropical Medicine, London, UK
| | - Tomos O. Prys-Jones
- TB Modelling Group and TB Centre, London School of Hygiene and Tropical Medicine
- Centre for the Mathematical Modelling of Infectious Diseases
- Department of Infectious Disease Epidemiology, London School of Hygiene and Tropical Medicine, London, UK
| | - Roel Bakker
- TB Modelling Group and TB Centre, London School of Hygiene and Tropical Medicine
- Centre for the Mathematical Modelling of Infectious Diseases
- Department of Infectious Disease Epidemiology, London School of Hygiene and Tropical Medicine, London, UK
- KNCV Tuberculosis Foundation, The Hague, Netherlands
| | - Gavin Churchyard
- The Aurum Institute
- School of Public Health, University of Witwatersrand, Johannesburg, South Africa
- Department of Medicine, Vanderbilt University, Nashville, Tennessee, USA
| | - Richard G. White
- TB Modelling Group and TB Centre, London School of Hygiene and Tropical Medicine
- Centre for the Mathematical Modelling of Infectious Diseases
- Department of Infectious Disease Epidemiology, London School of Hygiene and Tropical Medicine, London, UK
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3
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Smytheman T, Pecor T, Miller DE, Ferede D, Kaur S, Harband MH, Abdelaal HFM, Guerrero-Bustamante CA, Freeman KG, Harrington WE, Frenkel LM, Hatfull GF, Coler RN, Larsen SE. Evaluation of host immune responses to Mycobacteriophage Fionnbharth by route of delivery. Virol J 2025; 22:14. [PMID: 39833928 PMCID: PMC11748884 DOI: 10.1186/s12985-024-02552-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2024] [Accepted: 10/22/2024] [Indexed: 01/22/2025] Open
Abstract
For much of the last decade, tuberculosis (TB) was the leading cause of mortality due to an infectious pathogen (Mycobacterium tuberculosis, M.tb). Approximately 1.3 million deaths in 2023 worldwide were attributed to TB disease. Focused intervention strategies to block transmission would significantly reduce the global health burden of TB. Mycobacteriophages (phages) are a sorely underutilized biologic therapy for the pathogen M.tb, and here we aimed to address outstanding questions about their utility for clinical applications. We aimed to determine the impact of repeated mucosal or intravenous (IV) delivery of representative anti-M.tb phage FionnbharthΔ45Δ47 (Fionnbharth) in a preclinical mouse model. In addition, we specifically sought to understand which route induced anti-phage antibodies, which may reduce the long-term impact of phage therapy. C57BL/6 mice were dosed weekly for 6 weeks by either route and serum and bronchoalveolar lavage fluid (BALf) were evaluated for anti-phage humoral responses by ELISA. We found that aerosol delivery disperses phage across all lung lobes where M.tb is also found after experimental infection by the same route. Repeated aerosol delivery was well tolerated and did not induce robust neutralizing humoral immunity. In contrast, Mice receiving IV phage developed increasing magnitude and neutralizing total IgG and IgA responses over time. To determine whether pre-treatment environmental exposure to Fionnbharth-like phages could induce antibody responses that are potentially neutralizing, ~ 500 human plasma samples from normal donors were evaluated by ELISA. We observed that 5% of samples had antibodies to Fionnbharth (with end point titers > 10- 3 dilution), although none were neutralizing. Furthermore, we found that highly-purified phage preparations did not activate mouse or human derived toll like receptor (TLR) 4 or TLR9 in HEKblue reporter assays. These data together support using Fionnbharth in anti-M.tb therapy phage cocktail strategies and that aerosol delivery should be prioritized for further efficacy testing.
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Affiliation(s)
- Thomas Smytheman
- Center for Global Infectious Disease Research, Seattle Children's Research Institute, Seattle, WA, USA
| | - Tiffany Pecor
- Center for Global Infectious Disease Research, Seattle Children's Research Institute, Seattle, WA, USA
| | - Dana E Miller
- Center for Global Infectious Disease Research, Seattle Children's Research Institute, Seattle, WA, USA
| | - Debora Ferede
- Center for Global Infectious Disease Research, Seattle Children's Research Institute, Seattle, WA, USA
| | - Suhavi Kaur
- Center for Global Infectious Disease Research, Seattle Children's Research Institute, Seattle, WA, USA
| | - Matthew H Harband
- Center for Global Infectious Disease Research, Seattle Children's Research Institute, Seattle, WA, USA
| | - Hazem F M Abdelaal
- Center for Global Infectious Disease Research, Seattle Children's Research Institute, Seattle, WA, USA
| | | | - Krista G Freeman
- Department of Biological Sciences, University of Pittsburgh, Pittsburgh, PA, USA
| | - Whitney E Harrington
- Center for Global Infectious Disease Research, Seattle Children's Research Institute, Seattle, WA, USA
- Department of Pediatrics, University of Washington, Seattle, WA, USA
- Department of Global Health, University of Washington, Seattle, WA, USA
| | - Lisa M Frenkel
- Center for Global Infectious Disease Research, Seattle Children's Research Institute, Seattle, WA, USA
- Department of Pediatrics, University of Washington, Seattle, WA, USA
| | - Graham F Hatfull
- Department of Biological Sciences, University of Pittsburgh, Pittsburgh, PA, USA
| | - Rhea N Coler
- Center for Global Infectious Disease Research, Seattle Children's Research Institute, Seattle, WA, USA.
- Department of Pediatrics, University of Washington, Seattle, WA, USA.
- Department of Global Health, University of Washington, Seattle, WA, USA.
| | - Sasha E Larsen
- Center for Global Infectious Disease Research, Seattle Children's Research Institute, Seattle, WA, USA
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Clark RA, Portnoy A, Weerasuriya CK, Sumner T, Bakker R, Harris RC, Rade K, Mattoo SK, Tumu D, Menzies NA, White RG. Estimating the potential health and economic impacts of new tuberculosis vaccines under varying delivery strategies in Delhi and Gujarat, India: a modelling study. THE LANCET REGIONAL HEALTH. SOUTHEAST ASIA 2024; 31:100424. [PMID: 39957772 PMCID: PMC11827003 DOI: 10.1016/j.lansea.2024.100424] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 09/28/2023] [Revised: 04/24/2024] [Accepted: 04/29/2024] [Indexed: 02/18/2025]
Abstract
Background India has the largest tuberculosis burden, but the all-age prevalence in 2021 ranged from 747/100,000 in Delhi to 137/100,000 in Gujarat. No modelling studies have compared the potential impact of new tuberculosis vaccines in regions with differing disease and infection prevalence. Methods We used modelling to simulate hypothetical scenarios of introducing M72/AS01E (with 50% efficacy to prevent disease) and BCG-revaccination (with 45% efficacy to prevent infection) in Delhi and Gujarat. Findings The hypothetical M72/AS01E scenario could avert 16.0% of cases and 14.4% of deaths in Delhi, and 8.5% of cases and 7.6% of deaths in Gujarat between 2025 and 2050. The hypothetical BCG-revaccination scenario could avert 8.8% of cases and 8.3% of deaths in Delhi, and 5.1% of cases and 4.8% of deaths in Gujarat between 2025 and 2050. Interpretation Additional trials for both vaccines are underway, which will provide further evidence on the vaccine efficacy and narrow the range of uncertainty on the estimates. Funding Bill & Melinda Gates Foundation (INV-001754).
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Affiliation(s)
- Rebecca A. Clark
- TB Modelling Group and TB Centre, LSHTM, UK
- Centre for the Mathematical Modelling of Infectious Diseases, LSHTM, UK
- Department of Infectious Disease Epidemiology, LSHTM, UK
- Vaccine Centre, LSHTM, UK
| | - Allison Portnoy
- Department of Global Health, Boston University School of Public Health, USA
- Center for Health Decision Science, Harvard T.H. Chan School of Public Health, USA
| | - Chathika K. Weerasuriya
- TB Modelling Group and TB Centre, LSHTM, UK
- Centre for the Mathematical Modelling of Infectious Diseases, LSHTM, UK
- Department of Infectious Disease Epidemiology, LSHTM, UK
| | - Tom Sumner
- TB Modelling Group and TB Centre, LSHTM, UK
- Centre for the Mathematical Modelling of Infectious Diseases, LSHTM, UK
- Department of Infectious Disease Epidemiology, LSHTM, UK
| | - Roel Bakker
- TB Modelling Group and TB Centre, LSHTM, UK
- Centre for the Mathematical Modelling of Infectious Diseases, LSHTM, UK
- Department of Infectious Disease Epidemiology, LSHTM, UK
- KNCV Tuberculosis Foundation, Netherlands
| | - Rebecca C. Harris
- TB Modelling Group and TB Centre, LSHTM, UK
- Centre for the Mathematical Modelling of Infectious Diseases, LSHTM, UK
- Department of Infectious Disease Epidemiology, LSHTM, UK
- Sanofi Pasteur, Singapore
| | - Kirankumar Rade
- World Health Organization, India
- International Technical Consultant, The StopTB Partnership, New Delhi, India
| | - Sanjay Kumar Mattoo
- Central TB Division, National Tuberculosis Elimination Program, MoHFW Govt of India, New Delhi, India
| | - Dheeraj Tumu
- World Health Organization, India
- Central TB Division, National Tuberculosis Elimination Program, MoHFW Govt of India, New Delhi, India
| | - Nicolas A. Menzies
- Center for Health Decision Science, Harvard T.H. Chan School of Public Health, USA
- Department of Global Health and Population, Harvard T.H. Chan School of Public Health, USA
| | - Richard G. White
- TB Modelling Group and TB Centre, LSHTM, UK
- Centre for the Mathematical Modelling of Infectious Diseases, LSHTM, UK
- Department of Infectious Disease Epidemiology, LSHTM, UK
- Vaccine Centre, LSHTM, UK
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Buis JS, Jerene D, Gebhard A, Bakker R, Majidulla A, Kerkhoff AD, Limaye RJ, Pelzer PT. Mapping the existing body of knowledge on new and repurposed TB vaccine implementation: A scoping review. PLOS GLOBAL PUBLIC HEALTH 2024; 4:e0002885. [PMID: 39172796 PMCID: PMC11340902 DOI: 10.1371/journal.pgph.0002885] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/23/2024] [Accepted: 07/10/2024] [Indexed: 08/24/2024]
Abstract
There is global consensus on the urgent need for a safe and effective TB vaccine for adults and adolescents to improve global TB control, and encouragingly, several promising candidates have advanced to late-stage trials. Significant gaps remain in understanding the critical factors that will facilitate the successful implementation of new and repurposed TB vaccines in low- and middle-income countries (LMICs), once available. By synthesizing the existing body of knowledge, this review offers comprehensive insights into the current state of research on implementation of these adult and adolescent vaccines. This review explores four key dimensions: (1) epidemiological impact, (2) costing, cost-effectiveness, and/or economic impact, (3) acceptability, and the (4) feasibility of implementation; this includes implementation strategies of target populations, and health system capabilities. Results indicate that current research primarily consists of epidemiological and costing/cost-effectiveness/economic studies in India, China, and South Africa, mainly modelling with M72/AS01, BCG revaccination, and hypothetical vaccines. Varying endpoints, vaccine efficacies, and vaccination coverages were used. Globally, new, and repurposed TB vaccines are estimated to save millions of lives. Economically, these vaccines also demonstrate promise with expected cost-effectiveness in most countries. Projected outcomes were dependent on vaccine characteristics, target population, implementation strategy, timing of roll out, TB burden/country context, and vaccination coverage. Potential barriers for vaccine acceptability included TB-related stigma, need for a second dose, and cost, while low pricing, community and civil society engagement and heightened public TB awareness were potential enablers in China, India, and South Africa. Potential implementation strategies considered spanned from mass campaigns to integration within existing vaccine programs and the primary target group studied was the general population, and adults and adolescents. In conclusion, future research must have broader geographical representations to better understand what is needed to inform tailored vaccine programs to accommodate diverse country contexts and population groups to achieve optimal implementation and impact. Furthermore, this review underscores the scarcity of research on acceptability of new and repurposed TB vaccines and their delivery among potential beneficiaries, the most promising implementation strategies, and the health system capabilities necessary for implementation. The absence of this knowledge in these areas emphasizes the crucial need for future research to ensure effective TB vaccine implementation in high burden settings worldwide.
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Affiliation(s)
- Joeri S. Buis
- KNCV Tuberculosis Foundation, The Hague, The Netherlands
| | - Degu Jerene
- KNCV Tuberculosis Foundation, The Hague, The Netherlands
| | - Agnes Gebhard
- KNCV Tuberculosis Foundation, The Hague, The Netherlands
| | - Roel Bakker
- KNCV Tuberculosis Foundation, The Hague, The Netherlands
| | - Arman Majidulla
- Department of International Health, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland, United States of America
| | - Andrew D. Kerkhoff
- Division of HIV, Infectious Diseases and Global Medicine Zuckerberg San Francisco General Hospital and Trauma Center, Center for Tuberculosis, University of California San Francisco, San Francisco, California, United States of America
| | - Rupali J. Limaye
- Department of International Health, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland, United States of America
| | - Puck T. Pelzer
- KNCV Tuberculosis Foundation, The Hague, The Netherlands
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Clark RA, Sumner T, Weerasuriya CK, Bakker R, Scriba TJ, White RG. Estimating the Potential Public Health Value of BCG Revaccination. J Infect Dis 2024; 230:e139-e143. [PMID: 39052744 PMCID: PMC11272081 DOI: 10.1093/infdis/jiae089] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2023] [Accepted: 02/19/2024] [Indexed: 07/27/2024] Open
Abstract
An upcoming trial may provide further evidence that adolescent/adult-targeted BCG revaccination prevents sustained Mycobacterium tuberculosis infection, but its public health value depends on its impact on overall tuberculosis morbidity and mortality, which will remain unknown. Using previously calibrated models for India and South Africa, we simulated BCG revaccination assuming 45% prevention-of-infection efficacy, and we evaluated scenarios varying additional prevention-of-disease efficacy between +50% (reducing risk) and -50% (increasing risk). Given the assumed prevention-of-infection efficacy and range in prevention-of-disease efficacy, BCG revaccination may have a positive health impact and be cost-effective. This may be useful when considering future evaluations and implementation of adolescent/adult BCG revaccination.
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Affiliation(s)
- Rebecca A Clark
- TB Modelling Group and TB Centre, London School of Hygiene & Tropical Medicine, London, United Kingdom
- Centre for Mathematical Modelling of Infectious Diseases, London School of Hygiene & Tropical Medicine, London, United Kingdom
- Department of Infectious Disease Epidemiology, London School of Hygiene & Tropical Medicine, London, United Kingdom
- Vaccine Centre, London School of Hygiene & Tropical Medicine, London, United Kingdom
| | - Tom Sumner
- TB Modelling Group and TB Centre, London School of Hygiene & Tropical Medicine, London, United Kingdom
- Centre for Mathematical Modelling of Infectious Diseases, London School of Hygiene & Tropical Medicine, London, United Kingdom
- Department of Infectious Disease Epidemiology, London School of Hygiene & Tropical Medicine, London, United Kingdom
| | - Chathika K Weerasuriya
- TB Modelling Group and TB Centre, London School of Hygiene & Tropical Medicine, London, United Kingdom
- Centre for Mathematical Modelling of Infectious Diseases, London School of Hygiene & Tropical Medicine, London, United Kingdom
- Department of Infectious Disease Epidemiology, London School of Hygiene & Tropical Medicine, London, United Kingdom
| | - Roel Bakker
- TB Modelling Group and TB Centre, London School of Hygiene & Tropical Medicine, London, United Kingdom
- Centre for Mathematical Modelling of Infectious Diseases, London School of Hygiene & Tropical Medicine, London, United Kingdom
- Department of Infectious Disease Epidemiology, London School of Hygiene & Tropical Medicine, London, United Kingdom
- KNCV Tuberculosis Foundation, Division TB Elimination and Health System Innovations, the Hague, the Netherlands
| | - Thomas J Scriba
- South African Tuberculosis Vaccine Initiative (SATVI), Division of Immunology, Department of Pathology and Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Cape Town, South Africa
| | - Richard G White
- TB Modelling Group and TB Centre, London School of Hygiene & Tropical Medicine, London, United Kingdom
- Centre for Mathematical Modelling of Infectious Diseases, London School of Hygiene & Tropical Medicine, London, United Kingdom
- Department of Infectious Disease Epidemiology, London School of Hygiene & Tropical Medicine, London, United Kingdom
- Vaccine Centre, London School of Hygiene & Tropical Medicine, London, United Kingdom
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Dale KD, Schwalb A, Coussens AK, Gibney KB, Abboud AJ, Watts K, Denholm JT. Overlooked, dismissed, and downplayed: reversion of Mycobacterium tuberculosis immunoreactivity. Eur Respir Rev 2024; 33:240007. [PMID: 39048129 PMCID: PMC11267292 DOI: 10.1183/16000617.0007-2024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2024] [Accepted: 04/16/2024] [Indexed: 07/27/2024] Open
Abstract
Tuberculosis (TB) is caused by Mycobacterium tuberculosis (Mtb). Following infection, immune responses to Mtb antigens can be measured using the tuberculin skin test or an interferon-γ release assay. The gain of Mtb immunoreactivity, a change from a negative to a positive tuberculin skin test or interferon-γ release assay result, is called conversion and has long been used as a measure of Mtb exposure. However, the loss of immunoreactivity (reversion; a positive followed by a negative result) has often been overlooked. Instead, in clinical and epidemiological circles, Mtb immunoreactivity is commonly considered to persist lifelong and confer a lifetime of disease risk. We present a critical review, describing the evidence for reversion from cohort studies, ecological studies and studies of TB progression risk. We outline the inconsistent reasons why reversion has been dismissed from common understanding and present evidence demonstrating that, just as conversion predominantly indicates prior exposure to Mtb antigens, so its opposite, reversion, suggests the reduction or absence of exposure (endogenous or exogenous). Mtb immunoreactivity is dynamic in both individuals and populations and this is why it is useful for stratifying short-term TB progression risk. The neglect of reversion has shaped TB research and policy at all levels, influencing clinical management and skewing Mtb infection risk estimation and transmission modelling, leading to an underestimation of the contribution of re-exposure to the burden of TB, a serious oversight for an infectious disease. More than a century after it was first demonstrated, it is time to incorporate reversion into our understanding of the natural history of TB.
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Affiliation(s)
- Katie D Dale
- Victorian Tuberculosis Program, Royal Melbourne Hospital, at the Peter Doherty Institute for Infection and Immunity, Melbourne, Australia
| | - Alvaro Schwalb
- TB Modelling Group, TB Centre, London School of Hygiene and Tropical Medicine, London, UK
- Department of Infectious Disease Epidemiology, London School of Hygiene and Tropical Medicine, London, UK
- Instituto de Medicina Tropical Alexander von Humboldt, Universidad Peruana Cayetano Heredia, Lima, Peru
| | - Anna K Coussens
- Infectious Diseases and Immune Defence Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Australia
- Department of Medical Biology, University of Melbourne, Parkville, Australia
- Centre for Infectious Diseases Research in Africa, Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Observatory, Cape Town, South Africa
| | - Katherine B Gibney
- Victorian Tuberculosis Program, Royal Melbourne Hospital, at the Peter Doherty Institute for Infection and Immunity, Melbourne, Australia
- Department of Infectious Diseases, The University of Melbourne, at the Peter Doherty Institute for Infection and Immunity, Melbourne, Australia
- Victorian Infectious Disease Service, Royal Melbourne Hospital, at the Peter Doherty Institute for Infection and Immunity, Melbourne, Australia
| | - Alison J Abboud
- Department of Infectious Diseases, The University of Melbourne, at the Peter Doherty Institute for Infection and Immunity, Melbourne, Australia
| | - Krista Watts
- Victorian Tuberculosis Program, Royal Melbourne Hospital, at the Peter Doherty Institute for Infection and Immunity, Melbourne, Australia
- Department of Social Work, School of Health Sciences, University of Melbourne, Melbourne, Australia
| | - Justin T Denholm
- Victorian Tuberculosis Program, Royal Melbourne Hospital, at the Peter Doherty Institute for Infection and Immunity, Melbourne, Australia
- Department of Infectious Diseases, The University of Melbourne, at the Peter Doherty Institute for Infection and Immunity, Melbourne, Australia
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Jing S, Xue L, Wang H, Peng Z. Global analysis of an age-structured tuberculosis model with an application to Jiangsu, China. J Math Biol 2024; 88:52. [PMID: 38563991 DOI: 10.1007/s00285-024-02066-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2022] [Revised: 08/31/2023] [Accepted: 02/18/2024] [Indexed: 04/04/2024]
Abstract
Diagnostic delay for TB infected individuals and the lack of TB vaccines for adults are the main challenges to achieve the goals of WHO by 2050. In order to evaluate the impacts of diagnostic delay and vaccination for adults on prevalence of TB, we propose an age-structured model with latent age and infection age, and we incorporate Mycobacterium TB in the environment and vaccination into the model. Diagnostic delay is indicated by the age of infection before receiving treatment. The threshold dynamics are established in terms of the basic reproduction number R 0 . WhenR 0 < 1 , the disease-free equilibrium is globally asymptotically stable, which means that TB epidemic will die out; WhenR 0 = 1 , the disease-free equilibrium is globally attractive; there exists a unique endemic equilibrium and the endemic equilibrium is globally attractive whenR 0 > 1 . We estimate that the basic reproduction numberR 0 = 0.5320 (95% CI (0.3060, 0.7556)) in Jiangsu Province, which means that TB epidemic will die out. However, we find that the annual number of new TB cases by 2050 is 1,151 (95%CI: (138, 8,014)), which means that it is challenging to achieve the goal of WHO by 2050. To this end, we evaluate the possibility of achieving the goals of WHO if we start vaccinating adults and reduce diagnostic delay in 2025. Our results demonstrate that when the diagnostic delay is reduced from longer than four months to four months, or 20% adults are vaccinated, the goal of WHO in 2050 can be achieved, and 73,137 (95%CI: (23,906, 234,086)) and 54,828 (95%CI: (15,811, 206,468)) individuals will be prevented from being infected from 2025 to 2050, respectively. The modeling approaches and simulation results used in this work can help policymakers design control measures to reduce the prevalence of TB.
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Affiliation(s)
- Shuanglin Jing
- College of Mathematical Sciences, Harbin Engineering University, Harbin, 150001, Heilongjiang, China
| | - Ling Xue
- College of Mathematical Sciences, Harbin Engineering University, Harbin, 150001, Heilongjiang, China.
| | - Hao Wang
- Department of Mathematical and Statistical Sciences, University of Alberta, Edmonton, AB, T6G 2G1, Canada.
| | - Zhihang Peng
- Department of Epidemiology and Biostatistics, School of Public Health, Nanjing Medical University, Nanjing, 210029, Jiangsu, China
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Sumner T, Clark RA, Mukandavire C, Portnoy A, Weerasuriya CK, Bakker R, Scarponi D, Hatherill M, Menzies NA, White RG. Modelling the health and economic impacts ofM72/AS01 E vaccination and BCG-revaccination: Estimates for South Africa. Vaccine 2024; 42:1311-1318. [PMID: 38307747 DOI: 10.1016/j.vaccine.2024.01.072] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2023] [Revised: 01/11/2024] [Accepted: 01/22/2024] [Indexed: 02/04/2024]
Abstract
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 of these vaccines is unknown. METHODS We used an age-stratified transmission model of tuberculosis, calibrated to epidemiological data from South Africa, to estimate the potential health and economic impact of M72/AS01E vaccination and BCG-revaccination. We simulated M72/AS01E vaccination scenarios over the period 2030-2050 and BCG-revaccination scenarios over the period 2025-2050. We explored a range of product characteristics and delivery strategies. We calculated reductions in tuberculosis cases and deaths and costs and cost-effectiveness from health-system and societal perspectives. FINDINGS M72/AS01E vaccination may have a larger impact than BCG-revaccination, averting approximately 80% more cases and deaths by 2050. Both vaccines were found to be cost-effective or cost saving (compared to no new vaccine) across a range of vaccine characteristics and delivery strategies from both the health system and societal perspective. The impact of M72/AS01E is dependent on the assumed efficacy of the vaccine in uninfected individuals. Extending BCG-revaccination to HIV-infected individuals on ART increased health impact by approximately 15%, but increased health system costs by approximately 70%. INTERPRETATION Our results show that M72/AS01E vaccination or BCG-revaccination could be cost-effective in South Africa. However, there is considerable uncertainty in the estimated impact and costs due to uncertainty in vaccine characteristics and the choice of delivery strategy. FUNDING This work was funded by the Bill & Melinda Gates Foundation (INV-001754). This work used the Cirrus UK National Tier-2 HPC Service at EPCC (https://www.cirrus.ac.uk) funded by the University of Edinburgh and EPSRC (EP/P020267/1).
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Affiliation(s)
- Tom Sumner
- TB Modelling Group and TB Centre, London School of Hygiene and Tropical Medicine, United Kingdom; Centre for the Mathematical Modelling of Infectious Diseases, London School of Hygiene and Tropical Medicine, United Kingdom; Department of Infectious Disease Epidemiology, London School of Hygiene and Tropical Medicine, United Kingdom.
| | - Rebecca A Clark
- TB Modelling Group and TB Centre, London School of Hygiene and Tropical Medicine, United Kingdom; Centre for the Mathematical Modelling of Infectious Diseases, London School of Hygiene and Tropical Medicine, United Kingdom; Department of Infectious Disease Epidemiology, London School of Hygiene and Tropical Medicine, United Kingdom; Vaccine Centre, London School of Hygiene and Tropical Medicine, United Kingdom
| | - Christinah Mukandavire
- TB Modelling Group and TB Centre, London School of Hygiene and Tropical Medicine, United Kingdom; Centre for the Mathematical Modelling of Infectious Diseases, London School of Hygiene and Tropical Medicine, United Kingdom; Department of Infectious Disease Epidemiology, London School of Hygiene and Tropical Medicine, United Kingdom
| | - Allison Portnoy
- Department of Global Health, Boston University School of Public Health, Boston, USA; Center for Health Decision Science, Harvard T.H. Chan School of Public Health, Boston, USA
| | - Chathika K Weerasuriya
- TB Modelling Group and TB Centre, London School of Hygiene and Tropical Medicine, United Kingdom; Centre for the Mathematical Modelling of Infectious Diseases, London School of Hygiene and Tropical Medicine, United Kingdom; Department of Infectious Disease Epidemiology, London School of Hygiene and Tropical Medicine, United Kingdom
| | - Roel Bakker
- TB Modelling Group and TB Centre, London School of Hygiene and Tropical Medicine, United Kingdom; Centre for the Mathematical Modelling of Infectious Diseases, London School of Hygiene and Tropical Medicine, United Kingdom; Department of Infectious Disease Epidemiology, London School of Hygiene and Tropical Medicine, United Kingdom; KNCV Tuberculosis Foundation, USA
| | - Danny Scarponi
- TB Modelling Group and TB Centre, London School of Hygiene and Tropical Medicine, United Kingdom; Centre for the Mathematical Modelling of Infectious Diseases, London School of Hygiene and Tropical Medicine, United Kingdom; Department of Infectious Disease Epidemiology, London School of Hygiene and Tropical Medicine, United Kingdom
| | - Mark Hatherill
- South African Tuberculosis Vaccine Initiative, Institute of Infectious Disease and Molecular Medicine and Division of Immunology, Department of Pathology, University of Cape Town, South Africa
| | - Nicolas A Menzies
- Center for Health Decision Science, Harvard T.H. Chan School of Public Health, Boston, USA; Department of Global Health and Population, Harvard T.H. Chan School of Public Health, USA
| | - Richard G White
- TB Modelling Group and TB Centre, London School of Hygiene and Tropical Medicine, United Kingdom; Centre for the Mathematical Modelling of Infectious Diseases, London School of Hygiene and Tropical Medicine, United Kingdom; Department of Infectious Disease Epidemiology, London School of Hygiene and Tropical Medicine, United Kingdom
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10
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Malwe S, Bawiskar D, Wagh V. Tuberculosis and the Effectiveness of the Revised National Tuberculosis Control Program (RNTCP) to Control Tuberculosis: A Narrative Review. Cureus 2023; 15:e51418. [PMID: 38299135 PMCID: PMC10828526 DOI: 10.7759/cureus.51418] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2023] [Accepted: 12/30/2023] [Indexed: 02/02/2024] Open
Abstract
The revised National Tuberculosis (TB) Control Program is an initiative undertaken by the government of India and was active from 1997 to 2020. Later it was renamed as National TB Elimination Program, which eyes the complete eradication of TB by 2025. The revised National Tuberculosis Control Programme (RNTCP) is preceded by the National TB Control Program which was activated when the cases of TB were on the rise in the early 1960s and police intervention was needed. National Tobacco Control Cell (NTCP) guided the efforts until 1997 when various shortcomings, which were registered over the course of time, were addressed and the revised program was launched. It has been a mixed success as beneficiaries belonging to the reachable, urban areas were benefitted, and tribal, and backward areas were lagging behind. Although the RNTCP proved to be effective in containing TB and curing it to a certain extent, the successor of the program, which is NTEP, has set an ambitious goal of eradicating TB by 2025 which needs concerted efforts on behalf of all stakeholders.
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Affiliation(s)
- Shraddha Malwe
- Community Medicine, Jawaharlal Nehru Medical College, Datta Meghe Institute of Higher Education and Research, Wardha, IND
| | - Dushyant Bawiskar
- Sports Medicine, Abhinav Bindra Sports Medicine and Research Institute, Bhubaneswar, IND
| | - Vasant Wagh
- Community Medicine, Jawaharlal Nehru Medical College, Datta Meghe Institute of Higher Education and Research, Wardha, IND
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11
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Reid M, Agbassi YJP, Arinaminpathy N, Bercasio A, Bhargava A, Bhargava M, Bloom A, Cattamanchi A, Chaisson R, Chin D, Churchyard G, Cox H, Denkinger CM, Ditiu L, Dowdy D, Dybul M, Fauci A, Fedaku E, Gidado M, Harrington M, Hauser J, Heitkamp P, Herbert N, Herna Sari A, Hopewell P, Kendall E, Khan A, Kim A, Koek I, Kondratyuk S, Krishnan N, Ku CC, Lessem E, McConnell EV, Nahid P, Oliver M, Pai M, Raviglione M, Ryckman T, Schäferhoff M, Silva S, Small P, Stallworthy G, Temesgen Z, van Weezenbeek K, Vassall A, Velásquez GE, Venkatesan N, Yamey G, Zimmerman A, Jamison D, Swaminathan S, Goosby E. Scientific advances and the end of tuberculosis: a report from the Lancet Commission on Tuberculosis. Lancet 2023; 402:1473-1498. [PMID: 37716363 DOI: 10.1016/s0140-6736(23)01379-x] [Citation(s) in RCA: 23] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/23/2023] [Revised: 06/14/2023] [Accepted: 06/29/2023] [Indexed: 09/18/2023]
Affiliation(s)
- Michael Reid
- University of California San Francisco Center for Tuberculosis, University of California San Francisco, San Francisco, CA, USA; Institute for Global Health Sciences, University of California San Francisco, San Francisco, CA, USA.
| | - Yvan Jean Patrick Agbassi
- Global TB Community Advisory Board, Abidjan, Côte d'Ivoire, Yenepoya Medical College, Mangalore, India
| | | | - Alyssa Bercasio
- University of California San Francisco Center for Tuberculosis, University of California San Francisco, San Francisco, CA, USA; Institute for Global Health Sciences, University of California San Francisco, San Francisco, CA, USA
| | - Anurag Bhargava
- Department of General Medicine, Yenepoya Medical College, Mangalore, India
| | - Madhavi Bhargava
- Department of Community Medicine, Yenepoya Medical College, Mangalore, India
| | - Amy Bloom
- Division of Tuberculosis, Bureau of Global Health, USAID, Washington, DC, USA
| | | | - Richard Chaisson
- Johns Hopkins School of Medicine, Johns Hopkins University, Baltimore, MD, USA
| | - Daniel Chin
- Bill and Melinda Gates Foundation, Seattle, WA, USA
| | | | - Helen Cox
- Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Cape Town, South Africa
| | - Claudia M Denkinger
- Heidelberg University Hospital, German Center of Infection Research, Heidelberg, Germany
| | | | - David Dowdy
- Johns Hopkins Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, USA
| | - Mark Dybul
- Department of Medicine, Center for Global Health Practice and Impact, Georgetown University, Washington, DC, USA
| | - Anthony Fauci
- National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA
| | | | | | | | | | - Petra Heitkamp
- McGill International TB Centre, McGill University, Montreal, QC, Canada
| | - Nick Herbert
- Global TB Caucus, Houses of Parliament, London, UK
| | | | - Philip Hopewell
- University of California San Francisco Center for Tuberculosis, University of California San Francisco, San Francisco, CA, USA
| | - Emily Kendall
- Johns Hopkins School of Medicine, Johns Hopkins University, Baltimore, MD, USA
| | - Aamir Khan
- Interactive Research & Development, Karachi, Pakistan
| | - Andrew Kim
- University of California San Francisco Center for Tuberculosis, University of California San Francisco, San Francisco, CA, USA
| | | | | | - Nalini Krishnan
- Resource Group for Education and Advocacy for Community Health (REACH), Chennai, India
| | - Chu-Chang Ku
- School of Public Health, Faculty of Medicine, Imperial College London, London, UK
| | - Erica Lessem
- Johns Hopkins Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, USA
| | | | - Payam Nahid
- University of California San Francisco Center for Tuberculosis, University of California San Francisco, San Francisco, CA, USA
| | | | - Madhukar Pai
- Department of Epidemiology, Biostatistics and Occupational Health, McGill University, Montreal, QC, Canada; McGill International TB Centre, McGill University, Montreal, QC, Canada
| | - Mario Raviglione
- Centre for Multidisciplinary Research in Health Science, University of Milan, Milan, Italy
| | - Theresa Ryckman
- Johns Hopkins School of Medicine, Johns Hopkins University, Baltimore, MD, USA
| | | | - Sachin Silva
- Harvard TH Chan School of Public Health, Harvard University, Cambridge, MA, USA
| | | | | | | | | | - Anna Vassall
- Department of Global Health and Development, Faculty of Public Health and Policy, London School of Hygiene & Tropical Medicine, London, UK
| | - Gustavo E Velásquez
- University of California San Francisco Center for Tuberculosis, University of California San Francisco, San Francisco, CA, USA
| | | | - Gavin Yamey
- Center for Policy Impact in Global Health, Duke Global Health Institute, Duke University, Durham, NC, USA
| | | | - Dean Jamison
- Institute for Global Health Sciences, University of California San Francisco, San Francisco, CA, USA
| | | | - Eric Goosby
- University of California San Francisco Center for Tuberculosis, University of California San Francisco, San Francisco, CA, USA; Institute for Global Health Sciences, University of California San Francisco, San Francisco, CA, USA
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12
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Clark RA, Portnoy A, Weerasuriya CK, Sumner T, Bakker R, Harris RC, Rade K, Mattoo SK, Tumu D, Menzies NA, White RG. The potential health and economic impacts of new tuberculosis vaccines under varying delivery strategies in Delhi and Gujarat, India: a modelling study. MEDRXIV : THE PREPRINT SERVER FOR HEALTH SCIENCES 2023:2023.09.27.23296211. [PMID: 37808744 PMCID: PMC10557803 DOI: 10.1101/2023.09.27.23296211] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/10/2023]
Abstract
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 compared the potential impact of tuberculosis vaccines in regions within India with differing tuberculosis disease and infection prevalence. We used mathematical modelling to investigate how the health and economic impact of two potential tuberculosis vaccines, M72/AS01E and BCG-revaccination, could differ in Delhi and Gujarat under varying delivery strategies. Methods We applied a compartmental tuberculosis model separately for Delhi (higher disease and infection prevalence) and Gujarat (lower disease and infection prevalence), and projected epidemiological trends to 2050 assuming no new vaccine introduction. We simulated M72/AS01E and BCG-revaccination scenarios varying target ages and vaccine characteristics. We estimated cumulative cases, deaths, and disability-adjusted life years averted between 2025-2050 compared to the no-new-vaccine scenario and compared incremental cost-effectiveness ratios to three cost-effectiveness thresholds. Results M72/AS01E averted a higher proportion of tuberculosis cases than BCG-revaccination in both regions (Delhi: 16.0% vs 8.3%, Gujarat: 8.5% vs 5.1%) and had higher vaccination costs (Delhi: USD$118 million vs USD$27 million, Gujarat: US$366 million vs US$97 million). M72/AS01E in Delhi could be cost-effective, or even cost-saving, for all modelled vaccine characteristics. M72/AS01E could be cost-effective in Gujarat, unless efficacy was assumed only for those with current infection at vaccination. BCG-revaccination could be cost-effective, or cost-saving, in both regions for all modelled vaccine scenarios. Discussion M72/AS01E and BCG-revaccination could be impactful and cost-effective in Delhi and Gujarat. Differences in impact, costs, and cost-effectiveness between vaccines and regions, were determined partly by differences in disease and infection prevalence, and demography. Age-specific regional estimates of infection prevalence could help to inform delivery strategies for vaccines that may only be effective in people with a particular infection status. Evidence on the mechanism of effect of M72/AS01E and its effectiveness in uninfected individuals, which were important drivers of impact and cost-effectiveness, particularly in Gujarat, are also key to improve estimates of population-level impact.
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Affiliation(s)
- Rebecca A Clark
- TB Modelling Group and TB Centre, LSHTM
- Centre for the Mathematical Modelling of Infectious Diseases, LSHTM
- Department of Infectious Disease Epidemiology, LSHTM
- Vaccine Centre, LSHTM
| | - Allison Portnoy
- Department of Global Health, Boston University School of Public Health
- Center for Health Decision Science, Harvard T.H. Chan School of Public Health
| | - Chathika K Weerasuriya
- TB Modelling Group and TB Centre, LSHTM
- Centre for the Mathematical Modelling of Infectious Diseases, LSHTM
- Department of Infectious Disease Epidemiology, LSHTM
| | - Tom Sumner
- TB Modelling Group and TB Centre, LSHTM
- Centre for the Mathematical Modelling of Infectious Diseases, LSHTM
- Department of Infectious Disease Epidemiology, LSHTM
| | - Roel Bakker
- TB Modelling Group and TB Centre, LSHTM
- Centre for the Mathematical Modelling of Infectious Diseases, LSHTM
- Department of Infectious Disease Epidemiology, LSHTM
- KNCV Tuberculosis Foundation
| | - Rebecca C Harris
- TB Modelling Group and TB Centre, LSHTM
- Centre for the Mathematical Modelling of Infectious Diseases, LSHTM
- Department of Infectious Disease Epidemiology, LSHTM
- Sanofi Pasteur, Singapore
| | | | - Sanjay Kumar Mattoo
- Central TB Division, National Tuberculosis Elimination Program, MoHFW Govt of India. New Delhi, India
| | - Dheeraj Tumu
- World Health Organization, India
- Central TB Division, National Tuberculosis Elimination Program, MoHFW Govt of India. New Delhi, India
| | - Nicolas A Menzies
- Center for Health Decision Science, Harvard T.H. Chan School of Public Health
- Department of Global Health and Population, Harvard T.H. Chan School of Public Health
| | - Richard G White
- TB Modelling Group and TB Centre, LSHTM
- Centre for the Mathematical Modelling of Infectious Diseases, LSHTM
- Department of Infectious Disease Epidemiology, LSHTM
- Vaccine Centre, LSHTM
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13
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Tovar M, Moreno Y, Sanz J. Addressing mechanism bias in model-based impact forecasts of new tuberculosis vaccines. Nat Commun 2023; 14:5312. [PMID: 37658078 PMCID: PMC10474143 DOI: 10.1038/s41467-023-40976-6] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2022] [Accepted: 08/15/2023] [Indexed: 09/03/2023] Open
Abstract
In tuberculosis (TB) vaccine development, multiple factors hinder the design and interpretation of the clinical trials used to estimate vaccine efficacy. The complex transmission chain of TB includes multiple routes to disease, making it hard to link the vaccine efficacy observed in a trial to specific protective mechanisms. Here, we present a Bayesian framework to evaluate the compatibility of different vaccine descriptions with clinical trial outcomes, unlocking impact forecasting from vaccines whose specific mechanisms of action are unknown. Applying our method to the analysis of the M72/AS01E vaccine trial -conducted on IGRA+ individuals- as a case study, we found that most plausible models for this vaccine needed to include protection against, at least, two over the three possible routes to active TB classically considered in the literature: namely, primary TB, latent TB reactivation and TB upon re-infection. Gathering new data regarding the impact of TB vaccines in various epidemiological settings would be instrumental to improve our model estimates of the underlying mechanisms.
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Affiliation(s)
- M Tovar
- Institute for Biocomputation and Physics of Complex Systems (BIFI), University of Zaragoza, Zaragoza, 50009, Spain
- Department of Theoretical Physics, University of Zaragoza, Zaragoza, 50009, Spain
| | - Y Moreno
- Institute for Biocomputation and Physics of Complex Systems (BIFI), University of Zaragoza, Zaragoza, 50009, Spain
- Department of Theoretical Physics, University of Zaragoza, Zaragoza, 50009, Spain
- Centai Institute S.p.A, 10138, Torino, Italy
| | - J Sanz
- Institute for Biocomputation and Physics of Complex Systems (BIFI), University of Zaragoza, Zaragoza, 50009, Spain.
- Department of Theoretical Physics, University of Zaragoza, Zaragoza, 50009, Spain.
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14
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Clark RA, Weerasuriya CK, Portnoy A, Mukandavire C, Quaife M, Bakker R, Scarponi D, Harris RC, Rade K, Mattoo SK, Tumu D, Menzies NA, White RG. New tuberculosis vaccines in India: modelling the potential health and economic impacts of adolescent/adult vaccination with M72/AS01 E and BCG-revaccination. BMC Med 2023; 21:288. [PMID: 37542319 PMCID: PMC10403932 DOI: 10.1186/s12916-023-02992-7] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/24/2023] [Accepted: 07/20/2023] [Indexed: 08/06/2023] Open
Abstract
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 economic impact of M72/AS01E and BCG-revaccination in India and investigated the impact of variation in vaccine characteristics and delivery strategies. METHODS We developed an age-stratified compartmental tuberculosis transmission model for India calibrated to country-specific epidemiology. We projected baseline epidemiology to 2050 assuming no-new-vaccine introduction, and M72/AS01E and BCG-revaccination scenarios over 2025-2050 exploring uncertainty in product characteristics (vaccine efficacy, mechanism of effect, infection status required for vaccine efficacy, duration of protection) and implementation (achieved vaccine coverage and ages targeted). We estimated reductions in tuberculosis cases and deaths by each scenario compared to the no-new-vaccine baseline, as well as costs and cost-effectiveness from health-system and societal perspectives. RESULTS M72/AS01E scenarios were predicted to avert 40% more tuberculosis cases and deaths by 2050 compared to BCG-revaccination scenarios. Cost-effectiveness ratios for M72/AS01E vaccines were around seven times higher than BCG-revaccination, but nearly all scenarios were cost-effective. The estimated average incremental cost was US$190 million for M72/AS01E and US$23 million for BCG-revaccination per year. Sources of uncertainty included whether M72/AS01E was efficacious in uninfected individuals at vaccination, and if BCG-revaccination could prevent disease. CONCLUSIONS M72/AS01E and BCG-revaccination could be impactful and cost-effective in India. However, there is great uncertainty in impact, especially given the unknowns surrounding the mechanism of effect and infection status required for vaccine efficacy. Greater investment in vaccine development and delivery is needed to resolve these unknowns in vaccine product characteristics.
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Affiliation(s)
- Rebecca A Clark
- TB Modelling Group and TB Centre, London School of Hygiene and Tropical Medicine, Keppel Street, London, WC1E 7HT, UK.
- Centre for the Mathematical Modelling of Infectious Diseases, London School of Hygiene and Tropical Medicine, London, UK.
- Department of Infectious Disease Epidemiology, London School of Hygiene and Tropical Medicine, London, UK.
- Vaccine Centre, London School of Hygiene and Tropical Medicine, London, UK.
| | - Chathika K Weerasuriya
- TB Modelling Group and TB Centre, London School of Hygiene and Tropical Medicine, Keppel Street, London, WC1E 7HT, UK
- Centre for the Mathematical Modelling of Infectious Diseases, London School of Hygiene and Tropical Medicine, London, UK
- Department of Infectious Disease Epidemiology, London School of Hygiene and Tropical Medicine, London, UK
| | - Allison Portnoy
- Center for Health Decision Science, Harvard T.H. Chan School of Public Health, Boston, USA
- Department of Global Health, Boston University School of Public Health, Boston, USA
| | - Christinah Mukandavire
- TB Modelling Group and TB Centre, London School of Hygiene and Tropical Medicine, Keppel Street, London, WC1E 7HT, UK
- Centre for the Mathematical Modelling of Infectious Diseases, London School of Hygiene and Tropical Medicine, London, UK
- Department of Infectious Disease Epidemiology, London School of Hygiene and Tropical Medicine, London, UK
| | - Matthew Quaife
- TB Modelling Group and TB Centre, London School of Hygiene and Tropical Medicine, Keppel Street, London, WC1E 7HT, UK
- Centre for the Mathematical Modelling of Infectious Diseases, London School of Hygiene and Tropical Medicine, London, UK
- Department of Infectious Disease Epidemiology, London School of Hygiene and Tropical Medicine, London, UK
| | - Roel Bakker
- TB Modelling Group and TB Centre, London School of Hygiene and Tropical Medicine, Keppel Street, London, WC1E 7HT, UK
- Centre for the Mathematical Modelling of Infectious Diseases, London School of Hygiene and Tropical Medicine, London, UK
- Department of Infectious Disease Epidemiology, London School of Hygiene and Tropical Medicine, London, UK
- KNCV Tuberculosis Foundation, The Hague, Netherlands
| | - Danny Scarponi
- TB Modelling Group and TB Centre, London School of Hygiene and Tropical Medicine, Keppel Street, London, WC1E 7HT, UK
- Centre for the Mathematical Modelling of Infectious Diseases, London School of Hygiene and Tropical Medicine, London, UK
- Department of Infectious Disease Epidemiology, London School of Hygiene and Tropical Medicine, London, UK
| | - Rebecca C Harris
- TB Modelling Group and TB Centre, London School of Hygiene and Tropical Medicine, Keppel Street, London, WC1E 7HT, UK
- Centre for the Mathematical Modelling of Infectious Diseases, London School of Hygiene and Tropical Medicine, London, UK
- Department of Infectious Disease Epidemiology, London School of Hygiene and Tropical Medicine, London, UK
- Sanofi Pasteur, Singapore, Singapore
| | | | | | - Dheeraj Tumu
- World Health Organization, New Delhi, India
- Central TB Division, NTEP, MoHFW Govt of India, New Delhi, India
| | - Nicolas A Menzies
- Center for Health Decision Science, Harvard T.H. Chan School of Public Health, Boston, USA
- Department of Global Health and Population, Harvard T.H. Chan School of Public Health, Boston, USA
| | - Richard G White
- TB Modelling Group and TB Centre, London School of Hygiene and Tropical Medicine, Keppel Street, London, WC1E 7HT, UK
- Centre for the Mathematical Modelling of Infectious Diseases, London School of Hygiene and Tropical Medicine, London, UK
- Department of Infectious Disease Epidemiology, London School of Hygiene and Tropical Medicine, London, UK
- Vaccine Centre, London School of Hygiene and Tropical Medicine, London, UK
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15
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Scarponi D, Clark RA, Weerasuriya CK, Emery J, Houben RMGJ, White R, McCreesh N. Is neglect of self-clearance biasing TB vaccine impact estimates? BMJ Glob Health 2023; 8:e012799. [PMID: 37558271 PMCID: PMC10414120 DOI: 10.1136/bmjgh-2023-012799] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2023] [Accepted: 07/13/2023] [Indexed: 08/11/2023] Open
Abstract
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 infection may be common, which may affect the potential impact of new vaccines that only take in infected or uninfected individuals. We explored how the inclusion of self-clearance in models of tuberculosis affects the estimates of vaccine impact in China and India. METHODS For both countries, we calibrated a tuberculosis model to a scenario without self-clearance and to various scenarios with self-clearance. To account for the current uncertainty in self-clearance properties, we varied the rate of self-clearance, and the level of protection against reinfection in self-cleared individuals. We introduced potential new vaccines in 2025, exploring vaccines that work in uninfected or infected individuals only, or that are effective regardless of infection status, and modelling scenarios with different levels of vaccine efficacy in self-cleared individuals. We then estimated the relative disease incidence reduction in 2050 for each vaccine compared with the no vaccination scenario. FINDINGS The inclusion of self-clearance increased the estimated relative reductions in incidence in 2050 for vaccines effective only in uninfected individuals, by a maximum of 12% in China and 8% in India. The inclusion of self-clearance increased the estimated impact of vaccines only effective in infected individuals in some scenarios and decreased it in others, by a maximum of 14% in China and 15% in India. As would be expected, the inclusion of self-clearance had minimal impact on estimated reductions in incidence for vaccines that work regardless of infection status. INTERPRETATIONS Our work suggests that the neglect of self-clearance in mathematical models of tuberculosis vaccines does not result in substantially biased estimates of tuberculosis vaccine impact. It may, however, mean that we are slightly underestimating the relative advantages of vaccines that work in uninfected individuals only compared with those that work in infected individuals.
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Affiliation(s)
- Danny Scarponi
- Infectious Disease Epidemiology, London School of Hygiene & Tropical Medicine, London, UK
| | - Rebecca A Clark
- Infectious Disease Epidemiology, London School of Hygiene & Tropical Medicine, London, UK
| | | | - Jon Emery
- Infectious Disease Epidemiology, London School of Hygiene & Tropical Medicine, London, UK
| | - Rein M G J Houben
- Infectious Disease Epidemiology, London School of Hygiene & Tropical Medicine, London, UK
| | - Richard White
- Infectious Disease Epidemiology, London School of Hygiene & Tropical Medicine, London, UK
| | - Nicky McCreesh
- Infectious Disease Epidemiology, London School of Hygiene & Tropical Medicine, London, UK
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Portnoy A, Clark RA, Weerasuriya CK, Mukandavire C, Quaife M, Bakker R, Garcia Baena I, Gebreselassie N, Zignol M, Jit M, White RG, Menzies NA. The potential impact of novel tuberculosis vaccines on health equity and financial protection in low-income and middle-income countries. BMJ Glob Health 2023; 8:e012466. [PMID: 37438049 PMCID: PMC10347450 DOI: 10.1136/bmjgh-2023-012466] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2023] [Accepted: 06/10/2023] [Indexed: 07/14/2023] Open
Abstract
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 of introducing TB vaccines meeting the World Health Organization preferred product characteristics in 105 LMICs. For each country, we assessed the distribution of health gains, patient costs and household financial vulnerability following introduction of an infant vaccine and separately for an adolescent/adult vaccine, compared with a 'no-new-vaccine' counterfactual. Patient-incurred direct and indirect costs of TB disease exceeding 20% of annual household income were defined as catastrophic. RESULTS Over 2028-2050, the health gains resulting from vaccine introduction were greatest in lower income quintiles, with the poorest 2 quintiles in each country accounting for 56% of total LMIC TB cases averted. Over this period, the infant vaccine was estimated to avert US$5.9 (95% uncertainty interval: US$5.3-6.5) billion in patient-incurred total costs, and the adolescent/adult vaccine was estimated to avert US$38.9 (US$36.6-41.5) billion. Additionally, 3.7 (3.3-4.1) million fewer households were projected to face catastrophic costs with the infant vaccine and 22.9 (21.4-24.5) million with the adolescent/adult vaccine, with 66% of gains accruing in the poorest 2 income quintiles. CONCLUSION Under a range of assumptions, introducing novel TB vaccines would reduce income-based inequalities in the health and household economic outcomes of TB in LMICs.
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Affiliation(s)
- Allison Portnoy
- Department of Global Health, Boston University School of Public Health, Boston, MA, USA
- Center for Health Decision Science, Harvard T.H. Chan School of Public Health, Boston, MA, USA
| | - Rebecca A Clark
- Department of Infectious Disease Epidemiology, London School of Hygiene & Tropical Medicine, London, UK
- TB Modelling Group, London School of Hygiene & Tropical Medicine, London, UK
- Centre for the Mathematical Modelling of Infectious Diseases, London School of Hygiene & Tropica Medicine, London, UK
| | - Chathika K Weerasuriya
- Department of Infectious Disease Epidemiology, London School of Hygiene & Tropical Medicine, London, UK
- TB Modelling Group, London School of Hygiene & Tropical Medicine, London, UK
- Centre for the Mathematical Modelling of Infectious Diseases, London School of Hygiene & Tropica Medicine, London, UK
| | | | - Matthew Quaife
- Department of Infectious Disease Epidemiology, London School of Hygiene & Tropical Medicine, London, UK
- TB Modelling Group, London School of Hygiene & Tropical Medicine, London, UK
- Centre for the Mathematical Modelling of Infectious Diseases, London School of Hygiene & Tropica Medicine, London, UK
| | - Roel Bakker
- Department of Infectious Disease Epidemiology, London School of Hygiene & Tropical Medicine, London, UK
- TB Modelling Group, London School of Hygiene & Tropical Medicine, London, UK
- Centre for the Mathematical Modelling of Infectious Diseases, London School of Hygiene & Tropica Medicine, London, UK
- KNCV Tuberculosis Foundation, Den Haag, The Netherlands
| | - Inés Garcia Baena
- Global Tuberculosis Programme, World Health Organization, Geneva, Switzerland
| | | | - Matteo Zignol
- Global Tuberculosis Programme, World Health Organization, Geneva, Switzerland
| | - Mark Jit
- Department of Infectious Disease Epidemiology, London School of Hygiene & Tropical Medicine, London, UK
- Centre for the Mathematical Modelling of Infectious Diseases, London School of Hygiene & Tropica Medicine, London, UK
- School of Public Health, The University of Hong Kong, Hong Kong SAR, People's Republic of China
| | - Richard G White
- Department of Infectious Disease Epidemiology, London School of Hygiene & Tropical Medicine, London, UK
- TB Modelling Group, London School of Hygiene & Tropical Medicine, London, UK
- Centre for the Mathematical Modelling of Infectious Diseases, London School of Hygiene & Tropica Medicine, London, UK
| | - Nicolas A Menzies
- Center for Health Decision Science, Harvard T.H. Chan School of Public Health, Boston, MA, USA
- Department of Global Health and Population, Harvard T.H. Chan School of Public Health, Boston, MA, USA
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Scarponi D, Clark RA, Weerasuriya C, Emery JC, Houben RM, White RG, McCreesh N. Is neglect of self-clearance biassing TB vaccine impact estimates? MEDRXIV : THE PREPRINT SERVER FOR HEALTH SCIENCES 2023:2023.04.11.23288400. [PMID: 37090535 PMCID: PMC10120796 DOI: 10.1101/2023.04.11.23288400] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/25/2023]
Abstract
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 infection may be common, which may affect the potential impact of new vaccines that only take in infected or uninfected individuals. We explored how the inclusion of self-clearance in models of tuberculosis affects the estimates of vaccine impact in China and India. Methods For both countries, we calibrated a tuberculosis model to a scenario without self-clearance and to various scenarios with self-clearance. To account for the current uncertainty in self-clearance properties, we varied the rate of self-clearance, and the level of protection against reinfection in self-cleared individuals. We introduced potential new vaccines in 2025, exploring vaccines that work in uninfected or infected individuals only, or that are effective regardless of infection status, and modelling scenarios with different levels of vaccine efficacy in self-cleared individuals. We then estimated the relative incidence reduction in 2050 for each vaccine compared to the no vaccination scenario. Findings The inclusion of self-clearance increased the estimated relative reductions in incidence in 2050 for vaccines effective only in uninfected individuals, by a maximum of 12% in China and 8% in India. The inclusion of self-clearance increased the estimated impact of vaccines only effective in infected individuals in some scenarios and decreased it in others, by a maximum of 14% in China and 15% in India. As would be expected, the inclusion of self-clearance had minimal impact on estimated reductions in incidence for vaccines that work regardless of infection status. Interpretations Our work suggests that the neglect of self-clearance in mathematical models of tuberculosis vaccines does not result in substantially biased estimates of tuberculosis vaccine impact. It may, however, mean that we are slightly underestimating the relative advantages of vaccines that work in uninfected individuals only compared to those that work in infected individuals.
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Affiliation(s)
- Danny Scarponi
- Centre for Mathematical Modelling of Infectious Diseases, Department of Infectious Disease Epidemiology, London School of Hygiene and Tropical Medicine
| | - Rebecca A Clark
- Centre for Mathematical Modelling of Infectious Diseases, Department of Infectious Disease Epidemiology, London School of Hygiene and Tropical Medicine
| | - Chathika Weerasuriya
- Centre for Mathematical Modelling of Infectious Diseases, Department of Infectious Disease Epidemiology, London School of Hygiene and Tropical Medicine
| | - Jon C Emery
- Centre for Mathematical Modelling of Infectious Diseases, Department of Infectious Disease Epidemiology, London School of Hygiene and Tropical Medicine
| | - Rein Mgj Houben
- Centre for Mathematical Modelling of Infectious Diseases, Department of Infectious Disease Epidemiology, London School of Hygiene and Tropical Medicine
| | - Richard G White
- Centre for Mathematical Modelling of Infectious Diseases, Department of Infectious Disease Epidemiology, London School of Hygiene and Tropical Medicine
| | - Nicky McCreesh
- Centre for Mathematical Modelling of Infectious Diseases, Department of Infectious Disease Epidemiology, London School of Hygiene and Tropical Medicine
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Mao JJ, Zang X, Yue WL, Zhai PY, Zhang Q, Li CH, Zhuang X, Liu M, Qin G. Population-level health and economic impacts of introducing Vaccae vaccination in China: a modelling study. BMJ Glob Health 2023; 8:bmjgh-2023-012306. [PMID: 37257938 DOI: 10.1136/bmjgh-2023-012306] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2023] [Accepted: 05/06/2023] [Indexed: 06/02/2023] Open
Abstract
INTRODUCTION Given the ageing epidemic of tuberculosis (TB), China is facing an unprecedented opportunity provided by the first clinically approved next-generation TB vaccine Vaccae, which demonstrated 54.7% efficacy for preventing reactivation from latent infection in a phase III trial. We aim to assess the population-level health and economic impacts of introducing Vaccae vaccination to inform policy-makers. METHODS We evaluated a potential national Vaccae vaccination programme in China initiated in 2024, assuming 20 years of protection, 90% coverage and US$30/dose government contract price. An age-structured compartmental model was adapted to simulate three strategies: (1) no Vaccae; (2) mass vaccination among people aged 15-74 years and (3) targeted vaccination among older adults (60 years). Cost analyses were conducted from the healthcare sector perspective, discounted at 3%. RESULTS Considering postinfection efficacy, targeted vaccination modestly reduced TB burden (~20%), preventing cumulative 8.01 (95% CI 5.82 to 11.8) million TB cases and 0.20 (0.17 to 0.26) million deaths over 2024-2050, at incremental cost-effectiveness ratio of US$4387 (2218 to 10 085) per disability adjusted life year averted. The implementation would require a total budget of US$22.5 (17.6 to 43.4) billion. In contrast, mass vaccination had a larger bigger impact on the TB epidemic, but the overall costs remained high. Although both preinfection and postinfection vaccine efficacy type might have a maximum impact (>40% incidence rate reduction in 2050), it is important that the vaccine price does not exceed US$5/dose. CONCLUSION Vaccae represents a robust and cost-effective choice for TB epidemic control in China. This study may facilitate the practice of evidence-based strategy plans for TB vaccination and reimbursement decision making.
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Affiliation(s)
- Jun-Jie Mao
- Joint Division of Clinical Epidemiology, Affilated Hosptial of Nantong University, School of Public Health of Nantong University, Nantong, Jiangsu, China
| | - Xiao Zang
- Division of Health Policy and Management, University of Minnesota Twin Cities, Minneapolis, Minnesota, USA
| | - Wan-Lu Yue
- Department of Infectious Diseases, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong, Jiangsu, China
| | - Pei-Yao Zhai
- Department of Infectious Diseases, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong, Jiangsu, China
| | - Qiong Zhang
- Research Centre of Clinical Medicine, Affiliated Hospital of Nantong University, Nantong, Jiangsu, China
| | - Chun-Hu Li
- Joint Division of Clinical Epidemiology, Affilated Hosptial of Nantong University, School of Public Health of Nantong University, Nantong, Jiangsu, China
| | - Xun Zhuang
- Department of Epidemiology and Biostatistics, School of Public Health of Nantong University, Nantong, Jiangsu, China
| | - Min Liu
- Department of Epidemiology and Biostatistics, School of Public Health of Peking University, Beijing, China
| | - Gang Qin
- Joint Division of Clinical Epidemiology, Affilated Hosptial of Nantong University, School of Public Health of Nantong University, Nantong, Jiangsu, China
- National Key Clinical Construction Specialty-Department of Respiratory and Critical Care Medicine, Affiliated Hospital of Nantong University, Nantong, Jiangsu, China
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Larsen SE, Baldwin SL, Coler RN. Tuberculosis vaccines update: Is an RNA-based vaccine feasible for tuberculosis? Int J Infect Dis 2023; 130 Suppl 1:S47-S51. [PMID: 36963657 PMCID: PMC10033141 DOI: 10.1016/j.ijid.2023.03.035] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2023] [Revised: 03/16/2023] [Accepted: 03/16/2023] [Indexed: 03/24/2023] Open
Abstract
OBJECTIVES Despite concerted efforts, Mycobacterium tuberculosis (M.tb), the pathogen that causes tuberculosis (TB), continues to be a burden on global health, regaining its dubious distinction in 2022 as the world's biggest infectious killer with global COVID-19 deaths steadily declining. The complex nature of M.tb, coupled with different pathogenic stages, has highlighted the need for the development of novel immunization approaches to combat this ancient infectious agent. Intensive efforts over the last couple of decades have identified alternative approaches to improve upon traditional vaccines that are based on killed pathogens, live attenuated agents, or subunit recombinant antigens formulated with adjuvants. Massive funding and rapid advances in RNA-based vaccines for immunization have recently transformed the possibility of protecting global populations from viral pathogens, such as SARS-CoV-2. Similar efforts to combat bacterial pathogens such as M.tb have been significantly slower to implement. METHODS In this review, we discuss the application of a novel replicating RNA (repRNA)-based vaccine formulated and delivered in nanostructured lipids. RESULTS Our preclinical data are the first to report that RNA platforms are a viable system for TB vaccines and should be pursued with high-priority M.tb antigens containing cluster of differentiation (CD4+) and CD8+ T-cell epitopes. CONCLUSION This RNA vaccine shows promise for use against intracellular bacteria such as M.tb as demonstrated by the feasibility of construction, enhanced induction of cell-mediated and humoral immune responses, and improved bacterial burden outcomes in in vivo aerosol-challenged preclinical TB models.
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Affiliation(s)
- Sasha E Larsen
- Center for Global Infectious Disease Research, Seattle Children's Research Institute, Seattle, USA
| | - Susan L Baldwin
- Center for Global Infectious Disease Research, Seattle Children's Research Institute, Seattle, USA
| | - Rhea N Coler
- Center for Global Infectious Disease Research, Seattle Children's Research Institute, Seattle, USA; Department of Pediatrics, University of Washington School of Medicine, Seattle, USA; Department of Global Health, University of Washington, Seattle, USA.
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Clark RA, Mukandavire C, Portnoy A, Weerasuriya CK, Deol A, Scarponi D, Iskauskas A, Bakker R, Quaife M, Malhotra S, Gebreselassie N, Zignol M, Hutubessy RCW, Giersing B, Jit M, Harris RC, Menzies NA, White RG. The impact of alternative delivery strategies for novel tuberculosis vaccines in low-income and middle-income countries: a modelling study. Lancet Glob Health 2023; 11:e546-e555. [PMID: 36925175 PMCID: PMC10030455 DOI: 10.1016/s2214-109x(23)00045-1] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2022] [Revised: 11/03/2022] [Accepted: 01/13/2023] [Indexed: 03/15/2023]
Abstract
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 calibrated a tuberculosis model to 105 LMICs (accounting for 93% of global incidence). Vaccine scenarios were implemented as the base-case (routine vaccination of those aged 9 years and one-off vaccination for those aged 10 years and older, with country-specific introduction between 2028 and 2047, and 5-year scale-up to target coverage); accelerated scale-up similar to the base-case, but with all countries introducing vaccines in 2025, with instant scale-up; and routine-only (similar to the base-case, but including routine vaccination only). Vaccines were assumed to protect against disease for 10 years, with 50% efficacy. FINDINGS The base-case scenario would prevent 44·0 million (95% uncertainty range 37·2-51·6) tuberculosis cases and 5·0 million (4·6-5·4) tuberculosis deaths before 2050, compared with equivalent estimates of cases and deaths that would be predicted to occur before 2050 with no new vaccine introduction (the baseline scenario). The accelerated scale-up scenario would prevent 65·5 million (55·6-76·0) cases and 7·9 million (7·3-8·5) deaths before 2050, relative to baseline. The routine-only scenario would prevent 8·8 million (95% uncertainty range 7·6-10·1) cases and 1·1 million (0·9-1·2) deaths before 2050, relative to baseline. INTERPRETATION Our results suggest novel tuberculosis vaccines could have substantial impact, which will vary depending on delivery strategy. Including a one-off vaccination campaign will be crucial for rapid impact. Accelerated introduction-at a pace similar to that seen for COVID-19 vaccines-would increase the number of lives saved before 2050 by around 60%. Investment is required to support vaccine development, manufacturing, prompt introduction, and scale-up. FUNDING WHO (2020/985800-0). TRANSLATIONS For the French, Spanish, Italian and Dutch translations of the abstract see Supplementary Materials section.
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Affiliation(s)
- Rebecca A Clark
- TB Modelling Group and TB Centre, London School of Hygiene & Tropical Medicine, London, UK; Centre for the Mathematical Modelling of Infectious Diseases, London School of Hygiene & Tropical Medicine, London, UK; Department of Infectious Disease Epidemiology, London School of Hygiene & Tropical Medicine, London, UK; Vaccine Centre, London School of Hygiene & Tropical Medicine, London, UK.
| | - Christinah Mukandavire
- TB Modelling Group and TB Centre, London School of Hygiene & Tropical Medicine, London, UK; Centre for the Mathematical Modelling of Infectious Diseases, London School of Hygiene & Tropical Medicine, London, UK; Department of Infectious Disease Epidemiology, London School of Hygiene & Tropical Medicine, London, UK
| | - Allison Portnoy
- Center for Health Decision Science, Harvard TH Chan School of Public Health, Boston, MA, USA
| | - Chathika K Weerasuriya
- TB Modelling Group and TB Centre, London School of Hygiene & Tropical Medicine, London, UK; Centre for the Mathematical Modelling of Infectious Diseases, London School of Hygiene & Tropical Medicine, London, UK; Department of Infectious Disease Epidemiology, London School of Hygiene & Tropical Medicine, London, UK
| | - Arminder Deol
- TB Modelling Group and TB Centre, London School of Hygiene & Tropical Medicine, London, UK; Centre for the Mathematical Modelling of Infectious Diseases, London School of Hygiene & Tropical Medicine, London, UK; Department of Infectious Disease Epidemiology, London School of Hygiene & Tropical Medicine, London, UK
| | - Danny Scarponi
- TB Modelling Group and TB Centre, London School of Hygiene & Tropical Medicine, London, UK; Centre for the Mathematical Modelling of Infectious Diseases, London School of Hygiene & Tropical Medicine, London, UK; Department of Infectious Disease Epidemiology, London School of Hygiene & Tropical Medicine, London, UK
| | - Andrew Iskauskas
- Department of Mathematical Sciences, Durham University, Durham, UK
| | - Roel Bakker
- TB Modelling Group and TB Centre, London School of Hygiene & Tropical Medicine, London, UK; Centre for the Mathematical Modelling of Infectious Diseases, London School of Hygiene & Tropical Medicine, London, UK; Department of Infectious Disease Epidemiology, London School of Hygiene & Tropical Medicine, London, UK; KNCV Tuberculosis Foundation, The Hague, Netherlands
| | - Matthew Quaife
- TB Modelling Group and TB Centre, London School of Hygiene & Tropical Medicine, London, UK; Centre for the Mathematical Modelling of Infectious Diseases, London School of Hygiene & Tropical Medicine, London, UK; Department of Infectious Disease Epidemiology, London School of Hygiene & Tropical Medicine, London, UK
| | | | | | - Matteo Zignol
- Global TB Programme, World Health Organization, Geneva, Switzerland
| | - Raymond C W Hutubessy
- Department of Immunization, Vaccines, and Biologicals, World Health Organization, Geneva, Switzerland
| | - Birgitte Giersing
- The Initiative for Vaccine Research, World Health Organization, Geneva, Switzerland
| | - Mark Jit
- Centre for the Mathematical Modelling of Infectious Diseases, London School of Hygiene & Tropical Medicine, London, UK; Department of Infectious Disease Epidemiology, London School of Hygiene & Tropical Medicine, London, UK
| | - Rebecca C Harris
- TB Modelling Group and TB Centre, London School of Hygiene & Tropical Medicine, London, UK; Centre for the Mathematical Modelling of Infectious Diseases, London School of Hygiene & Tropical Medicine, London, UK; Department of Infectious Disease Epidemiology, London School of Hygiene & Tropical Medicine, London, UK; Global Medical Evidence Generation for Influenza Vaccines, Sanofi Pasteur, Singapore
| | - Nicolas A Menzies
- Center for Health Decision Science, Harvard TH Chan School of Public Health, Boston, MA, USA; Department of Global Health and Population, Harvard TH Chan School of Public Health, Boston, MA, USA
| | - Richard G White
- TB Modelling Group and TB Centre, London School of Hygiene & Tropical Medicine, London, UK; Centre for the Mathematical Modelling of Infectious Diseases, London School of Hygiene & Tropical Medicine, London, UK; Department of Infectious Disease Epidemiology, London School of Hygiene & Tropical Medicine, London, UK
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Abstract
PURPOSE OF REVIEW Tuberculosis (TB) remains a global public health emergency and caused 1.6 million deaths in 2021. The aim of this review is to provide recent updates on advances in TB vaccine development for prevention and adjunct therapy. RECENT FINDINGS Targets use indications guiding late stage TB vaccine development have been established, namely: (i) Prevention of disease (PoD), (ii) Prevention of recurrent disease (PoR), (iii) Prevention of established infection in previously uninfected patients (PoI), and (iv) Adjunctive immunotherapy. Novel approaches include vaccines designed to induce immune responses beyond established CD4+, Th1-biased T cell immunity, novel animal models for use in challenge/protection studies, and controlled human infection models to generate vaccine efficacy data. SUMMARY Recent efforts at developing effective TB vaccines for prevention and adjunct treatment utilising new targets and technologies have yielded 16 candidate vaccines demonstrating proof of concept for inducing potentially protective immune responses to TB which is currently under evaluation in different stages of clinical trials.
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Brown LK, Van Schalkwyk C, De Villiers AK, Marx FM. Impact of interventions for tuberculosis prevention and care in South Africa - a systematic review of mathematical modelling studies. S Afr Med J 2023; 113:125-134. [PMID: 36876352 DOI: 10.7196/samj.2023.v113i3.16812] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2023] [Indexed: 03/06/2023] Open
Abstract
BACKGROUND Substantial additional efforts are needed to prevent, find and successfully treat tuberculosis (TB) in South Africa (SA). In thepast decade, an increasing body of mathematical modelling research has investigated the population-level impact of TB prevention and careinterventions. To date, this evidence has not been assessed in the SA context. OBJECTIVE To systematically review mathematical modelling studies that estimated the impact of interventions towards the World HealthOrganization's End TB Strategy targets for TB incidence, TB deaths and catastrophic costs due to TB in SA. METHODS We searched the PubMed, Web of Science and Scopus databases for studies that used transmission-dynamic models of TB in SAand reported on at least one of the End TB Strategy targets at population level. We described study populations, type of interventions andtheir target groups, and estimates of impact and other key findings. For studies of country-level interventions, we estimated average annualpercentage declines (AAPDs) in TB incidence and mortality attributable to the intervention. RESULTS We identified 29 studies that met our inclusion criteria, of which 7 modelled TB preventive interventions (vaccination,antiretroviral treatment (ART) for HIV, TB preventive treatment (TPT)), 12 considered interventions along the care cascade for TB(screening/case finding, reducing initial loss to follow-up, diagnostic and treatment interventions), and 10 modelled combinationsof preventive and care-cascade interventions. Only one study focused on reducing catastrophic costs due to TB. The highest impactof a single intervention was estimated in studies of TB vaccination, TPT among people living with HIV, and scale-up of ART. Forpreventive interventions, AAPDs for TB incidence varied between 0.06% and 7.07%, and for care-cascade interventions between 0.05%and 3.27%. CONCLUSION We describe a body of mathematical modelling research with a focus on TB prevention and care in SA. We found higherestimates of impact reported in studies of preventive interventions, highlighting the need to invest in TB prevention in SA. However, studyheterogeneity and inconsistent baseline scenarios limit the ability to compare impact estimates between studies. Combinations, rather thansingle interventions, are likely needed to reach the End TB Strategy targets in SA.
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Affiliation(s)
- L K Brown
- South African DSI-NRF Centre of Excellence in Epidemiological Modelling and Analysis (SACEMA), Stellenbosch University, Cape Town, South Africa.
| | - C Van Schalkwyk
- South African DSI-NRF Centre of Excellence in Epidemiological Modelling and Analysis (SACEMA), Stellenbosch University, Cape Town, South Africa.
| | - A K De Villiers
- South African DSI-NRF Centre of Excellence in Epidemiological Modelling and Analysis (SACEMA), Stellenbosch University, Cape Town, South Africa; Desmond Tutu TB Centre, Department of Paediatrics and Child Health, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa.
| | - F M Marx
- South African DSI-NRF Centre of Excellence in Epidemiological Modelling and Analysis (SACEMA), Stellenbosch University, Cape Town, South Africa; Desmond Tutu TB Centre, Department of Paediatrics and Child Health, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa; Division of Infectious Disease and Tropical Medicine, Center for Infectious Diseases, Heidelberg University Hospital, Heidelberg, Germany.
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Arinaminpathy N, Rade K, Kumar R, Joshi RP, Rao R. The potential impact of vaccination on tuberculosis burden in India: A modelling analysis. Indian J Med Res 2023; 157:119-126. [PMID: 37202930 PMCID: PMC10319376 DOI: 10.4103/ijmr.ijmr_328_23] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2023] [Indexed: 05/20/2023] Open
Abstract
Background & objectives Vaccination will play an important role in meeting the end tuberculosis (TB) goals. While certain vaccine candidates in advanced stages of clinical trials raise hope for the future availability of new tools, in the immediate term, there is also increasing interest in Bacille Calmette-Guérin revaccination among adults and adolescents as a potential strategy. Here, we sought to estimate the potential epidemiological impact of TB vaccination in India. Methods We developed a deterministic, age-structured, compartmental model of TB in India. Data from the recent national prevalence survey was used to inform epidemiological burden while also incorporating a vulnerable population who may be prioritized for vaccination, the latter consistent with the burden of undernutrition. Using this framework, the potential impact on incidence and mortality of a vaccine with 50 per cent efficacy was estimated, if rolled out in 2023 to cover 50 per cent of the unvaccinated each year. Simulated impacts were compared for disease- vs. infection-preventing vaccines, as well as when prioritizing vulnerable groups (those with undernutrition) rather than the general population. A sensitivity analyses were also conducted with respect to the duration, and efficacy, of vaccine immunity. Results When rolled out in the general population, an infection-preventing vaccine would avert 12 per cent (95% Bayesian credible intervals (Crl): 4.3-28%) of cumulative TB incidence between 2023 and 2030, while a disease-preventing vaccine would avert 29 per cent (95% Crl: 24-34%). Although the vulnerable population accounts for only around 16 per cent of India's population, prioritizing this group for vaccination would achieve almost half the impact of rollout in the general population, in the example of an infection-preventing vaccine. Sensitivity analysis also highlights the importance of the duration and efficacy of vaccine-induced immunity. Interpretation & conclusions These results highlight how even a vaccine with moderate effectiveness (50%) could achieve substantial reductions in TB burden in India, especially when prioritized for the most vulnerable.
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Affiliation(s)
- Nimalan Arinaminpathy
- MRC Centre for Global Infectious Disease Analysis, Imperial College London, London, UK
| | - Kirankumar Rade
- WHO India Country Office, Ministry of Health & Family Welfare, New Delhi, India
| | - Ravinder Kumar
- Central TB Division, Ministry of Health & Family Welfare, New Delhi, India
| | - Rajendra P. Joshi
- Central TB Division, Ministry of Health & Family Welfare, New Delhi, India
| | - Raghuram Rao
- Central TB Division, Ministry of Health & Family Welfare, New Delhi, India
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24
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Portnoy A, Clark RA, Quaife M, Weerasuriya CK, Mukandavire C, Bakker R, Deol AK, Malhotra S, Gebreselassie N, Zignol M, Sim SY, Hutubessy RCW, Baena IG, Nishikiori N, Jit M, White RG, Menzies NA. The cost and cost-effectiveness of novel tuberculosis vaccines in low- and middle-income countries: A modeling study. PLoS Med 2023; 20:e1004155. [PMID: 36693081 PMCID: PMC9873163 DOI: 10.1371/journal.pmed.1004155] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/23/2022] [Accepted: 12/09/2022] [Indexed: 01/25/2023] Open
Abstract
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 (LMICs) for a range of product characteristics and delivery strategies. METHODS AND FINDINGS We developed a system of epidemiological and economic models, calibrated to demographic, epidemiological, and health service data in 105 LMICs. For each country, we assessed the likely future course of TB-related outcomes under several vaccine introduction scenarios, compared to a "no-new-vaccine" counterfactual. Vaccine scenarios considered 2 vaccine product profiles (1 targeted at infants, 1 at adolescents/adults), both assumed to prevent progression to active TB. Key economic inputs were derived from the Global Health Cost Consortium, World Health Organization (WHO) patient cost surveys, and the published literature. We estimated the incremental impact of vaccine introduction for a range of health and economic outcomes. In the base-case, we assumed a vaccine price of $4.60 and used a 1× per-capita gross domestic product (GDP) cost-effectiveness threshold (both varied in sensitivity analyses). Vaccine introduction was estimated to require substantial near-term resources, offset by future cost-savings from averted TB burden. From a health system perspective, adolescent/adult vaccination was cost-effective in 64 of 105 LMICs. From a societal perspective (including productivity gains and averted patient costs), adolescent/adult vaccination was projected to be cost-effective in 73 of 105 LMICs and cost-saving in 58 of 105 LMICs, including 96% of countries with higher TB burden. When considering the monetized value of health gains, we estimated that introduction of an adolescent/adult vaccine could produce $283 to 474 billion in economic benefits by 2050. Limited data availability required assumptions and extrapolations that may omit important country-level heterogeneity in epidemiology and costs. CONCLUSIONS TB vaccination would be highly impactful and cost-effective in most LMICs. Further efforts are needed for future development, adoption, and implementation of novel TB vaccines.
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Affiliation(s)
- Allison Portnoy
- Center for Health Decision Science, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, United States of America
| | - Rebecca A. Clark
- TB Modelling Group, London School of Hygiene and Tropical Medicine, London, United Kingdom
- Centre for the Mathematical Modelling of Infectious Diseases, London School of Hygiene and Tropical Medicine, London, United Kingdom
- Department of Infectious Disease Epidemiology, London School of Hygiene and Tropical Medicine, London, United Kingdom
| | - Matthew Quaife
- TB Modelling Group, London School of Hygiene and Tropical Medicine, London, United Kingdom
- Centre for the Mathematical Modelling of Infectious Diseases, London School of Hygiene and Tropical Medicine, London, United Kingdom
- Department of Infectious Disease Epidemiology, London School of Hygiene and Tropical Medicine, London, United Kingdom
| | - Chathika K. Weerasuriya
- TB Modelling Group, London School of Hygiene and Tropical Medicine, London, United Kingdom
- Centre for the Mathematical Modelling of Infectious Diseases, London School of Hygiene and Tropical Medicine, London, United Kingdom
- Department of Infectious Disease Epidemiology, London School of Hygiene and Tropical Medicine, London, United Kingdom
| | - Christinah Mukandavire
- TB Modelling Group, London School of Hygiene and Tropical Medicine, London, United Kingdom
- Centre for the Mathematical Modelling of Infectious Diseases, London School of Hygiene and Tropical Medicine, London, United Kingdom
- Department of Infectious Disease Epidemiology, London School of Hygiene and Tropical Medicine, London, United Kingdom
| | - Roel Bakker
- TB Modelling Group, London School of Hygiene and Tropical Medicine, London, United Kingdom
- Centre for the Mathematical Modelling of Infectious Diseases, London School of Hygiene and Tropical Medicine, London, United Kingdom
- Department of Infectious Disease Epidemiology, London School of Hygiene and Tropical Medicine, London, United Kingdom
- KNCV Tuberculosis Foundation, The Hague, the Netherlands
| | - Arminder K. Deol
- TB Modelling Group, London School of Hygiene and Tropical Medicine, London, United Kingdom
- Centre for the Mathematical Modelling of Infectious Diseases, London School of Hygiene and Tropical Medicine, London, United Kingdom
- Department of Infectious Disease Epidemiology, London School of Hygiene and Tropical Medicine, London, United Kingdom
- Coalition for Epidemic Preparedness Innovations, London, United Kingdom
| | - Shelly Malhotra
- Market Access, Global Alliance for TB Drug Development, New York, New York, United States of America
- Global Access, International AIDS Vaccine Initiative, New York, New York, United States of America
| | | | - Matteo Zignol
- Global TB Programme, World Health Organization, Geneva, Switzerland
| | - So Yoon Sim
- Department of Immunization, Vaccines and Biologicals, World Health Organization, Geneva, Switzerland
| | - Raymond C. W. Hutubessy
- Department of Immunization, Vaccines and Biologicals, World Health Organization, Geneva, Switzerland
| | | | | | - Mark Jit
- Centre for the Mathematical Modelling of Infectious Diseases, London School of Hygiene and Tropical Medicine, London, United Kingdom
- Department of Infectious Disease Epidemiology, London School of Hygiene and Tropical Medicine, London, United Kingdom
- School of Public Health, University of Hong Kong, Hong Kong SAR, China
| | - Richard G. White
- TB Modelling Group, London School of Hygiene and Tropical Medicine, London, United Kingdom
- Centre for the Mathematical Modelling of Infectious Diseases, London School of Hygiene and Tropical Medicine, London, United Kingdom
- Department of Infectious Disease Epidemiology, London School of Hygiene and Tropical Medicine, London, United Kingdom
| | - Nicolas A. Menzies
- Center for Health Decision Science, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, United States of America
- Department of Global Health and Population, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, United States of America
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25
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Jayawardana S, Weerasuriya CK, Pelzer PT, Seeley J, Harris RC, Tameris M, Tait D, White RG, Asaria M. Feasibility of novel adult tuberculosis vaccination in South Africa: a cost-effectiveness and budget impact analysis. NPJ Vaccines 2022; 7:138. [PMID: 36344523 PMCID: PMC9640704 DOI: 10.1038/s41541-022-00554-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2022] [Accepted: 10/10/2022] [Indexed: 11/09/2022] Open
Abstract
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/AS01E vaccine candidate. The strategies were defined in terms of target population, coverage, vaccination schedule and delivery mode. We modelled these strategies to estimate long-term resource requirements and health benefits arising from vaccination over 2025-2050. We presented these to experts who excluded strategies that were deemed infeasible, and estimated cost-effectiveness and budget impact for each remaining strategy. The four strategies modelled combined target populations: either everyone aged 18-50, or all adults living with HIV, with delivery strategies: either a mass campaign followed by routine vaccination of 18-year olds, or two mass campaigns 10 years apart. Delivering two mass campaigns to all 18-50-year olds was found to be the most cost-effective strategy conferring the greatest net health benefit of 1.2 million DALYs averted having a probability of being cost-effective of 65-70%. This strategy required 38 million vaccine courses to be delivered at a cost of USD 507 million, reducing TB-related costs by USD 184 million while increasing ART costs by USD 79 million. A suitably designed adult TB vaccination programme built around novel TB vaccines is likely to be cost-effective and affordable given the resource and budget constraints in South Africa.
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Affiliation(s)
- Sahan Jayawardana
- Department of Health Policy, London School of Economics (LSE), London, UK.
| | - Chathika K Weerasuriya
- TB Modelling Group, TB Centre and Centre for the Mathematical Modelling of Infectious Diseases, Department of Infectious Disease Epidemiology, Faculty of Epidemiology & Population Health, London School of Hygiene & Tropical Medicine, London, UK
| | - Puck T Pelzer
- TB Modelling Group, TB Centre and Centre for the Mathematical Modelling of Infectious Diseases, Department of Infectious Disease Epidemiology, Faculty of Epidemiology & Population Health, London School of Hygiene & Tropical Medicine, London, UK
- KNCV Tuberculosis foundation, Hague, Netherlands
| | - Janet Seeley
- Department of Global Health and Development, London School of Hygiene and Tropical Medicine, London, UK
| | - Rebecca C Harris
- TB Modelling Group, TB Centre and Centre for the Mathematical Modelling of Infectious Diseases, Department of Infectious Disease Epidemiology, Faculty of Epidemiology & Population Health, London School of Hygiene & Tropical Medicine, London, UK
- Sanofi Pasteur, Singapore, Singapore
| | - Michele Tameris
- South African Tuberculosis Vaccine Initiative (SATVI), Department of Pathology, Institute of Infectious Disease and Molecular Medicine, University of Cape Town (UCT), Cape Town, South Africa
| | - Dereck Tait
- Independent consultant, Cape Town, South Africa
| | - Richard G White
- TB Modelling Group, TB Centre and Centre for the Mathematical Modelling of Infectious Diseases, Department of Infectious Disease Epidemiology, Faculty of Epidemiology & Population Health, London School of Hygiene & Tropical Medicine, London, UK
| | - Miqdad Asaria
- Department of Health Policy, London School of Economics (LSE), London, UK
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26
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Miner MD, Hatherill M, Mave V, Gray GE, Nachman S, Read SW, White RG, Hesseling A, Cobelens F, Patel S, Frick M, Bailey T, Seder R, Flynn J, Rengarajan J, Kaushal D, Hanekom W, Schmidt AC, Scriba TJ, Nemes E, Andersen-Nissen E, Landay A, Dorman SE, Aldrovandi G, Cranmer LM, Day CL, Garcia-Basteiro AL, Fiore-Gartland A, Mogg R, Kublin JG, Gupta A, Churchyard G. Developing tuberculosis vaccines for people with HIV: consensus statements from an international expert panel. Lancet HIV 2022; 9:e791-e800. [PMID: 36240834 PMCID: PMC9667733 DOI: 10.1016/s2352-3018(22)00255-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2022] [Revised: 08/16/2022] [Accepted: 08/30/2022] [Indexed: 11/06/2022]
Abstract
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, a series of symposia was held that posed six framing questions to a panel of international experts: What is the use case or rationale for developing tuberculosis vaccines? What is the landscape of tuberculosis vaccines? Which vaccine candidates should be prioritised? What are the tuberculosis vaccine trial design considerations? What is the role of immunological correlates of protection? What are the gaps in preclinical models for studying tuberculosis vaccines? The international expert panel formulated consensus statements to each of the framing questions, with the intention of informing tuberculosis vaccine development and the prioritisation of clinical trials for inclusion of people with HIV.
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Affiliation(s)
| | - Mark Hatherill
- South African Tuberculosis Vaccine Initiative, Institute of Infectious Disease and Molecular Medicine and Division of Immunology, Department of Pathology, University of Cape Town, Cape Town, South Africa
| | - Vidya Mave
- Johns Hopkins India, Byramjee-Jeejeebhoy Government Medical College Clinical Research Site, Pune, India
| | - Glenda E Gray
- South African Medical Research Council, Cape Town, South Africa
| | - Sharon Nachman
- Department of Pediatrics, Renaissance School of Medicine, Stony Brook University, Stony Brook, NY, USA
| | - Sarah W Read
- Division of AIDS, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA
| | - Richard G White
- Department of Epidemiology and Population Health, London School of Hygiene & Tropical Medicine, London, UK
| | - Anneke Hesseling
- Desmond Tutu Tuberculosis Centre, Stellenbosch University, Stellenbosch, South Africa
| | - Frank Cobelens
- Department of Global Health, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, Netherlands
| | - Sheral Patel
- US Food and Drug Administration, Silver Spring, MD, USA
| | - Mike Frick
- Treatment Action Group, New York, NY, USA
| | | | - Robert Seder
- Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA
| | - Joanne Flynn
- Microbiology and Molecular Genetics, University of Pittsburgh Medical Center, Pittsburgh, PA, USA
| | | | - Deepak Kaushal
- Texas Biomedical Research Institute, San Antonio, TX, USA
| | - Willem Hanekom
- Africa Health Research Institute, Durban, KwaZulu-Natal, South Africa
| | | | - Thomas J Scriba
- South African Tuberculosis Vaccine Initiative, Institute of Infectious Disease and Molecular Medicine and Division of Immunology, Department of Pathology, University of Cape Town, Cape Town, South Africa
| | - Elisa Nemes
- South African Tuberculosis Vaccine Initiative, Institute of Infectious Disease and Molecular Medicine and Division of Immunology, Department of Pathology, University of Cape Town, Cape Town, South Africa
| | - Erica Andersen-Nissen
- Fred Hutchinson Cancer Research Center, Seattle, WA, USA; Cape Town HIV Vaccine Trials Network (HVTN) Immunology Laboratory, Cape Town, South Africa
| | | | - Susan E Dorman
- Department of Medicine, Medical University of South Carolina, Charleston, SC, USA
| | - Grace Aldrovandi
- Department of Pediatrics, University of California, Los Angeles, CA, USA
| | - Lisa M Cranmer
- Emory School of Medicine, Emory University, Atlanta, GA, USA
| | - Cheryl L Day
- Emory School of Medicine, Emory University, Atlanta, GA, USA
| | - Alberto L Garcia-Basteiro
- ISGlobal, Hospital Clínic Universitat de Barcelona, Barcelona, Spain; Centro de investigação de Saúde de Manhiça, Maputo, Mozambique
| | | | - Robin Mogg
- Takeda Pharmaceutical Company, Cambridge, MA, USA
| | - James G Kublin
- Fred Hutchinson Cancer Research Center, Seattle, WA, USA
| | - Amita Gupta
- Division of Infectious Diseases, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Gavin Churchyard
- The Aurum Institute, Johannesburg, South Africa; School of Public Health, University of Witwatersrand, Johannesburg, South Africa; Department of Medicine, Vanderbilt University, Nashville, TN, USA.
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27
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Evaluation of early innate and adaptive immune responses to the TB vaccine Mycobacterium bovis BCG and vaccine candidate BCGΔBCG1419c. Sci Rep 2022; 12:12377. [PMID: 35858977 PMCID: PMC9300728 DOI: 10.1038/s41598-022-14935-y] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2021] [Accepted: 05/03/2022] [Indexed: 12/30/2022] Open
Abstract
The vaccine Mycobacterium bovis Bacillus Calmette-Guérin (BCG) elicits an immune response that is protective against certain forms of tuberculosis (TB); however, because BCG efficacy is limited it is important to identify alternative TB vaccine candidates. Recently, the BCG deletion mutant and vaccine candidate BCGΔBCG1419c was demonstrated to survive longer in intravenously infected BALB/c mice due to enhanced biofilm formation, and better protected both BALB/c and C57BL/6 mice against TB-induced lung pathology during chronic stages of infection, relative to BCG controls. BCGΔBCG1419c-elicited protection also associated with lower levels of proinflammatory cytokines (i.e. IL6, TNFα) at the site of infection in C57BL/6 mice. Given the distinct immune profiles of BCG- and BCGΔBCG1419c-immunized mice during chronic TB, we set out to determine if there are early immunological events which distinguish these two groups, using multi-dimensional flow cytometric analysis of the lungs and other tissues soon after immunization. Our results demonstrate a number of innate and adaptive response differences between BCG- and BCGΔBCG1419c-immunized mice which are consistent with the latter being longer lasting and potentially less inflammatory, including lower frequencies of exhausted CD4+ T helper (TH) cells and higher frequencies of IL10-producing T cells, respectively. These studies suggest the use of BCGΔBCG1419c may be advantageous as an alternative TB vaccine candidate.
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28
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Garcia-Basteiro AL, White RG, Tait D, Schmidt AC, Rangaka MX, Quaife M, Nemes E, Mogg R, Hill PC, Harris RC, Hanekom WA, Frick M, Fiore-Gartland A, Evans T, Dagnew AF, Churchyard G, Cobelens F, Behr MA, Hatherill M. End-point definition and trial design to advance tuberculosis vaccine development. Eur Respir Rev 2022; 31:220044. [PMID: 35675923 PMCID: PMC9488660 DOI: 10.1183/16000617.0044-2022] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2022] [Accepted: 04/04/2022] [Indexed: 11/05/2022] Open
Abstract
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 urgently needed. There are several new vaccine candidates at different stages of clinical development. Given the limited funding for vaccine development, it is crucial that trial designs are as efficient as possible. Prevention of infection (POI) approaches offer an attractive opportunity to accelerate new candidate vaccines to advance into large and expensive prevention of disease (POD) efficacy trials. However, POI approaches are limited by imperfect current tools to measure Mycobacterium tuberculosis infection end-points. POD trials need to carefully consider the type and number of microbiological tests that define TB disease and, if efficacy against subclinical (asymptomatic) TB disease is to be tested, POD trials need to explore how best to define and measure this form of TB. Prevention of recurrence trials are an alternative approach to generate proof of concept for efficacy, but optimal timing of vaccination relative to treatment must still be explored. Novel and efficient approaches to efficacy trial design, in addition to an increasing number of candidates entering phase 2-3 trials, would accelerate the long-standing quest for a new TB vaccine.
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Affiliation(s)
- Alberto L Garcia-Basteiro
- Centro de Investigação em Sade de Manhiça (CISM), Maputo, Mozambique
- ISGlobal, Hospital Clínic - Universitat de Barcelona, Barcelona, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Infecciosas (CIBERINFECT), Barcelona, Spain
| | | | - Dereck Tait
- International AIDS Vaccine Initiative (IAVI) NPC, Cape Town, South Africa
| | | | - Molebogeng X Rangaka
- Institute for Global Health and MRC Clinical Trials Unit at University College London, London, UK
- CIDRI-AFRICA, Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Cape Town, South Africa
| | - Matthew Quaife
- London School of Hygiene and Tropical Medicine, London, UK
| | - Elisa Nemes
- South African Tuberculosis Vaccine Initiative, Institute of Infectious Disease and Molecular Medicine and Division of Immunology, Dept of Pathology, University of Cape Town, Cape Town, South Africa
| | - Robin Mogg
- Takeda Pharmaceutical Company Limited, Cambridge, MA, USA
| | - Philip C Hill
- Centre for International Health, University of Otago, Dunedin, New Zealand
| | - Rebecca C Harris
- London School of Hygiene and Tropical Medicine, London, UK
- Sanofi Pasteur, Singapore
| | - Willem A Hanekom
- Africa Health Research Institute, KwaZulu-Natal, South Africa
- Division of Infection and Immunity, University College London, London, UK
| | - Mike Frick
- Treatment Action Group, New York, NY, USA
| | - Andrew Fiore-Gartland
- Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
| | | | - Alemnew F Dagnew
- Bill and Melinda Gates Medical Research Institute, Cambridge, MA, USA
| | - Gavin Churchyard
- The Aurum Institute, Parktown, South Africa
- Vanderbilt University, Nashville, TN, USA
- University of the Witwatersrand, Johannesburg, South Africa
| | - Frank Cobelens
- Dept of Global Health and Amsterdam Institute for Global health and development, Amsterdam University Medical Centres, Amsterdam, The Netherlands
| | - Marcel A Behr
- Dept of Medicine, McGill University; McGill International TB Centre, Montreal, QC, Canada
| | - Mark Hatherill
- South African Tuberculosis Vaccine Initiative, Institute of Infectious Disease and Molecular Medicine and Division of Immunology, Dept of Pathology, University of Cape Town, Cape Town, South Africa
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29
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Evaluating Strategies For Tuberculosis to Achieve the Goals of WHO in China: A Seasonal Age-Structured Model Study. Bull Math Biol 2022; 84:61. [PMID: 35486232 DOI: 10.1007/s11538-022-01019-1] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2021] [Accepted: 03/28/2022] [Indexed: 11/02/2022]
Abstract
Although great progress has been made in the prevention and mitigation of TB in the past 20 years, China is still the third largest contributor to the global burden of new TB cases, accounting for 833,000 new cases in 2019. Improved mitigation strategies, such as vaccines, diagnostics, and treatment, are needed to meet goals of WHO. Given the huge variability in the prevalence of TB across age-groups in China, the vaccination, diagnostic techniques, and treatment for different age-groups may have different effects. Moreover, the statistics data of TB cases show significant seasonal fluctuations in China. In view of the above facts, we propose a non-autonomous differential equation model with age structure and seasonal transmission rate. We derive the basic reproduction number, [Formula: see text], and prove that the unique disease-free periodic solution, [Formula: see text] is globally asymptotically stable when [Formula: see text], while the disease is uniformly persistent and at least one positive periodic solution exists when [Formula: see text]. We estimate that the basic reproduction number [Formula: see text] ([Formula: see text]), which means that TB is uniformly persistent. Our results demonstrate that vaccinating susceptible individuals whose ages are over 65 and between 20 and 24 is much more effective in reducing the prevalence of TB, and each of the improved vaccination strategy, diagnostic strategy, and treatment strategy leads to substantial reductions in the prevalence of TB per 100,000 individuals compared with current approaches, and the combination of the three strategies is more effective. Scenario A (i.e., coverage rate [Formula: see text], diagnosis rate [Formula: see text], relapse rate [Formula: see text]) is the best and can reduce the prevalence of TB per 100,000 individuals by [Formula: see text] and [Formula: see text] in 2035 and 2050, respectively. Although the improved strategies will significantly reduce the incidence rate of TB, it is challenging to achieve the goal of WHO in 2050. Our findings can provide guidance for public health authorities in projecting effective mitigation strategies of TB.
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30
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Weerasuriya CK, Harris RC, McQuaid CF, Gomez GB, White RG. Updating age-specific contact structures to match evolving demography in a dynamic mathematical model of tuberculosis vaccination. PLoS Comput Biol 2022; 18:e1010002. [PMID: 35452459 PMCID: PMC9067655 DOI: 10.1371/journal.pcbi.1010002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2021] [Revised: 05/04/2022] [Accepted: 03/08/2022] [Indexed: 11/18/2022] Open
Abstract
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 matrix (M0), preserved contact reciprocity (M1), preserved contact assortativity (M2), and preserved average contacts per individual (M3). We updated the contact matrices of a deterministic compartmental model of tuberculosis transmission, calibrated to epidemiologic data between 2000 and 2019 derived from India. We additionally calibrated the M0, M2, and M3 models to the 2050 TB incidence rate projected by the calibrated M1 model. We stratified age into three groups, children (<15y), adults (≥15y, <65y), and the elderly (≥65y), using World Population Prospects demographic data, between which we applied POLYMOD-derived social contact matrices. We simulated an M72-AS01E-like tuberculosis vaccine delivered from 2027 and estimated the per cent TB incidence rate reduction (IRR) in 2050 under each update method. We found that vaccine impact estimates in all age groups remained relatively stable between the M0–M3 models, irrespective of vaccine-targeting by age group. The maximum difference in impact, observed following adult-targeted vaccination, was 7% in the elderly, in whom we observed IRRs of 19% (uncertainty range 13–32), 20% (UR 13–31), 22% (UR 14–37), and 26% (UR 18–38) following M0, M1, M2 and M3 updates, respectively. We found that model-based TB vaccine impact estimates were relatively insensitive to demography-matched contact matrix updates in an India-like demographic and epidemiologic scenario. Current model-based TB vaccine impact estimates may be reasonably robust to the lack of contact matrix updates, but further research is needed to confirm and generalise this finding. Mathematical models are increasingly used to predict the impact of new and existing tools, e.g., vaccines, that aim to control the transmission of infectious diseases. Within these models, investigators often assume that individuals contact each other according to specific patterns, particularly between and within different age groups. These patterns are typically derived from surveys of social contact or other models and reflect the particular age composition of their source population. However, when models are set over long time scales, e.g., decades, population age composition is likely to change. Despite this reality, few models update their contact patterns to match changing age composition. Furthermore, none have assessed whether their final estimates of disease-control intervention impact are affected by updating contact patterns. We measured whether different techniques to update social contact patterns to match evolving demography produce different vaccine impact estimates, using a mathematical model of tuberculosis set in an India-like scenario between 2025–2050. We found that vaccine impact was stable across a range of different update methods. Thus, existing model-based vaccine impact estimates may be stable to a lack of these updates, but further work is required to confirm these findings.
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Affiliation(s)
- Chathika Krishan Weerasuriya
- TB Modelling Group, TB Centre and Centre for the Mathematical Modelling of Infectious Diseases, Department of Infectious Disease Epidemiology, Faculty of Epidemiology & Population Health, London School of Hygiene and Tropical Medicine, London, United Kingdom
- * E-mail:
| | - Rebecca Claire Harris
- TB Modelling Group, TB Centre and Centre for the Mathematical Modelling of Infectious Diseases, Department of Infectious Disease Epidemiology, Faculty of Epidemiology & Population Health, London School of Hygiene and Tropical Medicine, London, United Kingdom
| | - Christopher Finn McQuaid
- TB Modelling Group, TB Centre and Centre for the Mathematical Modelling of Infectious Diseases, Department of Infectious Disease Epidemiology, Faculty of Epidemiology & Population Health, London School of Hygiene and Tropical Medicine, London, United Kingdom
| | - Gabriela B. Gomez
- Department of Global Health & Development, Faculty of Public Health & Policy, London School of Hygiene and Tropical Medicine, London, United Kingdom
| | - Richard G. White
- TB Modelling Group, TB Centre and Centre for the Mathematical Modelling of Infectious Diseases, Department of Infectious Disease Epidemiology, Faculty of Epidemiology & Population Health, London School of Hygiene and Tropical Medicine, London, United Kingdom
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31
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Cobelens F, Suri RK, Helinski M, Makanga M, Weinberg AL, Schaffmeister B, Deege F, Hatherill M. Accelerating research and development of new vaccines against tuberculosis: a global roadmap. THE LANCET. INFECTIOUS DISEASES 2022; 22:e108-e120. [PMID: 35240041 PMCID: PMC8884775 DOI: 10.1016/s1473-3099(21)00810-0] [Citation(s) in RCA: 43] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/27/2021] [Revised: 12/06/2021] [Accepted: 12/08/2021] [Indexed: 12/03/2022]
Abstract
To eliminate tuberculosis globally, a new, effective, and affordable vaccine is urgently needed, particularly for use in adults and adolescents in low-income and middle-income countries. We have created a roadmap that lists the actions needed to accelerate tuberculosis vaccine research and development using a participatory process. The vaccine pipeline needs more diverse immunological approaches, antigens, and platforms. Clinical development can be accelerated by validated preclinical models, agreed laboratory correlates of protection, efficient trial designs, and validated endpoints. Determining the public health impact of new tuberculosis vaccines requires understanding of a country's demand for a new tuberculosis vaccine, how to integrate vaccine implementation with ongoing tuberculosis prevention efforts, cost, and national and global demand to stimulate vaccine production. Investments in tuberculosis vaccine research and development need to be increased, with more diversity of funding sources and coordination between these funders. Open science is important to enhance the efficiency of tuberculosis vaccine research and development including early and freely available publication of study findings and effective mechanisms for sharing datasets and specimens. There is a need for increased engagement of industry vaccine developers, for increased political commitment for new tuberculosis vaccines, and to address stigma and vaccine hesitancy. The unprecedented speed by which COVID-19 vaccines have been developed and introduced provides important insight for tuberculosis vaccine research and development.
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Affiliation(s)
- Frank Cobelens
- Department of Global Health and Amsterdam Institute for Global Health and Development, Amsterdam University Medical Centers, Amsterdam, Netherlands.
| | - Rajinder Kumar Suri
- Department of Governance and Strategy, Developing Countries Vaccine Manufacturers' Network International, Nyon, Switzerland
| | - Michelle Helinski
- European & Developing Countries Clinical Trials Partnership, The Hague, Netherlands
| | - Michael Makanga
- European & Developing Countries Clinical Trials Partnership, The Hague, Netherlands
| | - Ana Lúcia Weinberg
- European & Developing Countries Clinical Trials Partnership, The Hague, Netherlands
| | | | | | - Mark Hatherill
- South African Tuberculosis Vaccine Initiative, Institute of Infectious Disease and Molecular Medicine, and Division of Immunology, Department of Pathology, University of Cape Town, Cape Town, South Africa
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32
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Larsen SE, Williams BD, Rais M, Coler RN, Baldwin SL. It Takes a Village: The Multifaceted Immune Response to Mycobacterium tuberculosis Infection and Vaccine-Induced Immunity. Front Immunol 2022; 13:840225. [PMID: 35359957 PMCID: PMC8960931 DOI: 10.3389/fimmu.2022.840225] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2021] [Accepted: 02/08/2022] [Indexed: 11/18/2022] Open
Abstract
Despite co-evolving with humans for centuries and being intensely studied for decades, the immune correlates of protection against Mycobacterium tuberculosis (Mtb) have yet to be fully defined. This lapse in understanding is a major lag in the pipeline for evaluating and advancing efficacious vaccine candidates. While CD4+ T helper 1 (TH1) pro-inflammatory responses have a significant role in controlling Mtb infection, the historically narrow focus on this cell population may have eclipsed the characterization of other requisite arms of the immune system. Over the last decade, the tuberculosis (TB) research community has intentionally and intensely increased the breadth of investigation of other immune players. Here, we review mechanistic preclinical studies as well as clinical anecdotes that suggest the degree to which different cell types, such as NK cells, CD8+ T cells, γ δ T cells, and B cells, influence infection or disease prevention. Additionally, we categorically outline the observed role each major cell type plays in vaccine-induced immunity, including Mycobacterium bovis bacillus Calmette-Guérin (BCG). Novel vaccine candidates advancing through either the preclinical or clinical pipeline leverage different platforms (e.g., protein + adjuvant, vector-based, nucleic acid-based) to purposefully elicit complex immune responses, and we review those design rationales and results to date. The better we as a community understand the essential composition, magnitude, timing, and trafficking of immune responses against Mtb, the closer we are to reducing the severe disease burden and toll on human health inflicted by TB globally.
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Affiliation(s)
- Sasha E. Larsen
- Center for Global Infectious Disease Research, Seattle Children's Research Institute, Seattle Children's Hospital, Seattle, WA, United States
| | - Brittany D. Williams
- Center for Global Infectious Disease Research, Seattle Children's Research Institute, Seattle Children's Hospital, Seattle, WA, United States,Department of Global Health, University of Washington, Seattle, WA, United States
| | - Maham Rais
- Center for Global Infectious Disease Research, Seattle Children's Research Institute, Seattle Children's Hospital, Seattle, WA, United States
| | - Rhea N. Coler
- Center for Global Infectious Disease Research, Seattle Children's Research Institute, Seattle Children's Hospital, Seattle, WA, United States,Department of Global Health, University of Washington, Seattle, WA, United States,Department of Pediatrics, University of Washington School of Medicine, Seattle, WA, United States
| | - Susan L. Baldwin
- Center for Global Infectious Disease Research, Seattle Children's Research Institute, Seattle Children's Hospital, Seattle, WA, United States,*Correspondence: Susan L. Baldwin,
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33
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Harris RC, Quaife M, Weerasuriya C, Gomez GB, Sumner T, Bozzani F, White RG. Cost-effectiveness of routine adolescent vaccination with an M72/AS01 E-like tuberculosis vaccine in South Africa and India. Nat Commun 2022; 13:602. [PMID: 35105879 PMCID: PMC8807591 DOI: 10.1038/s41467-022-28234-7] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2021] [Accepted: 01/07/2022] [Indexed: 12/26/2022] Open
Abstract
The M72/AS01E tuberculosis vaccine showed 50% (95%CI: 2-74%) efficacy in a phase 2B trial in preventing active pulmonary tuberculosis disease, but potential cost-effectiveness of adolescent immunisation is unknown. We estimated the impact and cost-effectiveness of six scenarios of routine adolescent M72/AS01E-like vaccination in South Africa and India. All scenarios suggested an M72/AS01E-like vaccine would be highly (94-100%) cost-effective in South Africa compared to a cost-effectiveness threshold of $2480/disability-adjusted life-year (DALY) averted. For India, a prevention of disease vaccine, effective irrespective of recipient's M. tuberculosis infection status at time of administration, was also highly likely (92-100%) cost-effective at a threshold of $264/DALY averted; however, a prevention of disease vaccine, effective only if the recipient was already infected, had 0-6% probability of cost-effectiveness. In both settings, vaccinating 50% of 18 year-olds was similarly cost-effective to vaccinating 80% of 15 year-olds, and more cost-effective than vaccinating 80% of 10 year-olds. Vaccine trials should include adolescents to ensure vaccines can be delivered to this efficient-to-target population.
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Affiliation(s)
- Rebecca C Harris
- TB Modelling Group, TB Centre, and Centre for Mathematical Modelling of Infectious Diseases, Department of Infectious Disease Epidemiology, London School of Hygiene and Tropical Medicine, London, UK. .,Sanofi Pasteur, Singapore, Singapore.
| | - Matthew Quaife
- TB Modelling Group, TB Centre, and Centre for Mathematical Modelling of Infectious Diseases, Department of Infectious Disease Epidemiology, London School of Hygiene and Tropical Medicine, London, UK
| | - Chathika Weerasuriya
- TB Modelling Group, TB Centre, and Centre for Mathematical Modelling of Infectious Diseases, Department of Infectious Disease Epidemiology, London School of Hygiene and Tropical Medicine, London, UK
| | - Gabriela B Gomez
- Department of Global Health and Development, London School of Hygiene and Tropical Medicine, London, UK.,Sanofi Pasteur, Lyon, France
| | - Tom Sumner
- TB Modelling Group, TB Centre, and Centre for Mathematical Modelling of Infectious Diseases, Department of Infectious Disease Epidemiology, London School of Hygiene and Tropical Medicine, London, UK
| | - Fiammetta Bozzani
- Department of Global Health and Development, London School of Hygiene and Tropical Medicine, London, UK
| | - Richard G White
- TB Modelling Group, TB Centre, and Centre for Mathematical Modelling of Infectious Diseases, Department of Infectious Disease Epidemiology, London School of Hygiene and Tropical Medicine, London, UK
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After 100 Years of BCG Immunization against Tuberculosis, What Is New and Still Outstanding for This Vaccine? Vaccines (Basel) 2021; 10:vaccines10010057. [PMID: 35062718 PMCID: PMC8778337 DOI: 10.3390/vaccines10010057] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2021] [Revised: 12/17/2021] [Accepted: 12/29/2021] [Indexed: 12/14/2022] Open
Abstract
In 2021, most of the world was reasonably still concerned about the COVID-19 pandemic, how cases were up and down in different countries, how the vaccination campaigns were ongoing, and most people were familiar with the speed with which vaccines against SARS-Co-V2 were developed, analyzed, and started to be applied in an attempt to curb the pandemic. Because of this, it may have somehow passed relatively inadvertently for people outside of the field that the vaccine used to control tuberculosis (TB), Mycobacterium bovis Bacille Calmette-Guérin (BCG), was first applied to humans a century ago. Over these years, BCG has been the vaccine applied to most human beings in the world, despite its known lack of efficacy to fully prevent respiratory TB. Several strategies have been employed in the last 20 years to produce a novel vaccine that would replace, or boost, immunity and protection elicited by BCG. In this work, to avoid potential redundancies with recently published reviews, I only aim to present my current thoughts about some of the latest findings and outstanding questions that I consider worth investigating to help develop a replacement or modified BCG in order to successfully fight TB, based on BCG itself.
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35
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Affordability of Adult Tuberculosis Vaccination in India and China: A Dynamic Transmission Model-Based Analysis. Vaccines (Basel) 2021; 9:vaccines9030245. [PMID: 33799544 PMCID: PMC7998179 DOI: 10.3390/vaccines9030245] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2021] [Revised: 02/25/2021] [Accepted: 03/06/2021] [Indexed: 11/30/2022] Open
Abstract
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 total cost that the public health sectors in India and China should expect to pay to introduce a M72/AS01E-like vaccine deemed cost-effective at country-specific willingness to pay thresholds for cost-effectiveness. To estimate the total disability adjusted life years (DALYs) averted by the vaccination programme, we simulated a 50% efficacy vaccine providing 10-years of protection in post-infection populations between 2027 and 2050 in India and China using a dynamic transmission model of M. tuberculosis. We investigated two mass vaccination strategies, both delivered every 10-years achieving 70% coverage: Vaccinating adults and adolescents (age ≥10y), or only the most efficient 10-year age subgroup (defined as greatest DALYs averted per vaccine given). We used country-specific thresholds for cost-effectiveness to estimate the maximum total cost (Cmax) a government should be willing to pay for each vaccination strategy. Adult/adolescent vaccination resulted in a Cmax of $21 billion (uncertainty interval [UI]: 16–27) in India, and $15B (UI:12–29) in China at willingness to pay thresholds of $264/DALY averted and $3650/DALY averted, respectively. Vaccinating the highest efficiency age group (India: 50–59y; China: 60–69y) resulted in a Cmax of $5B (UI:4–6) in India and $6B (UI:4–7) in China. Mass vaccination against tuberculosis of all adults and adolescents, deemed cost-effective, will likely impose a substantial budgetary burden. Targeted tuberculosis vaccination, deemed cost-effective, may represent a more affordable approach.
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36
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Weerasuriya CK, Harris RC, McQuaid CF, Bozzani F, Ruan Y, Li R, Li T, Rade K, Rao R, Ginsberg AM, Gomez GB, White RG. The epidemiologic impact and cost-effectiveness of new tuberculosis vaccines on multidrug-resistant tuberculosis in India and China. BMC Med 2021; 19:60. [PMID: 33632218 PMCID: PMC7908776 DOI: 10.1186/s12916-021-01932-7] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/12/2020] [Accepted: 01/29/2021] [Indexed: 02/08/2023] Open
Abstract
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 on RR/MDR-TB in China and India. METHODS We constructed a deterministic, compartmental, age-, drug-resistance- and treatment history-stratified dynamic transmission model of tuberculosis. We introduced novel vaccines from 2027, with post- (PSI) or both pre- and post-infection (P&PI) efficacy, conferring 10 years of protection, with 50% efficacy. We measured vaccine cost-effectiveness over 2027-2050 as USD/DALY averted-against 1-times GDP/capita, and two healthcare opportunity cost-based (HCOC), thresholds. We carried out scenario analyses. RESULTS By 2050, the P&PI vaccine reduced RR/MDR-TB incidence rate by 71% (UI: 69-72) and 72% (UI: 70-74), and the PSI vaccine by 31% (UI: 30-32) and 44% (UI: 42-47) in China and India, respectively. In India, we found both USD 10 P&PI and PSI vaccines cost-effective at the 1-times GDP and upper HCOC thresholds and P&PI vaccines cost-effective at the lower HCOC threshold. In China, both vaccines were cost-effective at the 1-times GDP threshold. P&PI vaccine remained cost-effective at the lower HCOC threshold with 49% probability and PSI vaccines at the upper HCOC threshold with 21% probability. The P&PI vaccine was predicted to avert 0.9 million (UI: 0.8-1.1) and 1.1 million (UI: 0.9-1.4) second-line therapy regimens in China and India between 2027 and 2050, respectively. CONCLUSIONS Novel TB vaccination is likely to substantially reduce the future burden of RR/MDR-TB, while averting the need for second-line therapy. Vaccination may be cost-effective depending on vaccine characteristics and setting.
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Affiliation(s)
- Chathika K Weerasuriya
- TB Modelling Group, TB Centre and Centre for the Mathematical Modelling of Infectious Diseases, Department of Infectious Disease Epidemiology, Faculty of Epidemiology & Population Health, London School of Hygiene and Tropical Medicine, London, UK.
| | - Rebecca C Harris
- TB Modelling Group, TB Centre and Centre for the Mathematical Modelling of Infectious Diseases, Department of Infectious Disease Epidemiology, Faculty of Epidemiology & Population Health, London School of Hygiene and Tropical Medicine, London, UK.,Currently employed at Sanofi Pasteur, Singapore, Singapore
| | - C Finn McQuaid
- TB Modelling Group, TB Centre and Centre for the Mathematical Modelling of Infectious Diseases, Department of Infectious Disease Epidemiology, Faculty of Epidemiology & Population Health, London School of Hygiene and Tropical Medicine, London, UK
| | - Fiammetta Bozzani
- Department of Global Health and Development, Faculty of Public Health & Policy, London School of Hygiene and Tropical Medicine, London, UK
| | - Yunzhou Ruan
- Chinese Centre for Disease Control and Prevention, Beijing, China
| | - Renzhong Li
- Chinese Centre for Disease Control and Prevention, Beijing, China
| | - Tao Li
- Chinese Centre for Disease Control and Prevention, Beijing, China
| | | | - Raghuram Rao
- National Tuberculosis Elimination Programme, New Delhi, India
| | - Ann M Ginsberg
- International AIDS Vaccine Initiative, New York, USA.,Current Affiliation: Bill and Melinda Gates Foundation, Washington DC, USA
| | - Gabriela B Gomez
- Department of Global Health and Development, Faculty of Public Health & Policy, London School of Hygiene and Tropical Medicine, London, UK.,Currently employed at Sanofi Pasteur, Lyon, France
| | - Richard G White
- TB Modelling Group, TB Centre and Centre for the Mathematical Modelling of Infectious Diseases, Department of Infectious Disease Epidemiology, Faculty of Epidemiology & Population Health, London School of Hygiene and Tropical Medicine, London, UK
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37
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Weerasuriya CK, Clark RA, White RG, Harris RC. New tuberculosis vaccines: advances in clinical development and modelling. J Intern Med 2020; 288:661-681. [PMID: 33128834 DOI: 10.1111/joim.13197] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/15/2020] [Revised: 09/02/2020] [Accepted: 10/20/2020] [Indexed: 01/04/2023]
Abstract
Tuberculosis remains a major source of morbidity and mortality worldwide, with 10 million cases and 1.5 million deaths in 2018. Achieving 'End TB' prevention and care goals by 2035 will likely require a new tuberculosis vaccine. The tuberculosis vaccine development pipeline has seen encouraging progress; however, questions around their population impact and implementation remain. Mathematical modelling investigates these questions to inform vaccine development and deployment strategies. We provide an update on the current vaccine development pipeline, and a systematic literature review of mathematical modelling of the epidemiological impact of new tuberculosis vaccines. Fourteen prophylactic tuberculosis vaccine candidates are currently in clinical trials. Two candidates have shown promise in phase II proof-of-concept efficacy trials: M72/AS01E demonstrated 49.7% (95% CI; 2.1, 74.2) protection against tuberculosis disease, and BCG revaccination demonstrated 45.4% (95% CI; 6.4, 68.1) protection against sustained Mycobacterium tuberculosis infection. Since the last modelling review, new studies have investigated the epidemiological impact of differential vaccine characteristics, age targeting and spatial/risk group targeting. Critical research priorities for M72/AS01E include completing the currently in-design trial, powered to improve the precision of efficacy estimates, include uninfected populations and further assess safety and immunogenicity in HIV-infected people. For BCG revaccination, the priority is completing the ongoing confirmation of efficacy trial. Critical modelling gaps remain on the full value proposition of vaccines, comparisons with other interventions and more realistic implementation strategies. Using carefully designed trials and modelling, we must prepare for success, to ensure that new vaccines will be promptly received by those most in need.
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Affiliation(s)
- C K Weerasuriya
- From the, TB Modelling Group, Department of Infectious Disease Epidemiology, London School of Hygiene and Tropical Medicine, London, UK
| | - R A Clark
- From the, TB Modelling Group, Department of Infectious Disease Epidemiology, London School of Hygiene and Tropical Medicine, London, UK
| | - R G White
- From the, TB Modelling Group, Department of Infectious Disease Epidemiology, London School of Hygiene and Tropical Medicine, London, UK
| | - R C Harris
- From the, TB Modelling Group, Department of Infectious Disease Epidemiology, London School of Hygiene and Tropical Medicine, London, UK
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