Safety and immunogenicity of VPM1002 versus BCG in South African newborn babies: a randomised, phase 2 non-inferiority double-blind controlled trial

Cotton, Mark F.; Madhi, Shabir А.; Luabeya, Angelique; Tameris, Michèle; Hesseling, Anneke C.; Shenje, Justin; Schoeman, Elisma; Hatherill, Mark; Desai, Sajjad; Kapse, Dhananjay; Brückner, Sina; Koen, Anthonet; Jose, Lisa; Moultrie, Andrew; Bhikha, Sutika; Walzl, Gerhard; Gutschmidt, Andrea; Kotze, Leigh A.; Allies, Devon; Loxton, André G.; Shaligram, Umesh; Abraham, M. Roselle; Johnstone, Hilary; Grode, Leander; Kaufmann, Stefan H. E.; Kulkarni, Prasad S.

doi:10.1016/s1473-3099(22)00222-5

Cited by 40 publications

(31 citation statements)

References 26 publications

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“…As a “pre- and post-infection” vaccine, the adolescent/adult vaccine was assumed to be equally effective regardless of previous infection status, which may have led to an overestimation of averted TB cases and deaths if the vaccine is less effective in infected vaccinees. We also restricted the analysis to focus on vaccine products that would prevent development of TB disease, and did not examine the possible impact of vaccine products that would prevent infection, such as recombinant BCG vaccines [44]. If successfully developed, such vaccines could provide another effective tool for accelerating TB control.…”

Section: Discussionmentioning

confidence: 99%

The cost and cost-effectiveness of novel tuberculosis vaccines in low- and middle-income countries: a modelling study

Portnoy¹,

Clark

Quaife

et al. 2022

Preprint

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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: 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. 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 1x per-capita GDP cost-effectiveness threshold (both varied in sensitivity analyses). Findings: Vaccine introduction was estimated to require substantial near-term resources, offset by future cost-savings from averted TB burden. From a health system perspective, vaccination was cost-effective in 65 of 105 LMICs. From a societal perspective (including productivity gains and averted patient costs), vaccination was projected to be cost-effective in 75 of 105 LMICs and cost-saving in 57 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 $258-447 billion in economic benefits by 2050. Interpretation: TB vaccination would be highly impactful and cost-effective in most LMICs.

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Section: Discussionmentioning

confidence: 99%

The cost and cost-effectiveness of novel tuberculosis vaccines in low- and middle-income countries: a modelling study

Portnoy¹,

Clark

Quaife

et al. 2022

Preprint

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“…In a phase 2 clinical trial performed in South African newborn babies, VPM1002 was found to be better tolerated than BCG regarding side effects. These included 15-fold less grade 3–4 vaccine-related adverse reactions or lymphadenopathy of 10 mm or greater in diameter, 3-fold less scarring, and 10-fold less abscess formation in those who received VPM1002 compared with the BCG-administered group; however, ex vivo immune responses were higher in the group that received the BCG vaccine [ 10 ]. Whether reduced ex vivo immunogenicity is linked to a reduced protective efficacy of VPM1002 remains to be determined.…”

Section: Introductionmentioning

confidence: 99%

Recent Developments in Mycobacteria-Based Live Attenuated Vaccine Candidates for Tuberculosis

2022

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Vaccination is an excellent approach to stimulating the host immune response and reducing human morbidity and mortality against microbial infections, such as tuberculosis (TB). Bacillus Calmette–Guerin (BCG) is the most widely administered vaccine in the world and the only vaccine approved by the World Health Organization (WHO) to protect against TB. Although BCG confers “protective” immunity in children against the progression of Mycobacterium tuberculosis (Mtb) infection into active TB, this vaccine is ineffective in protecting adults with active TB manifestations, such as multiple-, extensive-, and total-drug-resistant (MDR/XDR/TDR) cases and the co-existence of TB with immune-compromising health conditions, such as HIV infection or diabetes. Moreover, BCG can cause disease in individuals with HIV infection or other immune compromises. Due to these limitations of BCG, novel strategies are urgently needed to improve global TB control measures. Since live vaccines elicit a broader immune response and do not require an adjuvant, developing recombinant BCG (rBCG) vaccine candidates have received significant attention as a potential replacement for the currently approved BCG vaccine for TB prevention. In this report, we aim to present the latest findings and outstanding questions that we consider worth investigating regarding novel mycobacteria-based live attenuated TB vaccine candidates. We also specifically discuss the important features of two key animal models, mice and rabbits, that are relevant to TB vaccine testing. Our review emphasizes that the development of vaccines that block the reactivation of latent Mtb infection (LTBI) into active TB would have a significant impact in reducing the spread and transmission of Mtb. The results and ideas discussed here are only based on reports from the last five years to keep the focus on recent developments.

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“…The better protection and safety of VPM1002 compared to BCG were revealed in challenge experiments in mice [ 28 , 34 , 35 , 36 ]. Phase I and phase II vaccine trials in humans have shown an improved safety profile for VPM1002 compared to BCG [ 37 , 38 , 39 ]. The VPM1002 derivative BCG Δ ureC::hly Δ pdx1 (PDX) has an additional deletion which results in auxotrophy for vitamin B6 and further increases the safety in immunocompromised hosts [ 40 ].…”

Section: Introductionmentioning

confidence: 99%

Vaccine-Induced Subcutaneous Granulomas in Goats Reflect Differences in Host–Mycobacterium Interactions between BCG- and Recombinant BCG-Derivative Vaccines

Liebler-Tenorio

Heyl

Wedlich

et al. 2022

IJMS

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Tuberculous granulomas are highly dynamic structures reflecting the complex host–mycobacterium interactions. The objective of this study was to compare granuloma development at the site of vaccination with BCG and its recombinant derivatives in goats. To characterize the host response, epithelioid cells, multinucleated giant cells (MNGC), T cell subsets, B cells, plasma cells, dendritic cells and mycobacterial antigen were labelled by immunohistochemistry, and lipids and acid-fast bacteria (AFB) were labelled by specific staining. Granulomas with central caseous necrosis developed at the injection site of most goats though lesion size and extent of necrosis differed between vaccine strains. CD4+ T and B cells were more scarce and CD8+ cells were more numerous in granulomas induced by recombinant derivatives compared to their parental BCG strain. Further, the numbers of MNGCs and cells with lipid bodies were markedly lower in groups administered with recombinant BCG strains. Microscopic detection of AFB and mycobacterial antigen was rather frequent in the area of central necrosis, however, the isolation of bacteria in culture was rarely successful. In summary, BCG and its recombinant derivatives induced reproducibly subcutaneous caseous granulomas in goats that can be easily monitored and surgically removed for further studies. The granulomas reflected the genetic modifications of the recombinant BCG-derivatives and are therefore suitable models to compare reactions to different mycobacteria or TB vaccines.

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Safety and immunogenicity of VPM1002 versus BCG in South African newborn babies: a randomised, phase 2 non-inferiority double-blind controlled trial

Cited by 40 publications

References 26 publications

The cost and cost-effectiveness of novel tuberculosis vaccines in low- and middle-income countries: a modelling study

The cost and cost-effectiveness of novel tuberculosis vaccines in low- and middle-income countries: a modelling study

Recent Developments in Mycobacteria-Based Live Attenuated Vaccine Candidates for Tuberculosis

Vaccine-Induced Subcutaneous Granulomas in Goats Reflect Differences in Host–Mycobacterium Interactions between BCG- and Recombinant BCG-Derivative Vaccines

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