Efficacy, Safety and Immunogenicity Evaluation of MTBVAC in Newborns in Sub-Saharan Africa

Официальное название

Randomised, Double-Blind, Controlled Phase 3 Trial to Evaluate the Efficacy, Safety and Immunogenicity of MTBVAC in Healthy HIV Unexposed (HU) and HIV Exposed Uninfected (HEU) Newborns in Tuberculosis-Endemic Regions of Sub-Saharan Africa

Обзор

The objective of this project is to demonstrate safety, immunogenicity and improved efficacy of the new live attenuated M. tuberculosis vaccine called MTBVAC in a Phase 3 efficacy trial in HIV-uninfected infants born to HIV-infected and HIV-uninfected mothers as compared to standard of care BCG vaccination. The proposal builds upon a group of TB vaccine development partners in Europe and sub-Saharan Africa established in a previous EDCTP-supported project. It creates an expanded consortium of clinical trial partners for the optimal implementation of a large infant efficacy trial of MTBVAC in high TB incidence settings. New capacity for efficacy trials in infants will be a valuable resource for the TB vaccine development community. The proposal will create a network of institutions in three TB endemic African countries with enhanced laboratory capacity to conduct TB vaccine immunology studies and to bio-bank samples to discover immune correlates of vaccine-mediated protection.

Подробное описание

A new effective tuberculosis (TB) vaccine is essential to achieve World Health Organization End TB goals and eliminate TB by 2050. The optimal long-term strategy would be a combination of serial mass campaigns in adults, coupled with universal newborn vaccination. Newborns are the only human population without prior mycobacterial exposure in TB endemic countries and we hypothesize that live attenuated mycobacterial vaccines will offer better protection to this naïve population compared to adults.

The objective of this project is to demonstrate safety, immunogenicity and improved efficacy of the new live attenuated M. tuberculosis vaccine called MTBVAC in a Phase 3 efficacy trial in HIV-uninfected infants born to HIV-infected and HIV-uninfected mothers as compared to standard of care BCG vaccination. The proposal builds upon a group of TB vaccine development partners in Europe and sub-Saharan Africa established in a previous EDCTP-supported project. It creates an expanded consortium of clinical trial partners for the optimal implementation of a large infant efficacy trial of MTBVAC in high TB incidence settings. New capacity for efficacy trials in infants will be a valuable resource for the TB vaccine development community. The proposal will create a network of institutions in three TB endemic African countries with enhanced laboratory capacity to conduct TB vaccine immunology studies and to bio-bank samples to discover immune correlates of vaccine-mediated protection.

MTBVAC is a novel TB vaccine candidate based on an attenuated M. tuberculosis clinical isolate of the Euro-American lineage. Attenuation is based on two independent, stable genetic deletions of the genes phoP and fadD26 coding for two major virulence factors, the transcription factor PhoP and the cell-wall lipids PDIM, respectively. The hypothesis is that MTBVAC will provide improved protection, as individuals latently infected with live M.tuberculosis have an 80% lower chance of developing TB, and as MTBVAC contains most of the genes deleted from BCG and presents a wider collection of antigens to the host immune system. Preclinical studies in different animal models indicated that MTBVAC is safe and is able to induce an improved protection compared to BCG.

Phase 1 studies showed that MTBVAC was safe and immunogenic in naïve adults and newborns, and evoked an immune response that exceeded the magnitude of BCG-induced immune responses. Larger dose-defining Phase 2a studies in newborns and in adults at extended dose-ranges to confirm these findings will be finalised in early 2021, and allow selection of a vaccine dose to progress into the proposed multi-centre efficacy trial in infants.

Вмешательства

• Биопрепарат MTBVAC
  MTBVAC is a novel TB vaccine candidate based on an attenuated M. tuberculosis clinical isolate of the Euro-American lineage. Attenuation is based on two independent, stable genetic deletions of the genes phoP and fadD26 coding for two major virulence factors, the transcription factor PhoP and the cell-wall lipids PDIM, respectively. We hypothesize that MTBVAC will provide improved protection, as individuals latently infected with live M.tuberculosis have an 80% lower chance of developing TB, and
• Биопрепарат BCG
  BCG is a live attenuated M. bovis strain developed 100 years ago and is used as a preventive vaccine against tuberculosis. It is administered at birth.

Первичные конечные точки

• To demonstrate efficacy in terms of incidence of MTBVAC against TB disease in healthy HU and HEU newborns compared to BCG [Срок оценки: Minimum of 24 months to a maximum 80 months; or until study end in South Africa.]

Вторичные конечные точки (1)

• To assess the safety and reactogenicity of MTBVAC in healthy HU and HEU newborns compared to BCG. [Срок оценки: Minimum of 24 months to a maximum 80 months; or until study end in South Africa.]

Критерии участия

Критерии включения

• Male or female newborns within seven days of birth.
• Written informed maternal consent, including permission to access maternal antenatal, postnatal, and infant medical records.
• Infant participants and their caregivers available for trial follow-up and display the willingness and capacity to comply with trial procedures.
• Newborns must be in good general health during pregnancy and delivery, as assessed by medical history and targeted physical examination.
• Birth weight ≥ 2450 grams.
• Apgar score at 5 minutes ≥ 7.
• A maternal HIV test result (rapid test, enzyme-linked immunosorbent assay (ELISA), or Polymerase chain reaction (PCR)) taken within 30 days of delivery, or within seven days post-partum must be available and documented if HIV uninfected. If the mother is HIV infected, then she must be on antiretroviral (ARV) therapy as per in-country guidelines with a viral load of <50 copies/mL (within six months of labour).
• Estimated gestational age ≥ 37 weeks.
• Mother has not participated in a clinical trial within three months prior to the infant's birth.
• Mother has never participated in a TB vaccine trial before.
• Infant may not participate in any other clinical trials.

Критерии исключения

Receipt of BCG vaccination prior to enrolment.

• Significant antenatal, intrapartum, or postpartum complications that may affect the health of the newborn.
• Skin condition, bruising or birth mark at the intended injection site.
• Maternal HIV test (rapid test, ELISA, or PCR) result not available.
• HIV exposed Newborn's HIV PCR result positive or not available.
• Maternal history of TB during pregnancy.
• History of close/household contact with a TB patient, antenatal or postnatal, whether maternal, other family member or another household member who has not yet completed TB treatment.
• Clinically suspected neonatal sepsis.
• Any severe congenital malformation.
• History or evidence of any systemic disease on examination, or any illness that in the opinion of the Investigator may interfere with the evaluation of the safety and immunogenicity of the vaccine. Neonatal jaundice not considered clinically significant is not an exclusion.

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Да

Дизайн исследования

Распределение

Рандомизированное

Модель

Параллельные группы

Маскирование

Четверное слепое

Основная цель

Профилактика

Центры проведения

ЮАР · 1 центр

• South African Tuberculosis Initiative, Brewelskloof Hospital — Worcester

Публикации

• Tameris M, Mearns H, Penn-Nicholson A, Gregg Y, Bilek N, Mabwe S, Geldenhuys H, Shenje J, Luabeya AKK, Murillo I, Doce J, Aguilo N, Marinova D, Puentes E, Rodriguez E, Gonzalo-Asensio J, Fritzell B, Thole J, Martin C, Scriba TJ, Hatherill M; MTBVAC Clinical Trial Team. Live-attenuated Mycobacterium tuberculosis vaccine MTBVAC versus BCG in adults and neonates: a randomised controlled, double-blind PMID 31416768
• Spertini F, Audran R, Chakour R, Karoui O, Steiner-Monard V, Thierry AC, Mayor CE, Rettby N, Jaton K, Vallotton L, Lazor-Blanchet C, Doce J, Puentes E, Marinova D, Aguilo N, Martin C. Safety of human immunisation with a live-attenuated Mycobacterium tuberculosis vaccine: a randomised, double-blind, controlled phase I trial. Lancet Respir Med. 2015 Dec;3(12):953-62. doi: 10.1016/S2213-2600(15)00435 PMID 26598141
• Arbues A, Aguilo JI, Gonzalo-Asensio J, Marinova D, Uranga S, Puentes E, Fernandez C, Parra A, Cardona PJ, Vilaplana C, Ausina V, Williams A, Clark S, Malaga W, Guilhot C, Gicquel B, Martin C. Construction, characterization and preclinical evaluation of MTBVAC, the first live-attenuated M. tuberculosis-based vaccine to enter clinical trials. Vaccine. 2013 Oct 1;31(42):4867-73. doi: 10.1016/j.vacci PMID 23965219
• Aguilo N, Gonzalo-Asensio J, Alvarez-Arguedas S, Marinova D, Gomez AB, Uranga S, Spallek R, Singh M, Audran R, Spertini F, Martin C. Reactogenicity to major tuberculosis antigens absent in BCG is linked to improved protection against Mycobacterium tuberculosis. Nat Commun. 2017 Jul 14;8:16085. doi: 10.1038/ncomms16085. PMID 28706226
• Andrews JR, Noubary F, Walensky RP, Cerda R, Losina E, Horsburgh CR. Risk of progression to active tuberculosis following reinfection with Mycobacterium tuberculosis. Clin Infect Dis. 2012 Mar;54(6):784-91. doi: 10.1093/cid/cir951. Epub 2012 Jan 19. PMID 22267721
• Camacho LR, Ensergueix D, Perez E, Gicquel B, Guilhot C. Identification of a virulence gene cluster of Mycobacterium tuberculosis by signature-tagged transposon mutagenesis. Mol Microbiol. 1999 Oct;34(2):257-67. doi: 10.1046/j.1365-2958.1999.01593.x. PMID 10564470
• Copin R, Coscolla M, Efstathiadis E, Gagneux S, Ernst JD. Impact of in vitro evolution on antigenic diversity of Mycobacterium bovis bacillus Calmette-Guerin (BCG). Vaccine. 2014 Oct 14;32(45):5998-6004. doi: 10.1016/j.vaccine.2014.07.113. Epub 2014 Sep 6. PMID 25211768
• Gonzalo-Asensio J, Marinova D, Martin C, Aguilo N. MTBVAC: Attenuating the Human Pathogen of Tuberculosis (TB) Toward a Promising Vaccine against the TB Epidemic. Front Immunol. 2017 Dec 15;8:1803. doi: 10.3389/fimmu.2017.01803. eCollection 2017. PMID 29326700

Идентификаторы

NCT: NCT04975178 · MTBVACN3

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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