Bedaquiline Fumarate

结核病（TB）是全球重要公共卫生问题，每年导致大量死亡和新增病例。卡介苗（BCG）是目前唯一获批的 TB 疫苗，但在预防成人肺结核和潜伏感染方面效果有限，因此研发新疫苗和治疗药物迫在眉睫。 1、结核疫苗抗原选择 MTB 抗原多样，包括细胞壁和荚膜抗原、分泌抗原等多种类型。生物信息学和人工智能助力筛选潜在抗原，如 EsxA、EsxB 等关键抗原在免疫反应和疫苗设计中作用重大，相关研究为疫苗开发奠定基础。 2、临床前和临床试验中的结核疫苗 临床前候选疫苗：减毒活疫苗（如 MTBΔsigH、MTBΔlpqS 等）、病毒载体疫苗（如 LV::li-HAEPA、SeV85AB 等）、重组 BCG 疫苗（如 rBCG::XB、BCG::ESX-1Mmar 等）、亚单位疫苗（如 CysVac2/Advax、LT70 等）、DNA 疫苗（如 DNA-hsp65）和 mRNA 疫苗（如 repRNA-ID91）等在动物模型中展现出一定的免疫原性和保护效果，为后续临床试验提供了依据。 临床试验中的疫苗：涵盖灭活疫苗（如 MIP、SRL172 等）、减毒活疫苗（如 MTBVAC、BCG 复种）、重组 BCG 疫苗（如 VPM1002）、亚单位疫苗（如 M72/AS01E、GamTBvac 等）、病毒载体疫苗（如 MVA85A、ChAdOx1.85A 等）和 mRNA 疫苗（如 BNT164a1、BNT164b1）等多种类型。不同疫苗在安全性、免疫原性和疗效方面各有特点，部分已取得积极进展。 3、结核治疗药物研发 一线抗结核药物用于治疗敏感结核病，二线药物用于治疗耐药结核病，如贝达喹啉（BDQ）、德拉马尼（DLM）等。宿主导向疗法（HDT）通过调节宿主免疫反应来辅助治疗，是新兴的治疗途径，但目前仍面临一些挑战。 4、面临的挑战与未来方向 挑战：TB 疫苗和药物研发面临抗原多样性、免疫逃逸、不同人群疫苗疗效差异、新型疫苗平台和递送系统的优化以及成本和可及性等问题，同时还需应对耐药菌的挑战。 未来方向：通过组合策略提高疗效，开发针对 MTB 新途径的化合物，改进 HDT 辅助治疗，推进个性化医疗，并加强国际合作，以加速 TB 疫苗和药物的研发与应用。

New Delhi: For more than a century, the onus of combating TB has relied upon the 20th-century breakthrough called the BCG vaccine (Bacillus Calmette–Guérin), which helps activate the immune response against the disease-causing bacterium Mycobacterium tuberculosis (Mtb). The data speaks for the effectiveness of the vaccine, which made it an integral part of various global and individual government efforts that helped save around 79 million lives (since 2000) from the deadliest infectious disease . However, being administered at birth under various elimination programs, including in India since 1985, the Global TB report 's revelation of the disease shifting burden among adults, increasing drug resistance, and a temporary blip due to the pandemic—which reversed the long-maintained downward curve both in terms of incidence rate—points to the limits in the conventional safety net and further reflects the ample scope for exploring and introducing newer innovations. Source: Global TB report 2024, WHO Moreover, as per the WHO, the existing “neonatal BCG vaccination offers partial protection for infants and young children against severe forms of TB, but it does not protect adolescents and adults, who account for the majority of TB transmission. Vaccines also offer the best chance to contain the accelerating spread of multi-drug resistant tuberculosis.” “The entire mycobacterium used in BCG is one that is related to Mycobacterium tuberculosis, but not the same. It is missing about 170 genes that Mycobacterium tuberculosis has, and this is possibly why the immunity offered tends to be very limited,” Dr Lancelot Pinto, Consultant Pulmonologist and Epidemiologist, P. D. Hinduja Hospital & Medical Research Centre, told ET Pharma. Nevertheless, beneath this cloudy landscape, there are rising signs of hope to combat the disease through a handful of new vaccines. As per the GlobalData drug pipeline database, currently, there are 15 prophylactic vaccines under different clinical development stages. Of these 15 under-trial candidates, three innovations— MTBVAC , M72/AS01E , and VPM1002—are in the Phase 3 clinical trial phase, while one candidate, GC-3107A, developed by GC Biopharma, is in the pre-registration phase, which initiates the regulatory review required for market roll-out of a product. Source: GlobalData pipeline products database Unlike the other versions, GC-3107A is a therapeutic vaccine indicated for latent or active TB patients. Among the three late-stage frontrunners, MTBVAC (Mycobacterium Tuberculosis [Live Attenuated] Vaccine) is developed by the University of Zaragoza, whose industrial partner, BioFabri—a Spanish biotech firm—overtook the clinical development in partnership with India’s Bharat Biotech. The candidate is stated to be developed from a genetically modified form of the pathogen isolated from the disease bacterium and, as per the partners, unlike BCG, it contains all the antigens present in strains that infect humans. Currently, the vaccine is being tested on over 7,000 infants in South Africa, Senegal, and Madagascar, with the BCG control arm. The second candidate, M72/AS01E, was initially developed by MNC giant GlaxoSmithKline or GSK, with the final phase of clinical development led by the Gates Medical Research Institute , supported by the Gates Foundation, and Wellcome (a healthcare charitable trust). M72/AS01E is a two-dose regimen version developed from two Mtb antigens—MTB32A and MTB39A—and in March 2024, the partners announced the initiation of Phase 3 trials in South Africa to assess the efficacy of the vaccine. Later, the candidate was also introduced at trial sites in Indonesia, Kenya, Malawi, and Zambia, with a total cohort size of 20,000. The Phase 3 trials for both of the aforementioned candidates are expected to conclude by August 2029. Lastly, VPM-1002 is an innovation from Serum Institute of India, developed by Serum Institute of India (SII), as a potential replacement for the standard BCG vaccine, aiming for improved safety and efficacy in preventing tuberculosis (TB). The candidate is in the Phase 3 trial phase, being tested in a multisite, randomized, double-blinded, placebo-controlled Phase III clinical trial among 6,940 newborn infants from Gabon, Kenya, South Africa, Tanzania, and Uganda, with the BCG control arm. The trial is supported by India’s Department of Biotechnology’s National Biopharma Mission. Several attempts by ET Pharma to obtain additional information from the Serum Institute did not elicit any response. As per the government department, the objective of this trial is to evaluate the ability of VPM-1002 to reduce infection incidence and severe disease outcomes of COVID-19 among high-risk persons of advanced age or comorbidities and high-exposure healthcare workers (HCWs). According to the WHO TB research tracker, the vaccine's Phase 3 trials are expected to conclude by October 2025. Dissecting the targeting mechanism of these under-trial candidates with the existing option, Dr. Pinto told ET Pharma, “The BCG vaccine has been shown to be effective against severe forms of TB in childhood, but its effectiveness beyond this has not been proven, and this possibly explains why, despite having a universal BCG vaccination at birth since 1985, India has not been able to eradicate the disease.” Dr. Pinto explained that the newer vaccines attempt to improve BCG in different ways: MTBVAC is live and attenuated but uses Mtb (and not bovis), with genetic modifications that render them safe. Meanwhile, VPM-1002 uses a recombinant BCG strain and has enhanced immunogenicity because of the expression of Listeriolysin-O, which allows the antigens to enter the cells and stimulate a stronger T-cell response. As per the expert, the pre-registration candidate GC-3107A of GC Biopharma has a similar mechanism as in the case of MTBVAC. Commenting on the best potential candidate to deal with the rising prevalence of TB among adults, Dr. Pinto said, “M72/AS01E is possibly one of the most promising vaccines, as the Phase 2b vaccine trial recruited adults aged 18 to 50 years with M.TB infection, and was found to be 49.7 percent efficacious at preventing TB in the 3-year follow-up period with two doses.” This demographic is possibly the most prevalent presently, and protecting them would be the most important priority in reducing the prevalence of the disease. This vaccine is also closest to completing its Phase 3 trials and is therefore likely to be the most relevant presently, he added. In contrast to this, Anaelle Tannen, Infectious Disease Analyst at GlobalData, expects BioFabri’s MTBVAC will provide an alternative way to treat the disease and has been shown to be safe and effective thus far in clinical trials. Notably, the GSK candidate has also received endorsement from the WHO, and the UN subsidy has said that the vaccine results (Phase 2b trial) are “unprecedented in decades of TB vaccine research” in terms of clinical significance and strength of evidence, and constitute an important scientific breakthrough.” Moreover, the body has also urged the “tuberculosis vaccine community to discuss future development options for this vaccine candidate.” Sharing a WHO estimate, Alexander Schmidt, Interim Head of Development and Chief Medical Officer, Gates Medical Research Institute, told ET Pharma that, “Their vaccine could save 8.5 million lives, prevent 76 million new TB cases, and save $41.5 billion for TB-affected households.” Commenting on the post-trial plans, including possible regional launches, Schmidt replied that, “We are working with our trial partners, as well as multilateral, regional, and country partners, to understand the potential demand for the vaccine so that we can build an end-to-end plan to ensure long-term sustainable access in communities of high disease burden, should the trial be successful.” For India, both the TB incidence rate and mortality count have been on the downturn, but considering the changing demographic profile of TB, the policymakers are exploring options like “BCG revaccination in adults,” and in January 2024, the Ministry of Health and Family Welfare, in collaboration with the Indian Council of Medical Research (ICMR), launched the "Adult BCG Vaccination Study" to explore the vaccine's effectiveness among high-risk individuals. Last year, Bharat Biotech announced its plans to test its candidate MTBVAC among Indian adults, and a company release states that the trials “are planned to start in 2025 to evaluate the safety and immunogenicity of MTBVAC among adults in India.” Making the announcement, Dr. Krishna Ella, Executive Chairman, Bharat Biotech, had said that, “Our goal to develop TB vaccines to prevent disease in adults and adolescents has taken a big step today. We are honoured to partner with BioFabri in this noble effort to reinvent TB vaccines.” As per the latest available update, in October 2024, the Indian drug regulator, CDSCO, asked the Hyderabad-based vaccine player to share its trial protocols. Over the inclusion of other under-trial candidates under India’s Universal Immunisation Program or as a booster dose option among already vaccinated individuals, Dr. Pinto suggested analysing the cost-effectiveness of each candidate. One of the Phase 3 candidates, M72/AS01E, if cleared by the regulatory review, is estimated to be priced at around $2.5 (around ₹214) per dose and is a double-dose regimen, whereas the available single-shot BCG brands, such as one from SII, are priced at around ₹60 for a 40 ml vial. A study comparing the financial cost of M72/AS01E with BCG found that initiating BCG revaccination in India could incur an average annual cost of around $23 million, whereas the M72/AS01E vaccine is projected to cost around $190 million per year. The emergence of multi-drug resistant (MDR) and extensively drug-resistant (XDR) strains has made the challenging TB terrain more bumpy, and compounding this, Dr. Pinto expects “Mtb strains are likely to become resistant to newer drugs such as Bedaquiline and Delamanid (the current line of treatment) as their use increases, and unless the new drug pipeline matches such resistance, we are likely to face serious challenges with treating the disease in the future.” However, as of now, the under-trial vaccines are viewed as the best option to safeguard the population from a preventable challenge. Medical innovation takes years to reach fruition and requires a heavy purse to sustain and survive that period, but with bipartisan consensus, the world has made significant strides towards the elimination of a condition where the fate of around. By Abhijeet Singh ,