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PRINCETON, N.J.--( BUSINESS WIRE )-- Bristol Myers Squibb (NYSE: BMY) today announced the presentation of data across its cardiovascular portfolio at the American Heart Association (AHA) Annual Scientific Sessions, taking place November 16-18, 2024, in Chicago, Illinois. New analyses include updated results from the nearly two-year post-launch evaluation of the CAMZYOS ® (mavacamten) Risk Evaluation and Mitigation Strategy (REMS) Program and real-world and long-term extension data reinforcing the efficacy and safety profile of CAMZYOS, as well as data on behalf of the BMS-Pfizer Alliance on ELIQUIS ® (apixaban) and the BMS-Johnson & Johnson Collaboration on milvexian. “We look forward to AHA where we will share data that build on our 70-year legacy of pioneering cardiovascular research and delivering paradigm-changing medicines to address the growing burden of cardiovascular disease,” said Roland Chen, MD , senior vice president and head of Immunology, Cardiovascular & Neuroscience (ICN) Development at Bristol Myers Squibb. “Data to be presented at the meeting highlight our commitment to improving clinical outcomes for patients around the world by delivering transformational therapies, like CAMZYOS, the first and only approved cardiac myosin inhibitor.” With inclusion in both the ESC and AHA/ACC clinical guidelines as a recommended option for when symptoms persist after first-line therapy, CAMZYOS is a standard of care for NYHA class II-III symptomatic obstructive hypertrophic cardiomyopathy (oHCM). Research to be presented at the meeting supports the growing body of evidence of CAMZYOS, including compliance with the REMS Program. These data include: An updated analysis of results from the post-launch evaluation of the CAMZYOS REMS Program spanning nearly 2-years (22-months). A featured science presentation of the 128-week analysis (nearly 2.5 years) of the VALOR-HCM long-term study analyzing the efficacy and safety profile of CAMZYOS in reducing patient eligibility and/or decision to proceed with septal reduction therapy (SRT) in patients with symptomatic oHCM. New real-world evidence on CAMZYOS’ long-term effectiveness and safety profile, including data from MARVEL-HCM—the largest observational study on CAMZYOS’ effectiveness—and from COLLIGO-HCM, a real-world study examining racially diverse patients and those with higher disease burden than typically seen in clinical trials. Abstracts sponsored by Bristol Myers Squibb, the BMS-Pfizer Alliance and the BMS-Johnson & Johnson Collaboration to be presented at AHA Scientific Sessions 2024 can be found below. Complete abstracts may be accessed online here . Visit this page on BMS.com for more information on Bristol Myers Squibb’s scientific approach and resources on cardiovascular diseases. Abstract Title Primary Author Type Session Title Date/Time (CST) CAMZYOS (mavacamten) Investigating the natural history and risk factors underlying deterioration in early-stage hypertrophic cardiomyopathy: Findings from SOLENOID Bradlow, W. Moderated Poster Bulking Up: The Latest in Hypertrophic Cardiomyopathy Saturday, Nov. 16, 3:10 PM – 3:15 PM Beta blockers and calcium channel blockers in asymptomatic patients with hypertrophic cardiomyopathy: Prevalence, discontinuation, and effectiveness Bradlow, W. Moderated Poster Data to Discovery: Novel Methods in Cardiovascular Outcomes Research Saturday, Nov. 16, 3:50 PM – 3:55 PM Identification of obstructive and non-obstructive hypertrophic cardiomyopathy patients using natural language processing in a large integrated healthcare system Solomon, M. Moderated Poster Advances in Identification and Management of Hypertrophic Cardiomyopathy – MDP964 Sunday, Nov. 17, 9:30 AM – 9:35 AM Real-world treatment patterns of mavacamten and associated background therapies in patients with obstructive hypertrophic cardiomyopathy (HCM) in the United States Han, X. Traditional Poster Emerging Interventions for Heart Failure – Su2191 Sunday, Nov. 17, 3:15 PM – 4:15 PM Mavacamten: Real-world experience from 22 months of the Risk Evaluation and Mitigation Strategy (REMS) Program Desai, M. Oral Presentation From Bench to Bedside in Heart Failure Monday, Nov. 18, 9:00 AM – 9:10 AM Mavacamten treatment in patients with obstructive HCM referred for septal reduction therapy: 128-week results from VALOR-HCM trial Desai, M. Oral Featured Science Presentation Featured Science: Amyloid, Hypertrophic, and Danon Cardiomyopathies: Targeted Therapies and Specific Populations Monday, Nov. 18, 9:57 AM – 10:05 AM Long-term effectiveness and safety of mavacamten in a real-world, multi-center, global study: Preliminary results of COLLIGO-HCM from a diverse cohort in the United States MacNamara, J. Moderated Poster Hypertrophy and Heart Failure – MDP1368 Monday, Nov. 18, 11:50 AM – 11:55 AM Early insights on mavacamten usage in Canada: A retrospective cohort of the patient support program Ong, K. Moderated Poster Hypertrophy and Heart Failure – MDP1369 Monday, Nov. 18, 12:00 PM – 12:05 PM Real-world long-term effectiveness of mavacamten in patients with symptomatic obstructive hypertrophic cardiomyopathy: A multicenter observational study (MARVEL-HCM) Abraham, T. Moderated Poster Hypertrophy and Heart Failure – MDP1370 Monday, Nov. 18, 12:10 PM – 12:15 PM Integrated safety and tolerability of mavacamten treatment over 5 years in patients with obstructive hypertrophic cardiomyopathy Owens, A. Moderated Poster Hypertrophy and Heart Failure – MDP1371 Monday, Nov. 18, 12:20 PM – 12:25 PM Mavacamten in adolescent patients with symptomatic obstructive hypertrophic cardiomyopathy: Design of the Phase 3 SCOUT-HCM trial Rossano, J. Traditional Poster Pediatric Heart Failure, Transplantation, and Long-Term Outcomes – Mo2025 Monday, Nov. 18, 1:30 PM – 2:30 PM ELIQUIS (apixaban) – Sponsored by the Bristol Myers Squibb-Pfizer Alliance Understanding medication adherence to oral anticoagulants in atrial fibrillation management: Patient and provider perspectives in a mixed methods study Wendt, S. Moderated Poster Data to Discovery: Novel Methods in Cardiovascular Outcomes Research Monday, Nov. 18, 10:30 AM – 11:30 AM Milvexian – Sponsored by the Bristol Myers Squibb-Johnson & Johnson Collaboration Current oral anticoagulation use among patients with atrial fibrillation and risk factors associated with inadequate treatments: A report from a UK population cohort study Kang, A. Poster presentation Medications in Motion: Innovating Pharmacotherapy for Enhanced Treatment Outcomes Monday, Nov. 18, 1:30 PM – 2:30 PM About CAMZYOS ® (mavacamten) CAMZYOS ® (mavacamten) is the first and only cardiac myosin inhibitor approved in the U.S., indicated for the treatment of adults with symptomatic New York Heart Association (NYHA) class II-III obstructive hypertrophic cardiomyopathy (HCM) to improve functional capacity and symptoms, and in the European Union, indicated for the treatment of symptomatic (NYHA, class II-III) obstructive HCM in adult patients. It has also received regulatory approvals in countries and regions across five continents. CAMZYOS is an allosteric and reversible inhibitor selective for cardiac myosin. CAMZYOS modulates the number of myosin heads that can enter “on actin” (power-generating) states, thus reducing the probability of force-producing (systolic) and residual (diastolic) cross-bridge formation. Excess myosin actin cross-bridge formation and dysregulation of the super-relaxed state are mechanistic hallmarks of HCM. CAMZYOS shifts the overall myosin population towards an energy-sparing, recruitable, super-relaxed state. In HCM patients, myosin inhibition with CAMZYOS reduces dynamic left ventricular outflow tract (LVOT) obstruction and improves cardiac filling pressures. IMPORTANT SAFETY INFORMATION WARNING: RISK OF HEART FAILURE CAMZYOS reduces left ventricular ejection fraction (LVEF) and can cause heart failure due to systolic dysfunction. Echocardiogram assessments of LVEF are required prior to and during treatment with CAMZYOS. Initiation of CAMZYOS in patients with LVEF <55% is not recommended. Interrupt CAMZYOS if LVEF is <50% at any visit or if the patient experiences heart failure symptoms or worsening clinical status. Concomitant use of CAMZYOS with certain cytochrome P450 inhibitors or discontinuation of certain cytochrome P450 inducers may increase the risk of heart failure due to systolic dysfunction; therefore, the use of CAMZYOS is contraindicated with the following: Moderate to strong CYP2C19 inhibitors or strong CYP3A4 inhibitors Moderate to strong CYP2C19 inducers or moderate to strong CYP3A4 inducers Because of the risk of heart failure due to systolic dysfunction, CAMZYOS is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the CAMZYOS REMS PROGRAM. CONTRAINDICATIONS CAMZYOS is contraindicated with concomitant use of: Moderate to strong CYP2C19 inhibitors or strong CYP3A4 inhibitors Moderate to strong CYP2C19 inducers or moderate to strong CYP3A4 inducers WARNINGS AND PRECAUTIONS Heart Failure CAMZYOS reduces systolic contraction and can cause heart failure or totally block ventricular function. Patients who experience a serious intercurrent illness (e.g., serious infection) or arrhythmia (e.g., atrial fibrillation or other uncontrolled tachyarrhythmia) are at greater risk of developing systolic dysfunction and heart failure. Assess the patient’s clinical status and LVEF prior to and regularly during treatment and adjust the CAMZYOS dose accordingly. New or worsening arrhythmia, dyspnea, chest pain, fatigue, palpitations, leg edema, or elevations in N-terminal pro-B-type natriuretic peptide (NT-proBNP) may be signs and symptoms of heart failure and should also prompt an evaluation of cardiac function. Asymptomatic LVEF reduction, intercurrent illnesses, and arrhythmias require additional dosing considerations. Initiation of CAMZYOS in patients with LVEF <55% is not recommended. Avoid concomitant use of CAMZYOS in patients on disopyramide, ranolazine, verapamil with a beta blocker, or diltiazem with a beta blocker as these medications and combinations increase the risk of left ventricular systolic dysfunction and heart failure symptoms and clinical experience is limited. CYP 450 Drug Interactions Leading to Heart Failure or Loss of Effectiveness CAMZYOS is primarily metabolized by CYP2C19 and CYP3A4 enzymes. Concomitant use of CAMZYOS and drugs that interact with these enzymes may lead to life-threatening drug interactions such as heart failure or loss of effectiveness. Advise patients of the potential for drug interactions, including with over-the-counter medications (such as omeprazole, esomeprazole, or cimetidine). Advise patients to inform their healthcare provider of all concomitant products prior to and during CAMZYOS treatment. CAMZYOS Risk Evaluation and Mitigation Strategy (REMS) Program CAMZYOS is only available through a restricted program called the CAMZYOS REMS Program because of the risk of heart failure due to systolic dysfunction. Notable requirements of the CAMZYOS REMS Program include the following: Prescribers must be certified by enrolling in the REMS Program. Patients must enroll in the REMS Program and comply with ongoing monitoring requirements. Pharmacies must be certified by enrolling in the REMS Program and must only dispense to patients who are authorized to receive CAMZYOS. Wholesalers and distributors must only distribute to certified pharmacies. Further information is available at www.CAMZYOSREMS.com or by telephone at 1-833-628-7367. Embryo-Fetal Toxicity CAMZYOS may cause fetal toxicity when administered to a pregnant female, based on animal studies. Confirm absence of pregnancy in females of reproductive potential prior to treatment and advise patients to use effective contraception during treatment with CAMZYOS and for 4 months after the last dose. CHCs containing a combination of ethinyl estradiol and norethindrone may be used with CAMZYOS. However, CAMZYOS may reduce the effectiveness of combined hormonal contraceptives (CHC). If these CHCs are used, advise patients to add nonhormonal contraception (such as condoms) during concomitant use and for 4 months after the last dose of CAMZYOS. ADVERSE REACTIONS In the EXPLORER-HCM trial, adverse reactions occurring in >5% of patients and more commonly in the CAMZYOS group than in the placebo group were dizziness (27% vs 18%) and syncope (6% vs 2%). There were no new adverse reactions identified in VALOR-HCM. Effects on Systolic Function In the EXPLORER-HCM trial, mean (SD) resting LVEF was 74% (6) at baseline in both treatment groups. Mean (SD) absolute change from baseline in LVEF was -4% (8) in the CAMZYOS group and 0% (7) in the placebo group over the 30-week treatment period. At Week 38, following an 8-week interruption of trial drug, mean LVEF was similar to baseline for both treatment groups. In the EXPLORER-HCM trial, 7 (6%) patients in the CAMZYOS group and 2 (2%) patients in the placebo group experienced reversible reductions in LVEF <50% (median 48%: range 35-49%) while on treatment. In all 7 patients treated with CAMZYOS, LVEF recovered following interruption of CAMZYOS. DRUG INTERACTIONS Potential for Other Drugs to Affect Plasma Concentrations of CAMZYOS CAMZYOS is primarily metabolized by CYP2C19 and to a lesser extent by CYP3A4 and CYP2C9. Inducers and inhibitors of CYP2C19 and moderate to strong inhibitors or inducers of CYP3A4 may affect the exposures of CAMZYOS. Impact of Other Drugs on CAMZYOS: Moderate to Strong CYP2C19 Inhibitors or Strong CYP3A4 Inhibitors : Concomitant use increases CAMZYOS exposure, which may increase the risk of heart failure due to systolic dysfunction. Concomitant use is contraindicated. Moderate to Strong CYP2C19 Inducers or Moderate to Strong CYP3A4 Inducers : Concomitant use decreases CAMZYOS exposure, which may reduce CAMZYOS’ efficacy. The risk of heart failure due to systolic dysfunction may increase with discontinuation of these inducers as the levels of induced enzyme normalizes. Concomitant use is contraindicated. Weak CYP2C19 Inhibitors or Moderate CYP3A4 Inhibitors : Concomitant use with a weak CYP2C19 inhibitor or a moderate CYP3A4 inhibitor increases CAMZYOS exposure, which may increase the risk of adverse drug reactions. Initiate CAMZYOS at the recommended starting dose of 5 mg orally once daily in patients who are on stable therapy with a weak CYP2C19 inhibitor or a moderate CYP3A4 inhibitor. Reduce dose of CAMZYOS by one level (i.e., 15 to 10 mg, 10 to 5 mg, or 5 to 2.5 mg) in patients who are on CAMZYOS treatment and intend to initiate a weak CYP2C19 inhibitor or a moderate CYP3A4 inhibitor. Schedule clinical and echocardiographic assessment 4 weeks after inhibitor initiation, and do not up-titrate CAMZYOS until 12 weeks after inhibitor initiation. Avoid initiation of concomitant weak CYP2C19 and moderate CYP3A4 inhibitors in patients who are on stable treatment with 2.5 mg of CAMZYOS because a lower dose is not available. Potential for CAMZYOS to Affect Plasma Concentrations of Other Drugs CAMZYOS is an inducer of CYP3A4, CYP2C9, and CYP2C19. Concomitant use with CYP3A4, CYP2C19, or CYP2C9 substrates may reduce plasma concentration of these drugs. Closely monitor when CAMZYOS is used in combination with CYP3A4, CYP2C19, or CYP2C9 substrates unless otherwise recommended in the Prescribing Information. Certain Combined Hormonal Contraceptives (CHC): Progestin and ethinyl estradiol are CYP3A4 substrates. Concomitant use of CAMZYOS may decrease exposures of certain progestins, which may lead to contraceptive failure. CHCs containing a combination of ethinyl estradiol and norethindrone may be used with CAMZYOS, but if other CHCs are used, advise patients to add nonhormonal contraception (such as condoms) during concomitant use and for 4 months after the last dose of CAMZYOS. Drugs That Reduce Cardiac Contractility Expect additive negative inotropic effects of CAMZYOS and other drugs that reduce cardiac contractility. Avoid concomitant use of CAMZYOS in patients on disopyramide, ranolazine, verapamil with a beta blocker, or diltiazem with a beta blocker as these medications and combinations increase the risk of left ventricular systolic dysfunction and heart failure symptoms and clinical experience is limited. If concomitant therapy with a negative inotrope is initiated, or if the dose of a negative inotrope is increased, monitor LVEF closely until stable doses and clinical response have been achieved. SPECIFIC POPULATIONS Pregnancy CAMZYOS may cause fetal harm when administered to a pregnant female. Advise pregnant females about the potential risk to the fetus with maternal exposure to CAMZYOS during pregnancy. There is a pregnancy safety study for CAMZYOS. If CAMZYOS is administered during pregnancy, or if a patient becomes pregnant while receiving CAMZYOS or within 4 months after the last dose of CAMZYOS, healthcare providers should report CAMZYOS exposure by contacting Bristol Myers Squibb at 1-800-721-5072 or www.bms.com . Lactation The presence of CAMZYOS in human or animal milk, the drug’s effects on the breastfed infant, or the effects on milk production are unknown. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for CAMZYOS and any potential adverse effects on the breastfed child from CAMZYOS or from the underlying maternal condition. Females and Males of Reproductive Potential Confirm absence of pregnancy in females of reproductive potential prior to initiation of CAMZYOS. Advise females of reproductive potential to use effective contraception during treatment with CAMZYOS and for 4 months after the last dose. CHCs containing a combination of ethinyl estradiol and norethindrone may be used with CAMZYOS. However, CAMZYOS may reduce the effectiveness of certain other combined hormonal contraceptives (CHC). If these CHCs are used, advise patients to add nonhormonal contraception (such as condoms) during concomitant use and for 4 months after the last dose of CAMZYOS. Please see U.S. Full Prescribing Information , including Boxed WARNING and Medication Guide . About ELIQUIS ® (apixaban) ELIQUIS ® is an oral selective Factor Xa inhibitor. By inhibiting Factor Xa, a key blood clotting protein, ELIQUIS decreases thrombin generation and blood clot formation. ELIQUIS is approved for multiple indications in the U.S. based on efficacy and safety data from multiple Phase 3 clinical trials. ELIQUIS is a prescription medicine indicated to reduce the risk of stroke and systemic embolism in patients with non-valvular atrial fibrillation (NVAF); for the prophylaxis of deep vein thrombosis (DVT), which may lead to pulmonary embolism (PE), in patients who have undergone hip or knee replacement surgery; for the treatment of DVT and PE; and to reduce the risk of recurrent DVT and PE, following initial therapy. ELIQUIS continues to be developed and commercialized by The Bristol Myers Squibb-Pfizer Alliance. ELIQUIS Important Safety Information Indications ELIQUIS is indicated to reduce the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation. ELIQUIS is indicated for the prophylaxis of deep vein thrombosis (DVT), which may lead to pulmonary embolism (PE), in patients who have undergone hip or knee replacement surgery. ELIQUIS is indicated for the treatment of DVT and PE, and to reduce the risk of recurrent DVT and PE following initial therapy. Important Safety Information WARNING: (A) PREMATURE DISCONTINUATION OF ELIQUIS INCREASES THE RISK OF THROMBOTIC EVENTS, (B) SPINAL/EPIDURAL HEMATOMA (A) Premature discontinuation of any oral anticoagulant, including ELIQUIS, increases the risk of thrombotic events. If anticoagulation with ELIQUIS is discontinued for a reason other than pathological bleeding or completion of a course of therapy, consider coverage with another anticoagulant. (B) Epidural or spinal hematomas may occur in patients treated with ELIQUIS who are receiving neuraxial anesthesia or undergoing spinal puncture. These hematomas may result in long-term or permanent paralysis. Consider these risks when scheduling patients for spinal procedures. Factors that can increase the risk of developing epidural or spinal hematomas in these patients include: use of indwelling epidural catheters concomitant use of other drugs that affect hemostasis, such as nonsteroidal anti-inflammatory drugs (NSAIDs), platelet inhibitors, other anticoagulants a history of traumatic or repeated epidural or spinal punctures a history of spinal deformity or spinal surgery optimal timing between the administration of ELIQUIS and neuraxial procedures is not known Monitor patients frequently for signs and symptoms of neurological impairment. If neurological compromise is noted, urgent treatment is necessary. Consider the benefits and risks before neuraxial intervention in patients anticoagulated or to be anticoagulated. CONTRAINDICATIONS Active pathological bleeding Severe hypersensitivity reaction to ELIQUIS (e.g., anaphylactic reactions) WARNINGS AND PRECAUTIONS Increased Risk of Thrombotic Events after Premature Discontinuation: Premature discontinuation of any oral anticoagulant, including ELIQUIS, in the absence of adequate alternative anticoagulation increases the risk of thrombotic events. An increased rate of stroke was observed during the transition from ELIQUIS to warfarin in clinical trials in atrial fibrillation patients. If ELIQUIS is discontinued for a reason other than pathological bleeding or completion of a course of therapy, consider coverage with another anticoagulant. Bleeding Risk: ELIQUIS increases the risk of bleeding and can cause serious, potentially fatal, bleeding. Concomitant use of drugs affecting hemostasis increases the risk of bleeding, including aspirin and other antiplatelet agents, other anticoagulants, heparin, thrombolytic agents, SSRIs, SNRIs, and NSAIDs. Advise patients of signs and symptoms of blood loss and to report them immediately or go to an emergency room. Discontinue ELIQUIS in patients with active pathological hemorrhage. The anticoagulant effect of apixaban can be expected to persist for at least 24 hours after the last dose (i.e., about two half-lives). An agent to reverse the anti-factor Xa activity of apixaban is available. Please visit www.andexxa.com for more information on availability of a specific reversal agent. Spinal/Epidural Anesthesia or Puncture: Patients treated with ELIQUIS undergoing spinal/epidural anesthesia or puncture may develop an epidural or spinal hematoma which can result in long-term or permanent paralysis. The risk of these events may be increased by the postoperative use of indwelling epidural catheters or the concomitant use of medicinal products affecting hemostasis. Indwelling epidural or intrathecal catheters should not be removed earlier than 24 hours after the last administration of ELIQUIS. The next dose of ELIQUIS should not be administered earlier than 5 hours after the removal of the catheter. The risk may also be increased by traumatic or repeated epidural or spinal puncture. If traumatic puncture occurs, delay the administration of ELIQUIS for 48 hours. Monitor patients frequently and if neurological compromise is noted, urgent diagnosis and treatment is necessary. Physicians should consider the potential benefit versus the risk of neuraxial intervention in ELIQUIS patients. Prosthetic Heart Valves: The safety and efficacy of ELIQUIS have not been studied in patients with prosthetic heart valves and is not recommended in these patients. Acute PE in Hemodynamically Unstable Patients or Patients who Require Thrombolysis or Pulmonary Embolectomy : Initiation of ELIQUIS is not recommended as an alternative to unfractionated heparin for the initial treatment of patients with PE who present with hemodynamic instability or who may receive thrombolysis or pulmonary embolectomy. Increased Risk of Thrombosis in Patients with Triple Positive Antiphospholipid Syndrome (APS): Direct-acting oral anticoagulants (DOACs), including ELIQUIS, are not recommended for use in patients with triple-positive APS. For patients with APS (especially those who are triple positive [positive for lupus anticoagulant, anticardiolipin, and anti–beta 2-glycoprotein I antibodies]), treatment with DOACs has been associated with increased rates of recurrent thrombotic events compared with vitamin K antagonist therapy. ADVERSE REACTIONS The most common and most serious adverse reactions reported with ELIQUIS were related to bleeding. TEMPORARY INTERRUPTION FOR SURGERY AND OTHER INTERVENTIONS ELIQUIS should be discontinued at least 48 hours prior to elective surgery or invasive procedures with a moderate or high risk of unacceptable or clinically significant bleeding. ELIQUIS should be discontinued at least 24 hours prior to elective surgery or invasive procedures with a low risk of bleeding or where the bleeding would be noncritical in location and easily controlled. Bridging anticoagulation during the 24 to 48 hours after stopping ELIQUIS and prior to the intervention is not generally required. ELIQUIS should be restarted after the surgical or other procedures as soon as adequate hemostasis has been established. DRUG INTERACTIONS Combined P-gp and Strong CYP3A4 Inhibitors: Inhibitors of P-glycoprotein (P-gp) and cytochrome P450 3A4 (CYP3A4) increase exposure to apixaban and increase the risk of bleeding. For patients receiving ELIQUIS doses of 5 mg or 10 mg twice daily, reduce the dose of ELIQUIS by 50% when ELIQUIS is coadministered with drugs that are combined P-gp and strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, or ritonavir). In patients already taking 2.5 mg twice daily, avoid coadministration of ELIQUIS with combined P-gp and strong CYP3A4 inhibitors. Clarithromycin Although clarithromycin is a combined P-gp and strong CYP3A4 inhibitor, pharmacokinetic data suggest that no dose adjustment is necessary with concomitant administration with ELIQUIS. Combined P-gp and Strong CYP3A4 Inducers: Avoid concomitant use of ELIQUIS with combined P-gp and strong CYP3A4 inducers (e.g., rifampin, carbamazepine, phenytoin, St. John’s wort) because such drugs will decrease exposure to apixaban. Anticoagulants and Antiplatelet Agents: Coadministration of antiplatelet agents, fibrinolytics, heparin, aspirin, and chronic NSAID use increases the risk of bleeding. APPRAISE-2, a placebo-controlled clinical trial of apixaban in high-risk post-acute coronary syndrome patients treated with aspirin or the combination of aspirin and clopidogrel, was terminated early due to a higher rate of bleeding with apixaban compared to placebo. PREGNANCY The limited available data on ELIQUIS use in pregnant women are insufficient to inform drug-associated risks of major birth defects, miscarriage, or adverse developmental outcomes. Treatment may increase the risk of bleeding during pregnancy and delivery, and in the fetus and neonate. Labor or delivery: ELIQUIS use during labor or delivery in women who are receiving neuraxial anesthesia may result in epidural or spinal hematomas. Consider use of a shorter acting anticoagulant as delivery approaches. LACTATION Breastfeeding is not recommended during treatment with ELIQUIS. FEMALES AND MALES OF REPRODUCTIVE POTENTIAL Females of reproductive potential requiring anticoagulation should discuss pregnancy planning with their physician. The risk of clinically significant uterine bleeding, potentially requiring gynecological surgical interventions, identified with oral anticoagulants including ELIQUIS should be assessed in these patients and those with abnormal uterine bleeding. Please see U.S. Full Prescribing Information , including Boxed WARNINGS , available at BMS.com . About the Bristol Myers Squibb-Pfizer Collaboration The Bristol Myers Squibb-Pfizer Alliance (the Alliance) is committed to driving education and awareness about atrial fibrillation and deep vein thrombosis (DVT) and/or pulmonary embolism (PE). With long-standing cardiovascular leadership, global scale and expertise in this field, the Alliance strives to implement global, research-driven approaches to illuminate and address the unmet needs around strokes related to non-valvular atrial fibrillation, which are often fatal or debilitating. Through collaborations with non-profit organizations, the Alliance aims to provide patients, healthcare professionals and decision makers with the information they need to understand and take appropriate action on risk factors associated with stroke and other cardiovascular conditions. About Milvexian * Milvexian is an investigational oral, highly selective Factor XIa (FXIa) inhibitor, part of a new class of anticoagulants in development aimed at preventing harmful clotting that restricts blood flow (thrombosis) while preserving the normal clotting process (hemostasis). As a result, milvexian could potentially reduce major cardiovascular events due to harmful clotting without significantly increasing the risk of bleeding. It is currently being studied in the Phase 3 Librexia program, the most comprehensive FXIa clinical development program to date, for the prevention and treatment of major thrombotic conditions. * Milvexian is an investigational agent and has not been approved for use in any country, for any indication. About the Bristol Myers Squibb-Johnson & Johnson Collaboration Bristol Myers Squibb and Johnson & Johnson, two unsurpassed leaders in cardiovascular care, are determined to close the gap in unmet needs in thrombosis management by overcoming the limits of today’s treatments. The collaboration to develop and commercialize milvexian aims to leverage the combined scientific expertise and world-class commercial capabilities of each company, to improve patient outcomes. The alliance is uniquely equipped to deliver on the promise of FXIa inhibitors and is working diligently to ensure cutting-edge safe and effective treatment options are available for patients. About Bristol Myers Squibb Bristol Myers Squibb is a global biopharmaceutical company whose mission is to discover, develop and deliver innovative medicines that help patients prevail over serious diseases. For more information about Bristol Myers Squibb, visit us at BMS.com or follow us on LinkedIn , X , YouTube , Facebook and Instagram . Cautionary Statement Regarding Forward-Looking Statements This press release contains “forward-looking statements” within the meaning of the Private Securities Litigation Reform Act of 1995 regarding, among other things, the research, development and commercialization of pharmaceutical products. All statements that are not statements of historical facts are, or may be deemed to be, forward-looking statements. Such forward-looking statements are based on current expectations and projections about our future financial results, goals, plans and objectives and involve inherent risks, assumptions and uncertainties, including internal or external factors that could delay, divert or change any of them in the next several years, that are difficult to predict, may be beyond our control and could cause our future financial results, goals, plans and objectives to differ materially from those expressed in, or implied by, the statements. These risks, assumptions, uncertainties and other factors include, among others, that future study results may not be consistent with the results to date, that milvexian may not receive regulatory approval for the indications described in this release, any marketing approvals, if granted, may have significant limitations on their use, and, whether CAMZYOS (mavacamten), ELIQUIS (apixaban) or milvexian, if approved, for such indications described in this release will be commercially successful. No forward-looking statement can be guaranteed. Forward-looking statements in this press release should be evaluated together with the many risks and uncertainties that affect Bristol Myers Squibb’s business and market, particularly those identified in the cautionary statement and risk factors discussion in Bristol Myers Squibb’s Annual Report on Form 10-K for the year ended December 31, 2023, as updated by our subsequent Quarterly Reports on Form 10-Q, Current Reports on Form 8-K and other filings with the Securities and Exchange Commission. The forward-looking statements included in this document are made only as of the date of this document and except as otherwise required by applicable law, Bristol Myers Squibb undertakes no obligation to publicly update or revise any forward-looking statement, whether as a result of new information, future events, changed circumstances or otherwise. corporatefinancial-news

摘要:结核病（TB）是由基因密切相关的结核分枝杆菌复合群（MTBC）中的分枝杆菌引起的全球流行传染病。一个世纪以来，卡介苗（BCG）疫苗一直是预防结核病的主要措施。尽管它在有效预防儿童肺外结核方面效果显著，但在为成人提供肺结核保护方面缺乏一致的效力。因此，探索和开发能够为人群提供广泛保护的新型结核病疫苗，一直是医学研究中的一个重要领域。本文提供了目前正在进行临床试验的新型结核病疫苗的简要概述，讨论了它们的分类、保护效力、免疫原性、优点和局限性。在疫苗开发中，精心选择能够诱导强烈且多样化特定免疫反应的抗原至关重要。因此，我们总结了结核病疫苗所选抗原的分子特征、生物学功能、免疫原性以及相关研究。从疫苗和免疫原性蛋白中获得的这些见解将为新型分枝杆菌疫苗的开发提供信息，特别是mRNA疫苗，以有效控制结核病。 1.引言 结核病（TB）是由结核分枝杆菌复合群（MTBC）引起的一种传染性空气传播疾病。尽管它们的核苷酸序列高度相似（99.9%的相似性），但MTBC中的菌株根据宿主偏好和分子系统发育被分为不同的物种。全球人类结核病最常见的原因是结核分枝杆菌（M. tuberculosis 或 Mtb），其次是M. africanum，它在西非的病例中约占一半。此外，一些适应动物的物种，如M. bovis，可以感染广泛的宿主，导致人畜共患结核病，这对全球人类和兽医公共卫生构成了重大挑战。尽管治疗取得了进展，结核病仍然是最致命的传染病之一。根据世界卫生组织（WHO）的数据，2021年全球估计有1060万人感染了结核病，导致160万人死亡。目前，全球约四分之一的人口携带潜伏性结核感染（LTBI），虽然大多数人无症状，但大约5%-10%的人在一生中会发展成活动性结核病。2015年，WHO启动了结束结核病战略，旨在到2030年实现结核病发病率减少80%和结核病相关死亡率减少90%。然而，耐多药（MDR）菌株的全球传播，以及由人类免疫缺陷病毒（HIV）和2型糖尿病引起的并发症，增加了感染风险。此外，Mtb感染是HIV-1感染者死亡的主要原因。结核病和HIV-1共感染可以破坏宿主免疫系统，特别是通过损害CD4+ T细胞和巨噬细胞。开发创新的诊断方法、药物和疫苗对于有效应对这些挑战至关重要。疫苗接种被认为是实现全球结核病发病率和死亡率年度减少的最经济有效的策略之一。卡介苗（BCG）疫苗，目前唯一获得许可用于人类的结核病疫苗，为儿童提供了长期且强大的保护，预防粟粒性和脑膜炎结核病。然而，其在预防成人肺结核方面的有效性有限。由于Mtb的复杂基因组和结构，选择有效且安全的抗原一直是疫苗设计中的首要考虑因素。由于免疫学和分子生物学的进步，结核病疫苗开发取得了实质性进展。到2022年，有十六种疫苗候选处于不同的临床试验阶段，包括全细胞细菌疫苗、亚单位疫苗和mRNA疫苗。这些疫苗中使用的抗原涉及多种分枝杆菌菌株和十多种Mtb的结构或分泌蛋白，这些在实验室和临床实验中产生了不同的评估结果。本综述提供了传统和新型结核病疫苗的概述。此外，它还全面总结了结核病疫苗开发中选择的抗原在基础或临床研究中的发现，为开创性疫苗设计提供了宝贵的指导和策略。 2.全细胞细菌疫苗 全细胞细菌疫苗包括减毒、灭活和重组变体。卡介苗，源自减毒的M. bovis，被广泛使用，并对全球健康产生了重大影响。与亚单位疫苗相比，含有复杂抗原的全细菌疫苗可能潜在地诱导更多样化的免疫反应。卡介苗用于婴儿和幼儿，提供了80%的保护效力。然而，普遍接受卡介苗疫苗预防成人肺结核仍有待讨论。这表明卡介苗菌株可能与Mtb有不同的病理机制，可能导致免疫反应不足。实际上，在多年的连续传代过程中，卡介苗菌株经历了遗传变化，并失去了差异区域1（RD1）中的九个基因，这些基因已知对毒力很重要。卡介苗疫苗被发现可以预防播散性结核病，并降低全因死亡率。此外，它还可以提供一定程度的保护，防止由不相关病原体如疱疹和流感病毒引起的感染。这种广泛的保护被认为是通过触发先天免疫记忆和刺激异种淋巴细胞激活来实现的，这导致细胞因子分泌增加，巨噬细胞功能增强，T细胞反应改善，抗体水平提高。卡介苗疫苗在婴儿中触发的非特异性“训练免疫”可能比成人更有效，成人可能之前已经接触过非结核分枝杆菌（NTM）和其他病原体。为了解决卡介苗疫苗的局限性并增强其特异性，目前正在临床试验中研究几种新的全细胞细菌疫苗或疫苗接种策略。这些包括对BCG重新接种的研究，以及评估DAR-901（灭活M. obuense）、RUTI（Mtb细胞片段）、MIP（灭活M. indicus pranii）、MTBVAC（减毒M. tuberculosis）和VPM1002（重组BCG）等疫苗的IIb期和III期。 DAR-901是灭活的M. obuense，一种快速生长的分枝杆菌（RGM）的环境色素分枝杆菌。临床前研究表明，DAR-901可以诱导细胞和体液免疫，增强对Mtb的保护。然而，在坦桑尼亚进行的临床试验表明，观察到的效果可能在预防健康青少年结核病感染方面不显著。 RUTI®是一种由灭活的Mtb细胞片段制成的脂质体治疗疫苗。它可以诱导细胞免疫和体液免疫，特别是触发针对Mtb多种抗原的Th1反应。临床研究表明，RUTI安全且耐受性良好，最常见的不良反应是轻度至中度的注射部位反应。 MIP指的是灭活的M. indicus pranii，一种非致病性RGM。在一项随机、双盲、多中心临床试验中，MIP被证明是安全的，没有报告不良反应。此外，与安慰剂组（57%）相比，MIP组（67.1%）的患者在第四周实现痰培养转化的比例更高，表明MIP在清除Mtb方面可能发挥作用。 MTBVAC是设计了phoP和fadD26基因缺失的Mtb菌株的减毒疫苗，在洛桑进行的临床试验中显示出与卡介苗相当的安全性和免疫原性。MTBVAC是唯一一种减毒疫苗，包含所有Mtb的主要免疫优势抗原，如ESAT6和CFP10。 VPM1002是基于重组卡介苗的活疫苗，已在南非的新生儿中进行了临床试验，显示出安全性和比卡介苗更低的反应原性。然而，VPM1002的免疫原性被发现低于卡介苗疫苗。 Vaccae™是从非感染性结核分枝杆菌衍生的灭活疫苗，通过热灭活和高压空气剪切实现。Vaccae™已完成III期临床试验作为预防性结核病疫苗，疫苗可以诱导细胞免疫并减轻过敏炎症反应。此外，临床研究表明，使用Vaccae™作为辅助免疫疗法，显著提高了痰涂片阴性转化率（68%），促进了病变改善和空洞闭合，缩短了治疗时间，并减轻了化疗相关损伤。作为预防性疫苗，Vaccae™可以有效抑制Mtb的增殖和激活，阻碍LTBI的进展，并降低感染率。 鉴于它们与卡介苗相当的安全性和有效性，这些新型全细胞细菌疫苗有可能成为更好的替代品。特别是，应该注意到，减毒疫苗可能不适合免疫缺陷或HIV感染的个体，因为他们有更高的结核病进展风险。在这种情况下，开发灭活分枝杆菌和亚单位疫苗对于这一人群更为紧迫和合适。 3.亚单位疫苗 3.1 病毒载体疫苗 亚单位疫苗包括病毒载体疫苗和佐剂蛋白亚单位疫苗。与传统的灭活和减毒疫苗不同，这些疫苗使用整个病原体作为抗原，亚单位疫苗包含或表达特定的病原体蛋白，这降低了接种个体生病的可能性。目前，两种病毒载体疫苗（Ad5Ag85A 和 TB/FLU-04L）处于I期，而另一种（ChAdOx185A-MVA85A）处于IIa期。Ad5Ag85A 和 ChAdOx185A-MVA85A 疫苗分别基于人5型腺病毒（Ad5）和猴腺病毒。而TB/FLU-04L是一种活的重组流感A病毒疫苗。这些疫苗表达Mtb蛋白Ag85A，TB/FLU-04L也表达抗原ESAT-6。临床试验结果表明，ChAdOx185A-MVA85A疫苗诱导了特定的CD4+和CD8+ T细胞免疫反应，产生了IgG抗体，并且没有严重的不良反应。此外，TB/FLU-04L疫苗被发现是安全的，并且能够引发针对Mtb的特定Th1免疫反应。另一项研究表明，Ad5Ag85A肌肉注射疫苗是安全的，具有免疫原性，并刺激了多能T细胞反应，特别是在之前接种过BCG疫苗的个体中。病毒载体疫苗在生产效率和成本效益方面具有优势。与传统的灭活疫苗相比，它们能够通过诱导强烈且持久的免疫反应来提供持久的免疫力。然而，评估病毒载体疫苗的安全性和有效性时，必须考虑某些限制。一个担忧是，针对载体的预先存在的免疫力是否会影响其效力。研究表明，之前接触过流感病毒可能会影响对目标抗原的反应。腺病毒疫苗也面临类似的挑战，因为在接种个体中对Ad5的中和抗体水平升高已经显示出抑制重组腺病毒疫苗的免疫原性，特别是在Ad5抗体滴度高的地区。此外，存在与流通的野生型病毒发生遗传重组的风险，可能导致抗原基因的丢失和毒力的恢复。 3.2 佐剂蛋白亚单位疫苗 除了病毒载体疫苗外，目前有五种蛋白亚单位疫苗正在进行临床试验。这些包括ID93 + GLA-SE（QTP101）和AEC/BC02处于IIa期，H56: IC31和M72/AS01E处于IIb期，以及GamTBvac处于III期。 ID93 + GLA-SE是一种重组融合蛋白，由四种Mtb抗原（Rv1813c、Rv2608、Rv3619c和Rv3620c）与含有TLR4L的佐剂（GLA-SE）结合而成。I期临床试验表明，其安全性和有效性，能够诱导强烈的抗原特异性血清抗体和Th1型细胞免疫反应。 AEC/BC02包含Ag85B抗原和EC融合蛋白（ESAT6-CFP10），以及由未甲基化的胞嘧啶-磷酸-鸟嘌呤（CpG）DNA片段和铝盐衍生的佐剂BC02。虽然作为一种预防性疫苗效果不佳，但在LTBI的临床前模型中显示出作为免疫治疗对抗进展性疾病的潜力。 H56: IC31结合了三种Mtb抗原（Ag85B、ESAT-6和Rv2660c）和IC31佐剂。在动物上进行的研究表明，H56: IC31增强有潜力控制晚期Mtb感染并限制潜伏性结核病。尽管在I期试验中一些受试者观察到短暂的心血管不良事件，但疫苗诱导的抗原特异性IgG反应和表达Th1细胞因子的CD4+ T细胞。 M72/AS01E是由两种Mtb抗原Mtb32a（PepA）和Mtb39a（PPE18）组成的重组融合蛋白，带有基于脂质体的AS01佐剂系统。在感染的成年人中，它显示出54.0%的保护效果，防止活动性肺结核病，没有显著的安全问题。 GamTBvac包括两种分枝杆菌融合蛋白，Ag85A和ESAT6-CFP10，它们固定在右旋糖酐上。该疫苗还包含一种由DEAE-右旋糖酐核心以及TLR9激动剂组成的佐剂，即CpG寡脱氧核苷酸。它在小鼠和豚鼠结核模型中显示出强大的免疫原性和对Mtb H37Rv菌株的显著保护效果。II期研究表明，它能够在健康成年人中诱导抗原特异性IFN-γ释放和表达Th1细胞因子的CD4+ T细胞。 结核病亚单位疫苗提供了几个优势特点，包括低成本、易于准备和安全性。一些疫苗是非常有希望的LTBI潜在治疗方法。重要的是收集更多数据并进行研究，以更好地了解这些结核病亚单位疫苗的长期有效性和安全性，特别是在像HIV这样的合并症人群中。正在进行的研究将为这些疫苗在临床实践中的潜在使用提供宝贵的见解。 4.mRNA疫苗 信使RNA（mRNA）疫苗已成为一种新型疫苗类别，近年来在COVID-19 mRNA疫苗的开发和授权中获得了显著的关注和成功。由于它们在疫苗设计上的灵活性、生产时间短、成本效益以及激发细胞和体液免疫反应的能力，mRNA疫苗已成为抗击传染病的主要候选疫苗之一。mRNA疫苗的设计取决于仔细的抗原选择。理想的目标抗原应该是免疫原性的，并且能够激发保护性免疫反应，确保疫苗有效地产生针对特定病原体所需的免疫反应。然而，mRNA疫苗的热稳定性可能存在挑战，特别是在获得可靠冷藏系统的途径有限的地区。mRNA是脆弱的，如果不在适当的温度下储存和运输，容易降解，需要冷链储存和分发。 通过开发具有改进热稳定性的mRNA疫苗来克服这一限制，将增强它们在资源受限地区的可行性和可访问性。目前，唯一的一种结核病mRNA疫苗，BNT164，正在进行I期临床试验，以确定在三剂计划中的安全和耐受剂量。没有公开的报告可用，关于BNT164在预防结核病方面的保护效果、免疫原性和安全性。需要进一步的研究来验证mRNA疫苗是否可以激发针对结核病更强大和更全面的免疫反应。 5.结核病疫苗的抗原选择 如前所述，分枝杆菌的抗原在结核病亚单位和mRNA疫苗的开发中得到广泛使用（表1）。这些抗原包括结构蛋白、与毒力相关的蛋白以及细菌表面存在的免疫调节因子或分泌的蛋白。本综述部分深入探讨了特定基因及其编码的细胞组分，为未来的抗原选择和疫苗设计提供了有价值的见解。 表1:结核病亚单位疫苗的免疫原性蛋白。 5.1. fbpA（mpt44, Rv3804c; Ag85A） 纤连蛋白结合蛋白（Fbps），也称为抗原85复合物，包括FbpA、FbpB和FbpC，位于结核分枝杆菌（Mtb）的细胞壁中，并具有分泌能力。所有的Fbps都包含一个羧酸酯酶结构域，每种蛋白都作为酰基转移酶参与分枝杆菌细胞壁的形成。抗原85复合物在促进6,60-二酰基（TDM）的生物合成和维持Mtb细胞壁结构稳定性方面发挥关键作用。研究表明，FbpA表达的缺失抑制了Mtb在人和小鼠类巨噬细胞系中的复制，表明FbpA可能在致病机制中发挥作用。分泌的抗原85蛋白具有高度免疫原性，并持续由细菌表达，对刺激B细胞和T细胞反应至关重要。特别是T细胞，可以通过释放细胞因子和激活各种免疫细胞（如巨噬细胞、自然杀伤（NK）细胞、树突状细胞（DC）和细胞毒性T（Tc）细胞）来激活细胞和体液免疫系统。这种协调的免疫反应有助于破坏细胞内Mtb感染。在目前处于临床试验阶段的疫苗中，AEC/BC02、GamTBvac、Ad5Ag85A、TB/FLU-01/4L和ChadOx185A使用Ag85A作为抗原成分。 5.2. fbpB（mpt59, Rv1886c; Ag85B） FbpB是一种分泌蛋白，负责细菌细胞包膜的生物合成。Fbps在氨基酸水平上具有高度的相似性，有68-80%的一致性。这表明这三种酶可能都参与了细胞壁的酰基化，与FbpA和FbpB相比，FbpC可能发挥更关键的作用。由于它们的酶活性和作为分泌蛋白的状态，Fbps不仅作为潜在的药物靶点相关，而且作为诊断抗原。定量分析包括Fbps在内的分泌细菌蛋白的水平，可以提供有关Mtb生长阶段的见解。目前，只有一种疫苗H56:1C31使用Ag85B作为抗原。 5.3. PPE18（mtb39a, Rv1196） PPE18是PPE家族的成员，其特点是包含一个带有脯氨酸-脯氨酸-谷氨酸（PPE）基序的保守N端结构域。这些蛋白被认为参与了抗原变异和疾病致病机制。蛋白质组学结果鉴定了8种PE和PPE家族蛋白是Mtb培养滤液蛋白（CFP），包括PPE18以低丰度存在，这表明其可能被分泌。然而，另一项研究发现PPE18在Mtb的裂解物中但不在CFP中，表明它可能不是分泌抗原。额外的研究表明PPE18与Mtb的细胞壁相关并暴露在细胞表面。有建议称PPE18可以通过与巨噬细胞中的TLR2相互作用触发抗炎反应，从而产生白细胞介素-10（IL-10）。在先天免疫反应中，巨噬细胞分泌的细胞因子IL-12和TNF-α在促进Th1 T细胞的发展和增强细胞介导的免疫反应中发挥关键作用。这些免疫反应对于对抗细胞内感染，如结核病至关重要。然而，PPE18已证明能够在LPS刺激下抑制巨噬细胞中促炎细胞因子的产生。这是通过上调抑制因子3（SOCS3）的表达和酪氨酸磷酸化，随后抑制转录因子p50、p65和c-rel的核转移来实现的。此外，PPE18有能力阻碍巨噬细胞通过MHC II类介导的抗原呈递。这导致CD4+ T细胞的激活受损，随后影响B细胞的反应。总的来说，这些发现表明PPE18作为免疫抑制因子，并且在Mtb的免疫逃逸中发挥关键作用。疫苗M72/AS01E选择了PPE18作为抗原之一。 5.4. PPE42（Rv2608） PPE42是Mtb PPE蛋白家族的成员。PPE42作为强效的B细胞抗原，能够诱导强大的体液免疫反应，同时引发相对较低水平的T细胞反应。PPE42是ID93+GLA-SE/QTP101疫苗的抗原。 5.5. pepA（mtb32a, Rv0125） PepA是一种假定的丝氨酸蛋白酶，功能未知，被认为是一种分泌蛋白。它有能力促进外周血单核细胞（PBMC）的增殖并诱导IFN-γ的分泌。PepA在不同分枝杆菌物种中的高保守性表明其作为有希望的疫苗靶点的潜力。PepA在M72/AS01E疫苗中与PPE18融合。 5.6. esxA (esat-6, Rv3875) EsxA，也被称为早期分泌性抗原靶标6千道尔顿（ESAT-6）。它属于WXG100家族，该家族由大约23个蛋白质组成，这些蛋白质大小约为100个氨基酸。这个家族中的蛋白质表现出螺旋结构，并显示出由保守的W-X-G基序产生的独特的发夹弯曲。这种蛋白质通过ESAT-6分泌系统1（ESX-1），也称为VII型分泌系统（T7S），被分泌出来。编码ESAT-6以及一个10千道尔顿培养滤液蛋白（CFP10）的基因位于RD1区域。如前所述，这个区域存在于所有有毒力的Mtb和M. bovis菌株中，但在卡介苗菌株中不存在。将ESAT-6和CPF10重新引入卡介苗菌株会导致菌落形态的显著变化以及宿主内毒力的增加。ESAT-6作为Mtb中的毒力因子发挥着至关重要的作用，通过几种机制帮助免疫逃逸。首先，ESAT-6阻碍宿主细胞中的抗原呈递过程。它与内质网中的宿主蛋白beta-2-微球蛋白（β2M）相互作用，隔离β2M，并抑制MHC-I-β2M复合物在细胞表面的展示，从而降低MHC-I介导的抗原呈递。其次，ESAT-6与Mtb的先天免疫反应减少有关。它通过阻碍Toll样受体（TLR）信号传导，抑制转录因子NF-κB和干扰素调节因子（IRFs）的激活。此外，ESAT-6直接以p38 MAPK依赖性方式抑制IFN-γ的产生和人T细胞的增殖。第三，ESAT-6可以调节宿主细胞死亡。它在中性粒细胞中诱导坏死，以及在THP-1人巨噬细胞中诱导凋亡。ESAT-6是一种强效抗原，能够触发T细胞免疫反应，并在结核感染的早期阶段被T细胞识别。此外，它可以刺激B细胞产生特异性抗体。因此，ESAT-6经常被用作诊断工具，并包含在疫苗配方中。AEC/BC02、H56:1C31、GamTBvac、TB/FLU-01/4L 4种疫苗选择ESAT6作为共同抗原。 5.7. esxB (cfp10, Rv3874) CFP10是另一种WXG100家族蛋白，可以与ESAT-6形成紧密的1:1复合物，并通过ESX-1分泌。磷酸化蛋白质组学和分泌体数据显示，CFP10在T49位点的磷酸化由Mtb丝氨酸/苏氨酸激酶PknA和PknB促进，形成CFP10同源二聚体的形成，同时抑制ESAT6的分泌。CFP10/ESAT6复合物可以与细胞表面受体相互作用，影响宿主细胞行为。已经显示它可以抑制或促进巨噬细胞中TNF-α的产生，从而调节巨噬细胞细胞死亡。此外，该复合物抑制RAW264.7细胞中活性氧物种（ROS）的产生，并降低LPS诱导的NF-κB激活。此外，CFP-10，而不是ESAT-6，特别在人中性粒细胞中触发Ca2+反应，可能有助于它们在Mtb感染期间的招募和激活。CFP10和ESAT-6都具有高度免疫原性，并与人类的毒力有关。值得注意的是，CFP10引发强烈的细胞毒性T淋巴细胞（CTL）反应，这种反应被招募到肺部，在Mtb感染的小鼠中占肺部CD8+ T细胞的高达30%。这些发现为旨在引发CD8+ T细胞反应的疫苗策略提供了希望。AEC/BC02和GamTBvac疫苗选择EsxB作为抗原。 5.8. Rv1813c Rv1813c是一种分泌蛋白，其表达受Mtb的双组分信号系统（TCSS）调节。TCSS的DosR和MprA蛋白可以结合到Rv1813c的上游启动子，并在对缺氧、一氧化氮和一氧化碳的反应中增强其转录。Rv1813c靶向线粒体以操纵宿主代谢。在真核细胞中表达时，它被运输到线粒体的膜间空间，从而通过增强氧化磷酸化代谢途径来增加ATP产生。这反过来又影响感染Mtb的巨噬细胞的代谢和凋亡反应。作为保守的潜伏期抗原，Rv1813c是疫苗开发有希望的候选者。该蛋白能够被T细胞识别，并在小鼠中激活IFN-γ/TNF和TNF/IL-2细胞因子的表达，导致强烈的CD4+ T细胞反应。值得注意的是，与Rv3619c、Rv3620c和Rv2608相比，Rv1813c刺激了最多的IFN-γ和/或TNF阳性CD8+ T细胞。ID93+GLA-SE/QTP101选择Rv1813c作为抗原。 5.9. esxV (Rv3619c) 和 esxW (Rv3620c) Rv3619c和Rv3620c属于WXG100家族，并通过Mtb中的T7S排泄。与ESAT-6/CFP10类似，Rv3619c和Rv3620c相互作用形成1:1异二聚体复合物。Rv3619c和Rv3620c都可以诱导IFN-γ的产生和T细胞反应，表明它们是具有多个T细胞免疫原性表位的Mtb的良好疫苗候选者。Rv3619c和Rv3620c都是ID93+GLA-SE/QTP101疫苗中的抗原。 5.10. Rv2660c Rv2660是一种与潜伏期相关的蛋白质，其功能未知。研究表明，Rv2660可以在LTBI个体中诱导增加IFN-γ的产生，更多的活性T细胞数量，以及增强特定的CD4+ T细胞增殖。H56:1C31使用Rv2660c作为抗原。 6.结论和展望 结核病是人类历史上最古老且最致命的疾病之一，给健康、社会和经济带来了重大负担，特别是在低收入和中等收入国家。活动性肺结核患者可以通过咳嗽或打喷嚏将结核分枝杆菌散播到空气中。Mtb感染的主要靶点是肺泡巨噬细胞。如果不能及时清除，细菌在巨噬细胞内复制，然后感染其他细胞，引发强烈的免疫反应。中性粒细胞、淋巴细胞和其他免疫细胞迁移到感染部位，形成逐渐发展成特征性肉芽肿结构的细胞浸润，最终钙化。在这些肉芽肿中，Mtb可以保持休眠状态，非代谢活跃状态多年、几十年甚至一生。目前，全球有超过1亿人患有潜伏性结核感染（LTBI），这可能随时发展成高度传染性且可能致命的活动性结核病。 结核病的治疗主要依赖抗生素。然而，耐多药结核病（MDR-TB）的出现使得两种最有效的一线药物——异烟肼和利福平失效。替代的二线治疗方案需要大量昂贵且有毒的药物。此外，HIV-TB共感染的结核病管理变得更加具有挑战性。HIV阳性患者发展成活动性结核病的风险是未感染个体的26-31倍。HIV-TB共感染需要长期治疗，由于复杂的药物相互作用和不良反应，同时治疗两种疾病面临额外挑战。 在这种情况下，开发预防和治疗结核病的新型疫苗是紧迫和必要的。随着疫苗研究技术的进步，几种新的疫苗候选已经进行了临床试验。然而，目前的临床研究表明，这些新型疫苗在诱导免疫反应和清除病原体感染方面并未显示出比卡介苗（BCG）的显著优势。此外，这些疫苗在HIV患者和免疫功能低下个体中的有效性和安全性仍需评估。显然，在疫苗设计和抗原选择策略中存在值得注意的问题：（1）Mtb与宿主之间的相互作用，以及调节免疫系统的机制尚未完全理解。Mtb基因组由4.4 Mb组成，包含大约4000个基因，但大多数基因的功能仍然不清楚。研究与Mtb增殖、毒力和休眠相关的基因可能为疫苗设计或药物开发提供新目标。（2）开发预防性和治疗性结核病疫苗同等重要。一方面，我们需要开发卡介苗疫苗的替代品，以实现更持久和特定的保护。另一方面，需要针对活动性和潜伏性结核感染的治疗性疫苗，以消除体内的病原体并对抗耐药菌株。 （3）Mtb可以分泌多种抗原，作为免疫原性蛋白和毒力因子，参与调节宿主细胞死亡、抑制宿主免疫信号通路、调节宿主细胞抗原呈递和调节宿主细胞细胞因子产生等各种生理活动。修改这些抗原以增强其免疫原性并减少其副作用是需要解决的问题。 （4）目前的疫苗评估主要集中在辅助T细胞反应和IFN-γ分泌上，对体液免疫在抗击结核病感染方面的研究有限。考虑在疫苗抗原设计中纳入B细胞表位可能导致更平衡的细胞和体液免疫反应，可能产生更好的效果。 随着COVID-19大流行，mRNA疫苗的开发似乎已进入黄金时代。mRNA疫苗引入了一种新型疫苗，通过脂质纳米颗粒将编码病原体抗原的信使RNA传递到哺乳动物细胞中，引发强烈的细胞和体液免疫反应。mRNA疫苗提供了灵活性和适应性，只需要改变编码序列即可表达不同的抗原。多种mRNA疫苗可以共享相同的纯化方法和生产线，显著缩短开发周期。此外，mRNA疫苗在融合表达多种抗原方面具有优势。开发多价结核病疫苗以增强其免疫原性也是一个有希望的发展方向。如果mRNA疫苗能够解决生产成本、储存和运输稳定性方面的问题，它们在应用上可能具有更大的前景。 总之，新的研究理论和技术进步为疫苗开发注入了新的活力，敦促我们继续抗击结核病，进一步减少结核病给人类社会造成的损失。 识别微信二维码，添加生物制品圈小编，符合条件者即可加入 生物制品微信群！ 请注明：姓名+研究方向！ 版 权 声 明 本公众号所有转载文章系出于传递更多信息之目的，且明确注明来源和作者，不希望被转载的媒体或个人可与我们联系(cbplib@163.com)，我们将立即进行删除处理。所有文章仅代表作者观点，不代表本站立场。