Central Nervous System Infections

Expanded indication for this one-time infusion will provide more patients with a potential period away from their multiple myeloma treatment as early as first relapse Approval is based on results from the Phase 3 CARTITUDE-4 study, in which treatment with CARVYKTI® in 1-3 prior lines of therapy reduced the risk of disease progression or death by 59 percent compared to standard therapies HORSHAM, Pa., April 5, 2024 /PRNewswire/ -- Johnson & Johnson (NYSE: JNJ) announced today that the U.S. Food and Drug Administration (FDA) has approved CARVYKTI® (ciltacabtagene autoleucel; cilta-cel) for the treatment of adult patients with relapsed or refractory multiple myeloma who have received at least one prior line of therapy, including a proteasome inhibitor and an immunomodulatory agent, and are refractory to lenalidomide.1 With this approval, CARVYKTI® becomes the first and only B-cell maturation antigen (BCMA)-targeted therapy approved for the treatment of patients with multiple myeloma as early as first relapse. FDA approval is based on positive results from the Phase 3 CARTITUDE-4 study, which demonstrated that the earlier use of CARVYKTI® reduced the risk of disease progression or death by 59 percent compared to standard therapies—pomalidomide, bortezomib and dexamethasone (PVd) or daratumumab, pomalidomide and dexamethasone (DPd)—in adults with relapsed and lenalidomide-refractory multiple myeloma who received one to three prior lines of therapy.1 The study, which was presented at the 2023 American Society of Clinical Oncology (ASCO) Annual Meeting and published in The New England Journal of Medicine, also included and reported key secondary results such as overall response (OR) and overall survival (OS).1 "CARVYKTI demonstrated remarkable efficacy as a personalized, one-time infusion in the earlier treatment of relapsed/refractory multiple myeloma as shown through the CARTITUDE-4 study results," said Binod Dhakal, M.D., Associate Professor, Medical College of Wisconsin, Division of Hematology and Oncology.* "With this approval, I'm excited for patients who may have the opportunity for a treatment-free period for their multiple myeloma as early as first relapse, with the hope of eliminating the burden of having to be on continuous treatment while living with this challenging disease." More than 35,000 estimated new cases of multiple myeloma, an incurable blood cancer, will be diagnosed in 2024 in the United States.2 Real-world studies show that only an estimated 15 percent of patients initially diagnosed with multiple myeloma are able to start a 5th line of therapy.3 With this new indication, more patients will be able to access this innovative treatment. "This milestone underscores our commitment to improve outcomes for patients and transform the treatment of multiple myeloma with CARVYKTI," said Jordan Schecter, M.D., Vice President, Disease Area Leader, Multiple Myeloma, Johnson & Johnson Innovative Medicine. "We are proud to bring an important, highly effective immunotherapy that has demonstrated a favorable benefit/risk profile to physicians and patients for the earlier treatment of relapsed/refractory multiple myeloma, and we look forward to building on this latest milestone as we continue to focus on our ultimate goal of delivering a cure for multiple myeloma." CARVYKTI® is a cell therapy that works by harnessing a patient's immune system, or T cells, to fight the disease. Treatment requires extensive training, preparation, and certification to ensure a positive experience for patients. Since initial approval in February 2022, Johnson & Johnson has made significant advances in manufacturing to rapidly scale CARVYKTI® production. "We understand the urgency for patients in need of CARVYKTI, and we have been making considerable progress in increasing supply and availability in anticipation of this milestone approval," said Tyrone Brewer, President, U.S. Hematology, Johnson & Johnson Innovative Medicine. "We more than doubled manufacturing of CARVYKTI in 2023, we are striving to double again in 2024, and we will continue to invest in our capacity so we can provide this critical therapy to as many patients as possible." The safety profile for CARVYKTI® includes a boxed warning for Cytokine Release Syndrome (CRS), Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS), Parkinsonism and Guillain-Barre syndrome and their associated complications, Hemophagocytic Lymphohistiocytosis/Macrophage Activation Syndrome (HLH/MAS), Prolonged and Recurrent Cytopenias and Secondary Malignancies including myelodysplastic syndrome, acute myeloid leukemia and T-cell malignancies.1 Warnings and Precautions include Increased Early Mortality, Hypogammaglobulinemia, Infections, Hypersensitivity Reactions and Effects on Ability to Drive and Use Machines.1 The most common nonlaboratory adverse reactions (incidence greater than 20 percent) are pyrexia, cytokine release syndrome, hypogammaglobulinemia, hypotension, musculoskeletal pain, fatigue, infections-pathogen unspecified, cough, chills, diarrhea, nausea, encephalopathy, decreased appetite, upper respiratory tract infection, headache, tachycardia, dizziness, dyspnea, edema, viral infections, coagulopathy, constipation, and vomiting.1The most common Grade 3 or 4 laboratory adverse reactions (incidence greater than or equal to 50 percent) include lymphopenia, neutropenia, white blood cell decreased, thrombocytopenia, and anemia.1 About CARTITUDE-4 CARTITUDE-4 (NCT04181827) is the first international, randomized, open-label Phase 3 study evaluating the efficacy and safety of cilta-cel versus pomalidomide, bortezomib and dexamethasone (PVd) or daratumumab, pomalidomide and dexamethasone (DPd) in adult patients with relapsed and lenalidomide-refractory multiple myeloma who received one to three prior lines of therapy.4 Results were presented at the 2023 American Society of Clinical Oncology (ASCO) Annual Meeting and published in The New England Journal of Medicine. About CARVYKTI ® (ciltacabtagene autoleucel; cilta-cel) CARVYKTI® (cilta-cel) received U.S. Food and Drug Administration approval in February 2022 for the treatment of adults with relapsed or refractory multiple myeloma after four or more prior lines of therapy, including a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 monoclonal antibody.1 CARVYKTI® is now approved in the U.S. for the second-line treatment of adult patients with relapsed or refractory myeloma who have received at least one prior line of therapy including a proteasome inhibitor, an immunomodulatory agent, and who are refractory to lenalidomide. In addition to a unanimous (11 to 0) FDA Oncologic Drugs Advisory Committee (ODAC) recommendation in support of this new indication, in March 2024, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) recommended the approval of a Type II variation for CARVYKTI® for the treatment of adults with relapsed and refractory multiple myeloma who have received at least one prior therapy, including an immunomodulatory agent and a proteasome inhibitor, have demonstrated disease progression on the last therapy, and are refractory to lenalidomide. In September 2022, Japan's Ministry of Health, Labour and Welfare (MHLW) approved CARVYKTI® for the treatment of adults with relapsed or refractory multiple myeloma in patients that have no history of CAR-positive T cell infusion therapy targeting BCMA and who have received three or more lines of therapies, including an immunomodulatory agent, a proteasome inhibitor and an anti-CD38 monoclonal antibody, and in whom multiple myeloma has not responded to or has relapsed following the most recent therapy. CARVYKTI® is a BCMA-directed, genetically modified autologous T-cell immunotherapy, which involves reprogramming a patient's own T-cells with a transgene encoding chimeric antigen receptor (CAR) that directs the CAR positive T cells to eliminate cells that express BCMA. BCMA is primarily expressed on the surface of malignant multiple myeloma B-lineage cells, as well as late-stage B cells and plasma cells. The CARVYKTI® CAR protein features two BCMA-targeting single domains designed to confer high avidity against human BCMA. Upon binding to BCMA-expressing cells, the CAR promotes T-cell activation, expansion, and elimination of target cells. In December 2017, Janssen Biotech, Inc., a Johnson & Johnson company, entered into an exclusive worldwide license and collaboration agreement with Legend Biotech USA, Inc. to develop and commercialize CARVYKTI®. For more information, visit . About Multiple Myeloma Multiple myeloma is an incurable blood cancer that affects a type of white blood cell called plasma cells, which are found in the bone marrow.5 In multiple myeloma, these plasma cells change, spread rapidly and replace normal cells in the bone marrow with tumors.6 In 2024, it is estimated that more than 35,000 people will be diagnosed with multiple myeloma, and more than 12,000 people will die from the disease in the U.S.2 While some people diagnosed with multiple myeloma initially have no symptoms, most patients are diagnosed due to symptoms that can include bone fracture or pain, low red blood cell counts, tiredness, high calcium levels, kidney problems, or infections.7,8 INDICATIONS AND USAGE CARVYKTI® (ciltacabtagene autoleucel) is a B-cell maturation antigen (BCMA)-directed genetically modified autologous T cell immunotherapy indicated for the treatment of adult patients with relapsed or refractory multiple myeloma, who have received at least 1 prior line of therapy, including a proteasome inhibitor and an immunomodulatory agent, and are refractory to lenalidomide. IMPORTANT SAFETY INFORMATION WARNINGS AND PRECAUTIONS Increased early mortality - In CARTITUDE-4, a (1:1) randomized controlled trial, there was a numerically higher percentage of early deaths in patients randomized to the CARVYKTI® treatment arm compared to the control arm. Among patients with deaths occurring within the first 10 months from randomization, a greater proportion (29/208; 14%) occurred in the CARVYKTI® arm compared to (25/211; 12%) in the control arm. Of the 29 deaths that occurred in the CARVYKTI® arm within the first 10 months of randomization, 10 deaths occurred prior to CARVYKTI® infusion, and 19 deaths occurred after CARVYKTI® infusion. Of the 10 deaths that occurred prior to CARVYKTI® infusion, all occurred due to disease progression, and none occurred due to adverse events. Of the 19 deaths that occurred after CARVYKTI® infusion, 3 occurred due to disease progression, and 16 occurred due to adverse events. The most common adverse events were due to infection (n=12). Cytokine release syndrome (CRS), including fatal or life-threatening reactions, occurred following treatment with CARVYKTI®. Among patients receiving CARVYKTI® for RRMM in the CARTITUDE-1 & 4 studies (N=285), CRS occurred in 84% (238/285), including ≥Grade 3 CRS (ASCT 2019) in 4% (11/285) of patients. Median time to onset of CRS, any grade, was 7 days (range: 1 to 23 days). CRS resolved in 82% with a median duration of 4 days (range: 1 to 97 days). The most common manifestations of CRS in all patients combined (≥10%) included fever (84%), hypotension (29%) and aspartate aminotransferase increased (11%). Serious events that may be associated with CRS include pyrexia, hemophagocytic lymphohistiocytosis, respiratory failure, disseminated intravascular coagulation, capillary leak syndrome, and supraventricular and ventricular tachycardia. CRS occurred in 78% of patients in CARTITUDE-4 (3% Grade 3 to 4) and in 95% of patients in CARTITUDE-1 (4% Grade 3 to 4). Identify CRS based on clinical presentation. Evaluate for and treat other causes of fever, hypoxia, and hypotension. CRS has been reported to be associated with findings of HLH/MAS, and the physiology of the syndromes may overlap. HLH/MAS is a potentially life-threatening condition. In patients with progressive symptoms of CRS or refractory CRS despite treatment, evaluate for evidence of HLH/MAS. Ensure that a minimum of two doses of tocilizumab are available prior to infusion of CARVYKTI®. Of the 285 patients who received CARVYKTI® in clinical trials, 53% (150/285) patients received tocilizumab; 35% (100/285) received a single dose, while 18% (50/285) received more than 1 dose of tocilizumab. Overall, 14% (39/285) of patients received at least one dose of corticosteroids for treatment of CRS. Monitor patients at least daily for 10 days following CARVYKTI® infusion at a REMS-certified healthcare facility for signs and symptoms of CRS. Monitor patients for signs or symptoms of CRS for at least 4 weeks after infusion. At the first sign of CRS, immediately institute treatment with supportive care, tocilizumab, or tocilizumab and corticosteroids. Counsel patients to seek immediate medical attention should signs or symptoms of CRS occur at any time. Neurologic toxicities, which may be severe, life-threatening, or fatal, occurred following treatment with CARVYKTI®. Neurologic toxicities included ICANS, neurologic toxicity with signs and symptoms of parkinsonism, GBS, immune mediated myelitis, peripheral neuropathies, and cranial nerve palsies. Counsel patients on the signs and symptoms of these neurologic toxicities, and on the delayed nature of onset of some of these toxicities. Instruct patients to seek immediate medical attention for further assessment and management if signs or symptoms of any of these neurologic toxicities occur at any time. Among patients receiving CARVYKTI® in the CARTITUDE-1 & 4 studies for RRMM, one or more neurologic toxicities occurred in 24% (69/285), including ≥Grade 3 cases in 7% (19/285) of patients. Median time to onset was 10 days (range: 1 to 101) with 63/69 (91%) of cases developing by 30 days. Neurologic toxicities resolved in 72% (50/69) of patients with a median duration to resolution of 23 days (range: 1 to 544). Of patients developing neurotoxicity, 96% (66/69) also developed CRS. Subtypes of neurologic toxicities included ICANS in 13%, peripheral neuropathy in 7%, cranial nerve palsy in 7%, parkinsonism in 3%, and immune mediated myelitis in 0.4% of the patients. Immune Effector Cell-associated Neurotoxicity Syndrome (ICANS): Patients receiving CARVYKTI® may experience fatal or life-threatening ICANS following treatment with CARVYKTI®, including before CRS onset, concurrently with CRS, after CRS resolution, or in the absence of CRS. Among patients receiving CARVYKTI® in the CARTITUDE-1 & 4 studies, ICANS occurred in 13% (36/285), including Grade ≥3 in 2% (6/285) of the patients. Median time to onset of ICANS was 8 days (range: 1 to 28 days). ICANS resolved in 30 of 36 (83%) of patients with a median time to resolution of 3 days (range: 1 to 143 days). Median duration of ICANS was 6 days (range: 1 to 1229 days) in all patients including those with ongoing neurologic events at the time of death or data cut off. Of patients with ICANS 97% (35/36) had CRS. The onset of ICANS occurred during CRS in 69% of patients, before and after the onset of CRS in 14% of patients respectively. Immune Effector Cell-associated Neurotoxicity Syndrome occurred in 7% of patients in CARTITUDE-4 (0.5% Grade 3) and in 23% of patients in CARTITUDE-1 (3% Grade 3). The most frequent ≥2% manifestations of ICANS included encephalopathy (12%), aphasia (4%), headache (3%), motor dysfunction (3%), ataxia (2%) and sleep disorder (2%). Monitor patients at least daily for 10 days following CARVYKTI® infusion at the REMS-certified healthcare facility for signs and symptoms of ICANS. Rule out other causes of ICANS symptoms. Monitor patients for signs or symptoms of ICANS for at least 4 weeks after infusion and treat promptly. Neurologic toxicity should be managed with supportive care and/or corticosteroids as needed. Parkinsonism: Neurologic toxicity with parkinsonism has been reported in clinical trials of CARVYKTI®. Among patients receiving CARVYKTI® in the CARTITUDE-1 & 4 studies, parkinsonism occurred in 3% (8/285), including Grade ≥ 3 in 2% (5/285) of the patients. Median time to onset of parkinsonism was 56 days (range: 14 to 914 days). Parkinsonism resolved in 1 of 8 (13%) of patients with a median time to resolution of 523 days. Median duration of parkinsonism was 243.5 days (range: 62 to 720 days) in all patients including those with ongoing neurologic events at the time of death or data cut off. The onset of parkinsonism occurred after CRS for all patients and after ICANS for 6 patients. Parkinsonism occurred in 1% of patients in CARTITUDE-4 (no Grade 3 to 4) and in 6% of patients in CARTITUDE-1 (4% Grade 3 to 4). Manifestations of parkinsonism included movement disorders, cognitive impairment, and personality changes. Monitor patients for signs and symptoms of parkinsonism that may be delayed in onset and managed with supportive care measures. There is limited efficacy information with medications used for the treatment of Parkinson's disease for the improvement or resolution of parkinsonism symptoms following CARVYKTI® treatment. Guillain-Barré syndrome: A fatal outcome following GBS occurred following treatment with CARVYKTI® despite treatment with intravenous immunoglobulins. Symptoms reported include those consistent with Miller-Fisher variant of GBS, encephalopathy, motor weakness, speech disturbances, and polyradiculoneuritis. Monitor for GBS. Evaluate patients presenting with peripheral neuropathy for GBS. Consider treatment of GBS with supportive care measures and in conjunction with immunoglobulins and plasma exchange, depending on severity of GBS. Immune mediated myelitis: Grade 3 myelitis occurred 25 days following treatment with CARVYKTI® in CARTITUDE-4 in a patient who received CARVYKTI® as subsequent therapy. Symptoms reported included hypoesthesia of the lower extremities and the lower abdomen with impaired sphincter control. Symptoms improved with the use of corticosteroids and intravenous immune globulin. Myelitis was ongoing at the time of death from other cause. Peripheral neuropathy occurred following treatment with CARVYKTI®. Among patients receiving CARVYKTI® in the CARTITUDE-1 & 4 studies, peripheral neuropathy occurred in 7% (21/285), including Grade ≥3 in 1% (3/285) of the patients. Median time to onset of peripheral neuropathy was 57 days (range: 1 to 914 days). Peripheral neuropathy resolved in 11 of 21 (52%) of patients with a median time to resolution of 58 days (range: 1 to 215 days). Median duration of peripheral neuropathy was 149.5 days (range: 1 to 692 days) in all patients including those with ongoing neurologic events at the time of death or data cut off. Peripheral neuropathies occurred in 7% of patients in CARTITUDE-4 (0.5% Grade 3 to 4) and in 7% of patients in CARTITUDE-1 (2% Grade 3 to 4). Monitor patients for signs and symptoms of peripheral neuropathies. Patients who experience peripheral neuropathy may also experience cranial nerve palsies or GBS. Cranial nerve palsies occurred following treatment with CARVYKTI®. Among patients receiving CARVYKTI® in the CARTITUDE-1 & 4 studies, cranial nerve palsies occurred in 7% (19/285), including Grade ≥3 in 1% (1/285) of the patients. Median time to onset of cranial nerve palsies was 21 days (range: 17 to 101 days). Cranial nerve palsies resolved in 17 of 19 (89%) of patients with a median time to resolution of 66 days (range: 1 to 209 days). Median duration of cranial nerve palsies was 70 days (range: 1 to 262 days) in all patients including those with ongoing neurologic events at the time of death or data cut off. Cranial nerve palsies occurred in 9% of patients in CARTITUDE-4 (1% Grade 3 to 4) and in 3% of patients in CARTITUDE-1 (1% Grade 3 to 4). The most frequent cranial nerve affected was the 7th cranial nerve. Additionally, cranial nerves III, V, and VI have been reported to be affected. Monitor patients for signs and symptoms of cranial nerve palsies. Consider management with systemic corticosteroids, depending on the severity and progression of signs and symptoms. Hemophagocytic Lymphohistiocytosis (HLH)/Macrophage Activation Syndrome (MAS): Among patients receiving CARVYKTI® in the CARTITUDE-1 & 4 studies, HLH/MAS occurred in 1% (3/285) of patients. All events of HLH/MAS had onset within 99 days of receiving CARVYKTI®, with a median onset of 10 days (range: 8 to 99 days) and all occurred in the setting of ongoing or worsening CRS. The manifestations of HLH/MAS included hyperferritinemia, hypotension, hypoxia with diffuse alveolar damage, coagulopathy and hemorrhage, cytopenia and multi-organ dysfunction, including renal dysfunction and respiratory failure. Patients who develop HLH/MAS have an increased risk of severe bleeding. Monitor hematologic parameters in patients with HLH/MAS and transfuse per institutional guidelines. Fatal cases of HLH/MAS occurred following treatment with CARVYKTI®. HLH is a life-threatening condition with a high mortality rate if not recognized and treated early. Treatment of HLH/MAS should be administered per institutional standards. CARVYKTI® REMS: Because of the risk of CRS and neurologic toxicities, CARVYKTI® is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the CARVYKTI® REMS. Further information is available at or 1-844-672-0067. Prolonged and Recurrent Cytopenias: Patients may exhibit prolonged and recurrent cytopenias following lymphodepleting chemotherapy and CARVYKTI® infusion. Among patients receiving CARVYKTI® in the CARTITUDE-1 & 4 studies, Grade 3 or higher cytopenias not resolved by day 30 following CARVYKTI® infusion occurred in 62% (176/285) of the patients and included thrombocytopenia 33% (94/285), neutropenia 27% (76/285), lymphopenia 24% (67/285) and anemia 2% (6/285). After Day 60 following CARVYKTI® infusion 22%, 20%, 5%, and 6% of patients had a recurrence of Grade 3 or 4 lymphopenia, neutropenia, thrombocytopenia, and anemia respectively, after initial recovery of their Grade 3 or 4 cytopenia. Seventy-seven percent (219/285) of patients had one, two or three or more recurrences of Grade 3 or 4 cytopenias after initial recovery of Grade 3 or 4 cytopenia. Sixteen and 25 patients had Grade 3 or 4 neutropenia and thrombocytopenia, respectively, at the time of death. Monitor blood counts prior to and after CARVYKTI® infusion. Manage cytopenias with growth factors and blood product transfusion support according to local institutional guidelines. Infections: CARVYKTI® should not be administered to patients with active infection or inflammatory disorders. Severe, life-threatening, or fatal infections, occurred in patients after CARVYKTI® infusion. Among patients receiving CARVYKTI® in the CARTITUDE-1 & 4 studies, infections occurred in 57% (163/285), including ≥Grade 3 in 24% (69/285) of patients. Grade 3 or 4 infections with an unspecified pathogen occurred in 12%, viral infections in 6%, bacterial infections in 5%, and fungal infections in 1% of patients. Overall, 5% (13/285) of patients had Grade 5 infections, 2.5% of which were due to COVID-19. Patients treated with CARVYKTI® had an increased rate of fatal COVID-19 infections compared to the standard therapy arm. Monitor patients for signs and symptoms of infection before and after CARVYKTI® infusion and treat patients appropriately. Administer prophylactic, pre-emptive and/or therapeutic antimicrobials according to the standard institutional guidelines. Febrile neutropenia was observed in 5% of patients after CARVYKTI® infusion and may be concurrent with CRS. In the event of febrile neutropenia, evaluate for infection and manage with broad-spectrum antibiotics, fluids and other supportive care, as medically indicated. Counsel patients on the importance of prevention measures. Follow institutional guidelines for the vaccination and management of immunocompromised patients with COVID-19. Viral Reactivation: Hepatitis B virus (HBV) reactivation, in some cases resulting in fulminant hepatitis, hepatic failure and death, can occur in patients with hypogammaglobulinemia. Perform screening for Cytomegalovirus (CMV), HBV, hepatitis C virus (HCV), and human immunodeficiency virus (HIV) or any other infectious agents if clinically indicated in accordance with clinical guidelines before collection of cells for manufacturing. Consider antiviral therapy to prevent viral reactivation per local institutional guidelines/clinical practice. Hypogammaglobulinemia: can occur in patients receiving treatment with CARVYKTI®. Among patients receiving CARVYKTI® in the CARTITUDE-1 & 4 studies, hypogammaglobulinemia adverse event was reported in 36% (102/285) of patients; laboratory IgG levels fell below 500mg/dl after infusion in 93% (265/285) of patients. Hypogammaglobulinemia either as an adverse reaction or laboratory IgG level below 500mg/dl, after infusion occurred in 94% (267/285) of patients treated. Fifty six percent (161/285) of patients received intravenous immunoglobulin (IVIG) post CARVYKTI® for either an adverse reaction or prophylaxis. Monitor immunoglobulin levels after treatment with CARVYKTI® and administer IVIG for IgG <400 mg/dL. Manage per local institutional guidelines, including infection precautions and antibiotic or antiviral prophylaxis. Use of Live Vaccines: The safety of immunization with live viral vaccines during or following CARVYKTI® treatment has not been studied. Vaccination with live virus vaccines is not recommended for at least 6 weeks prior to the start of lymphodepleting chemotherapy, during CARVYKTI® treatment, and until immune recovery following treatment with CARVYKTI®. Hypersensitivity Reactions occurred following treatment with CARVYKTI®. Among patients receiving CARVYKTI® in the CARTITUDE-1 & 4 studies, hypersensitivity reactions occurred in 5% (13/285), all of which were ≤Grade 2. Manifestations of hypersensitivity reactions included flushing, chest discomfort, tachycardia, wheezing, tremor, burning sensation, non-cardiac chest pain, and pyrexia. Serious hypersensitivity reactions, including anaphylaxis, may be due to the dimethyl sulfoxide (DMSO) in CARVYKTI®. Patients should be carefully monitored for 2 hours after infusion for signs and symptoms of severe reaction. Treat promptly and manage patients appropriately according to the severity of the hypersensitivity reaction. Secondary Malignancies: Patients treated with CARVYKTI® may develop secondary malignancies. Among patients receiving CARVYKTI® in the CARTITUDE-1 & 4 studies, myeloid neoplasms occurred in 5% (13/285) of patients (9 cases of myelodysplastic syndrome, 3 cases of acute myeloid leukemia, and 1 case of myelodysplastic syndrome followed by acute myeloid leukemia). The median time to onset of myeloid neoplasms was 447 days (range: 56 to 870 days) after treatment with CARVYKTI®. Ten of these 13 patients died following the development of myeloid neoplasms; 2 of the 13 cases of myeloid neoplasm occurred after initiation of subsequent antimyeloma therapy. Cases of myelodysplastic syndrome and acute myeloid leukemia have also been reported in the post marketing setting. T-cell malignancies have occurred following treatment of hematologic malignancies with BCMA- and CD19-directed genetically modified autologous T-cell immunotherapies, including CARVYKTI®. Mature T-cell malignancies, including CAR-positive tumors, may present as soon as weeks following infusions, and may include fatal outcomes. Monitor life-long for secondary malignancies. In the event that a secondary malignancy occurs, contact Janssen Biotech, Inc. at 1-800-526-7736 for reporting and to obtain instructions on collection of patient samples. Effects on Ability to Drive and Use Machines: Due to the potential for neurologic events, including altered mental status, seizures, neurocognitive decline or neuropathy, patients receiving CARVYKTI® are at risk for altered or decreased consciousness or coordination in the 8 weeks following CARVYKTI® infusion. Advise patients to refrain from driving and engaging in hazardous occupations or activities, such as operating heavy or potentially dangerous machinery during this initial period, and in the event of new onset of any neurologic toxicities. ADVERSE REACTIONS The most common nonlaboratory adverse reactions (incidence greater than 20%) are pyrexia, cytokine release syndrome, hypogammaglobulinemia, hypotension, musculoskeletal pain, fatigue, infections-pathogen unspecified, cough, chills, diarrhea, nausea, encephalopathy, decreased appetite, upper respiratory tract infection, headache, tachycardia, dizziness, dyspnea, edema, viral infections, coagulopathy, constipation, and vomiting. The most common Grade 3 or 4 laboratory adverse reactions (incidence greater than or equal to 50%) include lymphopenia, neutropenia, white blood cell decreased, thrombocytopenia, and anemia. Please read full Prescribing Information, including Boxed Warning, for CARVYKTI®. About Johnson & Johnson At Johnson & Johnson, we believe health is everything. Our strength in healthcare innovation empowers us to build a world where complex diseases are prevented, treated, and cured, where treatments are smarter and less invasive, and solutions are personal. Through our expertise in Innovative Medicine and MedTech, we are uniquely positioned to innovate across the full spectrum of healthcare solutions today to deliver the breakthroughs of tomorrow, and profoundly impact health for humanity. Learn more at or at . Follow us at @JanssenUS and @JNJInnovMed. Janssen Research & Development, LLC, and Janssen Biotech, Inc., are both Johnson & Johnson companies. Cautions Concerning Forward-Looking Statements This press release contains "forward-looking statements" as defined in the Private Securities Litigation Reform Act of 1995 regarding product development of CARVYKTI®. The reader is cautioned not to rely on these forward-looking statements. These statements are based on current expectations of future events. If underlying assumptions prove inaccurate or known or unknown risks or uncertainties materialize, actual results could vary materially from the expectations and projections of Janssen Research & Development, LLC, Janssen Biotech, Inc., and/or Johnson & Johnson. Risks and uncertainties include, but are not limited to: challenges and uncertainties inherent in product research and development, including the uncertainty of clinical success and of obtaining regulatory approvals; uncertainty of commercial success; manufacturing difficulties and delays; competition, including technological advances, new products and patents attained by competitors; challenges to patents; product efficacy or safety concerns resulting in product recalls or regulatory actions; changes in behavior and spending patterns of purchasers of health care products and services; changes to applicable laws and regulations, including global health care reforms; and trends toward health care cost containment. A further list and descriptions of these risks, uncertainties and other factors can be found in Johnson & Johnson's Annual Report on Form 10-K for the fiscal year ended December 31, 2023, including in the sections captioned "Cautionary Note Regarding Forward-Looking Statements" and "Item 1A. Risk Factors," and in Johnson & Johnson's subsequent Quarterly Reports on Form 10-Q and other filings with the Securities and Exchange Commission. Copies of these filings are available online at , or on request from Johnson & Johnson. None of Janssen Research & Development, LLC, Janssen Biotech, Inc. nor Johnson & Johnson undertakes to update any forward-looking statement as a result of new information or future events or developments. * Dr. Dhakal has provided consulting, advisory, and speaking services to Johnson & Johnson; he has not been paid for any media work. CARVYKTI® [Prescribing Information]. Horsham, PA: Janssen Biotech Inc. American Cancer Society. Key statistics about multiple myeloma. Accessed March 2024. Fonseca R, Usmani S, Mehra M, et al. Frontline treatment patterns and attrition rates by subsequent lines of therapy in patients with newly diagnosed multiple myeloma. 2020. Accessed March 2024. . ClinicalTrials.Gov. A study comparing JNJ-68284528, a CAR-T therapy directed against B-cell maturation antigen (BCMA), versus pomalidomide, bortezomib and dexamethasone (PVd) or daratumumab, pomalidomide and dexamethasone (DPd) in participants with relapsed and lenalidomide-refractory multiple myeloma (CARTITUDE-4). Accessed March 2024. Gandhi U, Cornell R, Lakshman A, et al. Outcomes of patients with multiple myeloma refractory to CD38-targeted monoclonal antibody therapy. Leukemia. 2019;33(9). Accessed March 2024. National Cancer Institute. Plasma Cell Neoplasms. . Accessed March 2024. American Cancer Society. What is Multiple Myeloma? . Accessed March 2024. American Cancer Society. Multiple Myeloma Early Detection, Diagnosis, and Staging. . Accessed March 2024. SOURCE Johnson & Johnson

疫苗一词是“疫苗之父”巴斯德( Louis Pasteur) 为纪念先驱者琴纳( Edward Jenner) 发明牛痘苗( vaccine) 而创造，指由减毒或灭活微生物制成、能够针对疾病产生免疫力的生物制品。疫苗作为人类与疾病斗争的有力武器，消灭或控制了许多传染病。脊髓灰质炎、鼠疫、麻疹、狂犬病、百日咳、破伤风、乙型病毒性肝炎(乙肝) 等发病率也通过接种疫苗大幅降低。自 18 世纪天花疫苗诞生至今，疫苗研发经历了数百年的发展其技术发展经历了 3 次革命。第一次始于 19 世纪末，巴斯德研制成功鸡霍乱疫苗、羊炭疽疫苗和狂犬疫苗，并利用生物传代和物理化学方法处理病原体，得到减毒和灭活疫苗; 第二次发生在 20 世纪 80 年代，其标志是以酵母制造乙肝疫苗。这一阶段，以重组 DNA 技术为代表的分子生物学技术的发展，使疫苗的研究从整体病原体水平进阶到分子水平; 第三次是 20 世纪 90 年代研制成功核酸疫苗，该技术最早由美国的沃夫( Wolff) 等发明。人类使用疫苗预防疾病已有200多年的历史，疫苗作为人类与疾病斗争的有力武器，消灭或控制了许多传染病。今天我们就来回顾一下，疫苗经历了怎样的发展轨迹？疫苗发展历程梳理一、萌芽期疫苗的横空出世首先得从天花病毒说起。天花是一种烈性传染病，不论什么人，一旦与患者接触，几乎都会传染，并且死亡率极高。但是在长时间的医疗中发现，有两种人是对天花有抵抗力的：一是从天花中康复的人，二是曾经护理过天花病的人。我们的前人在这种现象的启发下，研究出了用人痘接种预防天花的方法。该方法是将沾有疤浆患者的衣服给正常儿童穿戴，或将天花愈合后局部皮肤组织研磨成细粉，经鼻使儿童吸入。我们的前人在这种现象的启发下，研究出了用人痘接种预防天花的方法。该方法是将沾有疤浆患者的衣服给正常儿童穿戴，或将天花愈合后局部皮肤组织研磨成细粉，经鼻使儿童吸入。不过因为风险太大，这个技术一直没有推广开来，但这个技术的发展却给了人们很大的启发，让他们找到了对抗天花的方法。在18世纪末，一名英国的乡下大夫爱德华-琴纳接待一名妇女，她患有发烧、腰疼、呕吐等症状，他从中意识到接种牛痘可以预防天花。为了证实这一设想，他于1796年5月14日从一名正患牛痘的挤奶女工身上的脓疤里取少量脓液注射至八岁男孩詹姆斯费普臂内。六周后，男孩的牛痘反应消退，所以正如琴纳所说：“尽管假性天花接种小孩手臂出现类似的脓疤，除此之外几乎不可觉察。”琴纳为了证实其效果，先后多次给费普接种，但费普却安然无恙。2个月后，再接种天花患者来源的痘液，费普仅局部手臂出现疤疹，未引起全身天花。据此，琴纳于1798年出版其专著《探究》，称此技术为疫苗接种。在琴纳那个时代，人们根本不知道天花是由一种病毒引起的，也不知道种痘能让身体产生一种对抗天花的免疫。但是，经过他的实际观察，经过试验，确定了一种新的疫苗接种法，它不仅安全，而且很有效，是一个划时代的发明。琴纳（公元1749年—公元1823年）二、第一次疫苗革命这一阶段疫苗的发展归功于路易·巴斯德于19世纪末在疫苗研制领域的先锋作用和卓越贡献。被誉为疫苗之父的巴斯德的伟大贡献在于：他选用免疫原性强的病原微生物经培养，用物理或化学方法将其灭活后，再经纯化制成。灭活疫苗使用的毒种一般是强毒株，但使用减毒的弱毒株也有良好的免疫原性，如用萨宾减毒株生产的脊髓灰质炎灭活疫苗。减毒活疫苗是采用人工定向变异的方法，或从自然界筛选出毒力高度减弱或基本无毒的活的微生物制成疫苗，并以此给人接种而达到预防传染病的目的。在19世纪末，科赫发明了在固体培养基上分离细菌培养物的方法，该法为巴斯德研制疫苗奠定了基础。巴斯德首次发现，长期在人工培养基上，如将鸡霍乱弧菌置于两个星期后，这种菌种对雏鸡不会造成致病性。还有一点很重要：即使再次给这些被注射过的雏鸡注射了霍乱，他们也不会感染。巴斯德提出，这可能是因为在老的培养基中，鸡霍乱弧菌的毒性降低，但是其免疫原性保持不变，从而导致雏鸡对霍乱弧菌有了免疫力。以此理论巴斯德将炭疽杆菌在42~43℃的环境下培养两周后，制成人工减毒炭疽活疫苗。在巴斯德光辉成就的启发下，1908年卡麦特和古林将一株牛型结核杆菌在含有胆汁的培养基上连续培养13年213代，终于在1921获得减毒的卡介苗(BCG)。最初卡介苗为口服，20世纪20年代末改为皮内注射，卡介苗在新生儿抵御粟粒性肺结核和结核性脑膜炎方面具有很好的效果。自1928年至今，卡介苗仍在全世界广泛地被用于儿童计划免疫接种，已有40多亿人接种过卡介苗。这一阶段疫苗革命中还包括白喉、破伤风类毒素、鼠疫疫苗、伤寒疫苗和黄热病等30多种疫苗的成功研制。巴斯德三、第二次疫苗革命第二次疫苗革命主要是从分子水平上制备基因工程亚单位疫苗。由于分子生物技术、生物化学、遗传学和免疫学的迅速发展，使得研制新疫苗和改进旧疫苗的工作能 够在分子水平上进行。以酵母制备乙肝疫苗作为二次疫苗革命的分水岭。采用重组DNA技术、蛋白质化学技术开创了疫苗研制的第二次革命。1.重组核酸技术美国斯坦福大学于1972年提出重组核酸技术，并以迅雷不及掩耳之势风靡世界，开创了生命科学的新局面，其中包括疫苗的研制。基因重组技术的运用，为疫苗的研发提供了一条崭新的道路。该技术不仅可以获得几乎所有的免疫原，还可以让病原微生物的研究者和疫苗的接种者变得更加安全。例如，乙肝疫苗最初是从人乙型肝炎表面抗原(HBsAg)携带者血浆中提取，对健康人来说，其接种的危险性显而易见。20世纪80年代，又有研究报道了 HBsAg的基因在酵母和真核细胞中的表达，该方法既可获得类似于血液疫苗的免疫效果，又可获得简单、快速、廉价、高效的 HBsAg的抗体，对接种人群具有较高的安全性。当前，在不改变疫苗抗原性的前提下，利用重组核酸技术，以病毒、细菌作为载体，将目标基因导入到疫苗菌株及其质粒的基因组中，从而在不改变其抗原性的情况下，实现对疫苗菌株的高表达。所以，该疫苗对人体所起到的免疫作用是双向的。例如，第一次疫苗革命产生的卡介苗，现在采用重组核酸技术将γ-干扰素(IFN-γ)、白细胞介素2(IL-2)等细胞因子基因导入卡介苗中，成为重组卡介苗(γBCG)。重组卡介苗不仅保留传统卡介苗的特性，同时还分泌γ-干扰素和白细胞介素2，这样重组卡介苗既可用于结核病的预防，又能用于肿瘤或其他免疫性疾病的治疗。2.蛋白质化学和化学技术由于疫苗中的保护性抗原大部分为蛋白质，所以要得到特异性的蛋白质抗原，必须先对其进行分离纯化，由此可见蛋白质化学技术的发展对疫苗的研制起着重大作用。另外，可根据骨髓依赖性(B)淋巴细胞表位或胸腺依赖性(T)淋巴细胞表位直接采用蛋白质化学和化学技术合成多肤抗原，用来制备多肤疫苗。四、第三次疫苗革命核酸疫苗的开发研制，标志着第三次疫苗革命的到来。1995年美国纽约科学院召开专门研讨核酸疫苗会议，称之为疫苗学的新纪元和疫苗的第三次革命。1.核酸疫苗的发现和研制沃夫等人偶然的研究成果以及阿瑟的基因递送体系，为发展新型核酸疫苗奠定了基础。20世纪80年代后期，90年代初期，人们利用表达基因的核酸进行基因疗法，发现不经任何处理的裸露基因，可以在肌肉细胞内表达蛋白质，并且可以在肌肉细胞内持续两个月，引起人体产生免疫反应，由此引发了一场核酸疫苗的研发。在最初的动物实验中有两个令人欣喜的结果:第一是A型流感病毒核酸疫苗注射给小鼠，结果诱发了小鼠产生抗体和细胞毒性T细胞。然后用A型流感(PR/8) 攻击，100%小鼠健康存活，而对照组100%在9天后死亡。几乎同时，费南(Fynan)等人使用基因枪和编码红细胞凝集素的核酸，其结果也使小鼠获得 保护性免疫应答。另一个重要的研究结果是乙肝表面抗原的核酸疫苗。该疫苗不但能诱导动物产生相应的抗体，还能让转基因动物体内的 HBV表面抗原呈阴性。因此，可以用核酸疫苗来预防和治疗疾病，特别是对乙型肝炎的核酸疫苗。该结果对目前国内乙型肝炎疫苗的研发具有一定的指导意义。2.核酸疫苗的应用前景核酸疫苗的研究进展令人鼓舞，核酸疫苗因其独特的优势，在免疫防治中发挥了重要作用。因此，自1994年以来，美国 FDA先后批准了包括 AIDS，流感，乙肝，单纯疤疹，疟疾，Cancer在内的几种核酸疫苗的临床试验。欧美各国都投入了大量的人力物力，对核酸疫苗进行了研发。核酸疫苗已用于淋巴瘤、黑色素瘤、结肠癌及前列腺癌的临床前治疗研究。据统计，1989年至2004年，全球得到认可的基因治疗临床试验共9987例，仅肿瘤治疗占66%。然而，由于其高致死率，迄今尚无针对肝癌 DNA疫苗进行临床研究的相关报道。因此，开展肝癌核酸疫苗临床应用的研究具有重要意义。核酸疫苗也被广泛应用于基因缺陷导致的免疫缺陷疾病的治疗，其中以 ADA基因为代表的基因治疗是目前最有效的一种。mRNA 疫苗技术在新冠疫情应对中市场前景得到较大提升。2020年是 mRNA 技术平台的突破元年，新冠 mRNA 疫苗的推出和广泛使用极大提升了mRNA 疫苗的融资和市场活力。目前开发中的 mRNA 制剂有3个主要应用：预防性疫苗、治疗性疫苗和治疗药物。复星与拜恩泰科研发的mRNA新冠疫苗样品人类在200多年前就开始应用疫苗，它为我们构筑了一道强有力的生物屏障，使我们免受病毒的攻击。在这次疫情之后，疫苗是人类的“保护神”，这一点是毋庸置疑的。随着技术的进步，经过科学家们的不懈努力，将会有更多的治疗性和预防性疫苗被研制出来。疫苗对于人体的作用，无论怎样夸张也不为过，因为每一种新型疫苗的出现，都代表着一场人类对某种疾病的胜利！参考：[1]许丽丽,陈艳,陈征宇等.疫苗的发展与创新：从天花疫苗到新型冠状病毒疫苗[J].医药导报,2021,40(07):876-881.[2]贾冰冰,李卫国.疫苗技术发展的历史与展望[J].生物学通报,2016,51(06):1-3.[3]https://www.nobelprize.org/prizes/lists/all-nobel-prizes/[4]https://www.nature.com/immersive/d42859-020-00005-8/index.html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。

▲ 详细日程见文末 ▲传染性支气管炎病毒（IBV）是家禽养殖场的重要病原体，可引发呼吸道、肾病理学、输卵管、前胃和肠道疾病。根据全长S1基因的系统发育分类，IBV分离物已被划分为包括38个谱系的九个基因型。在过去的60年中，中国已报道了GI（GI-1、GI-2、GI-3、GI-4、GI-5、GI-6、GI-7、GI-13、GI-16、GI-18、GI-19、GI-22、GI-28、和GI-29）、GVI-1和GVII-1。本综述介绍了中国IBV的简要历史，并突出了目前的流行株、已获许可的IBV疫苗株，以及IBV的预防和控制策略。此外，文章提出了对IBV更有效管理的独特观点和建议。表达IBV QX样和4/91株S基因的重组新城疫病毒（NDV）载体疫苗可能成为对抗NDV和IBV的主导疫苗株。1动物冠状病毒简介自2019年冠状病毒病（COVID-19）爆发以来，截至2022年12月7日，根据世界卫生组织网站，全球已有超过6.42亿例确认病例和6.6百万例由冠状病毒感染导致的确认死亡病例。自首例确认病例公布以来，COVID-19大流行已经持续了近3年，该病毒导致了全球范围内的显著经济损失（1）。为了应对这一病毒，科学家和卫生工作者展现了他们的专业素养。从最初的病例护理到当前的疫苗免疫，越来越多的国家将在疫苗接种率超过85%时考虑开放边界，表明疫苗免疫仍然是预防冠状病毒感染的关键技术。动物冠状病毒一直备受关注，有一些重要的冠状病毒严重危害牛群和家禽业经济，例如猪传染性胃肠炎病毒（TGEV）、猪流行性腹泻病毒（PEDV）、猪Delta冠状病毒（PDCoV）、犬冠状病毒（CCoV）、猫冠状病毒（FCoV）和禽传染性支气管炎病毒（IBV）（表1）。尽管第一个冠状病毒是在1930年代发现的，但在2002年至2003年间，由SARS冠状病毒引起的严重急性呼吸综合症（SARS）大流行在许多国家和地区席卷，引发了广泛的社会恐慌，冠状病毒因此引起了广泛关注（2）。在此之前，对冠状病毒的研究主要限于兽医领域。禽传染性支气管炎病毒在鸡中具有极高的传染性，是导致严重呼吸系统障碍的主要原因，并在中国家禽业中构成重大威胁。表1.主要的动物冠状病毒。注：BCoV，牛冠状病毒；ECoV，马冠状病毒；CrCoV，犬冠状病毒；MHV，小鼠肝炎病毒；PHEV，猪血凝病毒；BWCoV-SW1，白鲸冠状病毒SW1；CMCoV，普通水鸡冠状病毒。IBV属于冠状病毒的γ群。其完整基因组约为27.6kb，由5′-1a-1b-S（S1、S2）-3a-3b-3c（E）-M-5a-5b-N-Poly(A)-3′从5′端到3′端组成（3）。IBV基因组编码四种结构蛋白，即刺突蛋白（S）、小包膜蛋白（E）、膜蛋白（M）和核衣蛋白（N）。在这四种结构蛋白中，S蛋白包含IBV的主要保护性抗原表位，并能刺激机体产生中和抗体。同时，S蛋白在病毒吸附到细胞的过程中也发挥着至关重要的作用，因此在一定程度上决定了病毒对组织的病毒学亲和性（4）。S蛋白的C端的一小部分埋入包膜膜中，其余部分位于包膜膜外形成病毒刺突。S蛋白由氨基酸N端的S1和氨基酸C端的S2组成，它们分别由520和625个氨基酸组成，并通过二硫键连接（5, 6）。此外，S1蛋白有三个与IBV血清型密切相关的高度可变区，表明S1基因核苷酸是IBV基因分型的主要决定因素。2中国禽传染性支气管炎病毒（IBV）历史禽传染性支气管炎病毒（IBV）首次于1931年在美国被描述为鸡的呼吸道疾病。1965年，世界上首个人类冠状病毒被从患有普通感冒的患者的鼻分泌物中分离出来。1975年，冠状病毒正式被国际病毒命名委员会（现在更名为国际病毒分类委员会（ICTV））命名为冠状病毒科，目前根据病毒血清学特征和核苷酸序列差异，冠状病毒科被划分为两个属，即冠状病毒属和圆环病毒属。像严重急性呼吸综合症冠状病毒（SARSV）、禽传染性支气管炎病毒（IBV）、猪传染性胃肠炎病毒（TGEV）和猪流行性腹泻病毒（PEDV）等常见的重要冠状病毒属于冠状病毒属。IBV在中国已存在60多年（图1）。1958年，IBV爆发在中国台湾省。TW-I和TW-II基因型于1990年代初首次被鉴定，并被认为是明显不同的基因型。1972年，IBV首次在中国大陆的一家家禽养殖场报道。随后，IBV迅速成为家禽业中最重要的病原体之一。根据IBV的组织病毒学亲和性，最初将IBV分离株分类为肾病理学、输卵管、前胃或肠道类型。随着分子生物学技术的进步，根据全长S1基因的IBV分离株系统发育分类开始被划分为包括38个谱系的九个基因型，并且基因型已成为IBV分离株分类的最常用方法。基因型I包括30个不同的病毒谱系（暂命名为GI-1至GI-30），而其他基因型每个都由一个病毒谱系组成（GII-1、GIII-1、GIV-1、GV-1、GVI-1、GVII-1、GVIII-1和GIX-1）。基因突变和重组（特别是在S1基因中）可能导致变异或新的基因型产生。过去3年中许多SARS-CoV-2变异株的出现告诉我们包括IBV在内的所有冠状病毒具有快速的突变速率，可能引发新的病毒类型的出现，具有导致疾病的潜力。由于中国独特的地理地貌和气候环境的巨大差异，以及中国南北部的不同养殖品种和养殖方式，IBV的流行特征在不同时间和地区变化，中国存在多种IBV基因型和变异。GI（GI-1、GI-2、GI-3、GI-4、GI-5、GI-6、GI-7、GI-13、GI-16、GI-18、GI-19、GI-22、GI-28和GI-29）、GVI-1和GVII-1在过去几年中已在中国报道。在这些报道的病毒谱系中，更具代表性和重要的基因型是QX（GI-19）和4/91（GI-13），它们是中国的主导谱系。据报道，从2019年4月到2020年3月，南部地区分别分离出93株QX株和19株4/91株，分别是南部地区的第一和第二流行株。此外，TW（GI-7）和SAIBK（GI-22）偶尔在一些地区引发流行病。GI-28、GI-29和GVII-1是近年来分离的新基因型（图2）。1996年，青岛的病鸡群中首次分离出腺胃型IBV QX株，1999年，新疆的病鸡中分离出代表性株LX4，与韩国的肾病理学分离株KM91具有高度的核苷酸相似性。后来，发现了许多类似QX株的IBV株，并成为中国的主要流行株。2001年，类似的病毒在东欧以及包括英国在内的其他欧洲国家报告。由于其广泛的流行和分布以及与疫苗株和野外株的重组，QX样型IBV作为GI-19群的一员，如今代表全球最重要的IBV基因型之一。从注射H120和4/91疫苗的鸡中分离出的新型低毒性呼吸IBV ck/CH/LJX/2017/07（简称JX17）被证明是QX、TW和4/91基因型株的重组株。高毒性QX样IBV株CK/CH/JS/TAHY显示出典型的临床症状，包括咳嗽、鼻液流出以及肾损伤伴有严重的尿酸沉积。新型QX样IBV株不仅可以从严格的免疫方案下的密集家禽养殖场中分离出，而且还显示出各种临床症状，表明基于组织病毒学亲和性难以区分变异株。首个已知的4/91（也称为793/B和CR88）血清型分离株于1985年在法国分离，然后于1990年冬季进入英国。随后，这个血清型在欧洲大多数国家以及世界许多其他地区广泛流行，但其结构和抗原性似乎没有发生显著改变，因为最初设计的疫苗仍然提供有效的免疫力。2003年，中国首次分离出4/91血清型株，病毒分离物被命名为泰安-03（也叫TA03）。此后，4/91血清型病毒株在中国被发现并正在扩散。更重要的是，4/91疫苗和野外株参与的基因重组导致了一些新的株的出现，进一步增加了传染性支气管炎病毒的遗传多样性和复杂性。新的GI-28分离株CK/CH/SCMY/160315被发现是由弱毒活疫苗株H120（GI-1）、4/91（GI-13）、LDT3-A（GI-28）和野外株LJL/08–1（GI-19）的多重重组株。类似地，IBV株ck/CH/LHLJ/140906也是来自母本IBV株4/91和H120的天然重组株。先前的研究显示，4/91型株更容易发生重组，因此应谨慎或谨慎使用4/91型疫苗。图1.中国传染性支气管炎病毒（IBV）历史上的主要代表性事件。图2.基于IBV S1基因核苷酸序列分析的遗传进化树。该树是使用MEGA 11.0软件采用邻接法构建的。143个IBV参考株的S1基因序列被聚类成GI-GIX基因型，其中包括30个GI谱系。所有中国的分支线均突出显示。TW基因型是一种重要的基因型，最近开始成为中国大陆最常见的基因型之一。IBV台湾株被分为TW-I和TW-II基因型，并分组为相同的谱系GI-7。由于台湾和中国大陆之间的地理隔离，IBV台湾株在进化上与中国大陆的IBV分离株有明显差异。TW-I基因型株自1990年后在中国大陆频繁分离，表现为经典的肾炎症状。TW-II基因型株表现出呼吸系统症状，在1990年代之前分离自台湾中国，现在在中国大陆很少分离到这种基因型病毒。自2009年以来，TW-I基因型IBV在中国大陆的流行程度从7.5%（2009–2010）增加到27.4%（2013–2015）。值得注意的是，由于广泛疫苗接种和近距离选择性压力的影响，TW-I基因型在中国的广东、广西和福建三个南方省份中占主导地位。在中国，Genotype I IBV中新增了两个新的血清型。IBV株ck/CH/LGX/111119在S1序列分析和病毒交叉中和试验结果基础上，被发现在遗传和抗原学上与其他已知的IBV类型不同，并被命名为GI-28。它是一种肾病理学株，具有更广泛的组织亲和性，可能是LX4基因型（GI-19）和尚未鉴定的IBV的重组体。随后，在中国的不同地区分离出了许多GI-28基因型的IBV株，如CK/CH/SCMY/160315株和GX-NN-13。另一种新的基因型（GI-29）IBV株，包括γCoV/ck/China/I0111/14、γCoV/ck/China/I0114/14和γCoV/ck/China/I0118/14，是从中国南方的广西分离出的三株肾病理学株。GVII-1基因型是中国的另一种新型IBV谱系。GX-NN130021株是从2013年广西省疑似IBV阳性的21天龄病鸡中分离出的，这些病鸡接种了H120疫苗，并被确定为新型I 。对中国2016年1月至2017年12月的禽IBV基因多样性的流行病学研究显示，根据S1基因完整核苷酸序列的序列分析，发现了一种高度同源的新变种I0636/16，与GX-NN130021株相似。直到2019年，根据详细的系统发育分析和序列比较，I0636/16和GX-NN130021株都被归为GVII-1基因型。同时，病毒交叉中和结果显示GVII-1在抗原上与当前的基因型谱系有差异。GVII-1基因型在中国已经循环了9年。3当前中国对抗IBV的预防和控制策略目前，全球家禽养殖场中，使用弱毒或灭活疫苗接种仍然是保护鸡群免受IBV感染最有效的技术。除了全面的生物安全防疫措施外，制定适当的免疫方案对于预防和控制IBV感染至关重要。中国采用了多种类型的IBV疫苗，包括弱毒和灭活疫苗，以及单一和多重组合疫苗。此外，还存在许多类型的IBV疫苗株，如Mass、QX样和4/91样。所有商业上可获得的IBV疫苗已根据国家基础兽药数据库总结在表2中。这些疫苗具有一些特点。首先，所有的单一疫苗都是弱毒的IBV疫苗株，分为三类：Mass（H52、H120和W93）、QX样（LDT3-A和HC13-91）和4/91样（NNA和FNO-55），这代表了中国目前的主要流行株。其次，NDV-IBV联合疫苗分为活疫苗和灭活疫苗两种，而灭活NDV-IBV联合疫苗仅包括两种IBV株，即M41（Mass）和Jin 13（QX样）。活疫苗NDV-IBV联合疫苗有多种基因型，包括H52、H120、QXL87、B48和LDT3-A。所有的三联和四联灭活IBV疫苗都源自同一种IBV疫苗株M41。总的来说，IBV和NDV通常一起用来制作联合疫苗。表2.中国商业化IBV疫苗列表注：NDV，新城疫病毒；IBDV，传染性支气管炎病毒；EDSV，蛋降综合症病毒；AEV，禽脑脊髓炎病毒。尽管有许多疫苗可用，但存在许多占优势的IBV血清型株，这影响了疫苗的有效性。不同的IBV血清型之间只能引起有限的交叉保护免疫，因此经常报告疫苗免疫失败的情况。因此，预防IBV感染的关键是及时了解精确的本地流行株并选择适当的IBV血清型疫苗。近年来，中国市场上的鸡的数量从2017年到2020年显著增加，截至2020年底达到150亿只（图3）。IBV偶尔在大规模养殖场和散养家庭中爆发。为了应对IBV免疫失败，可以实施一些控制病毒感染的策略。近期研究已验证了传统中医学（尤其是针灸），传统中医药（TCM）在抗击冠状病毒和流感病毒感染中发挥了一定作用。注册的兽医药物舌甘地龙制剂与多西环素的联合已被证明能预防IBV感染和肉鸡呼吸道损伤。中药草药金银花在细胞中对IBV感染有超过90%的抑制率，在SPF鸡中对IBV的挑战有超过50%的保护率。此外，经典方剂清瘟败毒汤通常用于治疗各种病毒性传染病，包括COVID-19和IBV，具有积极的治疗效果，尽管该汤剂尚未正式批准用于治疗COVID-19。在中华人民共和国兽医药典中记录的甘草颗粒、止咳散、板青颗粒、金花平喘散、定喘散、银翘散等许多中药制剂可用于预防和治疗IBV感染。对于不给鸡接种疫苗、不仔细执行生物安全预防措施以及不严格遵循消毒方案的家禽养殖户，中药制剂在减少经济损失方面发挥着关键作用。图3.2017年至2020年中国上市鸡的数量。4对更好控制IBV的前景和建议毫无疑问，中医在中国一些家禽养殖场中对抗IBV感染发挥了重要作用。然而，对于未来高度密集、产业化、自动化和智能化的大规模养鸡场，疫苗免疫仍然是未来的趋势。面对IBV复杂多变的流行株，我们需要做的是研发更好的疫苗，实施更有效的免疫接种策略，并制定更优化的免疫方案。4.1.更好的IBV疫苗目前，中国IBV经典弱毒和灭活疫苗存在一个重要问题。问题在于新型经典疫苗的研发速度赶不上IBV病毒的变异速度。随着变异株和新血清型IBV的逐渐增多，经典疫苗无法为鸡提供足够的免疫保护，防范IBV感染。为了对抗IBV感染，迫切需要研发新型IBV疫苗。对于新型IBV疫苗，它不仅应避免与野外病毒株进行基因重组，还应为流行株提供足够的保护。下一代疫苗应该能够对抗未来的大流行病毒，并提高对IBV变异的长期保护。基于信使RNA（mRNA）的疫苗、病毒载体疫苗和亚单位疫苗可能是未来的研究方向。COVID-19大流行引起了全球人们对mRNA疫苗的关注。截至2022年11月15日，世卫组织报告了371种正在研发的COVID-19疫苗候选，其中65%是mRNA疫苗，其中40%已进入临床试验，表明mRNA在预防IBV感染方面具有潜在的未来。与弱毒和灭活疫苗等经典疫苗相比，mRNA疫苗具有许多优势，包括短的研发周期、易于产业化、简单的生产工艺、对新变异的灵活响应以及诱导更好免疫反应的能力。Brenner及其同事在1961年首次报告了mRNA分子，由于mRNA分子高度不稳定且容易降解，直到1984年首次成功使用SP6 RNA聚合酶体外转录和合成mRNA，为进一步的体外mRNA研究奠定了基础。1990年，体外转录mRNA首次被注射到小鼠肌肉中成功表达。然而，由于不令人满意的稳定性和安全性，mRNA疫苗一直受到广泛忽视。直到2005年，新的脲基核苷酸修饰被应用于合成mRNA，以改善mRNA在体内的稳定性和免疫原性。2018年，patisiran，第一个RNA干扰治疗药物，被许可并用于治疗成年人遗传性转甲状腺激素介导的淀粉样蛋白沉积病的多发性神经病变。直到2019年COVID-19大流行开始，mRNA疫苗成为当前的研究热点，mRNA疫苗辉瑞-联发科（BNT162b2）和莫德纳（mRNA-1273）获得了许多国家和地区的紧急使用授权，如美国、英国等。然而，在IBV mRNA疫苗问世之前仍然有许多问题需要解决。目前，mRNA疫苗面临的最大问题是冷链储存。全球最广泛使用的两种mRNA疫苗在灌装到接种前都必须在极具挑战的超低温环境中储存和运输。辉瑞/BioNTech疫苗需要在−80°C到−60°C之间的极低温下储存，解冻后在室温下只能稳定2小时；莫德纳疫苗稍微稳定，但仍需在−20°C储存。严格的储存条件限制了疫苗的远距离运输，极大地增加了疫苗的运输和储存成本，实际上推高了疫苗本身的价格，最终导致在发展中国家推广疫苗变得困难。已经设计了更多新的配方来确保mRNA疫苗的稳定性，例如辅料的选择、配方环境和制造过程。一些冻干的mRNA疫苗可以突破mRNA疫苗储存和运输的技术难题。因此，对于动物（尤其是禽类冠状病毒）的mRNA疫苗是可行的，值得期待。与mRNA疫苗和亚单位疫苗相比，病毒载体疫苗对IBV的商业化和在养禽场中的使用最有可能率先实现。已经有人类和动物成功使用病毒载体疫苗的例子。在中国，已注册的商业病毒载体疫苗主要包括毒囊病-马尔克病活体马尔克病载体疫苗和马尔克病、传染性囊病HVT载体疫苗。灭活重组杆状病毒疫苗是牲畜唯一的病毒载体疫苗，包括猪圆环病毒2型、貂瘟细小病毒和兔出血性病毒。此外，病毒载体疫苗最大的好处是单一疫苗可能对两种传染病提供保护，同时诱导体液和细胞免疫，而其他两种疫苗均无此能力。许多类型的病毒载体可供选择，已经报道了禽类的多种病毒载体，如新城病毒（NDV）、禽腺病毒（FAdV）、火鸡疱疹病毒（HVT）。每种病毒载体疫苗都有其优势。在NDV、FAdV和HVT病毒载体中，NDV在三个方面可能是IBV最佳的病毒载体。首先，在养禽场中，通常同时接种IBV和NDV，这就是为什么所有注册的IBV联合疫苗都含有NDV疫苗的原因，其中大多数是LaSota株（表2）。与FAdV和HVT病毒载体相比，NDV疫苗在养禽场中被广泛使用，NDV病毒载体适用于NDV和IBV的同时免疫。其次，不致病的NDV LaSota株作为疫苗载体在安全性和有效性方面具有悠久的记录，可以诱导强烈的局部和全身免疫反应对抗外源性抗原。第三，基于NDV的逆向遗传技术平台，可以快速开发针对当前流行IBV株的病毒载体疫苗，并可以避免弱毒病毒疫苗与野外株之间的基因重组的缺点。表达IBV抗原的重组NDV载体疫苗将从优化疫苗免疫方案、安全性和有效性以及疫苗研究的及时性等方面受到鸡场的欢迎。目前，中国家禽唯一的基因工程亚单位疫苗是传染性囊病病毒亚单位疫苗。对于猪，有几种已注册的亚单位疫苗，包括猪瘟、猪圆环病毒2型、链球菌和猪嗜血杆菌混合疫苗。此外，还有一种针对鸽弓菌的绵羊重组亚单位疫苗。总体而言，研发IBV亚单位疫苗需要克服许多困难。由于在体外制备的纯化病原体蛋白难以保持稳定的蛋白结构表位，因此无法产生持续而稳定的免疫应答。免疫应答通常仅影响体液免疫，无法激活细胞免疫。因此，亚单位疫苗的剂量增加，间接提高了养禽场的劳动成本。此外，蛋白提取和纯化的生产方法直接提高了亚单位疫苗的生产成本。因此，这一费时费力的亚单位疫苗并非生成新型IBV疫苗的最佳方法。4.2.新的接种途径呼吸黏膜免疫在预防呼吸道疾病，尤其是冠状病毒感染方面发挥着重要作用。经气雾腺病毒5型载体的COVID-19疫苗（Ad5-nCoV）已在临床试验中评估，并显示出良好的中和抗体反应。同时，许多养禽场主选择采用气雾吸入的方式在雏鸡孵化时对其进行新城疫和传染性支气管炎联合疫苗的免疫。与常规接种途径相比，雾化免疫具有很多优势，包括劳动强度极低，以及高黏膜免疫。黏膜免疫能够诱导高分泌免疫球蛋白IgA，这是一种抗感染免疫的重要屏障，对防止病原体在黏膜表面的附着和入侵、溶解细菌以及中和病毒和毒素方面产生强大的作用。雾化设备、飞沫大小和疫苗佐剂是影响雾化免疫的三个主要因素，下一步的研究方向是确定如何改进这三个特性。鸡，尤其是肉鸡/繁殖母鸡和蛋鸡，每只鸟在一个生产周期内平均接种12-20次疫苗。为了减轻疫苗免疫带来的应激并避免母源抗体的干扰，卵内接种可能是一种可行的免疫途径。卵内接种是在18天龄胚胎鸡蛋中进行的，正好与鸡蛋从孵化器转移到孵化室的过程相一致，现在已经成为全球普遍采用的常规操作。与粗喷雾或水接种不同，卵内接种确保每只鸡都能接种到精确、均匀分布的疫苗。更重要的是，卵内接种可以引发一日龄雏鸡对循环病原体的早期免疫反应，而后孵化接种则不具备这一点。因此，卵内疫苗针对IBV联合NDV是可行的，尽管需要考虑一些问题，包括疫苗株对鸡蛋的毒力、一些疫苗可能引起的母源抗体干扰和免疫抑制。4.3.更优化的免疫计划为了预防和管理传染性支气管炎病毒（IBV），一个合理和科学的免疫方案至关重要。在为鸡场设计免疫计划时，至少应考虑以下几个因素。首先，注意本地IBV的流行程度和严重程度。然后，评估通过免疫疫苗诱导的母体抗体和免疫反应。此外，选择合适的可用IBV疫苗，并确保疫苗接种途径和频率。最后，考虑IBV疫苗对其他疫苗和动物健康的影响。IBV有许多血清型，单一血清型的IBV疫苗接种无法对抗异源性挑战。因此，农民使用多种疫苗血清型来扩大家禽群体的保护范围，这一实践被称为“多价单独”。由于这种策略在实践和原理上的有效性，已在全球范围内的家禽养殖场得到应用。随着新的IBV血清型和变种的不断出现，Mass型和793/B型IBV血清型已被证明是广泛使用的疫苗类型，具有最大的交叉保护广度。在中国，有大量Mass型疫苗，并且商业化的793/B型IBV疫苗直到IBV NNA疫苗填补了2018年4/91型疫苗市场缺口之后才获得了临床使用批准，这为农民提供了使用这种策略的机会。5结论如此庞大的中国家禽存栏规模为IBV基因突变和重组提供了便利。IBV感染仍然是一种重要的禽流感。疫苗接种已经取代了中医疗法成为鸡场的主要治疗方法，除了严格的生物安全措施。最佳疫苗株应该能够阻止IBV变异和重组的传播，同时对经典IBV株提供足够的保护。QX样和4/91样株是目前中国主要的流行株。根据疫苗的生产成本、接种途径和效果，表达IBV QX样和4/91样株的重组NDV病毒载体疫苗将成为对NDV和IBV的主导疫苗株。参考资料：Li H, Liu G, Zhou Q, Yang H, Zhou C, Kong W, Su J, Li G, Si H, Ou C. Which strain of the avian coronavirus vaccine will become the prevalent one in China next? Front Vet Sci. 2023 May 5;10:1139089. doi: 10.3389/fvets.2023.1139089. PMID: 37215473; PMCID: PMC10196085.为了推动兽用生物制品行业交流，共同探讨该领域的最新研发进展、产业化现状及未来发展趋势，生物制品圈联合四叶草会展、乘风济海将于2024年4月17日-18日在南京共同举办“兽用生物制品研发和产业化大会”，系中国医药全产业链新资源大会（CBC大会）中的一个分领域专业会议。诚邀全国相关领域研究者共享学术盛会。名称：兽用生物制品研发和产业化大会时间：2024年4月17日-18日（周三-周四）地点：南京国际展览中心主办单位：生物制品圈、抗体圈、四叶草会展，乘风济海媒体支持：药时空、细胞基因研究圈报名方式：扫描下方二维码→ 填写表格 → 报名成功组委会获得报名信息后，根据报名信息进行初筛，并进一步与报名者沟通确认，实现精准邀请（严格审核通过）。注：大会日程以会议现场为准。中国医药全产业链新资源大会（CBC大会）是一场将“政、产、学、研、用、管、投”各方精英围绕全产业链新资源展开的合作大会，将于2024年4月16日-18日在南京国际展览中心举办。大会将主打“全产业链新资源对接”，围绕投资、立项、临床前研发、临床研究、生产、供应链国产化、销售、MAH合作、国际品种合作、公司股权合作与并购全产业链，为中国医药同仁带来全新的资源与商机。大会下设的同期会议包括：宠物药品、食品、保健品新资源大会兽用生物制品研发和产业化大会透皮技术研发生产与注册开年分享会吸入制剂研发、生产与注册新机遇新进展分享会中国改良新药与缓控释制剂全产业链合作大会多肽产业创新与发展大会新药典新型辅料与包材产品与技术交流会新药典新型实验室仪器与耗材实操演示交流会陆续更新中......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。