A Phase 1/2A, Randomized Study of a T Follicular Helper (TFH)-Targeting Genetic Vaccine Strategy Designed to Induce Broad, Durable Immune Responses
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 发起方
- 入组人数
- 80
- 试验地点
- 4
- 主要终点
- Frequency of solicited local reactogenicity adverse events (AEs) within 7 days after dosing.
研究概览
简要总结
The goal of this clinical trial is to test two investigational COVID-19 booster vaccines, called CoTend-s3BXBB and CoTend-BXBB, in healthy volunteers ages 40-64. The CoTend-s3BXBB vaccine includes a component called "s3", which was designed to improve the body's response to the vaccine. CoTend-BXBB is the same vaccine without s3.
The main questions the study aims to answer are: 1) Is the investigational vaccine safe? 2) Does "s3" lead to bigger, broader, and longer-lasting responses to the vaccine?
5 different doses of the vaccines will be studied. Participants will receive a single dose of either CoTend-s3BXBB, CoTend-BXBB, or placebo. Participants will be monitored for side effects. Saliva, nasal, and blood samples will be collected and immune responses to the vaccine will be measured.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Prevention
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 40 Years 至 64 Years（Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •Individuals 40 - 64 years of age
- •Received at least two doses of a COVID-19 mRNA vaccine (Moderna or Pfizer) > 120 days before study entry
- •Nasal SARS-CoV-2 negative by molecular (polymerase chain reaction, PCR) testing at screening
- •The following laboratory criteria must be met at screening:
- •Total white blood cell (WBC) count > 3500 cells/mm3
- •Absolute neutrophil count (ANC) > 1500 cells/mm3
- •Hemoglobin > 13.5 g/dL if male sex and > 12.0 g/dL if female sex
- •Platelet count > 140,000/uL
- •Estimated creatinine clearance (CrCl) > 50 mL/min by Cockroft-Gault equation
- •Total bilirubin ≤ 1.1x upper limit of normal (ULN)
- •Aspartate aminotransferase (AST) ≤ 1.3x ULN
- •Alanine aminotransferase (ALT) ≤ 1.3x ULN
- •Individuals of reproductive potential must have a negative serum or urine beta-human chorionic gonadotropin (ß-HCG) test at screening and within 48 hours prior to entry.
- •Reproductive potential is defined as:
- •Participants who have reached menarche
- •Participants who have not been post-menopausal for at least 12 consecutive months with follicle-stimulating hormone (FSH) ≥40 IU/mL or 24 consecutive months if an FSH is not available
- •Participants who have not undergone surgical contraception (e.g., hysterectomy, bilateral oophorectomy, bilateral tubal ligation, or bilateral salpingectomy) NOTE: Participants who have undergone bilateral tubal ligation within the 24 weeks prior to screening are considered to be of reproductive potential and, if participating in sexual activity that could lead to pregnancy, contraception is required as per 5.2.2 exclusion criterion
- •Able and willing to provide informed consent
排除标准
- •Participants are excluded from the study if any of the following criteria are met:
- •Pregnant or breastfeeding
- •For participants capable of becoming pregnant and engaging in sexual activity that can lead to pregnancy, unwillingness to use contraception during participation in the study. For participants capable of becoming pregnant, two of the following forms of contraception are required through 30 days following administration of study intervention, one of which must be a barrier method:
- •Condoms (male or female) with or without a spermicidal agent
- •Diaphragm or cervical cap with spermicide
- •Intrauterine device (IUD)
- •Hormone-based contraceptive such as oral birth control pills
- •Known close contact with anyone with confirmed SARS-CoV-2 infection (defined as positive SARS-CoV-2 nucleic acid or antigen testing by laboratory-based or home self-test) within 2 weeks prior to expected study entry
- •Plan to receive a non-study SARS-CoV-2 vaccine within 8 weeks after study entry
- •HIV infection
- •Hepatitis B core antibody or hepatitis B surface antigen positive at screening
- •Current active hepatitis C. Participants must be hepatitis C virus (HCV) antibody negative or have evidence of cleared HCV infection. If the participant is HCV antibody positive or indeterminate, an unquantifiable HCV RNA result (below lower limit of quantification, either target detected or target not detected) within 42 days prior to study entry is required. Those who are currently receiving HCV antiviral therapy or those who have received HCV treatment in the last 3 months prior to study entry will be excluded.
- •History of cirrhotic liver disease
- •History of thrombosis with thrombocytopenia syndrome (TTS), immune thrombocytopenia, thromboembolic events, capillary leak syndrome, other thrombotic disease or known increased risk of thrombosis due to genetic disorders or malignancy
- •History of or active autoimmune disease that has required systemic immunosuppressive or immunomodulatory therapy
- •History of myocarditis, pericarditis, or myopericarditis
- •Potential myocarditis or pericarditis identified at screening, defined as high-sensitivity troponin I (hsTnI) > ULN or 12-lead ECG compatible with pericarditis WITH compatible symptoms (regardless of troponin I level) at screening
- •History of Guillain-Barré syndrome
- •History of coagulopathy or bleeding disorder considered a contraindication to intramuscular injection or phlebotomy
- •Symptomatic acute or chronic illness requiring ongoing medical or surgical care, including requirement for new medications, in the past 3 months. Transient illnesses or injuries that are resolved prior to screening are not exclusionary. Minor adjustments in stable therapy for chronic conditions such as hypertension are not exclusionary. Use of over-the-counter medications for any acute or chronic illness is also not exclusionary.
- •Serious medical or psychiatric illness that, in the opinion of the site investigator, would interfere with the ability to adhere to study requirements or to give informed consent
- •Treatment with systemic immunosuppressive or immunomodulatory drugs, and/or exposure to any immunosuppressive/immunomodulatory drug in the 30 days prior to study entry (e.g. corticosteroid therapy equal to or exceeding a dose of 20 mg/day of prednisone for more than 10 days, interleukins, interferons, methotrexate, rituximab, and cancer chemotherapy). Use of topical, inhaled, intra-articular, or nasal steroid use is not exclusionary.
- •Active malignancy or history of malignancy within the 4 years prior to study entry. Non-melanoma skin cancers (such as basal or squamous cell skin cancers) and non-invasive cervical or anal intraepithelial lesions are not exclusionary.
- •History of solid organ or hematopoietic stem cell transplantation
- •History of primary immunodeficiency disorder
- •Ongoing complications or morbidity associated with prior diagnoses of malignancies requiring continued medical or surgical intervention. Chronic stable complications or morbidity not requiring new medications or other medical or surgical intervention in the past 3 months are not exclusionary.
- •Administration or planned administration of blood products or licensed non-SARS-CoV-2 vaccines <14 days prior to or within 14 days after study entry
- •Receipt of any antibody-based therapy (investigational or approved) for prophylaxis or treatment of COVID-19 in the preceding 6 months
- •Receipt of immunoglobulin therapy in the year prior to study entry or scheduled or anticipated immunoglobulin administration during the study period.
- •Prior receipt of any non-mRNA SARS-CoV-2 vaccine
- •Receipt of any SARS-CoV-2 vaccination in the 120 days prior to study entry
- •Documented SARS-CoV-2 infection in the 120 days prior to study entry
- •History of anaphylaxis, urticaria, or other significant adverse reaction requiring medical intervention (medications requiring a prescription or surgical intervention) after receipt of a vaccine or intervention that includes one or more of the same components contained in the study product
- •Have participated in an interventional clinical study within 28 days prior to screening (based on medical history interview) or plans to do so while participating in this study
- •Any clinical concerns as determined by the investigator that might affect the potential participant's safety in the study.
研究组 & 干预措施
Dose Cohort 3, Arm 3B
Intervention: CoTend-BXBB (SARS2-30404) Dose: 1x10^8 vp (0.5mL) IM once
干预措施: CoTend-BXBB (SARS2-30404) (Biological)
Dose Cohort 1, Arm 1A
Intervention: CoTend-s3BXBB (SARS2-17032) Dose: 1x10^6 vp (0.5mL) IM once
干预措施: CoTend-s3BXBB (SARS2-17032) (Biological)
Dose Cohort 1, Arm 1B
Intervention: CoTend-BXBB (SARS2-30404) Dose: 1x10^6 vp (0.5mL) IM once
干预措施: CoTend-BXBB (SARS2-30404) (Biological)
Dose Cohort 2, Arm 2A
Intervention: CoTend-s3BXBB (SARS2-17032) Dose: 1x10^7 vp (0.5mL) IM once
干预措施: CoTend-s3BXBB (SARS2-17032) (Biological)
Dose Cohort 2, Arm 2B
Intervention: CoTend-BXBB (SARS2-30404) Dose: 1x10^7 vp (0.5mL) IM once
干预措施: CoTend-BXBB (SARS2-30404) (Biological)
Dose Cohort 3, Arm 3A
Intervention: CoTend-s3BXBB (SARS2-17032) Dose: 1x10^8 vp (0.5mL) IM once
干预措施: CoTend-s3BXBB (SARS2-17032) (Biological)
Dose Cohort 4, Arm 4A
Intervention: CoTend-s3BXBB (SARS2-17032) Dose: 1x10^9 vp (0.5mL) IM once
干预措施: CoTend-s3BXBB (SARS2-17032) (Biological)
Dose Cohort 4, Arm 4B
Intervention: CoTend-BXBB (SARS2-30404) Dose: 1x10^9 vp (0.5mL) IM once
干预措施: CoTend-BXBB (SARS2-30404) (Biological)
Dose Cohort 5, Arm 5A
Intervention: CoTend-s3BXBB (SARS2-17032) Dose: 1x10^10 vp (0.5mL) IM once
干预措施: CoTend-s3BXBB (SARS2-17032) (Biological)
Dose Cohort 5, Arm 5B
Intervention: CoTend-BXBB (SARS2-30404) Dose: 1x10^10 vp (0.5mL) IM once
干预措施: CoTend-BXBB (SARS2-30404) (Biological)
Dose Cohort 6, Arm 6A
Intervention: CoTend-s3BXBB (SARS2-17032) Dose: 1x10^9 vp (0.5mL) IM once
干预措施: CoTend-s3BXBB (SARS2-17032) (Biological)
Dose Cohort 6, Arm 6B
Intervention: CoTend-BXBB (SARS2-30404) Dose: 1x10^9 vp (0.5mL) IM once
干预措施: CoTend-BXBB (SARS2-30404) (Biological)
Dose Cohort 6, Arm 6C
Intervention: Placebo (normal saline) Dose: 0.5mL IM once
干预措施: Placebo (Biological)
Dose Cohort 7, Arm 7A
Intervention: CoTend-s3BXBB (SARS2-17032) Dose: 1x10^10 vp (0.5mL) IM once
干预措施: CoTend-s3BXBB (SARS2-17032) (Biological)
Dose Cohort 7, Arm 7B
Intervention: CoTend-BXBB (SARS2-30404) Dose: 1x10^10 vp (0.5mL) IM once
干预措施: CoTend-BXBB (SARS2-30404) (Biological)
Dose Cohort 7, Arm 7C
Intervention: Placebo (normal saline) Dose: 0.5mL IM once
干预措施: Placebo (Biological)
结局指标
主要结局
Frequency of solicited local reactogenicity adverse events (AEs) within 7 days after dosing.
时间窗: 7 days
Number of participants with solicited local reactogenicity AEs (injection site pain, erythema, or swelling) within 7 days after dosing. An AE is any untoward medical occurrence in a clinical investigation of a patient administered a pharmaceutical product and that does not necessarily have a causal relationship with the treatment.
Frequency of solicited systemic reactogenicity AEs within 7 days after dosing.
时间窗: 7 days
Number of participants with solicited systemic reactogenicity AEs (malaise, participant-measured body temperature, fatigue, headache, chills, nausea, muscle aches/pain, joint pain) within 7 days after dosing.
Frequency of unsolicited AEs within 28 days after dosing.
时间窗: 28 days
Number of participants with unsolicited AEs within 28 days after dosing. Unsolicited AEs are AEs that were not pre-defined as solicited.
Frequency of serious adverse events (SAEs) within 28 days after dosing.
时间窗: 28 days
Number of participants with an SAE within 28 days after dosing. An SAE is defined as any adverse event that results in any of the following outcomes: death during a period of surveillance defined by the protocol, a life-threatening adverse experience, inpatient hospitalization or prolongation of existing hospitalization, a persistent or significant disability/incapacity, or a congenital anomaly/birth defect. The following are also considered SAEs for this study: severe COVID-19, defined as COVID-19 requiring hospitalization or supplemental oxygen, myocarditis or pericarditis within 6 weeks of study vaccination, and acute or new onset thrombosis or thromboembolism within 60 days of vaccination.
Frequency of adverse events of special interest (AESIs) within 28 days after dosing.
时间窗: 28 days
Number of participants with AESIs. AESIs defined as: thrombotic or thromboembolic events, thrombosis with thrombocytopenia syndrome, immune thrombocytopenia, or capillary leak syndrome occurring within 60 days; new thrombocytopenia \<150 x 10\^9/L or below the lower laboratory limit of normal or worsening in grade of thrombocytopenia within 60 days after study vaccination; new D-dimer elevation \>2000 ng/mL within 60 days; laryngospasm, bronchospasm, or anaphylaxis assessed as at least possibly related; generalized urticaria assessed as related; any other grade allergic/ hypersensitivity reaction within 7 days; any ulceration, abscess, or necrosis at injection site assessed as possibly related; myocarditis or pericarditis occurring within 6 weeks; new diagnosis of Guillain-Barré syndrome occurring within 60 days; any new or worsened immune mediated medical condition; grade 3+ lab abnormality for which there is a reasonable possibility of causal relationship to study treatment.
Frequency of medically attended adverse events (MAAEs) within 28 days after dosing.
时间窗: 28 days
Number of participants with MAAEs (MAAE defined as an AE resulting in a hospitalization, emergency room visit, or otherwise unscheduled visit with medical personnel for any reason) within 28 days after dosing.
Geometric mean titers (GMTs) of serum anti-XBB.1.5 neutralizing antibodies (NAb) through week 8.
时间窗: 8 weeks
Serum anti-XBB.1.5 NAb GMT
Proportion of participants achieving serum anti-XBB.1.5 NAb titers of 1:250 or better through week 8.
时间窗: 8 weeks
Proportion of participants achieving serum anti-XBB.1.5 NAb titers of 1:250 or better
Geometric mean fold rise (GMFR) from pre-dose to week 8 in serum anti-XBB.1.5 NAb responses.
时间窗: Pre-dose to 8 weeks
Geometric mean fold rise (GMFR) in serum anti-XBB.1.5 NAb levels
次要结局
- NAb GMTs through week 104.(104 weeks)
- Proportion of participants achieving NAb titers of 1:250 or better through week 26.(26 weeks)
- Proportion of participants achieving NAb titers of 1:250 or better through week 52.(52 weeks)
- Proportion of participants achieving NAb titers of 1:250 or better through week 104.(104 weeks)
- GMFR of NAb titers from pre-dose through week 26.(Pre-dose to 26 weeks)
- GMFR of NAb titers from pre-dose through week 52.(Pre-dose to 52 weeks)
- GMFR of NAb titers from pre-dose through week 104.(Pre-dose to 104 weeks)
- GMFR of binding Ab titers from pre-dose through week 26.(Pre-dose to 26 weeks)
- GMFR of binding Ab titers from pre-dose through week 52.(Pre-dose to 52 weeks)
- GMFR of binding Ab titers from pre-dose through week 104.(Pre-dose to 104 weeks)
- Fraction of RBD-specific CD4+ T cells through week 26.(26 weeks)
- Fraction of RBD-specific CD4+ T cells through week 52.(52 weeks)
- Fraction of RBD-specific CD4+ T cells through week 104.(104 weeks)
- Fraction of RBD-specific CD8+ T cells through week 26.(26 weeks)
- Fraction of RBD-specific CD8+ T cells through week 52.(52 weeks)
- Fraction of RBD-specific CD8+ T cells through week 104.(104 weeks)
- Serum anti-D614G NAb GMTs through week 8.(8 weeks)
- Serum anti-JN.1* NAb GMTs through week 8.(8 weeks)
- Proportion of participants achieving anti-D614G NAb titers of 1:250 or better through week 8.(8 weeks)
- Proportion of participants achieving anti-JN.1* NAb titers of 1:250 or better through week 8.(8 weeks)
- GMFR from pre-dose to week 8 in serum anti-D614G NAb responses.(Pre-dose to 8 weeks)
- GMFR from pre-dose to week 8 in serum anti-JN.1* NAb responses.(Pre-dose to 8 weeks)
- Serum anti-XBB.1.5 RBD IgG binding antibody (bAb) GMTs through week 8.(8 weeks)
- Serum anti-XBB.1.5 RBD IgA binding antibody GMTs through week 8.(8 weeks)
- Serum anti-D614G RBD IgG binding antibody (bAb) GMTs through week 8.(8 weeks)
- Serum anti-D614G RBD IgA binding antibody (bAb) GMTs through week 8.(8 weeks)
- Serum anti-JN.1* RBD IgG binding antibody (bAb) GMTs through week 8.(8 weeks)
- Serum anti-JN.1* RBD IgA binding antibody (bAb) GMTs through week 8.(8 weeks)
- Geometric mean fold rise (GMFR) from pre-dose to week 8 in serum anti-XBB.1.5 RBD IgG binding antibody responses.(Pre-dose to 8 weeks)
- Geometric mean fold rise (GMFR) from pre-dose to week 8 in serum anti-XBB.1.5 RBD IgA binding antibody responses.(Pre-dose to 8 weeks)
- Geometric mean fold rise (GMFR) from pre-dose to week 8 in serum anti-D614G RBD IgG binding antibody responses.(Pre-dose to 8 weeks)
- Geometric mean fold rise (GMFR) from pre-dose to week 8 in serum anti-D614G RBD IgA binding antibody responses.(Pre-dose to 8 weeks)
- Geometric mean fold rise (GMFR) from pre-dose to week 8 in serum anti-JN.1* RBD IgG binding antibody responses.(Pre-dose to 8 weeks)
- Fraction of RBD-specific CD8+ T cells through week 8.(8 weeks)
- NAb GMTs through week 26.(26 weeks)
- NAb GMTs through week 52.(52 weeks)
- Geometric mean fold rise (GMFR) from pre-dose to week 8 in serum anti-JN.1* RBD IgA binding antibody responses.(Pre-dose to 8 weeks)
- Frequency of grade 3 or higher AEs through week 26 visit.(26 weeks)
- Frequency of SAEs through week 26 visit.(26 weeks)
- Frequency of AESIs through week 26 visit.(26 weeks)
- Frequency of SAEs through end of study visit(Through end of study visit (52 or 104 weeks))
- Frequency of MAAEs through week 26 visit.(26 weeks)
- Frequency of AESIs through end of study visit(Through end of study visit (52 or 104 weeks))
- Fraction of RBD-specific CD4+ T cells through week 8.(8 weeks)
- Binding Ab GMTs through week 26.(26 weeks)
- Binding Ab GMTs through week 52.(52 weeks)
- Binding Ab GMTs through week 104.(104 weeks)
- Frequency of MAAEs through end of study visit(Through end of study visit (52 or 104 weeks))
研究者
Kara Chew
Associate Professor of Medicine
University of California, Los Angeles