A Phase 1/2A, Randomized Study of a T Follicular Helper (TFH)-Targeting Genetic Vaccine Strategy Designed to Induce Broad, Durable Immune Responses

Overview

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.

Interventions

• Biological CoTend-BXBB (SARS2-30404)
  Ad35-vectored SARS-CoV-2 RBD (XBB.1.5) vaccine
• Biological CoTend-s3BXBB (SARS2-17032)
  Ad35-vectored s3-SARS-CoV-2 RBD (XBB.1.5) vaccine
• Biological Placebo
  Sterile sodium chloride 0.9% for injection, preservative free

Primary outcome measures

• Frequency of solicited local reactogenicity adverse events (AEs) within 7 days after dosing. [Time frame: 7 days]
• Frequency of solicited systemic reactogenicity AEs within 7 days after dosing. [Time frame: 7 days]
• Frequency of unsolicited AEs within 28 days after dosing. [Time frame: 28 days]
• Frequency of serious adverse events (SAEs) within 28 days after dosing. [Time frame: 28 days]
• Frequency of adverse events of special interest (AESIs) within 28 days after dosing. [Time frame: 28 days]
• Frequency of medically attended adverse events (MAAEs) within 28 days after dosing. [Time frame: 28 days]
• Geometric mean titers (GMTs) of serum anti-XBB.1.5 neutralizing antibodies (NAb) through week 8. [Time frame: 8 weeks]
• Proportion of participants achieving serum anti-XBB.1.5 NAb titers of 1:250 or better through week 8. [Time frame: 8 weeks]
• Geometric mean fold rise (GMFR) from pre-dose to week 8 in serum anti-XBB.1.5 NAb responses. [Time frame: Pre-dose to 8 weeks]

Secondary outcome measures (12)

• Serum anti-D614G NAb GMTs through week 8. [Time frame: 8 weeks]
• Serum anti-JN.1* NAb GMTs through week 8. [Time frame: 8 weeks]
• Proportion of participants achieving anti-D614G NAb titers of 1:250 or better through week 8. [Time frame: 8 weeks]
• Proportion of participants achieving anti-JN.1* NAb titers of 1:250 or better through week 8. [Time frame: 8 weeks]
• GMFR from pre-dose to week 8 in serum anti-D614G NAb responses. [Time frame: Pre-dose to 8 weeks]
• GMFR from pre-dose to week 8 in serum anti-JN.1* NAb responses. [Time frame: Pre-dose to 8 weeks]
• Serum anti-XBB.1.5 RBD IgG binding antibody (bAb) GMTs through week 8. [Time frame: 8 weeks]
• Serum anti-XBB.1.5 RBD IgA binding antibody GMTs through week 8. [Time frame: 8 weeks]
• Serum anti-D614G RBD IgG binding antibody (bAb) GMTs through week 8. [Time frame: 8 weeks]
• Serum anti-D614G RBD IgA binding antibody (bAb) GMTs through week 8. [Time frame: 8 weeks]
• Serum anti-JN.1* RBD IgG binding antibody (bAb) GMTs through week 8. [Time frame: 8 weeks]
• Serum anti-JN.1* RBD IgA binding antibody (bAb) GMTs through week 8. [Time frame: 8 weeks]

Eligibility criteria

Inclusion criteria

• 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 2.
• Able and willing to provide informed consent

Exclusion criteria

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.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: Yes

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Quadruple blind

Primary purpose

Prevention

Study locations

United States · 2 centers

• UCLA Westwood — Los Angeles
• UCSF Community and Clinical Research Center — San Francisco

Publications

• Bowen JE, Park YJ, Stewart C, Brown JT, Sharkey WK, Walls AC, Joshi A, Sprouse KR, McCallum M, Tortorici MA, Franko NM, Logue JK, Mazzitelli IG, Nguyen AW, Silva RP, Huang Y, Low JS, Jerak J, Tiles SW, Ahmed K, Shariq A, Dan JM, Zhang Z, Weiskopf D, Sette A, Snell G, Posavad CM, Iqbal NT, Geffner J, Bandera A, Gori A, Sallusto F, Maynard JA, Crotty S, Van Voorhis WC, Simmerling C, Grifantini R, Ch PMID 36356052
• De Boer RJ, Perelson AS. How Germinal Centers Evolve Broadly Neutralizing Antibodies: the Breadth of the Follicular Helper T Cell Response. J Virol. 2017 Oct 27;91(22):e00983-17. doi: 10.1128/JVI.00983-17. Print 2017 Nov 15. PMID 28878083
• Wang Q, Iketani S, Li Z, Liu L, Guo Y, Huang Y, Bowen AD, Liu M, Wang M, Yu J, Valdez R, Lauring AS, Sheng Z, Wang HH, Gordon A, Liu L, Ho DD. Alarming antibody evasion properties of rising SARS-CoV-2 BQ and XBB subvariants. Cell. 2023 Jan 19;186(2):279-286.e8. doi: 10.1016/j.cell.2022.12.018. Epub 2022 Dec 14. PMID 36580913
• Havervall S, Marking U, Svensson J, Greilert-Norin N, Bacchus P, Nilsson P, Hober S, Gordon M, Blom K, Klingstrom J, Aberg M, Smed-Sorensen A, Thalin C. Anti-Spike Mucosal IgA Protection against SARS-CoV-2 Omicron Infection. N Engl J Med. 2022 Oct 6;387(14):1333-1336. doi: 10.1056/NEJMc2209651. Epub 2022 Sep 14. No abstract available. PMID 36103621
• Balachandran H, Phetsouphanh C, Agapiou D, Adhikari A, Rodrigo C, Hammoud M, Shrestha LB, Keoshkerian E, Gupta M, Turville S, Christ D, King C, Sasson SC, Bartlett A, Grubor-Bauk B, Rawlinson W, Aggarwal A, Stella AO, Klemm V, Mina MM, Post JJ, Hudson B, Gilroy N, Konecny P, Ahlenstiel G, Dwyer DE, Sorrell TC, Kelleher A, Tedla N, Lloyd AR, Martinello M, Bull RA; COSIN Study Group. Maintenance of PMID 35090598
• Fuchs JD, Bart PA, Frahm N, Morgan C, Gilbert PB, Kochar N, DeRosa SC, Tomaras GD, Wagner TM, Baden LR, Koblin BA, Rouphael NG, Kalams SA, Keefer MC, Goepfert PA, Sobieszczyk ME, Mayer KH, Swann E, Liao HX, Haynes BF, Graham BS, McElrath MJ; NIAID HIV Vaccine Trials Network. Safety and Immunogenicity of a Recombinant Adenovirus Serotype 35-Vectored HIV-1 Vaccine in Adenovirus Serotype 5 Seronegati PMID 26587311
• Nwanegbo E, Vardas E, Gao W, Whittle H, Sun H, Rowe D, Robbins PD, Gambotto A. Prevalence of neutralizing antibodies to adenoviral serotypes 5 and 35 in the adult populations of The Gambia, South Africa, and the United States. Clin Diagn Lab Immunol. 2004 Mar;11(2):351-7. doi: 10.1128/cdli.11.2.351-357.2004. PMID 15013987
• Qu P, Faraone JN, Evans JP, Zheng YM, Yu L, Ma Q, Carlin C, Lozanski G, Saif LJ, Oltz EM, Gumina RJ, Liu SL. Durability of Booster mRNA Vaccine against SARS-CoV-2 BA.2.12.1, BA.4, and BA.5 Subvariants. N Engl J Med. 2022 Oct 6;387(14):1329-1331. doi: 10.1056/NEJMc2210546. Epub 2022 Sep 7. No abstract available. PMID 36069925

Identifiers

NCT: NCT06810934 · 23-001884 · 1U01AI172800-01A1

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗