Clinical trial NCT06810934: A Phase 1/2A, Randomized Study of a T Follicular Helper (TFH)-Targeting Genetic Vaccine Strategy Designed to Induce Broad, Durable Immune Responses
Official title: A Phase 1/2A, Randomized Study of a T Follicular Helper (TFH)-Targeting Genetic Vaccine Strategy Designed to Induce Broad, Durable Immune Responses
Study type: INTERVENTIONAL
Overall status: NOT_YET_RECRUITING
Phase: PHASE1
PHASE2
Conditions: COVID-19
Keywords: COVID-19
vaccine
SARS-CoV-2
Lead sponsor: University of California, Los Angeles
Sponsor class: OTHER
Collaborators: name: University of California, San Francisco
name: University of California, Davis
name: Tendel Therapies, Inc.
First posted: 2025-02-06
Enrollment: 80
Sex: ALL
Minimum age (years): 40
Maximum age (years): 64
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

Brief summary: 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.


Eligibility criteria: Inclusion Criteria:

1. Individuals 40 - 64 years of age
2. Received at least two doses of a COVID-19 mRNA vaccine (Moderna or Pfizer) \> 120 days before study entry
3. Nasal SARS-CoV-2 negative by molecular (polymerase chain reaction, PCR) testing at screening
4. The following laboratory criteria must be met at screening:

   1. Total white blood cell (WBC) count \> 3500 cells/mm3
   2. Absolute neutrophil count (ANC) \> 1500 cells/mm3
   3. Hemoglobin \> 13.5 g/dL if male sex and \> 12.0 g/dL if female sex
   4. Platelet count \> 140,000/uL
   5. Estimated creatinine clearance (CrCl) \> 50 mL/min by Cockroft-Gault equation
   6. Total bilirubin ≤ 1.1x upper limit of normal (ULN)
   7. Aspartate aminotransferase (AST) ≤ 1.3x ULN
   8. Alanine aminotransferase (ALT) ≤ 1.3x ULN
5. 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.
6. Able and willing to provide informed consent

Exclusion Criteria:

Participants are excluded from the study if any of the following criteria are met:

1. Pregnant or breastfeeding
2. 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:

   1. Condoms (male or female) with or without a spermicidal agent
   2. Diaphragm or cervical cap with spermicide
   3. Intrauterine device (IUD)
   4. Hormone-based contraceptive such as oral birth control pills
3. 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
4. Plan to receive a non-study SARS-CoV-2 vaccine within 8 weeks after study entry
5. HIV infection
6. Hepatitis B core antibody or hepatitis B surface antigen positive at screening
7. 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.
8. History of cirrhotic liver disease
9. 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
10. History of or active autoimmune disease that has required systemic immunosuppressive or immunomodulatory therapy
11. History of myocarditis, pericarditis, or myopericarditis
12. Potential myocarditis or pericarditis identified at screening, defined as high-sensitivity troponin I (hsTnI) \&gt; ULN or 12-lead ECG compatible with pericarditis WITH compatible symptoms (regardless of troponin I level) at screening
13. History of Guillain-Barré syndrome
14. History of coagulopathy or bleeding disorder considered a contraindication to intramuscular injection or phlebotomy
15. 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.
16. 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
17. 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.
18. 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.
19. History of solid organ or hematopoietic stem cell transplantation
20. History of primary immunodeficiency disorder
21. 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.
22. Administration or planned administration of blood products or licensed non-SARS-CoV-2 vaccines \&lt;14 days prior to or within 14 days after study entry
23. Receipt of any antibody-based therapy (investigational or approved) for prophylaxis or treatment of COVID-19 in the preceding 6 months
24. Receipt of immunoglobulin therapy in the year prior to study entry or scheduled or anticipated immunoglobulin administration during the study period.
25. Prior receipt of any non-mRNA SARS-CoV-2 vaccine
26. Receipt of any SARS-CoV-2 vaccination in the 120 days prior to study entry
27. Documented SARS-CoV-2 infection in the 120 days prior to study entry
28. 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
29. 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
30. Any clinical concerns as determined by the investigator that might affect the potential participant's safety in the study.

Primary outcomes:
measure: Frequency of solicited local reactogenicity adverse events (AEs) within 7 days after dosing.
timeFrame: 7 days
measure: Frequency of solicited systemic reactogenicity AEs within 7 days after dosing.
timeFrame: 7 days
measure: Frequency of unsolicited AEs within 28 days after dosing.
timeFrame: 28 days
measure: Frequency of serious adverse events (SAEs) within 28 days after dosing.
timeFrame: 28 days
measure: Frequency of adverse events of special interest (AESIs) within 28 days after dosing.
timeFrame: 28 days
measure: Frequency of medically attended adverse events (MAAEs) within 28 days after dosing.
timeFrame: 28 days
measure: Geometric mean titers (GMTs) of serum anti-XBB.1.5 neutralizing antibodies (NAb) through week 8.
timeFrame: 8 weeks
measure: Proportion of participants achieving serum anti-XBB.1.5 NAb titers of 1:250 or better through week 8.
timeFrame: 8 weeks
measure: Geometric mean fold rise (GMFR) from pre-dose to week 8 in serum anti-XBB.1.5 NAb responses.
timeFrame: Pre-dose to 8 weeks
Secondary outcomes:
measure: Serum anti-D614G NAb GMTs through week 8.
timeFrame: 8 weeks
measure: Serum anti-JN.1* NAb GMTs through week 8.
timeFrame: 8 weeks
measure: Proportion of participants achieving anti-D614G NAb titers of 1:250 or better through week 8.
timeFrame: 8 weeks
measure: Proportion of participants achieving anti-JN.1* NAb titers of 1:250 or better through week 8.
timeFrame: 8 weeks
measure: GMFR from pre-dose to week 8 in serum anti-D614G NAb responses.
timeFrame: Pre-dose to 8 weeks
measure: GMFR from pre-dose to week 8 in serum anti-JN.1* NAb responses.
timeFrame: Pre-dose to 8 weeks
measure: Serum anti-XBB.1.5 RBD IgG binding antibody (bAb) GMTs through week 8.
timeFrame: 8 weeks
measure: Serum anti-XBB.1.5 RBD IgA binding antibody GMTs through week 8.
timeFrame: 8 weeks
measure: Serum anti-D614G RBD IgG binding antibody (bAb) GMTs through week 8.
timeFrame: 8 weeks
measure: Serum anti-D614G RBD IgA binding antibody (bAb) GMTs through week 8.
timeFrame: 8 weeks
measure: Serum anti-JN.1* RBD IgG binding antibody (bAb) GMTs through week 8.
timeFrame: 8 weeks
measure: Serum anti-JN.1* RBD IgA binding antibody (bAb) GMTs through week 8.
timeFrame: 8 weeks
measure: Geometric mean fold rise (GMFR) from pre-dose to week 8 in serum anti-XBB.1.5 RBD IgG binding antibody responses.
timeFrame: Pre-dose to 8 weeks
measure: Geometric mean fold rise (GMFR) from pre-dose to week 8 in serum anti-XBB.1.5 RBD IgA binding antibody responses.
timeFrame: Pre-dose to 8 weeks
measure: Geometric mean fold rise (GMFR) from pre-dose to week 8 in serum anti-D614G RBD IgG binding antibody responses.
timeFrame: Pre-dose to 8 weeks
measure: Geometric mean fold rise (GMFR) from pre-dose to week 8 in serum anti-D614G RBD IgA binding antibody responses.
timeFrame: Pre-dose to 8 weeks
measure: Geometric mean fold rise (GMFR) from pre-dose to week 8 in serum anti-JN.1* RBD IgG binding antibody responses.
timeFrame: Pre-dose to 8 weeks
measure: Geometric mean fold rise (GMFR) from pre-dose to week 8 in serum anti-JN.1* RBD IgA binding antibody responses.
timeFrame: Pre-dose to 8 weeks
measure: Frequency of grade 3 or higher AEs through week 26 visit.
timeFrame: 26 weeks
measure: Frequency of SAEs through week 26 visit.
timeFrame: 26 weeks
measure: Frequency of AESIs through week 26 visit.
timeFrame: 26 weeks
measure: Frequency of MAAEs through week 26 visit.
timeFrame: 26 weeks
measure: Frequency of SAEs through end of study visit
timeFrame: Through end of study visit (52 or 104 weeks)
measure: Frequency of AESIs through end of study visit
timeFrame: Through end of study visit (52 or 104 weeks)
measure: Frequency of MAAEs through end of study visit
timeFrame: Through end of study visit (52 or 104 weeks)
measure: Fraction of RBD-specific CD4+ T cells through week 8.
timeFrame: 8 weeks
measure: Fraction of RBD-specific CD8+ T cells through week 8.
timeFrame: 8 weeks
measure: NAb GMTs through week 26.
timeFrame: 26 weeks
measure: NAb GMTs through week 52.
timeFrame: 52 weeks
measure: NAb GMTs through week 104.
timeFrame: 104 weeks
measure: Binding Ab GMTs through week 26.
timeFrame: 26 weeks
measure: Binding Ab GMTs through week 52.
timeFrame: 52 weeks
measure: Binding Ab GMTs through week 104.
timeFrame: 104 weeks
measure: Proportion of participants achieving NAb titers of 1:250 or better through week 26.
timeFrame: 26 weeks
measure: Proportion of participants achieving NAb titers of 1:250 or better through week 52.
timeFrame: 52 weeks
measure: Proportion of participants achieving NAb titers of 1:250 or better through week 104.
timeFrame: 104 weeks
measure: GMFR of NAb titers from pre-dose through week 26.
timeFrame: Pre-dose to 26 weeks
measure: GMFR of NAb titers from pre-dose through week 52.
timeFrame: Pre-dose to 52 weeks
measure: GMFR of NAb titers from pre-dose through week 104.
timeFrame: Pre-dose to 104 weeks
measure: GMFR of binding Ab titers from pre-dose through week 26.
timeFrame: Pre-dose to 26 weeks
measure: GMFR of binding Ab titers from pre-dose through week 52.
timeFrame: Pre-dose to 52 weeks
measure: GMFR of binding Ab titers from pre-dose through week 104.
timeFrame: Pre-dose to 104 weeks
measure: Fraction of RBD-specific CD4+ T cells through week 26.
timeFrame: 26 weeks
measure: Fraction of RBD-specific CD4+ T cells through week 52.
timeFrame: 52 weeks
measure: Fraction of RBD-specific CD4+ T cells through week 104.
timeFrame: 104 weeks
measure: Fraction of RBD-specific CD8+ T cells through week 26.
timeFrame: 26 weeks
measure: Fraction of RBD-specific CD8+ T cells through week 52.
timeFrame: 52 weeks
measure: Fraction of RBD-specific CD8+ T cells through week 104.
timeFrame: 104 weeks
Other outcomes:
Locations:
Study officials:
affiliation: University of California, Los Angeles
name: Kara Chew, MD, MS
role: PRINCIPAL_INVESTIGATOR
affiliation: University of California, San Francisco
name: Steven Deeks, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of California, Davis
name: Dennis Hartigan-O'Connor, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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, Chu HY, Corti D, Veesler D. SARS-CoV-2 spike conformation determines plasma neutralizing activity elicited by a wide panel of human vaccines. Sci Immunol. 2022 Dec 23;7(78):eadf1421. doi: 10.1126/sciimmunol.adf1421. Epub 2022 Dec 23.
citation: 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.
citation: 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.
citation: 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.
citation: 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 broad neutralizing antibodies and memory B cells 1 year post-infection is predicted by SARS-CoV-2-specific CD4+ T cell responses. Cell Rep. 2022 Feb 8;38(6):110345. doi: 10.1016/j.celrep.2022.110345. Epub 2022 Jan 19.
citation: 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 Seronegative and Seropositive Individuals. J AIDS Clin Res. 2015 May;6(5):461. doi: 10.4172/2155-6113.1000461. Epub 2015 May 23.
citation: 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.
citation: 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.
citation: Gilboa M, Regev-Yochay G, Mandelboim M, Indenbaum V, Asraf K, Fluss R, Amit S, Mendelson E, Doolman R, Afek A, Freedman LS, Kreiss Y, Lustig Y. Durability of Immune Response After COVID-19 Booster Vaccination and Association With COVID-19 Omicron Infection. JAMA Netw Open. 2022 Sep 1;5(9):e2231778. doi: 10.1001/jamanetworkopen.2022.31778.
citation: Chen Y, Tong P, Whiteman NB, et al. Differential antibody dynamics to SARS-CoV-2 infection and vaccination. bioRxiv 2021:2021.09.09.459504.
citation: Planas D, Veyer D, Baidaliuk A, Staropoli I, Guivel-Benhassine F, Rajah MM, Planchais C, Porrot F, Robillard N, Puech J, Prot M, Gallais F, Gantner P, Velay A, Le Guen J, Kassis-Chikhani N, Edriss D, Belec L, Seve A, Courtellemont L, Pere H, Hocqueloux L, Fafi-Kremer S, Prazuck T, Mouquet H, Bruel T, Simon-Loriere E, Rey FA, Schwartz O. Reduced sensitivity of SARS-CoV-2 variant Delta to antibody neutralization. Nature. 2021 Aug;596(7871):276-280. doi: 10.1038/s41586-021-03777-9. Epub 2021 Jul 8.