Evaluation of Safety and Immunogenicity of Ad26.Mos4.HIV and CH505 TF chTrimer Combination in Healthy Adults

Human Immunodeficiency Virus Clinical Trial

— RV591  

Official title:

Phase I, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Safety, Tolerability, and Immunogenicity of an Ad26.Mos4.HIV and CH505 TF chTrimer (Env) Combination to Mimic Acute HIV Viral Replication Kinetics in Healthy Adults

Clinical Trial Details — Status: Not yet recruiting

Administrative data

• NCT number: NCT06205056
• Other study ID #: S-22-03
• Secondary ID: W81XWH-18-2-0040
• Status: Not yet recruiting
• Phase: Phase 1
• Start date: January 2024
• Est. completion date: September 2025

Study information

• Verified date: January 2024
• Source: U.S. Army Medical Research and Development Command
• Contact: Grace Mirembe, MBChB, MMed
• Phone: +256 312 330400
• Email: gmirembe[@]muwrp.org
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This is a Phase I, randomized, double-blind, placebo-controlled clinical study to define the safety and immunogenicity resulting from a rapid dose-escalating vaccination schedule as compared to that of a co-administered, dose-consistent vaccination schedule. Participants randomized to receive vaccines will get either dose-consistent injections of CH505 TF chTrimer+ALFQ co-administered with Ad26.Mos4.HIV or rapid, dose-escalating injections of CH505 TF chTrimer+ALFQ with an Ad26.Mos4.HIV prime, followed by dose-consistent injection of CH505 TF chTrimer+ALFQ co-administered with Ad26.Mos4.HIV

Description:

This study is exploratory and will be a randomized, placebo-controlled, double-blind trial. A total of 50 healthy male and female participants, aged 18 to 50 years, who are at low risk for Human Immunodeficiency Virus (HIV) acquisition will be enrolled and randomized across two Arms with 25 individuals per Arm. In each Arm, participants will be randomized 4:1 to active study vaccine versus placebo (normal saline) and followed for up to 18 months. All products will be administered by intramuscular (IM) injection into the same quadriceps muscle at each product administration visit. Participants randomized to receive active study vaccines in Arm 1 will receive dose-consistent injections of Ad26.Mos4.HIV (5x10^10 viral particles [vp]/0.5 mL) and CH505 TF chTrimer (300 µg)+ALFQ (200 µg MPLA/100 µg QS-21) co-administered on Study Days 1, 57, and 169. Participants randomized to receive active study vaccines in Arm 2 will receive a lower dose of Ad26.Mos4.HIV (2.5x10^10 vp/0.25 mL) and CH505 TF chTrimer (30 µg)+ALFQ (50 µg MPLA/25 µg QS-21) on Study Day 1, followed by rapid dose-escalating injections of CH505 TF chTrimer (100 µg, 150 µg, and 300 µg)+ALFQ (50 µg MPLA/25 µg QS-21) over a 14-day period, then injections of Ad26.Mos4.HIV (5x10^10 vp/0.5 mL) and CH505 TF chTrimer (300 µg)+ALFQ (200 µg MPLA/100 µg QS-21) on Study Days 57 and 169. Enrollment into Arms 1 and 2 will be concurrent. Sentinel groups, comprised of the first four participants enrolled in each Arm (3:1 active vaccine to placebo), will be included to facilitate an assessment of the safety of the combination of products and vaccination regimens.

Recruitment information / eligibility

• Status: Not yet recruiting
• Enrollment: 50
• Est. completion date: September 2025
• Est. primary completion date: December 2024
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 18 Years to 50 Years

Eligibility

Inclusion Criteria:

Participants must meet all of the following criteria to be eligible for participation:

1. Male or female, aged 18 to 50 years, inclusive, at the time of enrollment

2. Willing and able to read, sign, and date the informed consent form

3. Demonstrates an understanding of the study with a passing score (90% or greater) on the TOU by the third attempt, before study-related procedures are performed

4. Willing and able to comply with study requirements and be available to attend visits for the duration of study participation

5. Must have the means to be contacted by telephone for the duration of study participation

6. Willing to have photo or fingerprint taken for identification purposes

7. At low risk for HIV acquisition per investigator assessment

8. Agrees to refrain from donating blood or plasma outside of this study for at least the duration of study participation

9. Healthy based on the physician investigator's clinical judgment after review of past medical history, medication use, vital signs, and an abbreviated physical examination Note: Good health is defined by the absence of any medical condition described in the exclusion criteria in a participant with a normal abbreviated physical exam and vital signs. If the participant has a preexisting chronic condition not listed in the

exclusion criteria, the condition cannot meet any of the following criteria:

1. first diagnosed within the 12 weeks prior to screening; or

2. worsening in terms of clinical outcome in the 24 weeks prior to screening; or

3. involves the need for medication that may pose a risk to the participant's safety or impede assessment of adverse events or immunogenicity if they participate in the study. Note: Vital signs must be normal by Adverse Event Grading Scales, local normal ranges, or determined to be a normal variant by the physician investigator. Note: An abbreviated physical exam differs from a complete exam in that it does not include a genitourinary and rectal exam.

10. Laboratory criteria within 45 days prior to enrollment:

1. Hemoglobin =11.0 g/dL for females; =12.5 g/dL for males

2. White blood cells (WBC) range: 3,500-9,000 cells/mm^3

3. Platelets between 150,000 - 450,000 cells/µL

4. Normal liver function: Alanine aminotransferase (ALT), aspartate aminotransferase (AST) =1.25x upper limit of normal

5. Serum creatinine =1.25x upper limit of normal

6. Urinalysis: blood and protein less than 1+ and negative glucose

7. Negative HIV serology Note: HIV serology testing will be done via enzyme immunoassay with confirmatory testing of reactive results through a repeat enzyme immunoassay followed by an antibody differentiation immunoassay. After the repeat enzyme immunoassay, if an antibody differentiation immunoassay cannot be done for any reason, then confirmatory testing will be done via Western Blot. HIV rapid testing will not be performed in this study.

8. Negative hepatitis B surface antigen (HbsAg)

9. Negative hepatitis C serology or negative hepatitis C RNA (viral load) if antibodies are detected Note: Each laboratory screening test that is out of acceptable range can be repeated one time during the screening window if there is a possible alternative explanation for the out of range value or if the out of range value is due to a temporary condition that resolves within the screening visit window.

11. Biological Male-Specific Criteria:

1. Must agree to refrain from donating sperm from screening until at least 12 weeks after the last study injection

2. Must agree to consistently use a method of contraception from screening until at least 12 weeks after the last study injection

12. Biological Female-Specific Criteria:

1. Not pregnant within 12 weeks prior to screening, not pregnant or breastfeeding at screening, and not planning to become pregnant or breastfeed at any time from screening until 12 weeks after the last study injection

2. Must have a negative human chorionic gonadotropin (ß-HCG) pregnancy test (urine) at screening and at timepoints throughout the study, if of childbearing potential

3. Must agree to consistently practice a highly effective method of contraception at least 45 days prior to enrollment and for 12 weeks after the final injection, if of childbearing potential Exclusion Criteria:

Volunteers will be excluded if any of the following apply:

1. Body mass index (BMI) <18.0 kg/m^2 and >35.1 kg/m^2

2. Has a condition which affects immune function, including but not limited to:

1. Known or suspected congenital or acquired immunodeficiency

2. Diabetes mellitus type 1 or type 2 (including cases controlled with diet alone) Note: A history of isolated gestational diabetes is not an exclusion criterion.

3. Thyroid disease

4. Asplenia, defined as any condition resulting in the absence of a functional spleen

5. Conditions and diagnoses defined as potential immune-mediated medical conditions

3. Has a history of other chronic or clinically significant diseases or medical conditions that in the opinion of the investigator would jeopardize the safety or rights of the participant Note: Includes but is not limited to sickle cell anemia, chronic hepatitis or cirrhosis, chronic urticaria, chronic cardiac disease, hypertension not controlled by medication, severe asthma, chronic pulmonary disease, renal failure, and lymphatic filariasis.

4. Has a history of malignancy other than squamous cell or basal cell skin cancer, unless there has been definitive surgical and/or medical treatment that is considered to have achieved a cure

5. Had major surgery (per the physician investigator's judgment) within the 28 days prior to screening or has plans to have major surgery during the study

6. Has a personal or family history of a bleeding disorder, such as factor deficiency, coagulopathy, or platelet disorder requiring special precautions

7. Has a personal or family history of a blood clotting disorder, such as thrombosis with thrombocytopenia syndrome (TTS), heparin-induced thrombocytopenia and thrombosis (HITT), deep vein thrombosis, pulmonary embolism, acute myocardial infarction, and stroke

8. Has a condition known to increase risk of blood clotting, including but not limited to autoimmune disease, connective tissue and other inflammatory conditions, immobility, recent infection, and recent head trauma including cerebrovascular accidents (stroke)

9. Hepatitis B surface antigen positive at any time in the past

10. Untreated syphilis infection as confirmed by RPR or a similar quantitative nontreponemal test such as VDRL

11. Prior receipt or plans to receive any of the following:

1. Chronic use of therapies that may modify immune response, such as high dose inhaled and sprayed corticosteroids (>440 µg/twice daily doses of inhaled fluticasone equivalent) and systemic corticosteroids (>20 mg/day doses of prednisone equivalent for periods exceeding 10 days) within 14 days prior to enrollment or at any time during participation in this study Note: The following exceptions are permitted and will not exclude study participation: use of stable low/medium doses (<440 µg/twice daily doses of inhaled fluticasone equivalent) of inhaled and sprayed corticosteroids, topical corticosteroids for an acute uncomplicated dermatitis; or a short course (duration of 10 days or less, or a single injection) of corticosteroid for a non-chronic condition (based on the physician investigator's clinical judgment) at least 14 days prior to enrollment in this study. Includes other medications, which, in the opinion of the physician investigator(s), will impact the participant's immune response.

2. Blood products within 120 days prior to enrollment or at any time during participation in this study

3. Immunoglobulins within 90 days prior to enrollment or at any time during participation in this study

4. Therapy for active tuberculosis within 90 days prior to enrollment, unless the therapy is considered to have achieved a cure, or at any time during participation in this study

5. Licensed or authorized vaccine from 30 days prior to enrollment until 42 days (6 weeks) after the last study injection Note: Participants may receive inactivated seasonal influenza vaccine or COVID-19 vaccine during their participation in this study but not within 14 days prior or 6 weeks after each study injection

6. Any investigational study products for conditions other than HIV within 90 days prior to enrollment or at any time during participation in this study

7. An investigational HIV vaccine or HIV antibody at any time prior to or during participation in this study

8. Medications that increase the risk of bleeding (warfarin, clopidogrel, ticagrelor, dabigatran, rivaroxaban, apixaban, heparin and other heparinoids) or blood clots (heparin in participants who have a prior history of heparin-induced coagulopathy) within 30 days prior to enrollment or at any time during participation in this study

12. Has a known allergy or history of anaphylaxis or other serious reaction to a vaccine, vaccine component, or latex

13. Current or planned participation in another study requiring blood draws or exposure to investigational or non-investigational vaccine/product (pharmaceutical or device) throughout the study period

14. Has tattoos, scars, or other marks that would, in the opinion of the physician investigator, interfere with the assessment of the injection sites

15. Current or history of substance abuse within 12 months prior to enrollment that, in the physician investigator's opinion, could interfere with reliable participation

16. In the physician investigator's opinion, is unable to communicate reliably, is unlikely to adhere to study requirements, or has a condition that would limit completion of the study

17. Any other chronic or clinically significant medical condition that in the opinion of investigator would jeopardize the safety or rights of the participant or potentially impairs immune response or threatens conduct of the study according to protocol

18. Study site employee Final evaluation of eligibility will be based on the medical judgment of the physician investigator.

Related Conditions & MeSH terms

• Acquired Immunodeficiency Syndrome
• HIV Infections
• Human Immunodeficiency Virus

Intervention

Biological:
• Ad26.Mos4.HIV [Arm 1]
Participants in Arm 1 will receive dose-consistent injections (5x10^10 vp/0.5 mL) at each product administration visit (Days 1, 57, and 169)
• Ad26.Mos4.HIV [Arm 2]
Participants in Arm 2 will initially receive a lower dose (2.5x10^10 vp/0.25 mL) on Day 1, which will increase to the Arm 1 dose (5x10^10 vp/0.5 mL) when subsequently administered on Days 57 and 169.
• CH505 TF chTrimer+ALFQ [Arm 1]
Participants in Arm 1 will receive dose-consistent injections of CH505 TF chTrimer (300 µg) mixed with ALFQ (200 µg MPLA/ 100 µg QS 21) at each product administration visit on Days 1, 57, and 169
• CH505 TF chTrimer+ALFQ [Arm 2]
Participants in Arm 2 will receive 30 µg, 100 µg, 150 µg, and 300 µg doses of CH505 TF chTrimer mixed with ALFQ. Day 1: CH505 (30 µg) +ALFQ (50 µg MPLA/ 25 µg QS 21) Day 4: CH505 (100 µg) +ALFQ (50 µg MPLA/ 25 µg QS 21) Day 8: CH505 (150 µg) +ALFQ (50 µg MPLA/ 25 µg QS 21) Day 15: CH505 (300 µg) +ALFQ (50 µg MPLA/ 25 µg QS 21) Day 57: CH505 (300 µg) +ALFQ (200 µg MPLA/ 100 µg QS 21) Day 169: CH505 (300 µg) +ALFQ (200 µg MPLA/ 100 µg QS 21)
• ALFQ [Arm 1]
Participants in Arm 1 will receive dose-consistent injections of ALFQ (200 µg MPLA/100 µg QS-21) mixed with CH505 TF chTrimer on Days 1, 57, and 169
• ALFQ [Arm 2]
Participants in Arm 2 will receive a lower dose of ALFQ (50 µg MPLA/25 µg QS-21) mixed with CH505 TF chTrimer during the rapid, dose-escalating injections on Days 1, 4, 8, and 15 and a dose of ALFQ similar to that used in Arm 1 (200 µg MPLA/100 µg QS-21) mixed with CH505 TF chTrimer at subsequent injections on Days 57 and 169

Locations

Country	Name	City	State
Uganda	Makerere University Walter Reed Project (MUWRP)	Kampala

Sponsors (7)

Lead Sponsor	Collaborator
U.S. Army Medical Research and Development Command	Duke University, Henry M. Jackson Foundation for the Advancement of Military Medicine, Janssen Vaccines & Prevention B.V., Makerere University Walter Reed Project, National Institute of Allergy and Infectious Diseases (NIAID), Walter Reed Army Institute of Research (WRAIR)

Country where clinical trial is conducted

Uganda, 

References & Publications (6)

Cirelli KM, Carnathan DG, Nogal B, Martin JT, Rodriguez OL, Upadhyay AA, Enemuo CA, Gebru EH, Choe Y, Viviano F, Nakao C, Pauthner MG, Reiss S, Cottrell CA, Smith ML, Bastidas R, Gibson W, Wolabaugh AN, Melo MB, Cossette B, Kumar V, Patel NB, Tokatlian T, Menis S, Kulp DW, Burton DR, Murrell B, Schief WR, Bosinger SE, Ward AB, Watson CT, Silvestri G, Irvine DJ, Crotty S. Slow Delivery Immunization Enhances HIV Neutralizing Antibody and Germinal Center Responses via Modulation of Immunodominance. Cell. 2019 May 16;177(5):1153-1171.e28. doi: 10.1016/j.cell.2019.04.012. Epub 2019 May 9. Erratum In: Cell. 2020 Jan 9;180(1):206. — View Citation

Genito CJ, Beck Z, Phares TW, Kalle F, Limbach KJ, Stefaniak ME, Patterson NB, Bergmann-Leitner ES, Waters NC, Matyas GR, Alving CR, Dutta S. Liposomes containing monophosphoryl lipid A and QS-21 serve as an effective adjuvant for soluble circumsporozoite protein malaria vaccine FMP013. Vaccine. 2017 Jul 5;35(31):3865-3874. doi: 10.1016/j.vaccine.2017.05.070. Epub 2017 Jun 7. — View Citation

Havenar-Daughton C, Carnathan DG, Torrents de la Pena A, Pauthner M, Briney B, Reiss SM, Wood JS, Kaushik K, van Gils MJ, Rosales SL, van der Woude P, Locci M, Le KM, de Taeye SW, Sok D, Mohammed AUR, Huang J, Gumber S, Garcia A, Kasturi SP, Pulendran B, Moore JP, Ahmed R, Seumois G, Burton DR, Sanders RW, Silvestri G, Crotty S. Direct Probing of Germinal Center Responses Reveals Immunological Features and Bottlenecks for Neutralizing Antibody Responses to HIV Env Trimer. Cell Rep. 2016 Nov 22;17(9):2195-2209. doi: 10.1016/j.celrep.2016.10.085. — View Citation

Liao HX, Lynch R, Zhou T, Gao F, Alam SM, Boyd SD, Fire AZ, Roskin KM, Schramm CA, Zhang Z, Zhu J, Shapiro L; NISC Comparative Sequencing Program; Mullikin JC, Gnanakaran S, Hraber P, Wiehe K, Kelsoe G, Yang G, Xia SM, Montefiori DC, Parks R, Lloyd KE, Scearce RM, Soderberg KA, Cohen M, Kamanga G, Louder MK, Tran LM, Chen Y, Cai F, Chen S, Moquin S, Du X, Joyce MG, Srivatsan S, Zhang B, Zheng A, Shaw GM, Hahn BH, Kepler TB, Korber BT, Kwong PD, Mascola JR, Haynes BF. Co-evolution of a broadly neutralizing HIV-1 antibody and founder virus. Nature. 2013 Apr 25;496(7446):469-76. doi: 10.1038/nature12053. Epub 2013 Apr 3. — View Citation

Pauthner M, Havenar-Daughton C, Sok D, Nkolola JP, Bastidas R, Boopathy AV, Carnathan DG, Chandrashekar A, Cirelli KM, Cottrell CA, Eroshkin AM, Guenaga J, Kaushik K, Kulp DW, Liu J, McCoy LE, Oom AL, Ozorowski G, Post KW, Sharma SK, Steichen JM, de Taeye SW, Tokatlian T, Torrents de la Pena A, Butera ST, LaBranche CC, Montefiori DC, Silvestri G, Wilson IA, Irvine DJ, Sanders RW, Schief WR, Ward AB, Wyatt RT, Barouch DH, Crotty S, Burton DR. Elicitation of Robust Tier 2 Neutralizing Antibody Responses in Nonhuman Primates by HIV Envelope Trimer Immunization Using Optimized Approaches. Immunity. 2017 Jun 20;46(6):1073-1088.e6. doi: 10.1016/j.immuni.2017.05.007. — View Citation

Pitisuttithum P, Gilbert P, Gurwith M, Heyward W, Martin M, van Griensven F, Hu D, Tappero JW, Choopanya K; Bangkok Vaccine Evaluation Group. Randomized, double-blind, placebo-controlled efficacy trial of a bivalent recombinant glycoprotein 120 HIV-1 vaccine among injection drug users in Bangkok, Thailand. J Infect Dis. 2006 Dec 15;194(12):1661-71. doi: 10.1086/508748. Epub 2006 Nov 3. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Characterize binding antibody Fc engagement to a panel of HIV Envs as assessed by Antibody Profiling	Characterize binding antibody Fc engagement to a panel of HIV Envs.Antibody Profiling will be conducted to assess antibody breadth and correlation of Fc receptor usage with antibody function.The current capacity for Antibody Profiling is the assessment of over 300 samples in one experiment. The beads presenting the HIV antigens will be distributed robotically in a high-throughput manner into 384 well plates. Similarly, the samples will be diluted robotically and incubated with the beads. Detection reagents will be added to the wells after washing. These detection reagents are inclusive of subclass, isotype, and Fc receptor usage.	Visit Days 1, 15, 29, 57, 71, 85, 169, 183, and 337
Other	Characterize rate of B-cell specificity by quantifying antigen-specific responses as assessed through B-cell ELISPOT	Characterize rate of B-cell specificity by quantifying antigen-specific responses as assessed through B-cell ELISPOT	Visit Days 1, 8, 15, 29, 71, 169, 176, 183, and 337
Other	Characterize magnitude of cell-mediated immune responses elicited across vaccination regimens (including antigen -specific CD4 and CD8 T cell responses) assessed by CD4 and CD8 cellular response assays and after stimulation with HIV-specific antigens.	Characterize and assess the magnitude of cell-mediated immune responses elicited across vaccination regimens including but not limited to antigen -specific CD4 and CD8 T cell responses as assessed by CD4 and CD8 cellular response assays and after stimulation with HIV-specific antigens.	Visit Days 1, 4, 8, 29, 71, 169, 170, 176, 183, and 337
Other	Phenotype innate immune cells (NK cells) as assessed by flow cytometry	Characterize cytokines elicited by vaccine regimens	Visit Days 1, 4, 8, 29, 71, 169, 170, 176, 183, and 337
Primary	Occurrence and severity of solicited local and systemic adverse events (AEs) following candidate vaccine administration	Occurrence and severity of solicited local and systemic adverse events (AEs) following candidate vaccine administration	Day 0 - Day 505
Primary	Occurrence, severity, and relationship to vaccination of unsolicited adverse events after candidate vaccine administration	Occurrence, severity, and relationship to vaccination of unsolicited adverse events after candidate vaccine administration	Day 0 - Day 505
Primary	Occurrence of serious adverse events (SAEs) following candidate vaccine administration	Occurrence of serious adverse events (SAEs) following candidate vaccine administration	Day 0 - Day 505
Primary	Occurrence of adverse events of special interest (AESIs) following candidate vaccine administration	Occurrence of adverse events of special interest (AESIs) following candidate vaccine administration	Day 0 - Day 505
Secondary	Quantify IgG binding antibodies to HIV Env in magnitude between Arms as assessed by HIV-specific Binding Antibody ELISA Assays	Quantify IgG binding antibodies to HIV Env in terms of magnitude between Arms. HIV-specific Binding Antibody ELISA Assays will be performed to detect plasma IgG and IgA binding antibodies to HIV-1 Envelope antigens and assess their magnitude between Arms.	Visit Days 1, 4, 8, 15, 29, 57, 71, 85,169, 183, and 337
Secondary	Quantify rate of neutralizing antibodies to HIV Env in magnitude between Arms as assessed by Neutralizing Antibody Assays	Quantify rate of neutralizing antibodies to HIV Env in terms of magnitude between Arms. Neutralizing Antibody Assays will be measured as a function of reductions in luciferase (Luc) reporter gene expression after a single round of infection in TZM-bl cells using high throughput analysis.	Visit Days 1, 4, 8, 15, 29, 57, 71, 85,169, 183, and 337
Secondary	Quantify rate of IgG binding antibodies to HIV Env in durability between Arms as assessed by HIV-specific Binding Antibody ELISA Assays	Quantify rate of IgG binding antibodies to HIV Env in terms of durability between Arms as assessed by HIV-specific Binding Antibody ELISA Assays. Immune response over time (durability) will be assessed by the positive incremental area under the curve based on a graph with log endpoint titer on the y-axis and visit day and week on the x-axis. Durability of IgG responses will be assessed for each participant by estimating the decline in log10 IgG from peak to 6 months post final injection.	Visit Days 1, 4, 8, 15, 29, 57, 71, 85,169, 183, and 337
Secondary	Quantify rate of neutralizing antibodies to HIV Env in durability between Arms as assessed by Neutralizing Antibody Assays	Quantify rate of neutralizing antibodies to HIV Env in terms of durability between Arms as assessed by Neutralizing Antibody Assays. Neutralizing Antibody Assays will be measured as a function of reductions in luciferase (Luc) reporter gene expression after a single round of infection in TZM-bl cells using high throughput analysis.	Visit Days 1, 4, 8, 15, 29, 57, 71, 85,169, 183, and 337