Immune correlates analysis of the - PowerPoint Presentation

1. Immune correlates analysis of the Imbokodo HIV-1 vaccine efficacy trialLate Breaker Track AAvi Kenny, Department of Biostatistics, University of Washington, Seattle, USA

2. The Imbokodo trial was supported by a public-private partnership led by Janssen Vaccines & Prevention B.V., the National Institute of Allergy and Infectious Diseases, the Bill & Melinda Gates Foundation, and the HIV Vaccine Trials Network (HVTN). Additional partners providing support included the U.S. Army Medical Research and Development Command (USAMRDC) and the Ragon Institute of MGH, MIT and Harvard.The potential effects of relevant financial relationships with companies have been mitigated. Any clinical recommendations are based on evidence and are free of commercial bias.Conflict of interest disclosure

3. Mo 0 Mo 7 Mo 24 Mo 36Ad Ad Ad+Pr Ad+PrAd = Ad26.Mos4.HIV Pr = Clade C gp140Mo 0 3 6 12 Study population: HIV-uninfected women in sub-Saharan Africa aged 18-35 years at risk for HIV infectionPrimary objectives: (1) to assess vaccine efficacy (VE) to prevent HIV-1 infection between months 7 and 24, and (2) to evaluate vaccine safety and tolerability.The Imbokodo Trial (HVTN705/HPX2008)

4. Bloemfontein (165)Mamelodi (137)Ndola (110)Elandsdoorn (158)Lilongwe (157)Maputo (45)Seke South (211)Klerksdorp (55)Soweto – Kliptown (47)Soweto – Baragwanath (217)Mthatha (7)Soshanguve (144)Medunsa (39)Tembisa (66)Rustenburg (52)Ladysmith (171)Masiphumelele (157) Chatsworth (198) Tongaat (101)eThekwini (60)Lusaka –ZEHRP (113)St. Mary’s (120)Lusaka –Matero (107)The Imbokodo Trial (HVTN705/HPX2008)Enrollment: 2,637 women enrolled in 23 sites across 5 countriesTime period: 2017 to 2021

5. The Imbokodo Trial (HVTN705/HPX2008)Key findingsVaccine efficacy (between months 7 and 24) estimated to be 14% (95% CI: -22%, 40%)*The point estimate did not significantly differ from zeroEndpoints through M24Incidence rate per 100 PYRs through M24 (95% CI)Placebo653.94 (3.04, 5.03)Vaccine543.38 (2.54, 4.41)* Note that the VE point estimate of 14% was revised from the initial estimate of 25%, due to the detection of a statistical issue in which not all available participant data up to month 24 was used.

6. Correlates of risk (CoRs: associations)(Univariable CoR) To study each individual month 7 immune marker as a correlate of HIV-1 acquisition(Multivariable CoR) To build conditional HIV-1 risk models based on the full set of month 7 immune markers and baseline demographics and other potential HIV-1 risk factorsCorrelates of protection (CoPs: causal effects)(Controlled VE CoP) To study each individual month 7 immune marker as a controlled vaccine efficacy CoP (Gilbert, Fong, Kenny, and Carone 2021)(Mediation CoP) To assess each individual month 7 immune marker as a mediator of VE (Benkeser, Ran, and Diaz 2021)Objectives of the immune correlates analysisAntibody responsesVaccineOther immune responsesHIV-1 infectionHost immune factors?

7. Correlates of risk (CoRs: associations)(Univariable CoR) To study each individual month 7 immune marker as a correlate of HIV-1 acquisition(Multivariable CoR) To build conditional HIV-1 risk models based on the full set of month 7 immune markers and baseline demographics and other potential HIV-1 risk factorsCorrelates of protection (CoPs: causal effects)(Controlled VE CoP) To study each individual month 7 immune marker as a controlled vaccine efficacy CoP (Gilbert, Fong, Kenny, and Carone 2021)(Mediation CoP) To assess each individual month 7 immune marker as a mediator of VE (Benkeser, Ran, and Diaz 2021)Objectives of the immune correlates analysisAntibody responsesVaccineOther immune responsesHIV-1 infectionHost immune factors?

8. All analyses were prespecified (unless indicated otherwise) in a statistical analysis plan (SAP)All methods were developed, qualified and/or standardized prior to running the case-control analysisA case-control analysis involving a sub-cohort of the per-protocol study population, including 54 vaccinated cases and 270 vaccinated controls41 immune markers assessed (6 primary, 35 exploratory); primary markers selected based on prior correlates evidenceNHP Challenge studies of the Ad26 vaccine (Barouch et al. 2018)RV144 (Haynes et al. 2012, Yates et al. 2014)HVTN 505 (Neidich et al. 2019)The set of markers and the entire SAP were approved by the Imbokodo Public Private PartnershipMethods

9. #Short labelExpanded descriptionLab PI1Vaccine-take ELISAIgG to vaccine strain subtype C (ELISA)PPD (Janssen)2ELISpot PTE EnvLog10 transformed sum of the number of spot forming cells (SFC) / 106 PBMCs for PTE Env 1, PTE Env 2, and PTE Env 3D. Barouch3ADCP Vx-C97ZAADCP score to vaccine strain subtype CG. Tomaras4IgG3 V1V2 breadthMDW* average of IgG3 to V1V2 antigen panelG. Tomaras5IgG3 Env breadthMDW* average of IgG3 to gp120 and gp140 antigen panels, gp120 vaccine strainsG. Tomaras6Expanded Multi-epitope functionsMDW* average of: IgG Vx-VT-C, ADCP Vx-C97ZA, ADCP Vx-Mos1, IgG3 V1V2 breadth, IgG3 Env breadth, ELISPot PTE Env, IgGt V1V2 breadth, ADCC pAUC CAP8, ADCC pAUC CH58, ADCC pAUC WITO, CD4+ T cells, CD8+ T cells D. Barouch, G. Ferrari, J. McElrath,G. TomarasPrimary Month 7 Immune Markers* MDW = maximal signal diversity weighting (He and Fong 2019)We focus on markers 1,3,4,5 (assay work being finalized for markers 2,6)Every marker was measured using a validated or qualified assay

10. Results (CoR): univariable Cox modelsInference for Month 7 antibody marker covariate-adjusted correlates of risk of HIV in the vaccine group: hazard ratios per 10-fold increment in the marker*P-value0.57 0.98 0.24 0.74*Baseline covariates adjusted for: RSA + Age + BMI + Risk scoreVaccine-take ELISA ADCP Vx-C97ZA IgG3 V1V2 breadth IgG3 Env breadth Estimated hazard ratio (HR) Lower risk of HIV infection Higher risk of HIV infection 

11. Results (CoR): univariable Cox modelsInference for Month 7 antibody marker covariate-adjusted correlates of risk of HIV in the vaccine group: hazard ratios per 10-fold increment in the marker*P-value0.57 0.98 0.24 0.74*Baseline covariates adjusted for: RSA + Age + BMI + Risk scorePossible trend for V1V2 marker as inverse correlateof riskVaccine-take ELISA ADCP Vx-C97ZA IgG3 V1V2 breadth IgG3 Env breadth Estimated hazard ratio (HR) Lower risk of HIV infection Higher risk of HIV infection 

12. Results (CoP): controlled vaccine efficacyVaccine-take ELISA: Month 7Vaccine-take ELISA does not appear to impact vaccine efficacyVaccine-take ELISAControlled VE against HIV (Mth 7-24)

13. Results (CoP): controlled vaccine efficacyVaccine-matched ADCP Vx-C97ZA does not appear to impact vaccine efficacyADCP Vx-C97ZA: Month 7ADCP Vx-C97ZAControlled VE against HIV (Mth 7-24)

14. Results (CoP): controlled vaccine efficacyTrend of higher IgG3 V1V2 BAMA breadth scores associated with lower infection risk and partial vaccine protectionIgG3 V1V2 breadth: Month 7IgG3 V1V2 breadthControlled VE against HIV (Mth 7-24)

15. Results (CoP): controlled vaccine efficacyExploratory markerTrend of higher IgG3 Net MFI to gp70-001428.2.42 V1V2 associated with lower infection risk and partial vaccine protectionThis is the antigen in the V1V2 panel for which we observed the lowest hazard ratioIgG3 Net MFI to gp70-001428.2.42 V1V2: Month 7IgG3 Net MFI to gp70-001428.2.42 V1V2Controlled VE against HIV (Mth 7-24)

16. Results (CoR+CoP): exploratory markersNo evidence of immune CoR or CoP for most exploratory markers, including:ADCC (Peak/AUC baseline-subtracted pct loss LUC activity to CAP8/CH58/WITO)% CD4+ T-cells expressing IFN-g and/or IL-2 (in response to any envelope peptide)% CD8+ T-cells expressing IFN-g and/or IL-2 (in response to any envelope peptide)

17. ConclusionsThe analysis did not support statistically significant univariable CoRs or CoPs (P-values for univariable Cox model of primary markers: 0.24 to 0.98).Multiple statistical analyses revealed a (nonsignificant) trend of high IgG3 V1V2 BAMA breadth scores associated with lower infection risk and partial vaccine protection.Third HIV vaccine efficacy trial with some evidence of an IgG3 correlation (HVTN505, RV144, HVTN705) and third with a V1V2 epitope correlation (RV144, HVTN702, HVTN705)

18. Barouch et al. Evaluation of a mosaic HIV-1 vaccine in a multicentre, randomised, double-blind, placebo-controlled, phase 1/2a clinical trial (APPROACH) and in rhesus monkeys (NHP 13-19). Lancet, 2018. PMC6192527.Haynes et al. Immune-correlates analysis of an HIV-1 vaccine efficacy trial. NEJM 2012. PMC3371689Yates et al. Vaccine-induced Env V1-V2 IgG3 correlates with lower HIV-1 infection risk and declines soon after vaccination. Science Translational Medicine, 2014. PMC4116665.Neidich et al. Antibody Fc effector functions and IgG3 associate with decreased HIV-1 risk. The Journal of Clinical Investigation, 2019. PMC6819135.Gilbert, Fong, Kenny, and Carone. Assessment of immune correlates of protection via controlled vaccine efficacy and controlled risk. arXiv Preprint, 2021. 2107.05734.Benkeser, Ran, and Diaz. Inference for natural mediation effects under case-cohort sampling with applications in identifying COVID-19 vaccine correlates of protection. arXiv Preprint, 2021. 2103.02643.He and Fong. Maximum diversity weighting for biomarkers with application in HIV-1 vaccine studies. Statistics in Medicine, 2019. PMC6684395.Moodie et al. Analysis of the HVTN 702 Phase 2b-3 HIV-1 vaccine trial in South Africa assessing RV144 antibody and T-cell correlates of HIV-1 acquisition risk. The Journal of Infectious Diseases, 2022. PMID35758878.References

19. Abstract authors: Avi Kenny1, Alex Luedtke1,3, Ollivier Hyrien1,3, Youyi Fong1,3, Randy Burnham2, Jack Heptinstall4, Sheetal Sawant4, Sherry Stanfield-Oakley4, Faatima Laher Omar5, Sharon Khuzwayo5, One Dintwe3,5, Erica Borducchi6, Laura Pattacini7, Wouter Willems8, Ludo Lavreys9, Janine van Duijn7, Daniel J. Stieh7, Frank Tomaka10, Maria G. Pau7, Glenda E. Gray11, Susan Buchbinder12, Kathryn Mngadi13, M. Juliana McElrath3, Lawrence Corey3, Dan H. Barouch6, Stephen C. De Rosa3, Guido Ferrari4, Erica Andersen-Nissen3,5, Georgia Tomaras4,*, Peter B. Gilbert1,3,*1Department of Biostatistics, University of Washington, Seattle, WA, USA; 2Statistical Center for HIV/AIDS Research and Prevention (SCHARP), Fred Hutchinson Cancer Center, Seattle, WA, USA; 3Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, WA, USA; 4Duke University, Durham, NC, USA; 5Cape Town HVTN Immunology Laboratory, Hutchinson Centre Research Institute of South Africa, Cape Town, South Africa; 6Center for Virology & Vaccine Research, Beth Israel Deaconess Medical Center, Boston, MA, USA; 7Janssen Vaccines Research & Prevention BV, Leiden, The Netherlands; 8Janssen Research & Development BE, Beerse, Belgium; 9Janssen Infectious Diseases BV, Beerse, Belgium; 10Janssen Research & Development, LLC, Titusville, NJ, USA; 11South African Medical Research Council, Cape Town, South Africa; 12San Francisco Department of Public Health, San Francisco, CA, USA; 13The Aurum Institute, Johannesburg, South Africa.Additional collaborators: Michal Juraska, Shannon Grant, Hua Zheng, Chenchen Yu, Helen Lu, Kevin Gillespie, Namita Trikannad, David Bekenser, Bhavesh Borate, Lars Van der Laan, Derrick Goodman, Zelda Euler, Kelly Seaton, Betty Korber, Lu Zhang, Steven Nijs, Sanne Roels, Esmee Brams, Brooke Dunn, Taylor Keyes, Adam Zalaquett, Zunera KhanCollaborators

20. BloemfonteinCarine Pienaar, Back-Up Clinic CoordinatorGustav Venter, Clinic CoordinatorMarli Odendaal, PharmacistRonald Moate, CER Zaheer Hoosain, IoRCape Town - Emavundleni Thank you to all the study site investigators, clinic coordinators, CER teams, and site pharmacists.Durban - Chatsworth Thank you to all the study site investigators, clinic coordinators, CER teams, and site pharmacists.Durban - eThekwini Atika Moosa, PharmacistBongi Zuma, Data ManagerIvy Kaunda, CERKieara Ramtahal, Clinic CoordinatorNigel Garrett, IoRDurban - Tongaat Bomkazi Tutshana, Clinic CoordinatorMakandwe Nyirenda, Clinic Coord.Mandy Cobbing, PharmacistPhindile Guga, CER Reshmi Dassaye, Clinic CoordinatorVimla Naicker, IoRElandsdoornDesiree Pass, Clinic CoordinatorJerry  Marobyane, CERMasello Mohlala, Data SupervisorMiliiah Hlathi, Study NurseTrever Chokwe, PharmacistHarare - Seke SouthAngela Chishanga, Medical OfficerChiedza Chirisa, CERMarvelous Sibanda, PharmacistPortia Hunidzarira, IoRThandiwe Hildah Chirenda, Clinic CoordinatorHarare – St. Mary’s Thank you to all the study site investigators, clinic coordinators, CER teams, and site pharmacists.KlerksdorpThank you to all the study site investigators, clinic coordinators, CER teams, and site pharmacists.LadysmithBrian Groenewald, PharmacistMaryna Schoeman, Study coordinatorMichelle Nelson, Clinic CoordinatorPhillip Kotze, IoRLilongweJane Kilembe, Clinic CoordinatorMina Hosseinipour, IoRMitchMatoga, Co-investigatorMwai Chipeta, CER Terence Tafatatha, Co-investigatorVictor Palichina, PharmacistLusaka - MateroBupe Sichalwe, Clinic CoordinatorJoyce Mapanza, CER Mah Asombang, IoRSam Mundia, PharmacistLusaka - ZEHRPElias Chambula, PharmacistHilda Phiri, CER Sydney Kampamba, Lab TechnologistTyronza Sharkey, Clinic CoordinatorWilliam Kilembe, IoRMamelodiAnika Naidoo, Clinic CoordinatorAnnah Pitsi, IoRAnnalie Brits, Site ManagerAsia Sithole, PharmacistLucky Molefe, CER MaputoCarmélia Massingue, CER Edna Viegas, PIKátia Cossa, Clinic CoordinatorMárcia Mutisse, IoRNorma Mabota, PharmacistMasiphumeleleDr. Katherine Gill, IoRKeshani Naidoo, Clinical Operations CoordinatorLandisiwe Mzukwa, Clinic CoordinatorNgosa Mulubwe, PharmacistNomvo Henda, CER MedunsaSmangaliso Makubu, CER Innocentia Matjila, Clinic CoordinatorMatsontso Mathebula, IoRSelekane Marota, PharmacistOuma Machakela, Study NurseMthathaMpho Peter, Clinic CoordinatorPamela Mda, CRS leaderThozama Dubula, IoRThulile Mtubisi, PharmacistZoleka Fadane, CER NdolaThank you to all the study site investigators, clinic coordinators, CER teams, and site pharmacists.RustenburgThank you to all the study site investigators, clinic coordinators, CER teams, and site pharmacists.SoshanguveHosea Matlebjane, PharmacistKgomotso Phohu, Regulatory ManagerRoss Malamatsho, CER Thulisile Enough Mbatsane, Project CoordinatorVeronica Carmen Bailey, PISoweto - BaraAnesu Tongoona, Sub-investigatorKishendree Naicker, IoRUsha Singh, PharmacistYandisa Nyanisa, Clinic CoordinatorZiphezinhle Mpanza, CER Soweto - KliptownErica Lazarus, IoRPontsho Seitlhamo, CER Thokozani Makuhunga, Clinic CoordinatorMmamotsa Makhene, Sub-investigator - ClinicalMoeketsi Mole, CERTricia Philip, Sub-investigator - CERs & CounsellorsTembisa – Clinic 4Carita Marx, PharmacistYajna Duki , Project ManagerKathy Mngadi, IoRNondumiso Mngadi, Quality OfficerThabang Ntloko, CERThank you to the study participants and CAB and community members!Site acknowledgements