1. Impact à long terme de la participation aux essais vaccinaux VIH chez le volontaire sain Cohorte ANRS COHVAC C. Durier, C. Desaint, B. Silbermann, J.D. Lelièvre, L. Slama, P. Morineau-Le Houssine, L. Cuzin, I. Poizot- Martin, J.P. Aboulker, G Pialoux, B. Spire, O. Launay; pour la cohorte ANRS COHVAC

2. 2 Séminaire ANRS – 5 mai 2011 * in a previous HIV vaccine trial ANRS Phase I/II Vaccine Trials HIV-1 Lipopeptides representing CTL epitopes of Gag, Pol and Nef proteins ALVAC-HIV canarypox vectors expressing Env, Gag, Pro and CTL domains of Pol (vCP) Recombinant envelope protein subunit (rgp160) P24 / Env V3 MN synthetic peptide (CLTB-36) Env V3 MN synthetic peptide (peptideV3) 422 N (74) 99 15 68 10+21* 34 15 55 3 23* 13* 20 16 * 15 * 28 30 25 20 VAC 16 VAC 01 VAC 02 VAC 03 VAC 04 VAC 05 VAC 06 VAC 07 VAC 08 VAC 09 LIP 03 VAC 10 VAC 12 VAC 14 VAC 17 VAC 18-I VAC 18-II VAC 20 1992199419961998200020022004200620082010 Séminaires ANRS – 5/2011 COHVAC

3. 3 Séminaire ANRS – 5 mai 2011 HIV-1 healthy, 21-54 years Psychological and sociological stability HIV-neg status by Elisa and WB Pre-existing medical conditions, abnormal lab values exclusion Low risk of HIV infection Counseling regarding the need to avoid HIV exposure No financial incentive ANRS Volunteers Network Séminaires ANRS – 5/2011 COHVAC

4. 4 Séminaire ANRS – 5 mai 2011 ANRS Volunteers Network 1y+ TRIAL y0 Prospective follow-up Retrospective collection y1y2y3y4y5y6y7 Trial entry Trial completion Prospective multicenter cohort study for long term follow-up of safety, serological evolution and evaluation of the consequences of participation in HIV preventive vaccine trials ANRS COV1-COHVAC Séminaires ANRS – 5/2011 COHVAC

5. 5 Séminaire ANRS – 5 mai 2011 Primary endpoint Severe medical events (grade 3-4), neurological, ophthalmological, and immunological events Secondary endpoints Long-term HIV antibody response Psychosocial and behavioral consequences of participation in HIV vaccine trials Incidence of HIV infections ANRS COV1-COHVAC Séminaires ANRS – 5/2011 COHVAC

6. 6 Séminaire ANRS – 5 mai 2011 Medical and biological follow-up HIV antibodies with 2 different licensed enzyme immunoassays (EIA) performed locally, and Western-Blot assay if positive Vaccine-induced seropositivity (VISP) : 1 of EIA tests positive, regardless of Western-Blot results Self-administered questionnaire Socio-economic status Social life Concerns about trial participation Sexual behavior approved by the National Committee on Informatics and Freedom (CNIL) Methodology Séminaires ANRS – 5/2011 COHVAC

7. 7 Séminaire ANRS – 5 mai 2011 Presentations Long-term vaccine induced HIV seropositivity among HIV-uninfected healthy volunteers in ANRS COV1-COHVAC cohort 18th CROI 2011, Poster #372 Psychosocial consequences of participation in HIV preventive vaccine trials: a cross-sectional study in ANRS COV1-COHVAC cohort Conference AIDS VACCINE 2010, Oral abstr. 03-01 AIDS Research and Human Retroviruses. October 2010, 26(10): A-1-A-184. Séminaires ANRS – 5/2011 COHVAC

8. 8 Séminaire ANRS – 5 mai 2011 Séminaires ANRS – 5/2011 COHVAC 422 N (74) 99 15 68 10+21* 34 15 55 3 23* 13* 20 16 * 15 * 28 30 25 20 VAC 16 VAC 01 VAC 02 VAC 03 VAC 04 VAC 05 VAC 06 VAC 07 VAC 08 VAC 09 LIP 03 VAC 10 VAC 12 VAC 14 VAC 17 VAC 18-I VAC 18-II VAC 20 HIV-1 Lipopeptides representing CTL epitopes of Gag, Pol and Nef proteins ALVAC-HIV canarypox vectors expressing Env, Gag, Pro and CTL domains of Pol (vCP) Recombinant envelope protein subunit (rgp160) P24 / Env V3 MN synthetic peptide (CLTB-36) Env V3 MN synthetic peptide (peptideV3) ANRS Phase I/II Trials 1992199419961998200020022004200620082010 All were injected IM except one mucosal and one ID trial

9. 9 Séminaire ANRS – 5 mai 2011 ANRS Trials rgp160vCPLIPO muc gp160 Trials VAC01 VAC02 VAC03 VAC07 LIP03 VAC10 VAC04 VAC10 VAC17 VAC12 VAC16 VAC18 VAC14 ANRS Centers Tenon Cochin Tenon Cochin + Marseille Nantes Toulouse Mondor Tenon Cochin N in trials458026334 Séminaires ANRS – 5/2011 COHVAC

10. 10 Séminaire ANRS – 5 mai 2011 HIV antibodies at inclusion in COHVAC Characteristics of volunteers Dec 2008- Sep 2010 rgp160vCPLIPO muc gp160All N in trials458026334422 N enrolled in COHVAC (%)29 (64)47 (59)156 (59)25 (74)257 (61) N tested (%)26 (58)42 (53)150 (57)21 (62)239 (57) AgeMedian56.659.150.851.552.5 Min43.739.925.336.825.3 Max71.270.164.359.371.2 Gender % male655557053 Time (y) Median16.614.24.35.35.2 since Min16.38.12.25.12.2 injections Max17.515.613.26.517.5 HIV antibody testing period Dec08 to Mar10 Dec08 to Sep10 Dec08 to Sep10 Dec08 to Mar10 Dec08 to Sep10 Séminaires ANRS – 5/2011 COHVAC

11. 11 Séminaire ANRS – 5 mai 2011 Vaccine-induced seropositivity rate (VISP) by vaccine type % VISP (95% Confidence Interval) 0 20 40 60 80 100 rgp160 vCP LIPOmucgp160All N VISP/ N tested17/267/421/1500/2125/239 %VISP65.416.70.67010.5 [95% CI][44.3-82.8][7-31.4][0.02-3.7][0-16.1][6.9-15.1] Séminaires ANRS – 5/2011 COHVAC

12. 12 Séminaire ANRS – 5 mai 2011 Time since injections by vaccine type Years since injections (median, IQR, min-max) 0 2 4 6 8 10 12 14 16 18 20 rgp160vCPLIPOmucgp160All VISP / Tested N VISP/ N tested17/267/421/1500/2125/239 Median (years)16.59.79.1-16.4 Range16.3 to 16.88.5 to 15-- Séminaires ANRS – 5/2011 COHVAC

13. 13 Séminaire ANRS – 5 mai 2011 Volunteers presenting VISP (N=25) EIA testsWestern-blots assays GenderAge Vaccine Trial Vaccines received +adjuvant Time since injections (years) Genscreen ultraHIV BIORAD Vidas HIV duo BIOMERIEUX Anti-HIV Tetra ELISA BIOTESTReactive bands rgp160M55.6VAC01vCP125, rgp160+IFA16.4++gp160, gp120, p55, p24 (traces) rgp160F68.8VAC01vCP125, rgp160+IFA16.4++gp160 (traces) rgp160F70.3VAC01vCP125, rgp160+IFA16.4-+p68, p55 rgp160M56.8VAC01vCP125, rgp160+IFA16.4-+0 rgp160F46.9VAC01vCP125, rgp160+IFA16.3++0 rgp160M43.7VAC02rgp160+IFA, peptV316.5-+0 rgp160F64.9VAC02rgp160+IFA, peptV316.7-+ / -0 rgp160F58VAC02rgp160+IFA, peptV316.6+-0 rgp160M54.1VAC01vCP125, rgp160+alum16.4-+0 rgp160M69.1VAC01vCP125, rgp160+alum16.4++0 rgp160M56.3VAC02rgp160+alum16.7 Vitros Anti HIV1/2 + / Architect Ag Ac - 0 rgp160M57.5VAC02rgp160+alum16.4++ / -0 rgp160F71.2VAC02rgp160+alum16.8-+0 rgp160M50.1VAC02rgp160+alum, peptV316.5+-0 rgp160M68VAC02rgp160+alum, peptV316.7-+0 rgp160F46VAC02rgp160+alum, peptV316.7-+0 rgp160M48.4VAC02rgp160+alum, peptV316.7++0 vCPF61.3VAC03vCP205, CLTB-3615-+p55 vCPM62.9VAC10vCP14529.7-+p55, p25 vCPF62.1VAC10vCP14528.9-+p55, p25 vCPM48.7VAC10vCP14528.5-+p55, p25 vCPF49.9VAC10vCP14529.8-+p55, p25 vCPM43.8VAC10vCP14529.8-+p55, p25 vCPF60.1VAC10vCP1452, LIPO-6T 8.5-+p55, p25, p68 LIPOM61.5VAC10LIPO-59.1-+p25 (tr) Séminaires ANRS – 5/2011 COHVAC

14. 14 Séminaire ANRS – 5 mai 2011 VISP - conclusions More than 60% of recombinant envelope protein recipients remained HIV seropositive more than 16 years after vaccination. In contrast, vaccine-induced seropositivity was observed only in less than 20% of Alvac canarypox products recipients 8 years after vaccination and beyond. Long term persistence of vaccine-induced seropositivity should be considered as a possible consequence of HIV preventive vaccine trials and participants informed accordingly. Séminaires ANRS – 5/2011 COHVAC

15. 15 Séminaire ANRS – 5 mai 2011 Self-administered questionnaire Characteristics of volunteers Dec 2008 - Apr 2010 Trial participantsN=422% Enrolled in COHVAC24558 Y0 self-questionnaires23556 Men12151.5 Age (y) Median5225 to 78 Follow-up (y) Median52 to 18 Séminaires ANRS – 5/2011 COHVAC

16. 16 Séminaire ANRS – 5 mai 2011 Socio-economic status and social life %COHVACGP* High school graduate or more8669** Employed (25-54 y)9281 Employed (55-64 y)7538 Married / unmarried couple7171** Children at home4153 Home owner7558 Very comfortable home68 Non-profit organization6634 Blood donor40 4 Religion is (very) important22 * French general population: Insee, Eurostat, Invs data (2006 to 2008) ** 25 to 64 years Séminaires ANRS – 5/2011 COHVAC

17. 17 Séminaire ANRS – 5 mai 2011 Experience of trial-related problems 050100% 13Any trial-related problem 1 2 3 4 4 5 Other Bank or insurance Friends Family Employer Spouse / partner Séminaires ANRS – 5/2011 COHVAC

18. 18 Séminaire ANRS – 5 mai 2011 Regrets or constraints about participating 020406080100% 298 Regrets Rarely Never 94248 Constraints Many constraints Constraints Few constraints No constraints at all 1 Séminaires ANRS – 5/2011 COHVAC Often

19. 19 Séminaire ANRS – 5 mai 2011 Univariate ORp 0.400.054 1.580.087 2.290.038 1.670.12 1.540.14 0.580.059 0.630.080 Wald chi² P-value Multivariate ORp 0.340.030 3.180.007 0.500.021 53 42 52 39 45 55 46 57 45 66 42 54 50 29 0204060 Yes No Yes No Yes No Yes No Yes No >=5.2 < 5.2 y IM/ID Mucosal Blood donor Very comfortable home In couple Employment High school graduate Follow-up Route % reporting no constraints at all 80% Factors associated with no-constraints report Séminaires ANRS – 5/2011 COHVAC

20. 20 Séminaire ANRS – 5 mai 2011 Sexual behaviour Previous 12 months 7 1 34 174 8 11 050100150200 NA No Yes Steady partner NA No Yes Casual partners Number of volunteers Séminaires ANRS – 5/2011 COHVAC

21. 21 Séminaire ANRS – 5 mai 2011 Unsafe sex STEADY PARTNER UNSAFE SEX WITH CASUAL PARTNER CASUAL PARTNERS HIV STATUS UNKNOWN OR POSITIVE None of the volunteers acquired HIV infection at enrollment Séminaires ANRS – 5/2011 COHVAC

22. 22 Séminaire ANRS – 5 mai 2011 Questionnaires - Conclusions Regret and perceived negative consequences were infrequent in this group of HIV vaccine trial volunteers Very few volunteers reported unsafe sex, several years after selection with low HIV risk Trials well accepted and objectives understood Séminaires ANRS – 5/2011 COHVAC

23. 23 Séminaire ANRS – 5 mai 2011 Limitations ~60% of eligible participants were tested or returned questionnaires Different EIA tests were used Self-administered questionnaire less susceptible to bias of social desirability but limited item non-response (< 5%) Séminaires ANRS – 5/2011 COHVAC

24. 24 Séminaire ANRS – 5 mai 2011 Perspectives Relations VISP / negative consequences Abstract submitted to AIDS Vaccine 2011 conference HIV testing in volunteers ? Questionnaire for non-participants End of inclusions for past trials expected by 2011 Open cohort for future trials Séminaires ANRS – 5/2011 COHVAC

25. 25 Séminaire ANRS – 5 mai 2011 Acknowledgments to all the volunteers Participating Clinical Departments: AP-HP Hôpital Cochin, CIC Vaccinologie Cochin-Pasteur, Paris (O. Launay, P. Duchet Niedziolka, L. Belarbi, B. Phung) AP-HP Hôpital Tenon, Paris (G. Pialoux, L. Slama, T. LYavanc) AP-HP Hôpital Henri Mondor, Créteil (J-D Lelièvre, G. Melica) CHU Hôtel-Dieu, Nantes (B. Bonnet, P. Morineau Le Houssine, N. Feuillebois) Hôpital Sainte-Marguerite CISIH, Marseille (I. Poizot-Martin, M-P. Drogoul-Vey, A. Menard, E. Peyrousse) Hôpital Purpan, Toulouse (L. Cuzin, M. Chauveau) Coordinating Trial Center: INSERM, SC10, Villejuif (J-P. Aboulker, C. Desaint, C. Durier, M. Resch, C. Lascoux, S. Dioumassy, Y. Saïdi, B. Abdelkader, E. Moreau) Coordinating investigator: Odile Launay, Hôpital Cochin, Paris Co-coordinating investigators: Benjamin Silbermann, Hôpital Cochin, Paris and Jean- Daniel Lelièvre, Hôpital Henri Mondor, Créteil Scientific Committee: O. Launay, B. Silbermann, J-D Lelièvre, J-P Aboulker, C. Durier, C. Desaint, V. Meiffredy, S. Grabar, C. Lewden, L. Slama, B. Bonnet, L. Cuzin, I. Poizot-Martin, A. Brézin, A. Moulignier, O. Lidove, J-P Viard, F. Linard, H. Bertone, V. Doré, B. Spire, V. Rieux, A-L. Ross, A. Krivine, H. Fleury, E. Ziegler, M. Molina. ANRS Vaccine Research: Y. Lévy, A-L. Ross, V. Rieux, A. Bouakane ANRS Social Sciences: V. Doré, A. Collin ANRS COV1-COHVAC