Impact à long terme de la Impact à long terme de la participation aux essais vaccinaux participation aux essais vaccinaux
VIH chez le volontaire sainVIH chez le volontaire sain
Cohorte ANRS COHVACCohorte 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
2Séminaire 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)99156810+21*341555323*13*2016 *15 *28302520
VAC 16
VAC 01VAC 02VAC 03VAC 04VAC 05VAC 06VAC 07VAC 08VAC 09LIP 03VAC 10VAC 12VAC 14VAC 17
VAC 18-IVAC 18-IIVAC 20
1992 1994 1996 1998 2000 2002 2004 2006 2008 2010
Séminaires ANRS – 5/2011 COHVAC
3Séminaire 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
4Séminaire ANRS – 5 mai 2011
ANRSVolunteers
Network
1y+TRIAL
y0
Prospectivefollow-up
Retrospective collection
y1 y2 y3 y4 y5 y6 y7Trial entry
Trial completion
Prospective multicenter cohort study forlong 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
5Séminaire 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
6Séminaire 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 behaviorapproved by the National Committee on Informatics and
Freedom (CNIL)
Methodology
Séminaires ANRS – 5/2011 COHVAC
7Séminaire 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
8Séminaire ANRS – 5 mai 2011Séminaires ANRS – 5/2011 COHVAC
422
N(74)99156810+21*341555323*13*2016 *15 *28302520
VAC 16
VAC 01VAC 02VAC 03VAC 04VAC 05VAC 06VAC 07VAC 08VAC 09LIP 03VAC 10VAC 12VAC 14VAC 17
VAC 18-IVAC 18-IIVAC 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
1992 1994 1996 1998 2000 2002 2004 2006 2008 2010
All were injected IM except one mucosal and one ID trial
9Séminaire ANRS – 5 mai 2011
ANRS Trials
rgp160 vCP LIPOmuc
gp160Trials VAC01
VAC02VAC03 VAC07LIP03VAC10
VAC04VAC10 VAC17VAC12
VAC16VAC18
VAC14
ANRS CentersTenonCochin Cochin
TenonCochin
+ MarseilleNantes
Toulouse Mondor
TenonCochin
N in trials 45 80 263 34
Séminaires ANRS – 5/2011 COHVAC
10Séminaire ANRS – 5 mai 2011
HIV antibodies at inclusion in COHVACCharacteristics of volunteers
Dec 2008- Sep 2010
rgp160 vCP LIPOmuc
gp160 AllN in trials 45 80 263 34 422N 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)Age Median 56.6 59.1 50.8 51.5 52.5
Min 43.7 39.9 25.3 36.8 25.3 Max 71.2 70.1 64.3 59.3 71.2Gender % male 65 55 57 0 53Time (y) Median 16.6 14.2 4.3 5.3 5.2since Min 16.3 8.1 2.2 5.1 2.2injections Max 17.5 15.6 13.2 6.5 17.5HIV antibody testing period
Dec08 to
Mar10
Dec08 to
Sep10
Dec08 to
Sep10
Dec08 to
Mar10
Dec08 to
Sep10Séminaires ANRS – 5/2011 COHVAC
11Séminaire ANRS – 5 mai 2011
Vaccine-induced seropositivity rate (VISP) by vaccine type
% V
ISP
(95%
Con
fiden
ce I
nter
val)
0
20
40
60
80
100
rgp160 vCP LIPO mucgp160 AllN VISP/ N tested 17/26 7/42 1/150 0/21 25/239
%VISP 65.4 16.7 0.67 0 10.5[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
12Séminaire ANRS – 5 mai 2011
Time since injections by vaccine type
Yea
rs s
ince
inje
ctio
ns
(med
ian,
IQ
R,
min
-max
)
02468
101214161820
rgp160 vCP LIPO mucgp160 AllVISP / Tested VISP / Tested VISP / Tested VISP / Tested
N VISP/ N tested 17/26 7/42 1/150 0/21 25/239Median (years) 16.5 9.7 9.1 - 16.4
Range 16.3 to 16.8 8.5 to 15 - -
Séminaires ANRS – 5/2011 COHVAC
13Séminaire ANRS – 5 mai 2011
Volunteers presenting VISP (N=25)EIA tests Western-blots assays
Gender AgeVaccine
TrialVaccines received
+adjuvant
Time since
injections (years)
Genscreen ultraHIV BIORAD
Vidas HIV duo BIOMERIEUX
Anti-HIV Tetra ELISA
BIOTEST Reactive bandsrgp160 M 55.6 VAC01 vCP125, rgp160+IFA 16.4 + + gp160, gp120, p55, p24
(traces)rgp160 F 68.8 VAC01 vCP125, rgp160+IFA 16.4 + + gp160 (traces)rgp160 F 70.3 VAC01 vCP125, rgp160+IFA 16.4 - + p68, p55rgp160 M 56.8 VAC01 vCP125, rgp160+IFA 16.4 - + 0rgp160 F 46.9 VAC01 vCP125, rgp160+IFA 16.3 + + 0rgp160 M 43.7 VAC02 rgp160+IFA, peptV3 16.5 - + 0rgp160 F 64.9 VAC02 rgp160+IFA, peptV3 16.7 - + / - 0rgp160 F 58 VAC02 rgp160+IFA, peptV3 16.6 + - 0rgp160 M 54.1 VAC01 vCP125, rgp160+alum 16.4 - + 0rgp160 M 69.1 VAC01 vCP125, rgp160+alum 16.4 + + 0rgp160 M 56.3 VAC02 rgp160+alum 16.7 Vitros Anti HIV1/2 + / Architect Ag Ac - 0rgp160 M 57.5 VAC02 rgp160+alum 16.4 + + / - 0rgp160 F 71.2 VAC02 rgp160+alum 16.8 - + 0rgp160 M 50.1 VAC02 rgp160+alum, peptV3 16.5 + - 0rgp160 M 68 VAC02 rgp160+alum, peptV3 16.7 - + 0rgp160 F 46 VAC02 rgp160+alum, peptV3 16.7 - + 0rgp160 M 48.4 VAC02 rgp160+alum, peptV3 16.7 + + 0
vCP F 61.3 VAC03 vCP205, CLTB-36 15 - + p55vCP M 62.9 VAC10 vCP1452 9.7 - + p55, p25vCP F 62.1 VAC10 vCP1452 8.9 - + p55, p25vCP M 48.7 VAC10 vCP1452 8.5 - + p55, p25vCP F 49.9 VAC10 vCP1452 9.8 - + p55, p25vCP M 43.8 VAC10 vCP1452 9.8 - + p55, p25vCP F 60.1 VAC10 vCP1452,
LIPO-6T8.5 - + p55, p25, p68
LIPO M 61.5 VAC10 LIPO-5 9.1 - + p25 (tr)Séminaires ANRS – 5/2011 COHVAC
14Séminaire 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
15Séminaire ANRS – 5 mai 2011
Self-administered questionnaireCharacteristics of volunteers
Dec 2008 - Apr 2010
Trial participants N=422 %
Enrolled in COHVAC 245 58
Y0 self-questionnaires 235 56
Men 121 51.5
Age (y) Median 52 25 to 78
Follow-up (y) Median 5 2 to 18
Séminaires ANRS – 5/2011 COHVAC
16Séminaire ANRS – 5 mai 2011
Socio-economic status and social life
%COHVA
CGP*
High school graduate or more 86 69**
Employed (25-54 y) 92 81
Employed (55-64 y) 75 38
Married / unmarried couple 71 71**
Children at home 41 53
Home owner 75 58
Very comfortable home 68
Non-profit organization 66 34
Blood donor 40 4
“Religion is (very) important” 22
* French general population: Insee, Eurostat, Invs data (2006 to 2008) ** 25 to 64 yearsSéminaires ANRS – 5/2011 COHVAC
17Séminaire ANRS – 5 mai 2011
Experience of trial-related problems
0 50 100%
13Any trial-related problem
1
2
3
4
4
5
Other
Bank or insurance
Friends
Family
Employer
Spouse / partner
Séminaires ANRS – 5/2011 COHVAC
18Séminaire ANRS – 5 mai 2011
Regrets or constraints about participating
0 20 40 60 80 100%
2 98Regrets Rarely
Never
9 42 48Constraints
Many constraints
Constraints
Few constraints
No constraints at all
1
Séminaires ANRS – 5/2011 COHVAC
Often
19Séminaire ANRS – 5 mai 2011
UnivariateOR p0.40 0.054
1.58 0.087
2.29 0.038
1.67 0.12
1.54 0.14
0.58 0.059
0.63 0.080
Wald chi² P-value
MultivariateOR p0.34 0.030
3.18 0.007
0.50 0.02153
42
5239
4555
4657
4566
4254
5029
0 20 40 60
YesNo
YesNo
YesNo
YesNo
YesNo
>=5.2< 5.2 y
IM/IDMucosal
Blood donor
Very comfortablehome
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
20Séminaire ANRS – 5 mai 2011
Sexual behaviourPrevious 12 months
7
1
34
174
8
11
0 50 100 150 200
NA
No
Yes
Ste
ady
par
tner
NA
No
Yes
Casual partners
Number of volunteers
Séminaires ANRS – 5/2011 COHVAC
21Séminaire ANRS – 5 mai 2011
Unsafe sex
YesN=4
Volunteers reporting casual partners
N=19 (8%)
NoN=8
YesN=11
YesN=6
NoN=7
NoN=2
YesN=1
YesN=3
STEADY PARTNER
UNSAFE SEX WITHCASUAL PARTNER
CASUAL PARTNERSHIV STATUS UNKNOWN OR POSITIVE
None of the volunteers acquired HIV infection at enrollment
Séminaires ANRS – 5/2011 COHVAC
22Séminaire 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
23Séminaire 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
24Séminaire 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
25Séminaire ANRS – 5 mai 2011Acknowledgments 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. L’Yavanc)• 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, ParisCo-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