Transcript N enrolled in COHVAC

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. PoizotMartin, J.P. Aboulker, G Pialoux, B. Spire, O. Launay; pour
la cohorte ANRS COHVAC
ANRS Phase I/II Vaccine Trials
VAC 20
VAC 18-II
VAC 18-I
VAC 16
VAC 17
VAC 14
VAC 12
VAC 10
LIP 03
VAC 09
VAC 08
VAC 07
VAC 06
VAC 05
VAC 04
VAC 03
VAC 02
VAC 01
1992
1994
1996
1998
2000
2002
2004
2006
N
(74)
99
15
68
10+21*
34
15
55
3
23*
13*
20
16 *
15 *
28
30
25
20
2008 2010 422
Recombinant envelope protein subunit (rgp160)
ALVAC-HIV canarypox vectors expressing Env, Gag, Pro and CTL domains of Pol (vCP)
Env V3 MN synthetic peptide (peptideV3)
P24 / Env V3 MN synthetic peptide (CLTB-36)
HIV-1 Lipopeptides representing CTL epitopes of Gag, Pol and Nef proteins
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COHVAC
* in a previous HIV vaccine trial
2
ANRS Volunteers Network




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
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COHVAC
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ANRS COV1-COHVAC
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
TRIAL
ANRS
Volunteers
Network
1y+
Trial
Trial
entry completion
y0
y1
Retrospective
collection
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y2
y3
y4
y5
y6
y7
Prospective
follow-up
COHVAC
4
ANRS COV1-COHVAC
 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
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COHVAC
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Methodology
 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)
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COHVAC
6
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.
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ANRS Phase I/II Trials
N
(74)
99
15
68
10+21*
34
15
55
3
23*
13*
20
16 *
15 *
28
30
25
20
VAC 20
VAC 18-II
VAC 18-I
VAC 16
VAC 17
VAC 14
VAC 12
VAC 10
LIP 03
VAC 09
VAC 08
VAC 07
VAC 06
VAC 05
VAC 04
VAC 03
VAC 02
VAC 01
1992
1994
1996
1998
2000
2002
2004
2006
2008 2010 422
Recombinant envelope protein subunit (rgp160)
ALVAC-HIV canarypox vectors expressing Env, Gag, Pro and CTL domains of Pol (vCP)
Env V3 MN synthetic peptide (peptideV3)
P24 / Env V3 MN synthetic peptide (CLTB-36)
HIV-1 Lipopeptides representing CTL epitopes of Gag, Pol and Nef proteins
All were
IM except
one mucosal and one ID trial
maiinjected
2011
COHVAC
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ANRS Trials
rgp160
vCP
VAC01
VAC02
VAC03
VAC07
LIP03
VAC10
Trials
ANRS Centers
N in trials
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Tenon
Cochin
Cochin
45
80
COHVAC
LIPO
VAC04
VAC10
VAC17
VAC12
Tenon
Cochin
VAC16
VAC18
+
Marseille
Nantes
Toulouse
Mondor
263
muc
gp160
VAC14
Tenon
Cochin
34
9
HIV antibodies at inclusion in COHVAC
Characteristics of volunteers
Dec 2008- Sep 2010
N in trials
N enrolled in COHVAC (%)
N tested (%)
Age
Median
Min
Max
% male
Gender
Median
Time (y)
Min
since
injections Max
HIV antibody testing
period
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rgp160
45
29 (64)
26 (58)
56.6
43.7
71.2
65
16.6
16.3
17.5
Dec08
to
Mar10
vCP
80
47 (59)
42 (53)
59.1
39.9
70.1
55
14.2
8.1
15.6
Dec08
to
Sep10
COHVAC
LIPO
263
156 (59)
150 (57)
50.8
25.3
64.3
57
4.3
2.2
13.2
Dec08
to
Sep10
muc
gp160
34
25 (74)
21 (62)
51.5
36.8
59.3
0
5.3
5.1
6.5
Dec08
to
Mar10
All
422
257 (61)
239 (57)
52.5
25.3
71.2
53
5.2
2.2
17.5
Dec08
to
Sep10
10
% VISP
(95% Confidence Interval)
Vaccine-induced seropositivity rate
(VISP) by vaccine type
100
80
60
40
20
0
rgp160
N VISP/ N tested
17/26
%VISP
65.4
[95% CI] [44.3-82.8]
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vCP
7/42
16.7
[7-31.4]
COHVAC
LIPO
1/150
0.67
[0.02-3.7]
mucgp160
All
0/21
25/239
0
10.5
[0-16.1]
[6.9-15.1]
11
Years since injections
(median, IQR, min-max)
Time since injections
by vaccine type
20
18
16
14
12
10
8
6
4
2
0
N VISP/ N tested
Median (years)
Range
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rgp160
vCP
LIPO
mucgp160
VISP / Tested
VISP / Tested
VISP / Tested
VISP / Tested
17/26
16.5
16.3 to 16.8
7/42
9.7
8.5 to 15
1/150
9.1
-
0/21
-
mai 2011
COHVAC
All
25/239
16.4
12
Volunteers presenting VISP (N=25)
EIA tests
rgp160
rgp160
rgp160
rgp160
rgp160
rgp160
rgp160
rgp160
rgp160
rgp160
rgp160
rgp160
rgp160
rgp160
rgp160
rgp160
rgp160
vCP
vCP
vCP
vCP
vCP
vCP
vCP
LIPO
Gender
M
F
F
M
F
M
F
F
M
M
M
M
F
M
M
F
M
F
M
F
M
F
M
F
M
Age
55.6
68.8
70.3
56.8
46.9
43.7
64.9
58
54.1
69.1
56.3
57.5
71.2
50.1
68
46
48.4
61.3
62.9
62.1
48.7
49.9
43.8
60.1
61.5
Vaccine
Trial
VAC01
VAC01
VAC01
VAC01
VAC01
VAC02
VAC02
VAC02
VAC01
VAC01
VAC02
VAC02
VAC02
VAC02
VAC02
VAC02
VAC02
VAC03
VAC10
VAC10
VAC10
VAC10
VAC10
VAC10
Vaccines received
+adjuvant
vCP125, rgp160+IFA
vCP125, rgp160+IFA
vCP125, rgp160+IFA
vCP125, rgp160+IFA
vCP125, rgp160+IFA
rgp160+IFA, peptV3
rgp160+IFA, peptV3
rgp160+IFA, peptV3
vCP125, rgp160+alum
vCP125, rgp160+alum
rgp160+alum
rgp160+alum
rgp160+alum
rgp160+alum, peptV3
rgp160+alum, peptV3
rgp160+alum, peptV3
rgp160+alum, peptV3
vCP205, CLTB-36
vCP1452
vCP1452
vCP1452
vCP1452
vCP1452
vCP1452,
VAC10
LIPO-6T
LIPO-5
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Western-blots assays
Time
Anti-HIV
since Genscreen
injections ultraHIV Vidas HIV duo Tetra ELISA
BIORAD BIOMERIEUX BIOTEST
(years)
+
16.4
+
+
16.4
+
+
16.4
+
16.4
+
16.3
+
16.5
+
16.7
+/16.6
+
16.4
+
+
16.4
+
Vitros
Anti
HIV1/2
+ / Architect Ag Ac 16.7
16.4
+
+/+
16.8
16.5
+
+
16.7
+
16.7
+
16.7
+
+
15
+
9.7
+
8.9
+
8.5
+
9.8
+
9.8
+
8.5
9.1
COHVAC
-
+
Reactive bands
gp160, gp120, p55, p24 (traces)
gp160 (traces)
p68, p55
0
0
0
0
0
0
0
0
0
0
0
0
0
0
p55
p55, p25
p55, p25
p55, p25
p55, p25
p55, p25
p55, p25, p68
p25 (tr)
13
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.
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Self-administered questionnaire
Characteristics of volunteers
Dec 2008 - Apr 2010
Trial participants
Enrolled in COHVAC
Y0 self-questionnaires
Men
Age (y)
Median
Follow-up (y)
Median
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COHVAC
N=422
245
235
121
52
5
%
58
56
51.5
25 to 78
2 to 18
15
Socio-economic status and social life
High school graduate or more
Employed (25-54 y)
Employed (55-64 y)
Married / unmarried couple
Children at home
Home owner
Very comfortable home
Non-profit organization
Blood donor
“Religion is (very) important”
% COHVAC
86
92
75
71
41
75
68
66
40
22
GP*
69**
81
38
71**
53
58
34
4
* French general population: Insee, Eurostat, Invs data (2006 to 2008) ** 25 to 64 years
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Experience of trial-related problems
Any trial-related problem
13
Spouse / partner
5
Employer
4
Family
4
Friends
3
Bank or insurance
2
Other
1
0
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COHVAC
50
100%
17
Regrets or constraints about participating
Regrets
2
98
Constraints 1 9
0
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Often
Rarely
Never
42
20
Many constraints
Constraints
Few constraints
No constraints at all
48
40
COHVAC
60
80
100%
18
Factors associated with no-constraints report
Route
Mucosal
IM/ID
Follow-up < 5.2 y
>=5.2
High school
No
graduate
Yes
Employment
In couple
Univariate
Multivariate
OR
OR
pp
0.40
0.054
0.34 0.030
29
50
54
1.58
42
66
45
No
Yes
57
46
No
Yes
55
0.087
2.29
0.038
3.18 0.007
1.67
0.12
1.54
0.14
45
Very comfortable No
home
Yes
Blood donor
No
Yes
0.58
0.059
0.50 0.021
39
52
0.63
42
0.080
53
0
20
40
60
Wald chi²
80% P-value
% reporting no constraints at all
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Sexual behaviour
Steady partner
Previous 12 months
Casual partners
Yes 7
No
174
34
11
NA
No
8
Yes
NA 1
0
50
100
150
200
Number of volunteers
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Unsafe sex
Volunteers reporting
casual partners
N=19 (8%)
No
N=8
STEADY PARTNER
UNSAFE SEX WITH
CASUAL PARTNER
No
N=2
Yes
N=11
Yes
N=6
CASUAL PARTNERS
HIV STATUS UNKNOWN
OR POSITIVE
Yes
N=3
No
N=7
Yes
N=4
Yes
N=1
None of the volunteers acquired HIV infection
at enrollment
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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
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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%)
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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
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ANRS COV1-COHVAC
Participating Clinical Departments:
• AP-HP Hôpital Cochin, CIC Vaccinologie
Cochin-Pasteur, Paris (O. Launay, P.
Duchet Niedziolka, L. Belarbi, B. Phung)
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,
• AP-HP Hôpital Tenon, Paris (G. Pialoux, L.
Hôpital Cochin, Paris
Slama, T. L’Yavanc)
Co-coordinating investigators: Benjamin
• AP-HP Hôpital Henri Mondor, Créteil (J-D
Silbermann, Hôpital Cochin, Paris and JeanLelièvre, G. Melica)
Daniel Lelièvre, Hôpital Henri Mondor, Créteil
• CHU Hôtel-Dieu, Nantes (B. Bonnet, P.
Scientific Committee: O. Launay, B.
Morineau Le Houssine, N. Feuillebois)
Silbermann, J-D Lelièvre, J-P Aboulker, C.
• Hôpital Sainte-Marguerite CISIH,
Durier, C. Desaint, V. Meiffredy, S. Grabar, C.
Marseille (I. Poizot-Martin, M-P. Drogoul-Vey, Lewden, L. Slama, B. Bonnet, L. Cuzin, I.
A. Menard, E. Peyrousse)
Poizot-Martin, A. Brézin, A. Moulignier, O.
Lidove, J-P Viard, F. Linard, H. Bertone, V.
• Hôpital Purpan, Toulouse (L. Cuzin, M.
Doré, B. Spire, V. Rieux, A-L. Ross, A.
Chauveau)
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
Acknowledgments to all the volunteers
Séminaire ANRS – 5 mai 2011
25