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

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



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



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



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



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.


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


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



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


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]



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 - -



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


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.



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



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


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



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


Often


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



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



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



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



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%)



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


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

Documents

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