hiv vaccine clinical trial updates and novel vaccine design (punnee pitisuttithum)
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Clinical Trials and Trial Design
Punnee Pitisuttithum, MBBS,DTM&H,FRCPT
Faculty of Tropical Medicine, Mahidol University
AIDSVACCINE Conference ,BKK
Sept 13,2011
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Ongoing Trials of New HIV Prevention Optionsworldwide
www.avac.org (May 2009)
http://www.avac.org/http://www.avac.org/ -
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Working on the Puzzle of VaccineInduced Protection
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Recombinant protein (gp120)
synthetic peptides (V3)
naked DNA
Live-recombinant vectorsvirus-Ad5, Ad26, MVA,NYVA
Bacteria-rBCG
Whole-inactivated virus
Live-attenuated virus
HIV vaccine constructs
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Cumulative Vaccine Efficacy Over Time
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Randomized, Double Blind Evaluation of Late
Boost Strategies for HIV-uninfectedParticipants in the HIV Vaccine Efficacy Trial
RV 144: Aventis Pasteur* Live
Recombinant ALVAC-HIV (vCP1521) Priming
with VaxGen**gp120 B/E (AIDSVAXB/E) Boosting in HIV-uninfected Thai Adults
Punnee Pitisuttithum MD,FRCPTMahidol University
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Primary Objective
Characterize and compare cellular and humoral
responses in the systemic and mucosalcompartments following late boosts for eachstrategy tested
Assess the safety and tolerability of late boostregimens consisting of the RV144 combination ofregimen or one component of the combination(AIDSVAX B/E or ALVAC-HIV)
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Evaluate mucosal immune responses (humoral
and cellular) for each boost regimen Evaluate systemic and mucosal activation of
T cell target for HIV infection for eachboost regimen
compare innate immune responses betweeneach boost regimen
Define the residual humoral and cellular immuneresponse since completing the primaryprime-boost series within RV144
Secondary Objective
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GROUP
Number of
subjectsVaccine/Placebo
Week of Study
0 24
I
45 ALVAC-HIV +
AIDSVAXB/EALVAC-HIV +
AIDSVAXB/E
9 ALVAC-HIV placebo+
AIDSVAXplacebo
ALVAC-HIVplacebo +
AIDSVAXplacebo
II
45 AIDSVAXB/E AIDSVAXB/E
9 AIDSVAXplacebo AIDSVAXplacebo
III
45 ALVAC-HIV ALVAC-HIV
9 ALVAC-HIV placebo ALVAC-HIV
placebo
Mode of Administration:
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Visit no. 1 2 3 4a 4b 5 6 6a 7 8 Exit
week 0 2 24 26 48 50 72 74Informed Consent X
Test of understanding X
Enrollment & Randomization X
Vaccination & Diary card X X
Physical exam X X X X X X X
Medical history & Vital Signs X X X X X X X X
Concomitant Medications X X X X X X X
HIV Risk Reduction X X X X X X X X
Counseling (pre and/or post) X X X X X X X X X
Urine Pregnancy Test X X X X X
Urine dipstick, CBC, Cr., ALT X X
STI diagnostic tests X
Pap Smear HPV tests X
Schedule of Assessments
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Others ongoing Trials (1)
Phase Trial ID Strategy CandidateNo of
subject Clade
I Ad26.ENVA.01 Viral Vector Adeno
Ad26.EnvA-01 48 A
I Ad5HVR48.ENVA.01 Viral Vector- Adeno
Ad5HVR48.ENVA.01
48 A
I CN54gp140-hsp70Conjugate vaccine
Protein CN54gp140
I DCVax-001 Protein DCVax-001
I Extention HVTN073E/SAAVI 102
Protein Sub Cgp140
I HIVIS 05 DNA/ViralVector-Pox
HIVIS-DNA/MVA-CMDR
24
I HIVIS 07 DNA/ViralVector-Pox
48
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Ongoing Trials (2)
Phase Trial ID Strategy CandidateNo of
subject
Clade
I HPTN 027 Viral Vector Pox
ALVAC-HIVvCP1521
50
I HVRF-380-131004 Protein Vichrepol 15
I HVTN 073 DNA/Viral
Vector-Pox
SAAVI DNA-
C2/SAAVIMVA-C
48 C
I HVTN 076 DNA/ViralVector-Adeno
VRC-HIVDNA016-00-VP/VRC-HIVADV014-00-VP
45 A,B,C
Ib HVTN 077 Viral Vector-Adeno/ViralVector-Adeno/DNA
VRC-HIVADV027-00-VP/VRC-HIVADV038-00-VP/VRC-HIVDNA
044-00-VP
192
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Phase Trial ID Strategy CandidateNo of
subject
Clade
Ib HVTN 078 Viral VectorPox/viralVector-Adeno
NYVAC-B/VRC-HIVADV038-00-VP
80
I HVTN 082 DNA/ViralVector-Adeno
VRC-HIVDNA016-00-VP/VRC-HIVADV014-00-VP
I HVTN 083 Viral Vector-Adeno/ViralVector-
Adeno /ViralVector-Adeno
VRC-HIVADV038-00-VP/VRC-HIVADV
052-00-P/VRC-HIVADV027-00-VP
180 A,B
I/II HVTN 084 Viral Vector-Adeno/ViralVector-Adeno
VRC-HIVADV054-VP/VRC-HIVAVD014-00-VP
Ongoing Trials(3)
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Phase Trial ID Strategy CandidateNo of
subject
Clade
I HVTN 086, SAAVI103
Viral Vector Pox/DNA/Protein
SAAVI MVA-C/SAAVI DNA-C2/Oligomericgp140/MF59
184
IIa HVTN 205 DNA/ViralVector-Pox
pGA2/JS7DNA/MVA/HIV62
225 B
II HVTN 505 DNA/ViralVector-Adeno
VRC-HIVDNA016-00-VP/VRC-HIVADV
014-00-VP
2,200 B
I IAVI B001 Viral Vector-Adeno/ViralVector-Adeno
Ad35-GRIN/ENV/Ad35-GRIN/ENV
56 A
Ongoing Trials (4)
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Ongoing Trials (5)
Phase Trial ID Strategy CandidateNo of
subject
Clade
I IAVI B002 Protein/Protein/Viral Vector Adeno
AdjuvantedGSKinvestigationalHIV vaccinefomulation 1 /
AdjuvantedGSKinvestigationalHIV vaccinefomulation 2/Ad35-GRIN
140
I IAVI B003 Viral Vector-Adeno/ViralVector-Adeno
Ad26.EnvA-01/Ad35-ENV
212
I MV1-F4 Viral Vector-
Replicating
Measles
Vector-GSK
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Ongoing Trials (6)
Phase Trial ID Strategy Candidate
No of
subject Clade
I/II NCHECR-AE1 DNA/ViralVector-Pox
pHIS-HIV-AE/rFPV-HIV-AE
8
I PedVacc001&
PedVacc002
Viral Vector-
Pox
MVA.HIVA 48
I RV138; B011 Viral Vector-Pox
ALVAC-HIVMN120TMGstrain (vCP205)
36
I RV 262 DNA/Viral
Vector-Pox
Pennvax-G/
MVA-CMDR
92 A,B,C,
D,EI TAMOVAC-01-MZ DNA/Viral
Vector-PoxHIVIS-DNA/MVA-CMDR
24
I Three Russian HIVVaccines
21
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Ongoing Trials (7)
Phase Trial ID Strategy Candidate
No of
subject Clade
I Tiantian vacciniaHIV Vaccine
DNA / ViralVector-Replicating
Chinese DNA /Tiantianvaccinia
80
I VRC 012 (07-1-
0167)
Viral Vector-
Adeno/ViralVector-Adeno
VRC-HIVADV
027-00-VP/VRC-HIVADV038-00-VP
35 A
I VRC 015 (08-1-0171)
Viral Vector-Adeno
VRC-HIVADV014-00-VP
31 A,B,C
I VRC 016 DNA/ViralVector-Adeno
VRC-HIVDMA016-00-VP/VRC-HIVADV014-00-VP
24
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Trial Design:Why are Phase IIb trials an important
step in evaluating AIDS vaccine?
Phase I,II trials involve a small number of volunteers
Safety and immunogenicity of vaccineThe phase III trials
require large numbers of volunteer take a long time to set up and complete be the final step before a vaccine can getapproval for licensure for FDA
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Vaccine being tested will be effective To be not designed to establish the efficacy
The number of volunteers is smaller,only 2-5,000 volunteers Easier to design and manage and less cost
Disadvantage
Phase IIb trials are run in smaller
populations, the precision of the trial is less
A vaccine can not be licensed based on theresults of Phase IIb testing
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Why are test of concept trials especiallyuseful for AIDS vaccines?
The first Phase IIb trial of an AIDS vaccinecandidate, which is being conducted by Merckand the HIV Vaccine Trials Network.
MRKAd5 in approximately 3,000 volunteers.The MRKAd5 candidate primarily generates acellular immune responseUS-based Merck and GlaxoSmithKline
Biologicals tested their respective vaccinecandidates for human papilloma virus in PhaseIIb trials.
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Adaptive Clinical Trial Design
Test multiple candidates simultaneously, Comparing to the same placebo group in a
randomized, blinded, phase IIb trial
to if they are able to prevent HIV infection Adaptive trials allow investigators to modify
the trial while its underway
More flexibility to drop candidatesthat dont seem to be working It would allow investigators to rank
the different candidates
Trial Design
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The trials were blindedmeaning volunteers werenot aware during the trial whether they hadreceived the vaccine or the placebo
Safety Monitoring Boards (DSMB) collected and
analyzed safety and efficacy data at pre-specifiedtime points during the course of the trials andcould then determine whether the trials shouldcontinue or be stopped either for safety reasons
or for futility The interim data indicates that a vaccine candidate
is not meeting pre-determined efficacy levels
Adaptive Clinical Trial Design
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Researchers have the flexibility to shrink or drop
that arm of the study while continuing the others
Instance, in a trial population with a 4% annual
HIV incidence rate and 2,000 volunteers per
group
To be possible to reach a decision point in
approximately 20 months
Adaptive Clinical Trial Design
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One important caveat of adaptive clinical trial
is that they are not suitable for licensure
More frequent interim data analyses that are
conducted in adaptive trials
The flexibility that researchers will have to
respond to the data
To reduce the overall power of the study
To difficult to interpret the result
Adaptive Clinical Trial Design