ana guimar ã es- walker,
DESCRIPTION
Safe administration of DNA (pTHr.HIVA) and MVA.HIVA to 169 HIV-1 uninfected volunteers enrolled in Phase I/II trials in the UK. Ana Guimar ã es- Walker, I. Cebere, N. Mackie, T. Hanke, P. Fast, L. Dally, J. Weber and A. J. McMichael. XVI International AIDS Conference Toronto, Canada. - PowerPoint PPT PresentationTRANSCRIPT
Ana Guimarães- Walker, I. Cebere, N. Mackie, T. Hanke, P. Fast, L. Dally, J. Weber and A. J. McMichael.
Safe administration of DNA (pTHr.HIVA) and
MVA.HIVA to 169 HIV-1 uninfected
volunteers enrolled in Phase I/II trials in the UK.
XVI International AIDS ConferenceToronto, Canada.
2MRC Human Immunology Unit - WIMM - Oxford University
Vaccine CandidatesDNA vaccine (pTHr.HIVA)
Plasmid
Modified Vaccinia Ankara (MVA.HIVA)
Non-replicant live attenuated vector
HIVA-AClade A HIV-1 gag p17 and p24
25 CTL epitopes linked end-to-end (env, gag, pol and nef)
Humoral and cellular responses in rodents and macaques.
Hanke T, Nat Med 2000Hanke T, Nat Med 2000
SIV-specific CTL response in rhesus monkeys.
Wee EG, J Gen Virol 2002Wee EG, J Gen Virol 2002
Multifunctional HIV-1 specific T-cell responses in healthy seronegative subjects.
Goonetilleke N, J Virol, May 2006Goonetilleke N, J Virol, May 2006 Specific T-cell responses in
HIV-1 infected subjects.Dorrell L., J Virol, May 2006Dorrell L., J Virol, May 2006
3MRC Human Immunology Unit - WIMM - Oxford University
Study DesignTime Time pointspoints (WK)(WK)
00 33 44 88 1212 2020 2424 5252 104104DNA0.1 mg001
n=18
003n=8
005(n=9)
016n=18
006n=18
Early boost
DNA0.5 mg
DNA0.1 mg
DNA0.5 mg
DNA0.5 mg
DNA4 mg
DNA0.5 mg
DNA2 mg
DNA2 mg
DNA4 mg
MVA5x107 pfu
MVA5x107 pfu
MVA5x107 pfu
MVA5x107 pfu
MVA5x107 pfu
MVA5x107 pfu
MVA5x107 pfu
MVA5x107 pfu
MVA1x108 pfu
MVA1x108 pfu
MVA1x108 pfu
Late boost
END
END
END
END
END
END
END
4MRC Human Immunology Unit - WIMM - Oxford University
DemographicsAge #001 #003 #005 #006 #016
Median 34 34 43 36 43
Range 20-57 22-54 21-58 18-59 20-56
Gender
57% 43%
Female Male
Ethnicity 91%
4%3%
2%
Asian Black Caucasian Other
(n=73)
(n=96)
(n=155)
(n=6)(n=5
)
(n=3)
5MRC Human Immunology Unit - WIMM - Oxford University
Clinical Definitions Adverse Events:
Vaccine reactions Other AEs Solicited events Unsolicited events “Reactogenicity” “Ongoing
reactogenicity”
Types of cutaneous reactions:
• Pain, tenderness, itchiness• Erythema• Swelling x induration• Blister, vesicle ulceration• Rash
Grading parameters:• % of Arm circumference• Size• Duration• Use of medication• Other
Grading criteria cutaneous reactions:
6MRC Human Immunology Unit - WIMM - Oxford University
Maximum Local Reactions
(per volunteer during the 28 days post vaccination)
Severity
0%87%
13%
Mild Moderate Severe
volunteers x local reactions
18 18
8
3 4
11
04
16
1 0
16
0 0
16
0 0
8
0 03
0
5
10
15
20
Placebo DNA MVA
None Pain Tenderness Erythema
Induration Skin damage Crust/ scab
n=8 n=8 n= 16
# Trial 016 (n=24)
Typical local reactions:• Following DNA.HIVA Following MVA.HIVA
Pain/tenderness Pain/tendernessErythemaInduration
N vol
7MRC Human Immunology Unit - WIMM - Oxford University
Maximum Systemic Reactions
(per volunteer during the 28 days post vaccination)
Severity
0%84%
16%
Mild Moderate Severe
volunteers x systemic reactions
5 6 51 0
6
1 1
8
1 032 2
7
0 0 11 03
0 0 10
5
10
15
20
Placebo DNA MVA
None Chill Malaise Myalgia
Headache Fever Nausea Vomiting
# Trial 016 (n=24)
Typical local reactions:• Following DNA.HIVA Following MVA.HIVA
None Malaise/ myalgiaHeadache
N vol
n=8 n=8 n= 16
8MRC Human Immunology Unit - WIMM - Oxford University
0
20
40
60
80
100
Placebo(N=63)
Vaccine(N=190)
Placebo(N=42)
Vaccine(N=377)
None Unlikely Possible Probable
0
20
40
60
80
100
Placebo(N=63)
Vaccine(N=190)
Placebo(N=42)
Vaccine(N=377)
Mild Moderate Severe
Non-Serious Adverse Events (Excludes Local and Systemic Vaccine
Reactions)Severity Relationship
DNA DNA
MVAMVA
%
%
Over 1000 AEs reported across trials
~ 30% of AEs considered possibly or probably related to vaccine
< 10% of events related to vaccine graded as moderate or severe
9MRC Human Immunology Unit - WIMM - Oxford University
Serious Adverse Events (SAEs)
SAEs reported for 6 volunteers:
1.1. Hospitalization: fever, malaise, nausea & Hospitalization: fever, malaise, nausea & headacheheadache 2.2. Removal of gallbladderRemoval of gallbladder
Umbilical hernia repairUmbilical hernia repair
3.3. Hospitalization: cycle accidentHospitalization: cycle accident
4.4. Excavation of sinusesExcavation of sinusesRemoval of nasal polypsRemoval of nasal polypsRealignment of nasal septumRealignment of nasal septum
5.5. MesotheliomaMesothelioma
6.6. Hysterectomy and bilateral oophorectomyHysterectomy and bilateral oophorectomy
No SAES caused by Vaccine.
Days (n) Enrolment
Days (n) Last vac
04
30 02
787878
313-44830
179
175 91
03
50
261-12630
04
5050
10MRC Human Immunology Unit - WIMM - Oxford University
Laboratory assessment No positive ELISA HIV results.
No evidence of induction of auto-immune antibodies.
Liver function tests Grade 3 or greater laboratory values
leading to discontinuation of vaccinations (n=02 volunteers).
11MRC Human Immunology Unit - WIMM - Oxford University
Immunogenicity of DNA.HIVA and MVA.HIVA
Positive Responders across assays in 016 Trial
Subject Cultured
ELISPOT
3H Thymidine Proliferation
Ex vivo ELISPOT
ELISPOT +IL-7/IL-15
CFSE PROLIF.
IFN- WBICS
DNA-MVA -
1 77692 224.21 959 2165 0.56 0.46
2 104313 11.62 103 166 0.07 0.01
3 32062 44.41 514 ND4 ND 0.02
4 41812 7.33 36 86 0.03 0.01
5 14632 8.50 31 128 0.01 0.03
6 3882 4.28 30 96 0.00 0.02
7 4132 0.93 4 18 0.01 0.01
8 17692 1.59 5 13 0.01 0.01
MVA
9 2494 0.36 28 165 (CTL) ND 0.01
10 1250 (CTL) 0.15 -1 -3 ND ND
11 356 (CTL) 0.97 0 15 ND 0.00
12 3838 0.55 6 ND ND 0.00
13 ND 1.01 0 16 ND 0.00
14 ND 0.30 3 -18 ND 0.00
15 ND 0.69 -1 31 ND 0.00
16 ND 0.17 11 16 ND 0.00
PLACEBO
n=8 No positive responses
1 Background subtracted responses to Gag (CTL string response indicated in brackets). Responses shown are from Wk9 in the DNA/MVA arm and Wk1 in the MVA only arm2 Response from Wk10 (2 weeks post MVA) 3 Response from W12 (4 weeks post MVA)4 ND= no data available for Pool 90 specific responses
Responders in ELISPOT assays
0
4
0 0
21
0
4
8
0
10
DNA-MVA MVA Placebo
Cultured Ex-vivo +Il-7/ Il-15n=8 n=8
n=8
12MRC Human Immunology Unit - WIMM - Oxford University
Conclusions – Safety Overall both DNA.HIVA and MVA.HIVA vaccines were
safe and well tolerated.
Most local or systemic reactions following vaccination with DNA or MVA vaccinations were mild.
Local and systemic reactions were more frequently observed following MVA vaccination, compared to DNA-HIVA vaccination.
Ensuring consistency in the grading criteria is crucial within a programme consisting of overlapping trials.
13MRC Human Immunology Unit - WIMM - Oxford University
Acknowledgments: MRC Human MRC Human Immunology OxfordImmunology OxfordProfessor Andrew Professor Andrew
McMichaelMcMichaelDr Inese CebereDr Inese Cebere
Dr Jo RobertsDr Jo RobertsDr Nilu GoonetillekeDr Nilu Goonetilleke Dr Susana PinheiroDr Susana PinheiroDr Thomas HankeDr Thomas HankeMs Althea ThomasMs Althea Thomas Ms Denise BrownMs Denise Brown
Ms Nicola WinstoneMs Nicola WinstoneMr Stephen MooreMr Stephen MooreMs Vanessa LoachMs Vanessa Loach
Imperial College Imperial College LondonLondon
Professor Frances Professor Frances GotchGotch
Professor Jonathan Professor Jonathan WeberWeber
Dr Nicola MackieDr Nicola MackieDr Peter HayesDr Peter Hayes
Dr Tristan BarberDr Tristan BarberMr Carl DeSouzaMr Carl DeSouza
Mr Ken LeggMr Ken LeggMs Miranda CowenMs Miranda Cowen
MRC Clinical Trials MRC Clinical Trials Unit LondonUnit LondonDr Sheena McCormackDr Sheena McCormackMs Elizabeth BrodnickiMs Elizabeth Brodnicki
Mr Patrick KelleherMr Patrick Kelleher
EMMESEMMESDr Leonid GibianskiDr Leonid Gibianski
Ms Carol SmithMs Carol SmithMs Kelley Loughran Ms Kelley Loughran
Mr Len DallyMr Len DallyMs Sophia PallasMs Sophia Pallas
OriginOriginMs Stephanie MiallMs Stephanie Miall
IAVIIAVIDr Claudia Schmidt Dr Claudia Schmidt
Dr Jill GilmourDr Jill Gilmour Dr Patricia FastDr Patricia FastMr Carl VerlindeMr Carl VerlindeMr Dani VoojisMr Dani Voojis
ALL VOLUNTEE
RS
Safe administration of DNA (pTHr.HIVA) and
MVA.HIVA to 169 HIV-1 uninfected
volunteers enrolled in Phase I/II trials in the UK.Additional SlidesAdditional Slides
XVI International AIDS ConferenceToronto, Canada.
Number of Volunteers who Number of Volunteers who received each vaccination as received each vaccination as
scheduled – Trial 006scheduled – Trial 006119 Enrolled Volunteers
40/40 2 mg DNA
EARLY
boost
LATE
boost
DNA
PRIMING39/39 0.5 mg DNA 40/40 Placebo
17/17 MVA 1/2 Placebo
OR
16/19 MVA 2/2 Placebo
17/18 MVA 2/2 Placebo
16/19 MVA 2/2 Placebo
17/17 MVA 1/1 Placebo
18/18 MVA 2/2 Placebo
16MRC Human Immunology Unit - WIMM - Oxford University
DemographicsAge #001 #003 #005 #006 #016
Median 34 34 43 36 43
Range 20-57 22-54 21-58 18-59 20-56
Gender
1
66
1812
28
53
666
0
20
40
60
80
#001 #003 #005 #006 #016
Female Male
Ethnicity155
65 30
30
60
90
120
150
Asian Black Caucasian Other
Asian Black Caucasian Other
17MRC Human Immunology Unit - WIMM - Oxford University
Distribution of Responses according to Age Trial #006
Distribution of MVA Responders according to Age
All MVA responders MVA-only Age n Mean Median n Mean Median all 19 36 35 5 32 29
> 40 5 52 51 1 52 52 40 14 27 27 4 28 27
All Responders (DNA-MVA= 9; MVA-only = 5) MVA-only excludes Responders in the DNA-placebo group
18MRC Human Immunology Unit - WIMM - Oxford University
Local & Systemic Reactions- Trial 006
(per volunteer during the 28 days post vaccination)Local Reactions Systemic Reactions
DNA MVA DNA MVA
Reactions post MVA were not altered by DNA priming
0
20
40
60
80
100
Placebo(N=40)
Vaccine(N=79)
Placebo(N=10)
Vaccine(N=101)
None Mild Moderate Severe
0
20
40
60
80
100
Placebo(N=40)
Vaccine(N=79)
Placebo(N=10)
Vaccine(N=101)
None Mild Moderate Severe
% %
19MRC Human Immunology Unit - WIMM - Oxford University
0
20
40
60
80
100
Placebo(N=63)
Vaccine(N=190)
Placebo(N=42)
Vaccine(N=377)
None Unlikely Possible Probable
0
20
40
60
80
100
Placebo(N=63)
Vaccine(N=190)
Placebo(N=42)
Vaccine(N=377)
Mild Moderate Severe
Non-Serious Adverse Events – Trial 006
(Excludes Local and Systemic Reactogenicity)
Severity Relationship
DNA DNAMVA MVA
%%
20MRC Human Immunology Unit - WIMM - Oxford University
HIV.A Peptides
HIV-1 gag CTL epitopes
p24 p17
Pool 1 Pool 2 Pool 3 Pool 4
Pool 90 (1+2+3+4)
Pool 9
Responder = volunteer with a positive response in at least one pool on at least one occasion.