Professional Documents
Culture Documents
Linda-Gail Bekker
The Desmond Tutu HIV Centre
University of Cape Town
Women and Men with HIV in 2008
1.5 million
850,000
850,000
1.4 million
310,000
240,000 3.8 million
2 million 59,000
22.4 million
UNAIDS 2009
The War on HIV….
Male
HIV circumcision
PREVENTION
Condoms
Behavioural
Chemoprophylaxis
Counselling and
Testing MTCTp
Vaccines HSV-2 PEP
Test +Treat Suppressive
PrEP
therapy
Reported Prevention Trials
Efficacy of intervention (Padian,et al:AIDS 2010)
Behavioral
Counseling and Chemoprophylaxis
Testing
MTCTp
Intensive not PEP
better than
PrEP
standard
have unknown
efficacy
Partial efficacy
Circumcision (Orange F)
Prep
0% 100%
Low Utilization of Prevention
Methods
Methods Utilization
• AIDS Education
– Primary Schools 50%
– Secondary Schools 48%
• Maternal to Child Prevention 2-40%
• Sex Workers Outreach 16%
• IDU Harm Reduction 4.3%
• MSM Outreach 11%
• For licensure:
– Safety
– efficacy
Ultimately….
• We want a safe and effective vaccine for
all people but especially the most at risk
for HIV infection.
• This includes pregnant women, children,
adolescents, IVDUs, WSM, MSM, CSW
and HCW.
• On the way….we may want to optimise the
test population to give our candidate
vaccines the best chance.
In vaccinology….
• The measure of efficacy is going to be HIV
infection avoidance until….
Groups M, O and N
Subtypes A, B, C etc
(clades) Recombinants
-Circulating
Recombinant
Forms
-Unique recombinants
HIV-1 diversity
Transmission events
Transmission Events
VACCINE
APPROACHES
Naked DNA
Genetic Material from HIV
Cloned into Various Vectors
Bacterial Vectors
Viral
Vectors
Subunit Vaccines
Proteins and
Peptides
AL Williamson
WHAT SHOULD A VACCINE AIM TO DO?
Plasma Cells
Cytotoxic T
lymphocyte CD8+
Current HIV vaccine strategies
Traditional Strategies
• Live attenuated: significant safety concerns
• Whole killed virus: unable to induce broadly reactive
neutralizing responses and elicit CD8 T cell responses
• Protein subunits: same issues as whole killed virus
Novel Strategies
• Plasmid DNA vaccines: elicit immune responses
• Live recombinant vectors: immune response elicited
• Prime boost: DNA/live recombinant vectors
Human clinical trials
• Phase 1 – first time in humans
– healthy adults, small numbers, carefully done
• Phase 2- safety and immunogenicity
– Healthy participants, moderate numbers, exposure to
agent, lots of blood
• Phase 3- efficacy and safety
– General population at risk, large numbers, “real life”,
endpoints required.
• Phase 2a- dose finding, safety, immunogenicity
• Phase 2b- proof of concept
We need them because
• They tell us what we don’t know
• We don’t have a correlate of protection- a
marker that tells us the vaccine works
• Therefore need HIV as an endpoint to find
out if we are on the right track
• Choose products in a “best guess”
scenario
All about backing the right horse
• T cell modification approach…..
Course of HIV Infection in Unvaccinated Persons and the Hypothetical Course of Infection in
Vaccinated Persons in a “T-cell vaccine”
PHAMBILI
(HVTN 503)
“CTL based
approach”
What did this trial teach us
• Didn’t work in MSM
• Especially didn’t work in MSM with foreskin and
high background Ad5 immunity
• T cell strategy on its own probably insufficient
• Combo of foreskin and vector immunity a
problem but not sure how
• Some cause for pause around Ad5 as a vector
• Find ways to add antibody impact in prime or
boost…..
Phase IIB-TOC and Phase III pivotal trials
Trial STEP (HVTN HVTN 503 USMHRP RV- VaxGen 004 Vaxgen 003
502/MRK023) (Phambili) 144 Pivotal III Pivotal III
IIB-TOC IIB-TOC IIB-TOC
(USD33million) (USD33million) (USD60-88 (USD78million) (USD52million)
million)
Vaccine MRK ad5 MRK ad5 ALVAC vCP- AIDSVAX B/B, AIDSVAX B/B,
trivalent trivalent 1521 and rgp 120 B/B rgp 120 B/B
(gag/pol/nef) (gag/pol/nef) AIDSVAX B/E, (gp120) (gp120)
rgp120 B/E
(gag/pro/env
+gp120)
Population MSM,HW, USA, HM, HW, HM, HW MSM,HW, USA, IDU
Caribean, Latin South Africa Thailand Canada and the Thailand
America, Netherlands
Australia
• 16,402 participants
• 18-30 years old
• “Average” risk of HIV infection
• Study began October 2004
• Vaccines completed July 2006
• Trial concluded June 2009
Study Locations in Thailand
Thai Trial
16,402
(7 HIV+ at enrollment)
16,395
8,197 8,198
vaccine placebo
60% men
40% women
Results: RV 144
Thai Trial
200
91
IAVI Human
Immunology
Laboratory,
London
200
50
Monogram
Biosciences
200 215 238 200
81
200
Number of donor
samples from
each site 200
2.
1. Samples
Nearly 2,000
sentblood
to Monogram
samples Biosciences
collected from
for
HIV-positive
neutralization
individuals
screening
around the world
The Antibody Project: Identifying prospects
3. Screening results scored using new IAVI algorithm to identify donors of interest
Blood
About samples
10% are donors
collected
of interest
IAVI Human
Immunology
Laboratory,
London
IAVI
IAVI
NAC
at Scripps
5.
4. Samples
After datasent
review,
to IAVI
newHuman
samples
Immunology
Laboratory
requested from donors of interest
The Antibody Project: Partners in the hunt
IAVI Human
Immunology
Laboratory
Theraclone
HuMabs
Monogram* Rockefeller
University
IAVI
NAC
at Scripps
7. Theraclone is first
to find new broadly
neutralizing antibodies
8. Antibodies
characterized
IAVI Neutralizing
Antibody Center at
IAVI Human
Immunology
Lab
Lipoxen Pepscan
Avatar
Chembiotek
IAVI Neutralizing
Antibody Center
at the Scripps
Research Institute
Neutralizing Antibody
Consortium members
Chennai
Entebbe
Kilifi
Nairobi IAVI-supported
Kigali network
Masaka of clinical
research centers
Copperbelt
10. Ultimately, the
Lusaka
process will come
full circle with
clinical testing of
Rustenburg
vaccine candidates
Cape Town
New antibodies being added daily
• VRC01
– Site at CD4 receptor
• Others
• Broadly neutralising
• Role in passive immunity (monoclonal)
• Better design of antigens in active
immunisation (designer vaccines)
SAAVI 012/HVTN 073
• A phase 1
• Placebo controlled double blinded RCT
• Objective: Safety and immunogenicity
• Using:
– SAAVI DNA-C2 prime
– SAAVI MVA-C boost
• In: Healthy, HIV negative, vaccinia naïve adults
• From: USA, SA
Making an HIV vaccine
Clinical trials
Basic research Preclinical development
Phase I + II Phase III
Laboratory animal studies Human research
Safety,
1. Discovery 2. Exploration Immunogenicity Efficacy
SAAVI
SAAVI MVA-
DNA-
Number C 0 (0) 1 (28) 2 (56) 4 (112) 5 (140)
C2
(pfu)
(mg)
SAAVI SAAVI SAAVI SAAVI
SAAVI
40 4 1.45×10 9
DNA DNA- MVA- MVA-
DNA-C2
-C2 C2 C C
Total 48 (40/8)
In follow up- will add protein boost
Poly prevention expertise CAB with diverse
(IRB) + infrastructure expertise (youth)
Community
Community education and testing development
Women, men, youth,
MSM, CSW, IVDU
Laboratory/
Basic science
Need to conduct multiple
HIV vaccine trials
Efficacy of different
“vaccine concepts”
In different populations
(route of transmission,
genetic background, etc.)
Viremia
*Adapted Uberla, K Plos Pathog
2008;4(8)
Host Factors
• HIV risk type : parenteral, mucosal
• HIV level of susceptibility: incidence, genetics
• HIV subtype exposure: location/risk
• Vector infection exposure: Ad 5 prevalence
• Age: regulatory/immunology
• Political and ethical: vulnerability/representivity
• Co- morbidity : TB, malaria
• Other factors: nutrition, circumcision
LOW LEVEL EPIDEMICS
CONCENTRATED EPIDEMICS
AFRICA
SOUTHERN AFRICA ASIA
E EUROPE
IVDU Youth (<24) are HIV
infected:
% HIV
Country
infected
Russia 55
Brazil 56
Central Asia 48
E Europe 40
Belarus 60
•(WHO 2006)
Higher HIV prevalence in CSW
IDU
Gen
Prison Pop
CSW
MSM at higher risk of HIV…
Country MSM Gen pop
prev prev
Argentina 14 % < 1%
El 18 % < 1%
Salvador
40
35
30 MSM in community
% 25
20 males
15 females
10
5
0
15-19 20-29 30-39 40-49 50+
AGE
Peri-Urban Results
Descriptive Statistics
100
88.2
90
79
77
80
70
58.3
60
Sample (%)
50
40
30.6 25.9
30
16.6 20.9
20
14
10
2.2
0
HIV incidence estimation
• Eligibility profile
– Behavioural correlates of risk
• Ongoing assessment
Heather B Jaspan, Alan J Flisher, Landon Myer, Catherine Mathews, Chris Seebregts, Jessica R Berwick,
Robin Wood, Linda-Gail Bekker.
Sexual
debut is at a young age <15 yrs (14.6 yrs in Masi)
High risk sex:
–Multiple sexual partners (mean 2.6)
–Inconsistent/ poor condom use (<50%)
–Coercion and violence (10%)
–Transgenerational (25%)
–Transactional (25%)
–Strangers (12%)
Sampling Techniques
• Capture-Recapture
• Time Location
Sampling (TLS)
• Snowballing
• RDS
• Internet
Incidence: Recruitment vs location
• Two prevention studies 5
km apart
• A) 2004 : ANC prev 28%
• B) 2006 : ANC prev 29%
B A
B
A
B
B
Other
B
Other C
C E
B A A D
A
E Others 5%
(F, G, H,
D3.2%
D
5.3%
J, NT)
C
A
27%
C
47.2% B 12.3%
Host Factors
• HIV risk type : parenteral, mucosal
• HIV level of susceptibility: incidence, genetics
• HIV subtype exposure: location/risk
• Vector infection exposure: Ad 5 prevalence
• Age: regulatory/immunology
• Political and ethical: vulnerability/representivity
• Co- morbidity : TB, malaria
• Other factors: nutrition, circumcision
Cape Town in the late 80’s
100
90
80
70
60
%
B,D
50
C
40
30
20
10
0
85 86 89 90
Host Factors
• HIV risk type : parenteral, mucosal
• HIV level of susceptibility: incidence, genetics
• HIV subtype exposure: location/risk
• Vector infection exposure: prevalence
• Age: regulatory/immunology
• Political and ethical: vulnerability/representivity
• Co- morbidity : TB, malaria
• Other factors: nutrition, circumcision
Vaccine designs
• Novel strategies welcome
• Need a greater variety of options
• Need more surveillance data on potential
vector exposure
• This needs to be considered when
choosing vectors
Vaccine vector impact
Host Factors
• HIV risk type : parenteral, mucosal
• HIV level of susceptibility: incidence, genetics
• HIV subtype exposure: location/risk
• Vector infection exposure: Ad 5 prevalence
• Age: regulatory/immunology
• Political and ethical: vulnerability/representivity
• Co- morbidity : TB, malaria
• Other factors: nutrition, circumcision
Immunity by age
• Immunity is modified throughout age
Adolescent Immunology
• Adolescence is 500
450
marked by 400
hormones, 150
100
• Immunity is 50
0 DHEA: Boys
7 8 9 10 11 12 13 14 15
affected by sex DHEA: Girls
hormones
*Sizonenko et al, J Clin Endocrinol Metab. 1975(5), 894-904
Hormonally independent
differences
•Normal numbers of T cells vary
•CD4:CD8 ratios vary*
•Markers of immune activation, such as sIL-2R
vary **
•Adolescence is marked by the gradual
involution of the thymus, which affects the pool
of naïve T cells***
*Tollerud, Immunopath, 1990
**Satoh, Clin Immunol Immunopathol, 1998
***Rudy, J Adol Health, 2001
Vaccines shown to be affected by
age:
Len, et al.
Proposed strategy
Host Factors
• HIV risk type : parenteral, mucosal
• HIV level of susceptibility: incidence, genetics
• HIV subtype exposure: location/risk
• Vector infection exposure: Ad 5 prevalence
• Age: regulatory/immunology
• Political and ethical: vulnerability/representivity
• Co- morbidity : TB, malaria
• Other factors: nutrition, circumcision
In STEP
• Lack of MALE CIRCUMCISION played a
key role in infection
Circumcision: status in CT
• Circumcision at birth –
• No circumcision-
• Traditional circumcision (amaXhosa)
– 200 men 15-45 yrs
– 70% circumcised at mean age 21 yrs (self
report)
– 40% of these no evidence of circ
– 20% partial circ
Stefan, Claudia Hanson
summary
• Probably not an “ideal” population
• High incidence will give you “hurry up” but
may have other downsides which will need
to be catered for……
Given adaptive design discussion
• Many different products into tailored
populations that give candidate the best
chance.
• But this will also need some
standardization for realistic comparison
purposes.
• Then take a really, really promising
product to many different relevant
populations.
Vaccine factors
• Sub type : homo or hetero- clade
• Design- viral components
• Design- vector
• Design
– antibody mediated
– Cell mediated
The effect of dose and diversity
• Swarms of virus assaulting host and thus
vaccine induced immunity
– Large diversity
– High frequency
• HLA-A, B &C
Viral Load as a measure of efficacy may be
affected by
• Gender
• Age
• Sub-type
• Region
Kaufmann GR, JAIDS, 1999
• HLA (HLA*B5701 allele)
• Route of infection
Summary
• Vaccine trials are going to need large
populations at risk for HIV
• Multiple factors to consider
• The “ideal” population may not exist
• Either need to find “designer” populations
• or aim for “broader” and “deeper” vaccine
products
• Formative research, planning and diverse
expertise.
• “KNOW OUR EPIDEMICS”
So-what if something works?
• In well designed and well run studies
• With robust results
• That show sufficient reduction in
acquisition
• To be deemed effective as well as
efficacious
• That can be rolled out to trial participants?
What then?
Future for Prevention Research
• Before we have the “small pox equivalent”
vaccine against HIV
(Padian)
The challenge is an opportunity
• Prevention research will need to move beyond
the silos and cabales
• Vaccine, Microbicide, T+T, behavioural, PrEP,
Circumcision, etc should get into one room when
trials are designed.
• Social Scientists, epidemiologists, modelers,
basic scientists, clinical trialists and clinicians
need to be on the team.
• We should consider a variety of innovative trials
design methodologies that take into account the
need to test more than one modality or
combination.
PREP in Non-Human Primates
Garcia-Lerma et al