Vaccine Clinical research

What can we learn?

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….

• 7400 new infections

daily.
• 5.5 Million in MLIC
need ART
• For every 2 on ART
another 5 infected.
Why prevention must work…
 Management of
genital infections Microbicides
(STIs)
Cervical Barriers

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)

Type Positive Adverse Nil Total

behavioural -* - 7 7
µfinance - - 1 1
diaphragm - - 1 1
Vag microb -* 1* 11 12
PrEP - - 1 1
Male Circ 3 - 1 4
STI treat 1* - 8 9
vaccine 1 -* 3 4
total 5 1 33 39
 Male
circumcision
Not known to
be helpful for
men who have
sex with men
HIV
PREVENTION
Condoms

Behavioral
Counseling and Chemoprophylaxis
Testing
MTCTp
Intensive not PEP
better than
PrEP
standard
have unknown
efficacy
 Partial efficacy

PMTCT (HIVNET 012)

Circumcision (Orange F)

Vaccine (RV 144)

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%

USAID, UNAIDS, UNICEF, Policy Project, June 2004

Back to the Basics

• HIV Infection is The Cause of AIDS

– Not Sex, Not Drugs
– Antiretroviral Agents Target HIV Directly

• People Like Sex

– Pleasure, Intimacy, Company, Livelihood,
Pregnancy
– Prevention is utilized less if it alters sex
 Vaccines
.

The AIDS vaccine field has never been a

place for people who craved certainty
25 years of HIV/AIDS
 Poliomyelitis
- paralysis

ALW Three-year-old child in an “iron lung” in the 1930s

POLIO CASES WORLDWIDE 1974-1999
 We do Human clinical trials :
• In the development of a product
– Assess safety
– Some measure of promise
– Dose, dosing interval, PK, PD
– Efficacy

• 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….

• A reliable indirect measure of efficacy is

found, eg. An antibody titre or some other
immunological marker
 licensure
• Safety in all populations in which the
vaccine will be used
• Efficacy and dose in all populations in
which the vaccine will be used, unless
some means to extrapolate efficacy and
dose.
• Level of efficacy….
• Durability of effect…..
Vaccinology
HOST
VACCINE

WILD TYPE INFECTION

 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, STIs
• Other factors: nutrition, circumcision, pregnancy
 Wild type infection factors
• Sub-type : geography, risk factor
• Dose : mucosal vs parenteral vs maternal
• Port of entry : IV vs mucosal
 Vaccine factors
• Sub type : homo or hetero- clade
• Design- vector
• Design- viral components
• Design
– antibody mediated
– Cell mediated
 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

Understand how Test vaccine in animals Human trials

HIV works
Design a Vaccine

Is it safe, does it give a promising Phase IV licensed

immune response?
vaccine
 It may also protect
humans
 Obstacles to HIV Vaccine
Development
The window of opportunity for the immune system to clear
the initial infection is narrow, since HIV integrates and
establishes latent infection within days/weeks
Destruction of CD4+T cells begins early after infection

Enormous genetic diversity and mutations enable HIV to

avoid immune surveillance

Conserved antibody targets on the outer envelope protein

are “hidden” from immune recognition

Johnston, Fauci, NEJM 2008, 359;9

 Most diverse virus known

Global diversity in Influenza in one year

HIV Diversity within one person

Global HIV Diversity

Current Classification of HIV

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?

1. Neutralizing 2. Cytotoxic T cells

antibodies stop the destroy cells infected
virus entering cells with HIV

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”

Johnston M, Fauci A. N Engl J Med

2007;356:2073-2081
 STEP TRIAL: Phase IIb
HVTN 502 / Merck 023
 Ad5 vector expressing 3 internal HIV genes
 gag, pol, nef (clade B)
 N= 3000 volunteers
(low and high Ad5 titers)
 Primary Endpoints
 Safety
 Reduction in HIV-1 infection
rate and/or viral load at
3 months post-diagnosis
 Initiated Dec 2004; fully enrolled Mar 2007
STEP
(HVTN502)

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

HIV infection 100 120 129 368 211

endpoints

Sample size 3000 3000 16 000 5 400 2550

WHO/UNAIDS/IAVI International Expert Group, AIDS,

2007
Thai Trial Results
 The Vaccines

• Prime: ALVAC-HIV (vCP1521) (Sanofi Aventis)

– Recombinant canarypox expressing CRF01_AE HIV-1 HIV-1
gp120 linked to transmembrane portion of gp41 from Clade B (LAI)
– Gag, prot from Clade B (LAI)
– Dose is 106.5
– Given at 0, 1, 3 and 6 months

• Boost: AIDSVAX B/E

– gp120 Clade E (CRF01_AE envelope, strain A244) + gp120 Clade
B (strain MN)
– CHO cells (300 ug each) in alum 
– Given at 3 and 6 months
S Nitayaphan, et al. JID 2004:190 (15 August)
 Study Details

• 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

• VE female – 39%; 50 cases total

• VE male – 26%; 75 cases total
– p = 0.61

No effect on viral load or CD4 T cell count

 First sign that something had
worked
• Infections were stopped
• For a time at least
• In a moderately low risk heterosexual
population
• In Thailand
 What did we learn?
• Not sure what it tells us about risk?
• Probably wont find a correlate of
protection?
• Not sure HOW it worked !
• Need a combo of T cell and antibodies
• Need durability
 Classical Vaccine Approach
• Neutralizing Antibodies
First choice for vaccine-induced immunity
against HIV
Research for the first 10 years focused on
humoral anti-HIV immunity
But antibodies and soluble CD4 molecules
failed to neutralize primary HIV isolates
The neutralizing antibody challenge
 Most licensed vaccines work by
inducing the body to produce
antibodies that attack the infecting
virus, neutralizing most of it and
enabling the immune system to clear
remaining virus before the onset of
disease
 In the blood of certain HIV-infected
individuals, scientists have identified
special antibodies that are broadly
neutralizing—they neutralize many of
the types of HIV in circulation
worldwide 2G12

 An AIDS vaccine will almost certainly

need to elicit a sufficient amount of CD4 b12
these broadly neutralizing antibodies
gp120
2F5
gp41
4E10/Z13
This is the neutralizing
antibody challenge
 The Antibody Project: Protocol G

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

About 1% are “elite neutralizers”

 The Antibody Project: Closing in

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

6. Samples sent to four partner labs for antibody

rescue—each using a different technology

*Monogram received new samples to verify neutralization screenings

TheAntibody Project: Discovery

7. Theraclone is first
to find new broadly
neutralizing antibodies

8. Antibodies
characterized

IAVI Neutralizing
Antibody Center at

AIDS Vaccine Design

and Development
Laboratory
The Antibody Project: Next steps

IAVI Human
Immunology
Lab

Lipoxen Pepscan
Avatar

IAVI AIDS Vaccine

ProSci Strand
Design and
Development Lab Life Sciences

Chembiotek

IAVI Neutralizing
Antibody Center
at the Scripps
Research Institute

Neutralizing Antibody
Consortium members

IAVI Innovation Fund Elevation Biotech

recipients

9. With antibodies characterized, IAVI’s

immunogen design partners take over
The
Antibody
Project:
The return
Pune

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

Understand how Test vaccine in animals Human trials

HIV works
Design a Vaccine

Is it safe, does it give a promising Phase IV licensed

immune response?
vaccine
 It may also protect
humans
 Sites and population
• USA : Boston
– 12 participants
• SA : Johannesburg and Cape Town
– 18 participants each

• Low Risk, healthy HIV negative adults

Six Clinical Trial
Sites
 HVTN 073/SAAVI 102
Dose Months (days) after first injection

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

8 0 0 Placebo Placebo Placebo Placebo Placebo

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

Generic prevention literacy

Specific discussion grps
Informed
consent Variety of protocols
groups

Laboratory/
Basic science
 Need to conduct multiple
HIV vaccine trials
 Efficacy of different
“vaccine concepts”

 Against different HIV

strains (subtypes?)

 In different populations
(route of transmission,
genetic background, etc.)

Need of multiple “sites”

Trial Design Challenges:
Who to recruit?
Could stop here!!
 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
 Source of infection
• Vertically
– In utero
– Peri partum
– Via breast milk
• Per blood, eg. IVDU, needle stick, open
wound
• Sexually, eg. Mucosal
– Vaginal
– Anal
Sexual HIV risk
Model of the Early Stages of Mucosal HIV Infection and Proposed Enhancement*.

Free virus crosses the epithelial barrier of the

mucosa leading to a single HIV-infected cell
located in the lamina propria.

CTL needs to kill the first HIV

infected cell
Additional replication of the virus and transmission
to secondary target cells

Spread of the virus to the regional lymph node

Activation and expansion of HIV

specific T cells may be too slow to
prevent spread

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

IVDU CSW MSM PRISONERS OTHER

HYPERENDEMIC GENERALISED 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

Country CSW General

population
Myanmar 27% 1.8%
Ghana 40% 3%
Ecuador 11% 0.3%

73% in Ethiopia, 68% in Zambia, 50% in South Africa

Global prevention efforts: 16% •(WHO 2006)

Bridging in concentrated epidemics

IDU

Gen
Prison Pop

CSW
 MSM at higher risk of HIV…
Country MSM Gen pop
prev prev
Argentina 14 % < 1%

El 18 % < 1%
Salvador

Global prevention efforts : 11%

< 1 : 20 of MSM receive care or prevention
 HIV Prevalence

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

• direct longitudinal follow-up of populations;

• biomarkers that indicate recent infection
on cross-sectional samples, eg STAHRs
• Mathematical models that rely on serial
prevalence data

• (other indirect indicators)

Incidence….
Acute HIV infection assays
 To enhance sampling of high
incidence
• Target particular populations
– Region
– Ethnicity
– Risk factor
• Shooting galleries
• CSW beats
• Bath houses
• Discordant partner
• Target particular behaviours
– Self reported behaviours within a group
ethnicity
 Risk behaviour assessment and
monitoring
• Healthy dose of social science interaction

• Eligibility profile
– Behavioural correlates of risk
• Ongoing assessment

• How do we get authentic assessments??

 Assessment of risk
• Self report :
– Interviewer based
– Paper based
– Technology, eg ACASI
– Other supporting biomedical markers
• Use of impartial/anonymous assessment

• MUCH more research needed!

 Methods for collecting sexual behaviour information from South African
adolescents: a comparison of paper versus personal digital assistant
questionnaires.

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%

• Incidence in clinical trial

• A) <3%
• B) > 6%
 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
HIV-1 diversity
 Geographical distribution of HIV-1
env genetic subtypes in 2002
WHO-UNAIDS Network for HIV Isolation and Characterization

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

extreme changes 350

300

in sex steroid 250

200

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:

• Live attenuated: mumps, BCG, varicella

• Killed: Hep A
• Protein subunit: Hep B, Malaria, HPV

In most cases : better response in younger vaccinees.

Proposed strategy

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

= May “overwhelm” or “sidestep” a vaccine

“Breakthrough
science”
 Vaccine factors
• Sub type : homo or hetero- clade
• Design- viral components
• Design- vector
• Design
– antibody mediated
– Cell mediated
Course of HIV Infection in Unvaccinated Persons and the Hypothetical Course of Infection in
Vaccinated Persons in a “T-cell vaccine”

Johnston M, Fauci A. N Engl J Med

2007;356:2073-2081
 Host Determinants of HIV
Pathogenesis
Viral Control
• HLA-B57, HLA-B27, HLA-B51
• HLA-C gene polymorphisms
• HLA/KIR interactions
Decreased susceptibility & delayed clinical
progression
• CCR5Δ32
• CCL3L1
• RFP 39
• ZNRD1
 Host factors affecting susceptibility and
disease progression
• Chemokine & Chemokine Receptor
Polymorphisms:
CCR5-Δ32, CCR2-641 & SDf1-3’A
• Cytokines:
IL4-589T, IL-10 (IL10-5’592A)

• 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

• Just as research money “flat lines”

• the job just got harder and more

costly…….
 Since it got harder- we gotta get
smarter….
• Principle 1: Trial participants must receive the best
available (evidence based) standard of prevention.
• Principle 2 : prevention in the future will be drawn from a
menu-combo prevention already exists
• Principle 3: this may be an opportunity to design more
creative, broader clinical trials with innovative methods.
• Principle 4: this behoves us to really know volunteer
populations:
– Accurate incidence estimations with modeling input
– Accurate risk measurements
– Accurate Adherence measurements
– Good idea of preference/acceptability/feasibility
Incidence Adherence

(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

• Decreased plasma RNA level after

seroconversion during PREP
• Appears to persist after PREP stops
• Immune correlates being sought
• SIVmac239 in macaque monkeys causes high viral
load and simian AIDS in 1 year.
• Tenofovir dosing from 1-28 days after exposure
– caused durable decreases in viral load.
– Partial protection during viral rechallenge.
– Some antiviral immune responses.
Exposed Seronegatives
Douglas Nixon and Ann Erickson with iPrEx team

• PrEP Participants start as

exposed seronegatives:
– Anti-HIV immune responses
were detected in 4/20
– An antiviral clone was
derived in one
– No viral RNA (<2 copies)
• iPrEx will test whether:
– PrEP increases the
occurrence of immune
responses without systemic
infection
– Whether such immune
responses alter the course of
infection
 Other possibilities…
• PrEP/microb in a vaccine trial may attract
participants who make up a subpopulation
with higher HIV incidence
• On the other hand, PrEP may reduce viral
load sufficiently for the immune response
in a vaccinated individual to abort
infection.
 Thanks to
• Bob Grant, Pedro and the iPrEx Team
• Annalene Nel from IPM
• Pat Fast and Team from IAVI
• Jim Kublin and the HVTN
• Glenda Gray from PHRU
• Fabulous team at DTHF
• The thousands of volunteers who are
currently involved in prevention research.