Developments & Challenges

in HIV Vaccine Research

October 18, 2009

Katharine Kripke, Ph.D.

Assistant Director, Vaccine Research Program
Division of AIDS, NIAID, NIH, HHS
Our ultimate aim
Confronting HIV
in the 21st Century
 PrEP Microbicides
Vaccine Test and Treat

Education Partner Reduction Condoms

MTCT interruption
Circumcision
Circumcision
Drug/alcohol
Harm Etc.
Harmreduction
reduction treatment
Time between discovery of infectious agents
and development of vaccines

Years to develop
Disease
vaccine
Typhoid 105
Haemophilus influenzae 92
Pertussis 89
Polio 47
Measles 42
Rotavirus 33
Human Papillomavirus 23
Hepatitis B 15
Herpes 45 + ?
HIV 25 + ?
 How Many Molecules Does it Take
to Develop an Approved Drug?

 10,000 molecules screened for activity in lab

 250 evaluated in full preclinical tests
 5 enter phase I clinical testing
 1 approved drug
– 30% fail for lack of efficacy
– 40% fail for safety issues
– 10% fail for other reasons
– 20% approved

Pharmaceutical Manufacturers of America, 2006

Who develops HIV vaccines?

From AVAC Report 2007, “Resetting the Clock”

Our Universe
 Immune system basics
 The immune system can specifically recognize
unique molecules in bacteria and viruses
(called antigens)
 The immune system has memory
 T cells
– Recognize chopped up antigens presented by
infected cells and other immune cells
– Tell other immune cells what to do, OR
– Kill cells that are infected with bacteria or viruses
 B cells
– Secrete antibodies, which stick to intact antigens
outside of cells
HIV Viral Structure
Proteins on the viral envelope
(e.g. gp120)

Membrane or envelope

Matrix proteins

Nucleus (genes)
(e.g., Env, Gag, Pol, nef, Tat)

Core proteins (e.g p24, p17)

 How do vaccines work?

Vaccines stimulate the development of memory

T cells and B cells against specific antigens
found in a virus or a bacterium.

You won’t get Good-bye, Measles!

away this time.
I’ve got you!
Killer
T cell

B cell Macrophage

YUM! This Infected cell

looks like
lunch.
 Vaccines

 Later, if exposed to
the actual virus or
bacterium, the
immune system is
 A vaccine stimulates ready to attack and
the immune system to can often fight off
develop cells that the infection even
specifically recognize before disease
portions of foreign occurs, or lessen
molecules found in an
infectious agent symptoms
HIV is different
 HIV hides inside some long-lived
cells where it can’t be reached by
drugs or the immune system
 HIV attacks the immune system
itself
 HIV is a shape-shifter
 HIV hides its keys

Vaccine-induced immune
responses have to be unusually
quick and smart to combat HIV
 How an HIV/AIDS Vaccine might work

HIV
PREVENT
 Effective in most people
ESTABLISHED
 Effective in some people
INFECTION?

*****
C

A B HAART

A. Lower Initial Peak of Viremia

Vaccine
Administered B. Lower Set Point

C. Stop Progression
 Why do we think an HIV vaccine
may be possible?

 Neutralizing antibodies can prevent infection

by SIV in monkeys
 Some people’s immune systems can
naturally control the virus for years,
sometimes decades
 Vaccines can protect monkeys from SIV
infection or significantly delay disease
The spectrum of HIV vaccine
strategies

X
X
 Vaccine Research and Development

DISCOVERY VACCINE PRECLINICAL CLINICAL

DESIGN RESEARCH TRIALS
 Information Cycle
Iterative Process Forward

Preclinical
Discovery Research & Clinical Research
Development
 Efficacy trials
Product safety and immune Clinical
response testing (phase I research
and II clinical trials)
Product
development
and animal
testing

New vaccine
strategies

Fundamental
research
 Phases of Clinical Trials
Phase I Phase II Phase III
12 to 18 months Up to 2 years 3 to 4 years
Small group of healthy, Hundreds of HIV Thousands of
HIV negative negative participants participants at risk to
participants to test to test safety and test safety and
safety immune responses efficacy
 ALL participants receive the best risk
reduction education available

HIV Negative Volunteers, Randomly Assigned to Vaccine or Placebo

Vaccine and Counseling & Risk Reduction Tools Placebo and Counseling & Risk Reduction Tools

Follow for years Follow for years

Monitor HIV Status Monitor HIV Status

End of study, End of study,

count number count number
who became infected who became infected

If there are fewer infections in the vaccine

group – the vaccine works.
 NIAID Supported HIV Vaccine Clinical Trials
(as of October 1, 2009)

 To date, NIAID has supported 114

vaccine trials involving 67 different
products and 18 adjuvants and >27,500
volunteers
• 104 Phase I, Ib, I/IIa or I/II
• 5 Phase II
• 2 Phase IIa
• 2 Phase IIb
• 1 Phase III
 Key Clinical Trial Milestones:
HIV Vaccine Research

HVTN 505
enrollment
begins
First HIV
vaccine Results of
trial opens Phase III
Phase II Step
Thai Trial
and Phambili
(RV144)
studies halted

1980 1990 2000 2010 ?

HIV identified VaxGen

candidate fails
in Phase III
trials
 STEP Study: 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 04; fully enrolled Mar 07
 Step Study Results

 Vaccine did not protect against infection

 Vaccine did not lower the viral “setpoint”
 There were more infections in vaccinees
than placebo recipients
This trend was most notable in
uncircumcised participants with antibodies
to Ad5 at enrollment, prior to vaccination
No apparent increased risk in Ad5(-),
circumcised men
 Thai trial (RV144)
 Canarypox prime + envelope protein boost
[ALVAC-HIV (vCP1521) + gp120 B/E (AIDSVAX® B/E)]

 Phase III trial; 16,000+ volunteers

 125 infections: Incidence:

– 74 placebo – 0.28% placebo
– 51 vaccine – 0.19% vaccine

 VE = 31.2%; p = .0385; CI = 1.1 - 52.1

 No effect on setpoint viral load

 No safety issues apparent

What do the Thai trial
results mean?
 Why do we think an HIV vaccine
may be possible?

 Neutralizing antibodies can prevent infection

by SIV in monkeys
 Some people’s immune systems can
naturally control the virus for years,
sometimes decades
 Vaccines can protect monkeys from SIV
infection or significantly delay disease
 A vaccine has provided modest protection
from HIV infection in humans
What are the correlates of protection?

Vaccines stimulate the development of T cells

and B cells against specific antigens found in a
virus or a bacterium.

Hasta la vista,
You won’t get Measles!
away this time.
I’ve got you!
Killer
T cell

B cell Macrophage

YUM! This Infected cell

looks like
lunch.
 Thai trial take-home messages
 The vaccine regimen is safe and, at 31.2% efficacy,
is modestly protective; however more research is
needed
 A major scientific achievement, this study provides
first compelling evidence that development of a safe
and effective preventive vaccine is possible
 Additional studies needed to better understand how
the vaccine regimen reduced the risk of HIV infection
 Study has important implications for future HIV
vaccine design and testing
 Process for trial follow-up
Product Development
Advisory Group
Further clinical development of the
RV144 and related products
Scientific
Advisory Groups
Scientific inquiry into the RV144 result and
evaluation /design of other vaccine
candidates and studies

Animal Models

Cellular Immunity

Host Genetics

Humoral/Innate
Immunity
 Information Cycle
Iterative Process Forward

Preclinical
Discovery Research & Clinical Research
Development
Developing a vaccine—a long road

a t s
n
th tio
i es es
t ud qu
l s ey
i ca ss k
l in re
C dd
a
 How an HIV/AIDS Vaccine might work

HIV
PREVENT
 Effective in most people
ESTABLISHED
 Effective in some people
INFECTION?

*****
C

A B HAART

A. Lower Initial Peak of Viremia

Vaccine
Administered B. Lower Set Point

C. Stop Progression
The spectrum of HIV vaccine
strategies

X
X
 HVTN 505
 An exploratory Phase II study designed to determine
whether a T-cell-based vaccine (different from the
one used in the STEP study) will significantly reduce
viral load in individuals who become infected with
HIV.
 Study population limited to men who:
– live in the U.S.,
– have sex with men (MSM),
– are circumcised,
– do not have antibodies to Adenovirus type 5.

In the Step Study, there was no evidence of

increased risk of HIV infection among men who fit
these criteria and received the vaccine compared to
similar men who received the placebo.
 Step & Thai trials illustrate key
concepts in HIV vaccine development:
 We can learn important lessons from products that
don't work
 Science proceeds in small steps

 Clinical trials are essential

 Interaction between clinical, basic, and preclinical

research
 Every study raises new questions

 Humility
 An HIV vaccine is possible!
 Scientific Questions
 What types of immune responses prevent HIV
infection or control the virus after infection?
 How do different vaccine approaches influence the
type and magnitude of immune responses?
 How can HIV vaccines outsmart HIV genetic
variation (shape-shifting)?
 What are the early events in HIV infection?

 How can we improve the science of HIV vaccine

research and development (e.g. animal models,
clinical trials, etc.)?
 PrEP Microbicides
Vaccine Test and Treat

Education Partner Reduction Condoms

MTCT interruption
Circumcision
Circumcision
Drug/alcohol
Harm Etc.
Harmreduction
reduction treatment
 HIV Prevention Research:
Guiding Principles
 Multiple strategies needed to assemble a
well-rounded “prevention toolkit.”
 No one prevention strategy will be 100%
effective, appropriate to or accepted by
everyone.
 Multiple prevention strategies must be
evaluated in different populations,
domestically and globally, to determine
the best combinations for a given
population.
 Approaches to HIV Prevention

 Education and behavior modification

 Condoms, and other barrier methods
 Treatment/prevention of drug/alcohol abuse
 Clean syringes (i.e., needle exchange programs)
 Interruption of mother-to-child transmission
 Circumcision
 HIV/STI Testing
 Antiretroviral treatment as prevention
 Pre-exposure prophylaxis (PrEP)
 Topical microbicides
 Vaccination
 Pre-exposure Prophylaxis (PrEP)

 PrEP for HIV is the

use of antiretroviral
drugs by HIV-
uninfected people at
high risk for HIV, to
Illustration reprinted by permission from Macmillan Publishers
reduce their risk of
Ltd: Nature Medicine, Vol. 15(2), pp. 126-129, copyright 2009
HIV infection
Microbicides

 A microbicide is a
chemical product applied
to the vagina or rectum to
reduce or eliminate
transmission of HIV and/or
other STD pathogens
 Prevention Trials Landscape

Vaccine –
HVTN 505
Vaccine – Vaccine –
Merck Adeno x2 VRC PAVE 100
STEP/Phambili
HSV-2 Treatment Microbicides Oral PrEP
Female Barrier • TDF/PMPA • Heterosexual
– Infectiousness (CAPRISA)
Diaphragm (FemPrEP)
Oral PrEP –
Microbicides – Oral PrEP – Oral PrEP
MSM USA
Carraguard IDU/Thai • Sero-disc
Safety
(Partners)
Microbicides – Oral PrEP –
Male Community Vaccine –
CS-1 MSM Vaginal & Oral
Circumcision – VCT and HIV Thai
CS-2 (iPrEx) PrEP (VOICE)
Susceptibility Support Prime/Boost

Male HSV-2 Microbicides Oral PrEP Index

Oral PrEP – Circumcision – Treatment – • BG/Pro2000 • Heterosexual Partner
West Africa Infectiousness Susceptibility •Pro2000 (Botswana) Treatment

2006 2007 2008 2009 2010 2011++

See also http://www.avac.org/timeline-website/index.htm

 Considerations for prevention
technologies
 Is it licensed?  Is it acceptable?
 What is the level of  Do people use it as
efficacy? indicated?
 Is it only proven for  Can it be used in
certain modes of combination with
transmission? other prevention
approaches?
 In what populations
 Is use associated
has it been tested?
with decreased use of
 How much does it other prevention
cost? approaches?
What you say matters
Thank You
BeTheGeneration.NIH.gov