Challenges in HIV Vaccine

Research and Development

September 27, 2010

Katharine Kripke, Ph.D.

Assistant Director, Vaccine Research Program
Division of AIDS, NIAID, NIH, HHS
Our ultimate aim
 Overview

 Transmission and infection

 How vaccines work
 Scientific challenges
 Transmission
 Unprotected sexual contact
– vaginal sex
– anal sex
– oral sex (very low risk)
 Direct blood contact
– injection drug needles/equipment
– blood transfusions
– accidents in health care settings
 Mother to baby
– before birth
– during birth
– through breast milk
 Mechanisms of vaginal transmission

Infection of macaques after vaginal exposure to cell-associated simian

immunodeficiency virus. Sallé B, Le Grand R.J et al. Infect Dis. 2010 ;202(3):337-44.
For any prevention technology, success will
depend on maintaining protective inhibitor
concentrations at the mucosal portals of entry.
 Time

Hours

Days

Weeks

Haase T., Ashley, 11 March 2010, Nature, v. 464, p. 217-223.

Genetic bottleneck during
transmission of HIV
Transmission
Re-emergence of viral
diversity

Diverse virus population

in chronically infected
“donor”

Zhu et. Al. Science, 1993; Derdeyn et. al., Science, 2004; Keele et. al.,
PNAS, 2008; Salazar et. al., J. Virol., 2008; Haaland et. al., PLoS Path.,
2009; Abrahams et. al., J. Virol., 2009;
 Overview

 Transmission and infection

 How vaccines work
 Scientific challenges
 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
 How do vaccines work?

You won’t get Good-bye, HIV!

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

B cell Macrophage

YUM! This Infected cell

looks like
lunch.
What does the immune system see?

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)

 Vaccines
 After vaccination, if
exposed to the actual virus or
bacterium, the immune
system is ready to attack
and can often fight off the infection
even before disease occurs, or lessen
symptoms
 Vaccine research and development

DISCOVERY VACCINE PRECLINICAL CLINICAL

DESIGN RESEARCH TRIALS
 Information cycle
Iterative process forward

Preclinical
Discovery Research & Clinical Research
Development
 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

 Overview

 Transmission and infection

 How vaccines work
 Scientific challenges
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
Viral vaccine strategies
 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
Key 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
 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.
 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?
 Thai trial follow-up
 Immune correlates of protection
 Follow-up trials in Thailand
– Late boosting of a subset of RV144 participants
– Detailed studies of immune responses to RV144
regimen
– Next IIB study in Thailand among MSM?
 Reproducing RV144 results in monkey models
 Additional human studies in the works
– Evaluate impact of protein boosts
– Determine if RV144 results can be extended to other
populations
 HVTN 505
 Exploratory Phase II study
 Vaccine regimen designed by NIAID VRC
 Will the vaccine significantly reduce VL in
individuals who become infected with HIV?
 Participants: 1350 U.S. men or trans-
women who have sex with men
– Circumcised
– No measurable Ad5 antibodies
 Current scientific questions

■ What types of immune responses prevent HIV

infection or control the virus after infection, and how
can we stimulate them?

■ 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.)?
 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
Developing a vaccine—a long road
 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.
 Future 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 other
transmission? prevention
■ In what populations has approaches?
it been tested? ■ Is use associated with
■ How much does it cost? decreased use of other
prevention
approaches?
ARV protection Immunological protection

Can they be
combined?
 How might new prevention
options work together?

Combining microbicides or PreP with vaccines may deliver

even better protection – the window for placebo controlled trials
my be closing
 Provides protection during the immunization period
 Reduces infectious challenge.
 Boosts local immunity (virus/antigen)
 Broadening localized immunity through protected exposure
to prevalent virus.
 Converting high risk challenge to low risk challenge
(RV144)
 Vaccine induced immunity may cover intermittent
compliance, break through virus and prevent resistance
evolution
What you say matters
Thank You
BeTheGeneration.NIH.gov

39
BACKUP SLIDES
 Vaccine-induced seropositivity
 HIV vaccines are designed to provoke immune
responses – this includes antibody production.
 Standard tests for HIV detect antibodies, not virus.
 Study participants who receive HIV vaccines will
often test positive (seropositive) on these standard
tests but it doesn’t mean they are HIV-infected.
 Frequency varies by immunogen—can be >80%
 Durability: Potentially >10 years
 We refer to this as Vaccine-Induced SeroPositivity,
or VISP.
Isn’t VISP just a “false positive?”

NO.
 If an HIV test is designed to look for
antibodies to HIV, then the test has done
exactly what it was supposed to, and got an
accurate result.
 What may be false is the interpretation of the
results
 We want to get away from saying “false
positive” so that we do not undermine public
confidence in HIV testing.
 Issues related to VISP
Several factors may affect study participants who have VISP:

Personal issues – feelings of anxiety, stress, frustration

Social issues – stigma or discrimination if you are mistakenly
thought to be HIV-infected
Medical issues – what do you need to talk about with your
doctor? Do providers believe their patients when they decline
testing because of being in a study?
Public Health policy – what is the HIV testing policy in your
community/country? Can people opt out?
Research – what if someone wants to join another trial (of
any kind) in the future? What are the implications for that
research?