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HIV Vaccine Development: Cautious Optimism about a Formidable Foe

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Title: HIV Vaccine Development: Cautious Optimism about a Formidable Foe


1
HIV Vaccine DevelopmentCautious Optimism about
a Formidable Foe
2
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3
Why Has It Been So Diffficult?
  • We know more about the molecular biology
    mechanism of attachment and the immunology of
    HIV than any other virus in history
  • We acknowledge HIV as the most important Health
    Problem in the world
  • The NIH research budget for HIV is over 4 billion
    dollars yearly and has been over 2 billion
    yearly for 10 years
  • Yet there is no vaccine

4
The obstacles are large and are both Scientific
and Structural
5
The genetic diversity is larger than any other
agent
  • Fact none of over 30 million people infected
    with the virus have cured themselves

6
Scientific Reasons Why an HIV Vaccine Has Been
Difficult to Develop
  • No definitive marker of protection exists, even
    among long term non-progressors
  • HIV employs several immune evasion strategies
  • HIV proteins mask their neutralizing sites
  • HIV-1 proteins down regulate T cell immune
    response to the virus
  • Antigenic diversity results in escape from both
    neutralizing antibodies, as well as CD8 and CD4
    T cell responses

7
Evidence Suggesting an HIV Vaccine is Possible
  • Protection against experimental challenge can be
    achieved
  • Acquired resistance after infection does occur
    Superinfection with divergent strains of HIV-1
    less common per exposure than primary infection
  • Exposure to infected secretions either by sexual
    contact or birth is not absolute
  • 30 by birth
  • 5-10,000 by sexual exposure
  • Transient infection does occur
  • Acquired resistance has been documented
  • Innate resistance exists

8
Goals for an HIV Vaccine
  • Prevent infection
  • Allow transient infection
  • Allow subclinical persistent infection

9
What Does an HIV Vaccine Need to Do?
  • Bind up free virions in infected secretions

10
Neutralizing Primary Isolates of HIV-1
  • No recombinant protein has to date effectively
    neutralized primary field isolates
  • Even available monoclonal antibodies to HIV-1
    have modest breadth and neutralizing potential
  • Autologous neutralization does occur during the
    course of primary HIV
  • Level of neutralization required to prevent
    experimental infection is high
  • likely we will need to achieve levels higher
    than natural infection

11
Is this what we will have to achieve?
Immunogenicity for Merck HPV 16 Vaccine Study
with 100 Efficacy
1510
25.7
Source Koutsky LA, et al. NEJM 2002 3471645-51
12
Designing Immunogens that Achieve Broadly
Reactive Neutralizing Antibodies 4 General
Approaches
  • Define the native envelope trimer and produce
    molecules that mimic the mature trimeric
    structure
  • Enhance the neutralizing activity of currently
    available envelope structures through molecular
    manipulation of loop structures and glycosylation
    sites
  • Generate immunogens that expose cryptic
    epitopes that arise during the course of
    binding, fusion and entry
  • Produce epitopes mimicking those defined by
    broadly reactive monoclonal antibodies

13
Reality re Neutralizing Antibody Inducing
Vaccines
  • We are in essence starting over in this arena
  • Several new groups will be starting novel
    approaches with funding from the Bill and
    Melinda Gates Foundation in July 2006
  • We will likely not see interesting candidates
    until 2010

14
The Cautious Optimism comes form the CTL inducing
Vaccines
15
CTL Based vaccines
  • Current Emphasis on HIV vaccines is based upon
    vaccines that are directed at inducing
    Cytotoxic T cell responses
  • Major goal is to control viremia
  • These vaccines do this effectively in SIV
    challenge models

16
Vaccines that do not prevent infection but modify
viral replication after acquisition of HIV
infection
Placebo
Vaccine
17
CTL Inducing Vaccines
  • Many CTL inducing Vaccines control viremia after
    experimental challenge by a variety of
    challenge routes
  • For some of the vectors especially recombinant
    adenovirus vaccines the degree of protection is
    prolonged and without breakthrough
  • Immunogenicity Studies in humans have shown that
    the levels of T cell responses induiced by these
    vaccines are similar to that seen with effective
    vaccines in humans such as smallpox

18
SHIV Challenge of Ad5-SIV gag Immunized Rhesus
Monkeys
19
We need these CTL Inducing Vaccines to Work
  • Recent studies in NHP have shown that the
    depletion of CD-4 T cells is so rapid that
    only approaches that prevent infection or
    control viremia rapidly will make a major impact
    on pathogenesis.
  • Antiretroviral therapy as currently conceived
    does not restore immunity to normal ie even
    with effective HAART these gut lymphoid CD4 T
    cells are infected

20
New Concepts in HIV Pathogenesis
  • This Gut contains most of our memory T cells
  • These cells are rapidly depleted within 2-3 weeks
    after infection
  • The loss is permanent
  • Even with suppressive ART there is enough
    ongoing replication of virus that these cells
    are not restored in adults with no thymus.

21
The Old Model HIV Disease is Gradual
22
The New reality
23
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Targets for HIV
  • There is an abundant supply of CCR5 CD4 T cells
    in gut through which HIV can rapidly propagate

25
Massive Loss of CD4 T-cells in Acute SIV
(Mattapallil, et al Nature 2005)
Acute CD4 depletion in first 2 weeks after SIV
26
Loss of CC4 Naïve Memory Cells in Acute SIV
(Mattapallil, et al Nature 2005)
27
How Much CD4 T Cell Depletion Occurs?
  • Loss of about 80 of memory T cells from all
    compartments by day 17

28
Where Does CD4 T Cell Depletion Occur?
  • Substantial depletion of mucosal CD4 T cells in
    acute SIV infection

29
The Consequences Of Being Targeted
HIV-
HIV
  • There is a marked reduction in mucosal lymphoid
    tissue even in acute infection

30
Quantification of SIV by Single Cell qPCR
  • Infected CD4 cells carry 1-2 copies of gag DNA
  • As much as 60 of memory CD4 T cells can be
    infected at the peak of viremia

31
The Consequences Of Being Targeted
HIV-
32
Summary
  • During acute infection, the primary target is the
    total memory CD4 T cell compartment
  • The majority of memory CD4 T cells are mucosal
  • As much as 60 of all memory CD4 T cells can be
    infected
  • This rate of infection is much higher (gt100x)
    than in chronic infection
  • By day 14, 80 of infected cells disappear this
    represents a loss of 50 of all memory CD4 T
    cells in just 4 days, with more lost later
  • The majority of memory CD4 T cells are lost
    during the acute phase
  • The loss of memory CD4 T cells can be solely
    ascribed to the consequences of viral infection

33
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34
What does this mean for vaccine development?
35
Recent Studies from the VRC
  • Recent studies in SIV model using high dose DNA
    and Adenovirus SIV vaccines show that these
    vaccines protect gut lymphoid CD-4 cell depletion
    by as much as 80 ie reduce jejunal depletion
    at 3 weeks from 80 to 60
  • This is associated with only modest degree of
    viremic loss
  • Animals with persistent memory CD-8 T cells
    were most likely to survive as well as those with
    best response to vaccine as measured by ELISpot
    assays

36
Whether this will be seen in humans requires
efficacy studies
  • These are starting

37
Efficacy Trials of CTL Based Vaccines
  • Canarypox Vector Vaccine in Thailand
  • 20,00 persons enrolled albeit 120 total
    endpoints
  • HVTN 502 STEP study USA/Caribbean and South
    America
  • HVTN 503 MRK Vaccine in Republic of South Africa
  • July 2006
  • PAVE 100 DNA/Ad5 vaccine from VRC March 2007

38
MRKAd5 Trivalent Vaccine
111 mixture of 3 vectors
39
ELISpot Responses Elicited by gag Only and
Trivalent Vaccine
40
Frequency of ELISpot Responses in PBMC in MRKAd5
Trivalent gag/pol/nef Vaccine
ELISpot responder for any antigen gt55 SFC/106
PBMCs and gt4-fold over media control.
41
MRKAd5 Trivalent gag/pol/nef at 31010 Vp
ELISpot Response at Week 30
ELISpot responder for any antigen 55 SFC/106
PBMCs and 4-fold over media control
42
Breadth of CTL Responses Monovalent (gag) vs
Trivalent (gag/pol/nef) Vaccinees
Samples with robust ELISPOT 9mer responses were
selected for testing. Gag 62 peptide minipools
Pol 105 minipools Nef 27 minipools. Each
minipool consists of eight 9-aa peptides (with
8-aa overlaps).
43
Distribution of Ad5 90 Neutralization Antibody
Titers by Site
44
Big Picture Question
  • How do we establish whether CTL based vaccines
    offer any benefit in reducing acquisition of HIV
    and/or decrease disease progression?
  • Just how immunogenic should the initial CTL
    vaccine based vaccines be to enter clinical
    trials and once the lead prototypes enter
    clinical trials what next?

45
Primary Efficacy Hypotheses
  • Infection endpoint
  • Subjects who receive the vaccine will have a
    lower likelihood of acquiring HIV-1 infection
    than those who receive placebo
  • AND/OR
  • Viral load endpoint
  • Among subjects who become HIV-1 infected, those
    who receive the vaccine will have a smaller
    average viral load set-point than those who
    receive placebo

46
Primary Endpoint Assessment
  • Infection endpoint
  • Screen for HIV infection
  • Begin 12 weeks post first immunization, then
    every 6 months
  • Envelope based serological screening test
  • Confirmatory plasma HIV viral RNA, Western blot
  • All cases confirmed by Endpoint Adjudication
    Committee
  • Viral load endpoint
  • Primary viral load endpoint 3 months
    post-infection
  • Later timepoints to look at durability of
    suppression
  • Planned analyses to deal with early initiation of
    ART

47
Enrollment Projected Endpoints
Ad5 lt200
Total
Total
Ad5 gt200
48
CTL Based Vaccine Endpoints What Should They Be?
  • Will a CMI-based vaccine be effective in either
    preventing or modifying the course of HIV
    infection in man?
  • If the vaccine does not prevent acquisition of
    infection
  • What is the magnitude of the vaccine effect on
    viral load set point?
  • Is the effect on viral load set point accompanied
    by preservation of CD4 cell count?
  • What is the durability of the clinical response?

49
  • Would such a vaccine reduce transmission?

50
Relationship to Viral Load and Heterosexual
Transmission(Rakai Discordant Couple Trial,
n415)
Quinn et al, NEJM 342(13)921-9, 2000 Mar 30
Annual Frequency of Transmission
RNA Viral Load in HIV Source Partner
51
Issues Raised by Vaccines that Modify Replication
  • It is well recognized that persons with low grade
    viremia can be infectious and exhibit high levels
    of mucosal shedding of HIV
  • Vaccines that reduce viremia require greater long
    term modification of sexual behavior than
    vaccines which reduce infection/seroconversion

52
NIAID Vaccine Research Center
  • DNA prime Ad5 boost Approach

53
DNA, Adeno, DNA/Adeno
54
DNA and Adenovirus Recombinant Vaccines
55
Summary
  • Efficacy trials for CTL based vaccines are
    underway in both Ad 5 seronegative and Ad 5
    seropositive persons
  • Pray that they work enough so that we can
    decipher what more needs to be done to develop
    more potent and long lasting vaccines
  • Pray even more that we can develop a correlate
    of protection

56
Summary
  • The CTL based vaccine filed is starting to
    generate data
  • The initial basis of comparison will be number of
    ?IFN producing T cells (CD4 or CD8) after
    vaccination
  • But is this the best comparator?
  • What constitutes protective T cell memory
    responses?
  • Will breadth be a more effective measure of
    protection than magnitude? How do we develop and
    measure regimens with greater breadth?

57
Science, Volume 300, June 27, 2003
58
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59
Summary
  • We will need to embark on a defined number of
    efficacy trials to answer the critical question
    regarding CTL based vaccines
  • Test of Concept trials seem to be both the
    scientifically and financially prudent approach
    at present
  • 3-4 test of concept trials with vaccines with
    relatively similar immunogenicity but different
    immunogens would provide data on how unique is
    the vector versus the overall concept of
    induction of T cell immunity in controlling
    viremia or reducing acquisition
  • Subsequent trials should then involve immunogen
    regimens with increased immunogenicity either in
    breadth or magnitude (preferably both)

60
Acknowledgements
  • HVTN
  • Ann Duerr
  • ---- Marnie Elizaga
  • Judy Wasserheit
  • Steve Self
  • Scott Hammer
  • Susan Buchbinder
  • Julie McElrath
  • Glenda Gray
  • Jim Kublin
  • Tuofu Zhu
  • Jim Mullins
  • Merck Research Labs
  • Robin Isaacs
  • Jeff Chodakewitz
  • VRC
  • Gary Nabel
  • Barney Graham
  • John Mascola
  • Richard Koup
  • Aventis
  • Jim Tartaglia
  • Sanjay Gurunathan
  • EuroVacc
  • Gepi Pantaleo
  • Peter Liljestrom
  • Gates Foundation
  • Jorge Esparza
  • Helene Gayle
  • Nina Russell

61
Developing a Globally Effective HIV Vaccine
Requires More Resources
  • Answering questions requires experiments
  • Performing experiments requires reagents
  • Producing more reagents requires changing some of
    the structural inefficiencies in the current
    system for developing vaccines
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