Title: HIV Vaccine Development: Cautious Optimism about a Formidable Foe
1HIV Vaccine DevelopmentCautious Optimism about
a Formidable Foe
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3Why 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
4The obstacles are large and are both Scientific
and Structural
5The genetic diversity is larger than any other
agent
- Fact none of over 30 million people infected
with the virus have cured themselves
6Scientific 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
7Evidence 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
8Goals for an HIV Vaccine
- Prevent infection
- Allow transient infection
- Allow subclinical persistent infection
9What Does an HIV Vaccine Need to Do?
- Bind up free virions in infected secretions
10Neutralizing 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
11Is 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
13Reality 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
14The Cautious Optimism comes form the CTL inducing
Vaccines
15CTL 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
16Vaccines that do not prevent infection but modify
viral replication after acquisition of HIV
infection
Placebo
Vaccine
17CTL 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
18SHIV Challenge of Ad5-SIV gag Immunized Rhesus
Monkeys
19We 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
20New 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.
21The Old Model HIV Disease is Gradual
22The New reality
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24Targets for HIV
- There is an abundant supply of CCR5 CD4 T cells
in gut through which HIV can rapidly propagate
25Massive Loss of CD4 T-cells in Acute SIV
(Mattapallil, et al Nature 2005)
Acute CD4 depletion in first 2 weeks after SIV
26Loss of CC4 Naïve Memory Cells in Acute SIV
(Mattapallil, et al Nature 2005)
27How Much CD4 T Cell Depletion Occurs?
- Loss of about 80 of memory T cells from all
compartments by day 17
28Where Does CD4 T Cell Depletion Occur?
- Substantial depletion of mucosal CD4 T cells in
acute SIV infection
29The Consequences Of Being Targeted
HIV-
HIV
- There is a marked reduction in mucosal lymphoid
tissue even in acute infection
30Quantification 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
31The Consequences Of Being Targeted
HIV-
32Summary
- 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
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34What does this mean for vaccine development?
35Recent 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
36Whether this will be seen in humans requires
efficacy studies
37Efficacy 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
38MRKAd5 Trivalent Vaccine
111 mixture of 3 vectors
39ELISpot Responses Elicited by gag Only and
Trivalent Vaccine
40Frequency 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.
41MRKAd5 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
42Breadth 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).
43Distribution of Ad5 90 Neutralization Antibody
Titers by Site
44Big 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?
45Primary 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
46Primary 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
47Enrollment Projected Endpoints
Ad5 lt200
Total
Total
Ad5 gt200
48CTL 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?
50Relationship 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
51Issues 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
52NIAID Vaccine Research Center
- DNA prime Ad5 boost Approach
53DNA, Adeno, DNA/Adeno
54DNA and Adenovirus Recombinant Vaccines
55Summary
- 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
56Summary
- 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?
57Science, Volume 300, June 27, 2003
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59Summary
- 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)
60Acknowledgements
- 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
61Developing 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