precedence

1
precedence

• 1. the condition of preceding others in
  importance, order or rank
• 2. an acknowledged or legally determined right
  to such precedence

2
Clinical trials take precedence for vaccine
development at the current time yes or no?

• clinical trials should go ahead of, be
  prioritized relative to, basic research at the
  current time yes or no?

3
Yes/No?

• No!!
• Why not?
• Because there are too few quality vaccine
  candidates in the pipeline at the current time.
• We need more quality candidates if we are to
  succeed. We need basic research to find those
  quality candidates.

4
NOT saying

• That clinical trials are not very important
• That empiricism is not very important

and make a clear distinction between phase I, II
and III clinical trials
5
The HIV vaccine candidate pipeline is trickling
rather than gushing with quality immunogens at
this time. Why?

• We dont have immunogens that elicit (broadly)
  neutralizing antibodies.
• There are many uncertainties about what kind of
  vaccine-induced cellular immune responses are
  going to provide benefit against exposure to HIV.

6
Why is the vaccine candidate pipeline trickling
with quality immunogens rather than gushing?

• We dont have immunogens that elicit (broadly)
  neutralizing antibodies
• There are many uncertainties about what kind of
  vaccine-induced cellular immune responses are
  going to provide benefit against exposure to HIV.

7
We dont have immunogens that elicit neutralizing
antibodies

• 1. Virtually all current effective vaccines
  elicit neutralizing antibodies.
• 2. For HIV, because of viral variation, we
  require broadly neutralizing antibodies.
• 3. The VaxGen efficacy trials showed no
  protection by monomeric gp120 subunit vaccine.

8
We dont have immunogens that elicit neutralizing
antibodies

• 1. Virtually all current effective vaccines
  elicit neutralizing antibodies.
• 2. For HIV, there is the added problem of viral
  variation, requiring broadly neutralizing
  antibodies
• 3. The VaxGen efficacy trials showed no
  protection by monomeric gp120 subunit vaccine.

9
Pantaleo and Koup (2004) Nature Med 10, 806.
10
We dont have immunogens that elicit broadly
neutralizing antibodies

• 1. Virtually all current effective vaccines
  elicit neutralizing antibodies.
• 2. For HIV, because of viral variation, we
  require broadly neutralizing antibodies
• 3. The VaxGen efficacy trials showed no
  protection by monomeric gp120 subunit vaccine.

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The enormous variability of HIV means that the
NAbs we elicit by vaccination must recognize a
multitude of viruses of differing sequences
Sequence divergence of HIV gp120 (V2-C5) as
compared to influenza A
12
All neutralizing antibodies are directed to Env
spikes on the virion surface
gp120
CD4bs
gp41
Viral envelope
13
The Env spike has evolved to avoid broadly
neutralizing antibodies
(low accessibility of conserved regions of Env)
Functional oligomeric gp120/gp41 (virion surface)
14
Broadly neutralizing antibody epitopes on the
HIV-1 Env spike chinks in the armor
Virus Membrane
4E10
2F5
2G12
b12
CD4i Fabs
V3 loop Abs
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CROSS-CLADE NEUTRALIZATION OF HIV-1
?none ?1-30 ?31-60 ?61-90 ?gt90
IC50 ?50 ?g/ml
Binley et al, J Virol, 78, 13232-13252, 2004.
16
Basic research to exploit these chinks and
design immunogens to elicit broadly neutralizing
antibodies should not receive a lowered priority
17
We dont have immunogens that elicit neutralizing
antibodies

• 1. Virtually all current effective vaccines
  elicit neutralizing antibodies.
• 2. For HIV, because of viral variation, we
  require broadly neutralizing antibodies
• 3. The VaxGen efficacy trials showed no
  protection by monomeric gp120 subunit vaccine.

18
The Env spike has evolved to avoid broadly
neutralizing antibodies
(low accessibility of conserved regions of Env)
host cell-derived carbohydrates (silent face)
non-neutralizing face
CD4bs (neutralizing face)
Monomeric gp120
Functional oligomeric gp120/gp41 (virion surface)
19
The AIDSVAX trials

• Monomeric gp120 subunit vaccine (VaxGen Inc),
  designed to induce neutralizing antibodies.
• Monomeric gp120s protected chimps against
  homologous challenge with a neutralization
  sensitive lab strain (IIIB), and heterologous
  challenge with a minimally replicating,
  neutralization sensitive virus (SF-2).
• Monomeric gp120s fail to induce neutralizing
  antibodies against representative primary
  isolates.
• Monomeric gp120s failed to protect humans
  against HIV-1 infection in two Phase III trials
  (N. America/Europe and Thailand).

20
Why is the vaccine candidate pipeline trickling
with quality immunogens rather than gushing?

• We dont have immunogens that elicit broadly
  neutralizing antibodies
• There are many uncertainties about what kind of
  vaccine-induced cellular immune responses are
  going to provide benefit against exposure to HIV.

21
There are many uncertainties about what kind of
vaccine-induced cellular immune responses are
going to provide benefit against exposure to HIV.

• 1. Superinfection by HIV in the face of cellular
  immune responses is well documented.
• 2. Many promising vaccine approaches have failed
  to protect even against homologous challenge by
  SIVmac239 in macaques.
• 3. Live attenuated vaccination does protect
  against SIVmac239 challenge but we dont know
  why.

22
There are many uncertainties about what kind of
vaccine-induced cellular immune responses are
going to provide benefit against exposure to HIV.

• Superinfection by HIV in the face of cellular
  immune responses is well documented.
• 2. Many promising vaccine approaches have failed
  to protect even against homologous challenge by
  SIVmac239 in macaques.
• 3. Live attenuated vaccination does protect
  against SIVmac239 challenge but we dont know
  why.

23
Superinfection

• Superinfection rates in newly infected
  individuals reported to approach those in VaxGen
  trial i.e. 5
• Rates reportedly lower in chronic infection.
• Nevertheless suggestion that infection is
  occurring in face of quite vigorous immune
  (particularly T cell) responses
• Smith, Richman Little (2005) JID 192, 438.

24
There are many uncertainties about what kind of
vaccine-induced cellular immune responses are
going to provide benefit against exposure to HIV.

• 1. Superinfection by HIV in the face of cellular
  immune responses is well documented.
• 2. Many promising vaccine approaches have failed
  to protect even against homologous challenge by
  SIVmac239 in macaques.
• 3. Live attenuated vaccination does protect
  against SIVmac239 challenge but we dont know
  why.

25
Vaccine Protection Against Pathogenic SIV in
Indian Rhesus Macaques
Koff et al, Nature Immunology, submitted.
26
Basic research to understand protection against
SIV by live attenuated vaccines should not
receive a lowered priority
27
So whats all the fuss about?

• Where is the tension between advocates of
  clinical trials and basic research in HIV vaccine
  development?

28
The ALVAC gp120 Thai trial
Science 303, 961 (13 February 2004)
Science 303, 316 (16 January 2004)
A difference of opinion exists over the merits of
this trial
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The ALVAC gp120 Thai trial

• A large (n 16,000), simple trial with the sole
  goal of determining efficacy, cost 120m.
• Primary end-point protection from infection
• Secondary endpoint protection from disease (IF
  enough VL data collected)
• Initial assumption was 5 infection rate, this
  may be much less

30
The ALVAC gp120 Thai trial

• ALVAC induces CTL activity with a cumulative freq
  of only 24 and a sustained freq of only 10
• Monomeric gp120 does not induce NAbs
• Vaccine induces moderate CD4 T cell responses
• Such a clinical trial should not take precedence
  over basic research

31
Clinical trials take precedence for vaccine
development at the current time yes or no?

• No.
• Not enough good candidates to put into clinical
  trials costing 100ms.
• Much basic research needs to be done to find
  better candidates.

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Contrasting ways to do efficacy trials

• Vaccine ALVAC gp120
  MRKAd5 adenovirus/HIV
• Sponsor Aventis DoD (NIH)
  Merck NIH (HVTN)
• Trial location Thailand
  N.America/Caribbean
• Immunogenicity (CTL) lt 30
  80
• Trial size 16,000
  1,500
• Trial cost 119m
  ?? 25m ??
• Corporate funds used No
  Yes
• Road to FDA licensure No
  Yes
• Primary endpoint Infection rate
  Infection rate and VL
• Immunological analyses Some, n 300
  Samples saved from all
• Which trial design gives more bangs per buck and
  per volunteer?
• Corporate funding (answering to stock-holders)
  creates fiscal discipline. This appears not to
  apply when Uncle Sam picks up the tab.
• Who will be held accountable when the results
  come in from Thailand?

34
The ALVAC gp120 Thai trial

• Pal R, et al. 2002. ALVAC-SIV-gag-pol-env-based
  vaccination and macaque major histocompatibility
  complex class I (A01) delay simian
  immunodeficiency virus SIVmac-induced
  immunodeficiency. J Virol 76, 292-302.
• Cited by McNeil et al. (Science) as supporting
  the use of ALVAC gp120
• BUT, IN FACT..
• None of the animals was protected all would
  have failed the primary end-point for the Thai
  trial.
• The inclusion of gp120 had no effect, to the
  extent that animals that did or not receive gp120
  were pooled to make a common control group for
  subsequent immunological and virological
  analyses, showing that
• ".... the gp120 subunit immunization (did not
  influence) the virological outcome. i.e., ALVAC
  alone was as good (or bad) as ALVAC gp120.

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The ALVAC gp120 Thai trial

• Buge SL et al. 2003. Gp120-alum boosting of a
  Gag-Pol-Env DNA/MVA AIDS vaccine poorer control
  of a pathogenic viral challenge. AIDS Res Hum
  Retroviruses 19, 891-900.
• ..... the plus-gp120 group had less
  consistent control of viremia and higher levels
  of plasma viral RNA for the first year post
  challenge.
• We conclude that gp120 inoculations that fail
  to raise neutralizing antibody do not improve the
  efficacy of Gag-Pol-Env DNA/MVA vaccines.
• An ineffective gp120 vaccine may actually detract
  from the protective potential of the CMI-inducing
  vaccines!

36
Human clinical trials have an important role to
play in vaccine development

• New immunogens need to carefully evaluated in
  humans.
• BUT
• Product availability should not be the main
  driving force behind a trial.
• The design of small trials needs to be aimed as
  much as gathering information as at product
  development, per se.
• There must be a compelling reason to move from
  small trials to larger trials, then to Phase III
  trials.
• Comparability among immunogens of similar
  design is critical.
• A non-controversial way to end trials of poorly
  performing immunogens needs to be devised and
  adhered to.

37
Combine different vaccine technologies

• Rather than try to devise one immunogen to do
  everything (a probably impossible task)
• Make the best possible NAb-inducing antigen
• Make the best possible CTL-inducing vector
• Find the best available adjuvant or delivery
  system
• Find a way to combine these different
  technologies into one vaccine
• MAKE THE OMELETTE FROM MANY SMALL EGGS,
• NOT ONE LARGE ONE!

38
Not every vaccine hypothesis is worth testing
If I argued that the moon were made of green
cheese, would NASA fly me there to check it out?
39
Empiricism vs Understanding?

• All the old-time vaccines were made without
  much knowledge of the immune correlates or how
  the vaccines actually worked.
• This is a perfectly fine approach, IF IT WORKS!
• HIV-1 is so much more formidable an enemy that
  we MUST structure are approaches differently.
• We need to use a knowledge-based approach, and
  we must increase our knowledge, particularly of
  the underlying immunology.

40
Cell Mediated Immunity Based Vaccines in Monkeys
Which Model Mimics Human-HIV?
Virtually all vaccine candidates effective
SHIV 89.6P
Very easy to protect
Monkey Challenge Study
Some viral vectors effective
More rigorous challenge than SHIV 89.6P
SIVE660
SIVmac239
Live-attenuated
Most difficult to protect
Protection is defined as greater than 1 log of
suppression of viral load compared to control
animals slower progression to AIDS
41
T cell vaccine trials based on Adenovirus
vectors

• Merck trial, rAd5, n1,500
• NIH VRC, DNA/rAd5,
• Trials will test the concept of protection
  against HIV challenge by a vaccine eliciting
  robust T cell responses