precedence

precedence

1. the condition of preceding others in importance, order or rank

2. an acknowledged or legally determined right to such precedence

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?

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.

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

The HIV vaccine candidate pipeline is trickling rather than gushing with quality immunogens at this time.

Why?

•We don’t 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.

Why is the vaccine candidate pipeline trickling with quality immunogens

rather than gushing?

•We don’t 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.

We don’t 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.

We don’t 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.

Pantaleo and Koup (2004) Nature Med 10, 806.

We don’t 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.

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

Viral envelope

gp41

CD4bs

gp120

All neutralizing antibodies are directed to Env spikes on the virion surface

The Env spike has evolved to avoid broadly neutralizing antibodies

Functional oligomeric Functional oligomeric gp120/gp41 (virion surface)gp120/gp41 (virion surface)

(low accessibility of conserved regions of Env)

Broadly neutralizing antibody epitopes on the HIV-1 Env spike; chinks in the armor

VirusMembrane

4E10

2F5

CD4i Fabs V3 loop Absb12

2G12

none 1-30% 31-60% 61-90% >90%

CROSS-CLADE NEUTRALIZATION OF HIV-1

IC50 50 g/ml

Binley et al, J Virol, 78, 13232-13252, 2004.

Basic research to exploit these chinks and design immunogens to

elicit broadly neutralizing antibodies should not receive a lowered priority

We don’t 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.

CD4bsCD4bs(neutralizing face)(neutralizing face)

The Env spike has evolved to avoid broadly neutralizing antibodies

Monomeric Monomeric gp120gp120

Functional oligomeric Functional oligomeric gp120/gp41 (virion surface)gp120/gp41 (virion surface)

non-neutralizingnon-neutralizingfaceface

host cell-derived host cell-derived carbohydratescarbohydrates(‘silent face’)(‘silent face’)

(low accessibility of conserved regions of Env)

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).

Why is the vaccine candidate pipeline trickling with quality immunogens

rather than gushing?

•We don’t 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.

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 don’t know why.

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 don’t know why.

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.

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 don’t know why.

Vaccine Protection Against Pathogenic SIV in Indian Rhesus

MacaquesVaccine Strategy Monkeys Protected (>3log

suppression of viral load)

Live attenuated 74/78 (95%)

All other strategies 18/256 (7%)

Koff et al, Nature Immunology, submitted.

Basic research to understand protection against SIV by live

attenuated vaccines should not receive a lowered priority

So what’s all the fuss about?

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

A difference of opinion exists over the merits of this trial

The ALVAC + gp120 Thai trial

Science 303, 961 (13 February 2004)Science 303, 316 (16 January 2004)

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

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

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 $100m’s.

Much basic research needs to be done to find better candidates.

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) < 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?

The ALVAC + gp120 Thai trial

Pal R, et al. 2002. ALVAC-SIV-gag-pol-env-based vaccination and macaque major histocompatibility complex class I (A*01) 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.

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!

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.

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!

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?

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.

Cell Mediated Immunity Based Vaccines in Monkeys:

Which Model Mimics Human-HIV?

Monkey

Challenge

Study

SHIV 89.6P

SIVE660

SIVmac239

Very easy to protect*

More rigorous challenge than

SHIV 89.6P

Most difficult to protect

Virtually all vaccine candidates

effective

Some viral vectors effective

Live-attenuated

*Protection is defined as greater than 1 log of suppression of viral load compared to control animals; slower progression to AIDS

“T cell vaccine” trials based on Adenovirus vectors

•Merck trial, rAd5, n=1,500

•NIH VRC, DNA/rAd5,

•Trials will test the concept of protection against HIV challenge by a vaccine eliciting “robust” T cell responses