TRATTO DALLA CONFERENZA : AIDS/ARC di SINTEL/SINTAGMA

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THIS IS A CONTINUATION

Subject: BETA (text)

Date: February 1991 (1790 lines)

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Bulletin of Experimental Treatments

for AIDS

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B-E-T-A (Bulletin of Experimental Treatments for AIDS)

A publication of the San Francisco AIDS Foundation

February, 1991

Contents: [items are separated by "*****" for this display]

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Vaccines for HIV

Bill Hayes

1990 marked a fundamental change in opinion among researchers

from "if" an HIV vaccine could be developed to "when." With 7

possible vaccines now in human testing, skepticism about

producing vaccines for both the uninfected and those infected

with HIV has given way to cautious optimism. Many obstacles

remain, yet there are encouraging signs: none of the clinical

trials of HIV vaccines under way have yet reported toxic side

effects; there are indications in animal studies and in

preliminary data from human testing that several vaccines may

boost antibodies and, more significantly, may enhance T cells.

Some scientists estimate that a meaningful vaccine breakthrough

could occur within the next two years.

Vaccines: Immunization

or Immunogen

Vaccines work by mimicking a disease-causing organism, thus

stimulating the body's immune system against it. This immune

response could be a humoral response-production of antibodies to

control or neutralize the organism-or a cellular response, which

would mobilize white blood cells such as macrophages and natural

killer T-cells to attack it.

The term vaccine is broadly used to describe three different

approaches being used against HIV: immunization of those

uninfected; protection of perinatal transmission from infected

mother to fetus; and prevention of disease progression in people

a1ready infected with the virus. The premise of the latter, a

"therapeutic" or "immunogen" vaccine, is not to eliminate the

virus from the body entirely, but to render it dormant

permanently, effectively making the latency period of the virus a

lifelong state.

At present, there is more success, and activity, with

therapeutic vaccines than those to prevent primary infection, for

several reasons. The first is rather practical: a vaccine to

prevent primary infection will take much longer to test due to

the difficulties in establishing efficacy and the long latency

period of HIV. I other words, a vaccine's success or failure is

more immediately evident in those already infected.

Further, some feel the virus is s complex that a single

vaccine to immunize against HIV infection may be impossible-a

"cocktail" of treatments for the various strains of the virus may

be necessary. By first learning how to stop the activity of

these various strains in infected subjects, researchers will then

know how to immunize the uninfected population against them.

Most studies have found diminished benefits from therapeutic

vaccines in people who already have ARC or AIDS. But it is hoped

that therapeutic vaccines in combination with antivirals like

AZT, ddI, ddC or alpha interferon might help people at all stages

of disease progression.

Animal Research

FDA regulations stipulate that animal research must precede

testing of potential HIV vaccines in humans. Only chimpanzees

can be infected with HIV, yet they never develop full-blown AIDS,

making leaps from chimp data to humans problematic. Further,

because chimps are an endangered species, few are available, and

they are expensive. Rhesus monkeys, on the other hand, are

plentiful, relatively inexpensive, and easier to handle. Though

they do not react to HIV, they can be infected with simian

immunodeficiency virus (SIV), a retrovirus similar to HIV that,

to a degree, can be used as a model for human HIV infection.

A more recent development in animal models is the creation

through genetic engineering of an immunodeficient mouse, called

the SCID-hu (Severe Combined Immune Deficient) mouse, that will

not reject human white blood cells, and can therefore be infected

with HIV. The development of these altered mice, which are

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neither as scarce nor as expensive as chimpanzees, has vastly

improved the pace of vaccine research.

Different Vaccine

Approaches

Thirty possible approaches for developing a safe and effective

vaccine against HIV are now under scrutiny. Some use a whole HIV

virus, which is "killed" by chemicals or radiation (the technique

used to create the polio vaccine). Others use a "recombinant"

approach, which isolates a portion or "subunit" of HIV from the

outer surface (the envelope) or the core of the virus by genetic

engineering. A related approach uses "virus-like particles" that

are created synthetically in the laboratory.

Certain recombinant vaccines incorporate an adjuvant, a

compound that improves the body's response to the vaccine.

Adjuvants are needed because proteins of HIV, which constitute

the majority of experimental vaccines developed so far, may not

elicit an immune response that is strong enough to confer

protection

Along with advances, scientists are encountering drawbacks in

their vaccine approaches. There is some concern that vaccines

using a whole virus could infect the uninfected, should a single

virus slip through the purification process. In those whose

immune systems are already compromised, boosting immunity might

boost HIV replication rather than suppress it. Finally, because

HIV mutates so rapidly, a vaccine must target a wide range of HIV

strains.

The 7 possible vaccines described below are listed

alphabetically by the company that holds the patent.

Bristol-Myers Squibb

Bristol-Myers Squibb of New York City is developing a

recombinant vaccine made by inserting fragments of gp160, a

protein on the envelope of the virus, into live but weakened

smallpox virus, which itself may provide an additional boost to

the immune system. (A similar vaccine has been developed by Dr.

Daniel Zagury -- see "Vaccine Research Abroad" below.) The

vaccine is being evaluated in uninfected people in Phase I safety

trials conducted by the National Institute of Allergy and

Infectious Diseases (NIAID). The company also has conducted a

toxicity study of its vaccine in combination with a booster shot

of the MicroGeneSys formula, and reports no side effects.

Chiron Corporation

Chiron Corporation of Emeryville, California, has begun Phase

I safety trials involving uninfected people of a recombinant

vaccine that also uses the gp160 protein. It is described as a

"pi 20" vaccine because the "g" or sugar molecule has been

removed. In addition, Chiron uses what it describes as a highly

potent synthetic adjuvant called MTP.

An earlier version of this vaccine was used in a small Swiss

study on uninfected men, with no side effects observed. Four men

involved in the study showed an immune response against the

virus. Chiron hopes to begin Phase I safety trials of a new

formulation for HIV negative subjects sometime this year.

Genentech, Inc.

Genentech's recombinant vaccine is based on an exact synthetic

copy of a portion of the HIV virus' envelope called gp120.

Researchers theorize that the immune system will spot the

injected bit of copied virus and battle the infection anew,

ultimately arresting disease progression in people who are

infected with HIV. Shots for rabies work in a similar fashion.

The South San Francisco company announced in November 1990

that it had begun Phase I safety studies of the vaccine at Walter

Reed Army Institute of Research in Washington, D. C. The 10-month

study involves 55 HIV positive military volunteers, both men and

women.

Genentech is enthusiastic about the potential vaccine because

it produced a powerful immune response in chimpanzees. The two

vaccinated animals reportedly remain uninfected more than a year

after exposure to the virus. The company is currently evaluating

the possibility of a separate human pilot study to test

recombinant gp120 as a potential vaccine to immunize uninfected

individuals.

Immune Response

Corporation

Perhaps the most highly publicized vaccine research has been

conducted by Immune Response Corporation of San Diego, which is

headed by Jonas Salk, who developed the first widely used polio

vaccine. Alone among potential vaccines, the "Salk Immunogen"

consists of killed HIV -- a whole virus with its genes scrambled

and the envelope protein gp120 removed. Salk hopes this killed

virus will act as a harmless decoy, tricking the body into

mounting a more aggressive response to HIV.

While Salk's critics contend that a killed-virus vaccine is

too blunt an instrument against so sophisticated an invader, Salk

adheres to his belief that a vaccine will have a greater chance

if it contains a wide spectrum of viral proteins, not just a

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single fragment.

Research has been underway in HIV positive human volunteers

since November 1987. Early safety trials indicated that the

vaccine may have bolstered the volunteers' immune systems, but

results were not conclusive. Its efficacy will be clearer after

a current trial involving 100 people in early stages of HIV

infection is completed late this year. This trial will be

followed by a 3-year study involving 650 people who are infected

with HIV. Salk is hoping eventually to try the vaccine on

uninfected people.

IMMUN0-Ag

IMMUNO-Ag, a potential vaccine developed by scientists from

NIAID, the National Cancer Institute and IMMUNO-Ag of Vienna,

Austria, consists of gp160, a genetically engineered combination

of a protein carbohydrate termed a glycoprotein. Its composition

and structure precisely mimic the 3-dimensional shape of one of

the glycoproteins that forms part of the HIV envelope. Research

with other diseases in developing vaccines based on viral protein

has shown that matching the exact molecular shape of the protein

seems to be important. Recognizing the unique shape of the

harmless protein, it is theorized, the body will produce a strong

immune response against HIV.

Phase I safety trials involving 60 uninfected volunteers over

approximately 5 years, was announced by the NIAID in November

1990.

In earlier tests using IMMUNO-Ag, 2 versions of the potential

vaccine have been injected into 4 chimpanzees and "challenged"

with doses of pure HIV virus 100 times more than the amount

needed to cause infection. The vaccine prompted an immune

response in all the animals, and one of the chimpanzees has now

been free of HIV infection for nearly 3 years, according to the

company.

MicroGeneSys, Inc.

MicroGeneSys, of West Haven, Connecticut, is developing a

vaccine for both the uninfected and those who already have HIV.

The recombinant vaccine, produced by genetic engineering,

contains HIV envelope protein, gp160. The company says that its

formula seems to attack a wide range of strains, combats both

free virus and infected cells, and doesn't damage healthy cells

that have picked up harmless stray viral proteins. Like all

vaccines composed of viral particles, this one can't cause

infection.

In the first completed clinical trial of a potential HIV

vaccine, the MicroGeneSys formula was found to be safe after 2

years of study in 72 uninfected volunteers. No unusual reactions

were found, according to a January 1991 report in the Annals of

Internal Medicine. Researchers said that in general, the immune

response among trial volunteers were considerably weaker than

those seen after naturally occurring infection with HIV.

MicroGeneSys has begun a new round of tests, injecting higher

doses of the vaccine in 72 people. Hopes are that this dosage

will stimulate a stronger immune response.

MicroGeneSys is now finalizing plans for an efficacy trial.

Further studies are being planned to test the vaccine on HIV

positive pregnant women and on patients taking AZT. The FDA

recently granted approval for Phase I safety testing of a second

MicroGeneSys vaccine based on the core protein p24. If it

passes, the company hopes to run a study combining the 2

vaccines.

Viral Technologies, Inc. (CEL-SCI Corporation and Alpha-I

Biomedicals, Inc.)

San Francisco General Hospital announced in December 1990 that

would begin Phase I safety testing of a vaccine developed by

Viral Technologies, Inc., a joint venture of Cel-Sci Corporation

of Alexandria, Virginia, and Alpha-I Biomedicals, Inc.,

Washington, D. C.

The vaccine, which is intended to protect uninfected people,

is made from a synthetic form of the pI 7 protein found in the

core of the HIV virus. This protein is common to all strains of

the virus and would not be vulnerable to the usual genetic

mutation that affects the usefulness of other vaccines.

The company is encouraged about the vaccine's prospects. In

earlier human studies, the vaccine stimulate production of CD8+

cells, which re able to attack HIV-infected cells a~~~~0~g~0~~

the body, not just in the immune system. This is significant,

because infected cells are factories for the production of new

viruses. In order to stabilize the disease, infected cells need

to be destroyed before the virus overcomes the immune system.

Furthermore, the presence of CD8+ killer T-cells has been found

to be associated with a greater longevity of HIV-infected people.

Vaccine Research Abroad

There are encouraging prospects among reports of HIV vaccine

development outside the United States: British researchers have

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