Bethesda (12/01/02)- Some 20 years after HIV first appeared, AIDS
has reached pandemic proportions with dire long-term socioeconomic and political
implications for both the developed and developing world. An effective vaccine
remains the elusive but essential goal of biological researchers around the
world. A new generation of vaccines now entering clinical trials could represent
an important new front in the battle against AIDS.
the virus that causes AIDS, poses a particularly difficult challenge to vaccine
developers. For one thing, there are several strains of the virus circulating
in the world, and an effective vaccine would need to immunize the public against
all of the major strains. Second, the virus is constantly mutating as part
of its strategy to elude the immune system, so an effective vaccine would
need to disable the virus in spite of these mutations. Early candidate vaccines
targeted one strain of the virus, and tended to attack or block the virus
on one front only. The new generation of vaccines are designed to block the
virus on several fronts.
Most HIV vaccine candidates that have been developed so far have been designed
to generate antibodies to a protein called gp120 that is found on the surface
of the AIDS virus. While some of the vaccines have elicited immune responses
to some forms of gp120, researchers have a had a hard time developing a vaccine
that can generate antibodies against the many forms of gp120 that occur naturally.
In November of this year, clinical trials began with a new vaccine that targets
the three most globally important HIV subtypes, or clades. The vaccine incorporates
genetic material from the A, B and C clades of HIV, which together are associated
with some 90 percent of all HIV infections worldwide.
"This is the first multigene, multiclade HIV vaccine to enter human trials.
It marks an important milestone in our search for a single vaccine that targets
US subtypes of HIV as well as clades causing the global epidemic," said Anthony
S. Fauci, M.D, Director of the National Institute of Allergic and Infectious
The novel vaccine incorporates modified elements of four HIV genes known
as gag, pol, nef and env. Previous clinical trials have shown
that this type of DNA vaccine is very safe and cannot induce HIV infection.
Each of the HIV genes play an important role in infection. For example, the
env gene codes for a protein on the outer coat of the virus that allows
it to recognize and attach to human cells. The current candidate vaccine includes
env components from several HIV subtypes.
The researchers say that the current trial represents an important step in
an ongoing process of HIV vaccine development. If an when the multicalde vaccine
is shown to be safe and to elicit an effective immune response, the researchers
would then add additional HIV protein components in an attempt to increase
the immune response even further.
"Ultimately, we aim to build a potent vaccine designed to prevent HIV
infection. Any HIV vaccine must hit a constantly moving target. Essentially,
we are trying to enlarge that target through a multiclade vaccine," notes
Gary Nabel, M.D., Ph.D., director of the Dale and Betty Bumpers Vaccine Research
Center where the vaccine was developed.
The initial stage of the trial is being conducted at the National Institutes
of Health in Bethesda, MD. The Phase I trial will enroll 50 volunteers who
are not infected with HIV and is designed solely to confirm the safety of
the vaccine. Volunteers between the ages of 18 and 40 years old will be vaccinated
with either the test vaccine or an inactive placebo solution in a series of
increasing doses. The trial is a double-blind design, meaning neither the
volunteers nor the doctors will know which group receives the active compound.
The researchers will check the volunteers regularly for one year to look for
immune responses and adverse effects. Once the safety of the vaccine has been
established, the trial will be expanded to include volunteers in the US, Haiti
and South Africa
"We want the community to understand and support the process of vaccine development
so that together we can attain the goal of stopping or slowing the AIDS pandemic.
Although thousands have already volunteered to take part in HIV vaccine trials,
many more are needed. The importance of community participation cannot be
overemphasized," notes Barney Graham, M.D., Ph.D., lead investigator in the
multiclade vaccine trial.
Clinical trials are ongoing around the world with both therapeutic and prophylactic
HIV vaccine candidates. Prophylactic vaccines are the more familiar kind that
are designed to prevent infection with a virus, e.g. the small pox, influenza
and varicella vaccines. Therapeutic vaccines are those which might prove useful
in bolstering the immune response of those already infected with HIV. There
have been more than 50 HIV vaccine clinical trials since 1988, involving more
than 26 different vaccine candidates. More than two dozen clinical trials
are now underway, although only one has reached the final Phase III stage.
There is a growing consensus among researchers that an effective vaccine
against HIV infection will be developed within the next ten years. Public
health authorities will then face a new set of logistic and political challenges
as they determine how to get the vaccine to where it is needed most in a long-term
global effort both in the the developed world and in areas of the developing
world already decimated by the effects of the pandemic.