anonymous

http://focus.hms.harvard.edu/2005/Jan14_2005/microbiology.html

A new study provides evidence that a herpes vaccine developed by David
Knipe, the Higgins professor of microbiology and molecular genetics at
HMS, is a strong candidate for testing in humans. The research, in the
January Journal of Virology, compared three different experimental
vaccines for herpes simplex virus 2 (HSV-2), which causes most cases of
genital herpes.

David Knipe

David Knipe’s herpes vaccine can stimulate the immune system from inside
host cells, a quality that previous vaccines have lacked. (Photo by Liza
Green, HMS Media Services)

Lead author Stephen Straus, senior investigator in the Medical Virology
Section in the Laboratory of Clinical Infectious Diseases at the
National Institute of Allergy and Infectious Diseases, tested the
vaccines in two established animal models of herpes infection. Knipe’s
vaccine, called dl5-29, outperformed the other two vaccines, one of
which has already been tested in humans. Straus said that the results
argue strongly for taking dl5-29 into human trials. “Based upon dl5-29’s
biological and immunological properties, it appears to be the most
compelling new vaccine candidate for genital herpes,” he said.
Danger to Developing Countries

HSV-2 infects one in five Americans, and its prevalence has reached 50
percent in some developing countries, where it also seems to be helping
to fuel the spread of HIV. HSV-2 infection, though incurable, typically
does not cause major health problems, but can be life-threatening in
immunocompromised people and newborn babies infected by their mothers.

Herpes vaccines so far have been disappointing in clinical trials.
Beginning in the late 1980s, Straus helped design and conduct clinical
studies of vaccines for genital herpes. “It was a very instructive
process,” he said. “It taught us that developing a vaccine for a chronic
and recurrent viral infection such as genital herpes was harder than we
imagined.”

Straus said that dl5-29 seemed especially promising because it works in
a way that previous candidate vaccines have been known to fail. The
dominant approach to herpes vaccine development over the past two
decades has been to deliver one or two glycoproteins found in the outer
envelope of the virus to induce an antibody response. One glycoprotein
vaccine failed to protect people from HSV-2 infection, while a second
version showed a protective effect only in a subset of women who had not
been infected previously with either HSV-2 or HSV-1, the common cause of
cold sores.

In contrast, dl5-29 is a live, mutant strain of HSV-2 that is missing a
set of genes enabling it to replicate and persist inside its host. “The
proteins that are expressed are able to induce immune responses, but the
virus can’t spread,” said Knipe, who was a co-author on the paper.
Normally, HSV-2 infects the cells lining genital areas, but makes its
way into nearby sensory neurons, where it persists in a latent state.
Because dl5-29 actually enters host cells and expresses its proteins
within them, it not only elicits many antibodies, but also stimulates T
cells, which directly attack infected host cells and release cytokines
that further strengthen the immune response. The clinical trials of
previous herpes vaccines suggested that T cells as well as antibodies
must be activated to launch an effective defense.

The story in many ways parallels the early trials of HIV vaccines, which
also failed because they only elicited antibodies. “For herpes or HIV,
you need a good T cell response and T cell immunity. Those are more
difficult vaccines to get,” Knipe said.
Test Design

Straus compared dl5-29 with a glycoprotein vaccine previously tested in
humans and a third vaccine comprising a circular strand of DNA that
encoded the glycoprotein. Such ***** DNA vaccines have generated
interest in recent years for their potential to bring out a stronger
cellular immune response than simply injecting the protein. Straus said
that he tested dl5-29 against “the best tested standard vaccine plus the
competing new concept in the field,” in order to get a better sense of
how well the vaccine performed. His team tested the vaccines in mice and
in guinea pigs. The latter is the best known model of HSV-2 infection
because it is the only one that mimics many of the aspects of the human
disease such as a recurring infection interspersed with periods of
latency. The researchers studied how well the vaccines worked
prophylactically to prevent infection and the****utically to help
control existing infection.

Straus and his team at the NIH found that in all measures dl5-29
performed as well or better than the other two candidates. It was as
effective as the glycoprotein vaccine in preventing acute and recurrent
disease in guinea pigs. When given the****utically to infected guinea
pigs, dl5-29 reduced the rate of recurrent infections slightly better
than the other candidates. The vaccine also induced a stronger T cell
response than either of the other two vaccines.

Dl5-29 even stimulated a stronger antibody response in animals than
either of the other vaccines. Straus and Knipe said this result was
surprising because it was thought that a single glycoprotein alone was
enough to stimulate sufficient antibodies. Knipe said that as a live
virus, dl5-29 produces many more viral proteins, and perhaps the
resulting broader antibody response is important in preventing infection.

Because other vaccines have prevented infection in animals, but failed
in humans, the results do not guarantee success. Yet Straus said that
the stronger T cell response provides a theoretical reason to think
dl5-29 would be better. “The vaccine induced very good levels of
immunity of the antibody type. It induced far better levels of immunity
of the cellular type. It was enormously safe and didn’t seem to persist
in the animals,” he said. “With dl5-29, we believe there are now
sufficient data to justify clinical studies.”

Straus hopes to be involved in those trials and to help Knipe realize a
longstanding dream. Knipe first began developing the vaccine nearly 15
years ago, but has had difficulty finding an industry partner to bring
it to human trials. “It has been frustrating,” he said. Vaccines have
never been seen as lucrative investments for drug companies, and the
disappointments of previous trials also have made companies wary. Knipe
believes that the new results will provide the evidence needed to move
the vaccine forward.

m2slo2cht

Interesting find. Thanks.
As a layman, there are parts of the article that are a bit confusing.
Anyone else wondering the same things? Maybe Tim or someone else with
an advanced understanding of virology can clear things up.
For instance:


Does this mean that the vaccine somehow allows the immune system to
get "inside" host cells? Or that it simply "stimulates" the outside
immune system from the "inside"? And if the latter, why does it matter
"from" where it is stimulated as long as it *is*?.


This part I wondered about too. When the T cells attack the host cell,
do they destroy it?? I hope not. That'd be like cutting off your nose
to spite your face. Now. If the T cells attack the latentcy within the
host but leave the host unharmed, I'd say that *does* sound promising.


This seems to indicate that it can prevent as well as eliminate
infection in guinea pigs so I guess it doesn't destroy host cells
(assuming the "cured" guinea pigs had any feeling left in their
genital area). I still don't understand how/why the others can't do
the same thing. Where's the difference?
Hopefully, human trials won't be just another disappointment.


Maybe this helps answer my "difference" question? ...... I dunno.

M2