By David N. Leff
Editor's note: Science Scan is a round-up of recently published biotechnology-related research:
Vaccinations against the polio and hepatitis viruses have proven strikingly successful, but the AIDS virus so far resists such immunization strategies.
Now the National Institute of Allergy and Infectious Diseases (NIAID), which manages the National Institutes of Health anti-AIDS efforts, is launching a three-pronged attack against HIV's stubborn stonewalling of a vaccine. Like an artillery offensive, it aims to hit the enemy virus from three sides — a novel projectile, a savvier trajectory and an innovative explosive charge.
In other words, NIAID's AIDS Vaccine Evaluation Group (AVEG) is launching separate clinical trials of three new HIV-targetting vaccines, to test an innovative vaccine strategy, a novel route of immunization, and an unorthodox vaccine booster, or adjuvant
The new strategy enlists the common Salmonella bacterium to smuggle HIV-1 antigenic proteins up close to the immune system's attention. As Salmonella multiplies only inside human cells, it can present the HIV immunogens in a way that better activates the immune defenses.
This hitherto-untried vector vaccine approach uses the live but replication-disabled bacterium to transport the viral gene for HIV-1's antigenic gp120 protein into the body. VaxGen Inc., of South San Francisco, is manufacturing the vaccine for the trial, which is enrolling 47 adults at low risk of HIV-1 infection.
The new route of administratin attacks HIV at the point it enters its victim's body, rather than via conventional intramuscular injection
That point of entry is the moist tissues lining the oral, respiratory, vaginal and rectal tracts. AVEG vaccinologists reasoned that a vaccine that induces antibodies of the mucosal immune system may work better than the injectable ones.
They will compare sequential doses of live recombinant canarypoxvirus vaccine, delivered first by needle, then by swab or drops to the mucosa. This experimental preventive vaccine carries genes encoding three pieces of HIV-1 — surface protein, core protein and an enzyme. When these are expressed inside HIV's target cells, those cells package the proteins into HIV-like pseudovirions. These noninfectious particles fool the immune system into triggering a strong response.
This is the first study in humans to examine a mucosa-directed HIV vaccine. It will enroll 84 volunteers.
Clinical trials of a new adjuvant will aim at getting more immunogenic bang from the basic vaccine buck. To date, the only adjuvants licensed for use in human vaccines are compounds of alum — complex salts of aluminum.
The novel adjuvant, granulocyte-macrophage colony-stimulating factor (GM-CSF), a recombinant cytokine, is being combined with that canarypoxvirus vaccine. As an adjuvant it may elicit stronger antibody and cellular responses than alum. The 36 volunteers enrolled in this study will be followed for 18 months.
Immunex Corp., Seattle, is supplying the GM-CSF, and Pasteur Mérieux Connaught, of Lyon, France, the canarypoxvirus vaccine.
Enzyme Fragment Slows Human Tumor Growth In Hens' Eggs By Blocking Blood Vessel Proliferation
Malignant tumors gorge themselves on blood shipped in to them by angiogenesis. This process, spinning webs of unwanted arterioles, venules and capillaries, causes not only cancer metastasis but blindness and arthritis. Diabetics suffer retinopathy, in which dense networks of blood vessels cloud, and eventually destroy, vision. A similar phenomenon afflicts many elderly persons with macular degeneration of the retina.
Wearing its white hat, angiogenesis gives a newly gestating embryo its whole-body network of blood vessels. In healthy people, it sprouts new vessels to heal wounds, and provides the wherewithal of menstruation. Otherwise, in normal individuals, the angiogenesis process lies low.
How to turn it off, in tumors, retinas and arthritic joints is a challenge taken up by a growing movement of anti-angiogenesis researchers. The latest entry in their race is a paper in the current issue of Cell, dated Feb. 6, 1998, titled: "Disruption of angiogenesis by PEX, a noncatalytic metalloproteinase fragment with integrin binding activity."
The article's senior author is molecular cell biologist David Cheresh, at the Scripps Research Institute, in La Jolla, Calif. "Our findings show," Cheresh commented, "how an enzyme that promotes angiogenesis can be naturally cleaved to produce a fragment that inhibits this process. We determined that this enzyme fragment likely plays a role in normal blood vessel development." (See BioWorld Today, Jan. 4, 1995, p. 1)
The fragment, PEX, apparently serves to turn off blood vessel proliferation.
In in vivo experiments with fertilized hen's eggs instead of mice, the Scripps co-authors seeded eggs with human tumors; these began to attract new blood vessels in a few hours. A day later, the team injected PEX into the eggs. It significantly curbed the tumor growth, and produced a considerable decrease in blood vessel density.
Martin Friedlander, a co-author of the Cell paper, said: "Our observation that a naturally occurring PEX fragment is present in angiogenic tumors as well as vascularizing eyes, suggests that there is a common mechanism for regulating the development of new blood vessels." *