By David N. Leff

The number of school-age youngsters slain each year in the U.S. by guns, knives, even baseball bats, is a chilling statistic. But there are other killers that take the lives of babies in their first week or two of life. These neonatal deaths are perpetrated by sexually transmitted infections, which pass from infected mother to naove infant during the minutes or hours of parturition - the process of birth.

The World Health Organization estimates that during 1995, a typical year, 5 million neonates worldwide died during their first week of life from perinatal infections.

"These infants were born 100 percent susceptible to certain diseases," observed molecular virologist Lorne Babiuk at the University of Saskatchewan in Saskatoon, Canada. "If you vaccinate them the minute they're born, it takes two to three weeks before the vaccine takes hold.

"What's more," he continued, "in children especially, there are some diseases of which the child is really at life-threatening risk during birth, during labor. For example, herpes simplex virus. If the mother is infected with genital herpes, we have to deliver the unborn child by Caesarean section because if it is exposed to virus in the birth canal, it has a 90 percent chance of being infected, and an 80 percent chance of dying within a few weeks.

"With hepatitis B virus," Babiuk went on, "women can be chronic carriers. The way we protect that child now is by treating it with gamma globulin right away. Other sexually transmitted pathogens - chlamydia, group B streptococcus - are infections that occur almost instantaneously at birth or during parturition. Obviously, you can't vaccinate against those life-threatening risks.

"So at present," Babiuk summed up, "you can't treat a lot of these kids in time. If you want them born immune, immunization in utero offers a much better chance of them either suffering much milder disease or no disease at all. So that's the rationale for our experimental pre-birth vaccination, aimed at closing that window of susceptibility."

Babiuk, who directs the University's Veterinary Infectious Disease Organization, is second author of a paper in the August issue of Nature Medicine titled: "Fetal immunization by a DNA vaccine delivered into the oral cavity." Those prenatal mouths were not in mice, or in human fetuses, but in the unborn lambs of pregnant ewes.

Gene In Plasmid Targeted Herpesvirus Antigen

"We started out by making the vaccine," Babiuk told BioWorld Today. "It's a novel DNA plasmid - a gene of double-stranded, naked DNA. It's not encapsulated in liposomes or anything like that - just naked DNA." That gene expressed a bovine herpesvirus 1 glycoprotein D, with its transmembrane sequence removed."

The team had bred eight ewes, and confirmed their pregnancy. "So then," Babiuk recounted, "we could administer our vaccine into their amniotic fluid. Under general anesthetic, we opened up each animal, to make sure that we could expose the fetus in its amniotic fluid. We could feel where the proximity of its mouth was, and injected the DNA by needle into the fetal oral cavity." Four of the pregnant ewes got the vaccine - a half-milligram dose -- and four a control injection of saline.

"We wanted to guarantee that we knew exactly where we put the DNA vaccine," he said. "So we opened the ewes by half Caesarean, half amniocentesis - an experimental process -- then, after vaccination, sewed them back up again. It's comparable to amniocentesis."

The Saskatchewan team carried out the prenatal vaccination 21 days before the expected date of parturition. (A ewe's gestation runs 148 days.)

"The reason we chose 21 days," Babiuk pointed out, "is because it takes two to three weeks for an immune response to come up. So it gave us that much time to have the animals develop an immune response.

"When the lambs were born," he continued, "we tested their immune responses, both humoral [antibody-producing] and cellular [antigen-killing]. To our fantastic surprise, it was marvelous. We have now repeated the entire experiment with an even dozen ewes - twice as many animals as reported in the Nature Medicine paper - and every single one of the six vaccine recipients in these subsequent experiments had better immune responses than the four previously reported vaccinees."

The co-authors have since extended that current trial, boosting the neonatal lambs immediately after they were born. Result? "They got a fantastic anamnestic response - their immune systems' ability to 'remember' the viral glycoprotein antigen against which the DNA vaccine had raised B and T cells. And right now," he said, "we are in the process of challenging these newborn animals with virulent herpesvirus to prove that they are protected against infection."

Next on the team's drawing board is to concoct a vaccine cocktail combining three sexually transmitted pathogens - human herpesvirus, human hepatitis B virus and human chlamydia bacteria. As Babiuk observed, "If there was a vaccine for HIV, we would try HIV - but there isn't one yet." He added, "Our model is going to be sheep until we get adequate data, safety and efficacy results, before we go into human patients. We're the first people in the world to show that a DNA vaccine could work in an animal other than a mouse."

Only Sex-Spread Infections Need Apply

Babiuk doesn't see any practical potential for animal husbandry, being too expensive. "It would really be more a human-neonatal issue," he suggested. "And it wouldn't be for every disease. For example, you wouldn't use our naked-DNA vaccine for polio, or measles. These are diseases you can vaccinate against, and they occur well after birth. Rather, it's intended for those particular infections for which the newborn infant is at risk.

"Amniocentesis is not 100 percent risk-free, either," he pointed out. "Nothing is risk-free, so you're not going to go jamming pregnant women with every vaccine in the world. You would do so selectively where there is a risk." (The accepted risk factor of fetal loss in human amniocentesis is 0.5 percent above the normal risk of parturition.)

Once ready for clinical trials, Babiuk expects to apply for investigational new drug permission to both the FDA in Rockville, Md., and Health-Canada in Ottawa. "We would probably approach them simultaneously," he said. "We're a research institute so we would have to partner with a commercial company, which would be the one to get the license and invest the dollars that are required. So far we've had no contact."

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