Once a rabid animal bites a person, the victim's chances ofrecovering add up to zero, unless he or she gets effectiveimmunotherapy in time. Vaccination against rabies has improved alot since Pasteur saved a teen-ager's life in 1885 by giving him shotsof weakened rabies virus.

Today, veterinarians, outdoors people such as forest rangers andresearchers exposed to the virus in vitro, routinely receive injectionsof virus grown in cell culture, then killed and purified. So doindividuals bitten by an animal suspected of being infected.

To boost the specific immunity that rabies vaccination confers, acourse of treatment also includes shots of non-specificimmunoglobulin (Ig). Originally derived from horse serum, thisinflux of foreign antigenic antibodies triggered an immune responsethat recipients often swore was worse than the death it prevented.Now, less-antigenic Ig is available, and recombinant versions are inthe works.

To wreak its fatal effect, the rabies virus must penetrate its victim'sbloodstream, with an animal's tooth or claw serving as thehypodermic needle. By the same logic, to generate a systemicimmune response, the vaccine must enter by the same blood-seekingpathway, via a real hypodermic needle.

Putting The Virus Where the Mouth Is

There must be a better way, say many vaccinologists. Polio vaccine,for instance, is swallowed, not injected. This mucosal port of entryreflects the way that virus itself gets inside a body, by ingestion orinhalation.

The oral vaccine against polio, developed in the 1950s by NobelistAlfred Sabin, consists of a live but attenuated virus, which actuallycauses a mild infection in the vaccinee. It also causes the recipient'smucosal immune system _ not the bloodstream pathway _ to revup lifelong immune defenses against poliomyelitis.

A similar mucosal-route strategy is far advanced toward developingan oral vaccine against cholera. (see BioWorld Today, Sept. 6, 1944,p. 1.) This microbe, Vibrio cholerae, also hits its in vivo target byingestion -- of contaminated food, drink or feces.

Why not, then, an oral vaccine against rabies?

Immunologist D. Craig Hooper heartily agrees: Why not indeed? AtThomas Jefferson University's Center for Neurovirology inPhiladelphia, he and his co-workers are pursuing a major researchproject to create an orally delivered rabies vaccine. So far, it showssigns of working in mice.

So much so that the group is supported by Lederle-Praxis Biologicalsin West Henrietta, N.Y., a division of Lederle Laboratories inWayne, N.J. Last week, Hooper told BioWorld Today, Lederle-Praxis "started experiments to test some of their rabies antigens inmice, with our group's rabies nuclear protein as a vehicle."

Because, unlike polio or cholera, rabies attacks the bloodstream, notthe nasal or intestinal mucosa, an oral rabies vaccine will take a lotmore doing. For starters, the Jefferson group has stripped the rabiesvirus of its outer capsid shell, leaving the viral RNA, largely coveredby its ribonuclear proteins (RNP).

"One of the big questions we're working on," Hooper said; "is howmuch does the RNP contribute to the immunogenic effect? Howmuch does the RNA contribute?"

To help solve this puzzle, they are also looking at recombinant RNP,"which does not appear to have the same sort of activity."

Mice Rise to Oral Vaccine Occasion

Hooper is first author of a paper in the current Proceedings of theNational Academy of Sciences (PNAS), dated Nov. 8. Its title:"Rabies ribonucleocapsid as an oral immunogen and immunologicalenhancer."

They found, as PNAS reported, that administering the RNP orally tomice "primed specific T cells and elicited N-protein-specificantibodies." Priming, Hooper explained, "is what happens in theimmune system of a naive animal when it sees a specific antigen forthe first time. Priming generates T cells whose immune memory has'seen' that antigen before."

Although priming per se, Hooper continued, "may not be protective,the primed T cells are going to be able to help the B cells makeantibody more quickly." He cited a current concept amongimmunologists "that in humans, the T cell memory is believed to bevery long-lived, and may be more important than B cell memory."

Mice primed orally with RNP and subsequently boosted withintraperitoneal injections of inactivated rabies virus, "producedsignificantly enhanced amounts of virus-neutralizing antibody,compared with non-immune controls."

The result suggests, the paper added, that both a mucosal and asystemic immune response arose to the RNP.

"In terms of protection from rabies, Hooper commented, the majorthing is to actually get a systemic response. It's very very rare thatsomething that doesn't replicate, that doesn't invade -- in this case,RNP -- actually stimulates the immune response when you feed itorally."

Over the past decade, thousands of rabies-prone foxes in Europe, andhundreds of racoons in the northeastern U.S. have wolfed downtempting edible morsels encapsulating doses of oral rabies vaccine.Thus immunized, the racoons -- which are increasingly invadingsuburban back yards _ become less likely to spread the infection tohousehold pets and humans.

These wildlife field trials, Hooper said, lace their chicken-head baitwith a recombinant rabies-virus antigen packaged in a vaccinia-virusglycoprotein antigen. He surmises that the construct that lures andimmunizes racoons "is probably delivering T cell help throughdeterminants of the vaccinia glycoprotein as well as rabiesglycoprotein. He added, "We are delivering the T cell helper signalthrough the rabies nucleoproteins in this case, and so boosting thesubsequent response to other antigens." n

-- David N. Leff Science Editor

(c) 1997 American Health Consultants. All rights reserved.