Adenovirus (AV) has two claims to fame or rather notoriety. No. 1: The ubiquitous but non-lethal pathogen is responsible for eye, ear, nose and throat infections in young and old. But no effective vaccine is in sight, outside the U.S. Army. No. 2: AV is the popular poster vector of innumerable gene therapy trials for better or worse.
“There’s a problem with this adenovirus used as a vaccine,” observed virus immunologist Hildegund Ertl at the Wistar Institute in Philadelphia. “Most people get that virus naturally by age 1, and then they get it periodically thereafter. So they’ve acquired a pretty good immune response to AV. And the sense of an immune response is to prevent re-infection. The immune response not only prevents reinfection, it also prevents the good efficacy of the vaccine.”
Ertl also raps AV for its dubious rep as a gene therapy viral vector. “Nevertheless,” she said, “there have been lots of gene therapy trials using adenoviral vectors, so how do they succeed?” Her crisp reply: “They don’t. The reason the human gene therapy trials with adenoviruses don’t succeed is that adenoviruses are so very immunogenic. In gene therapy in a classical sense you aim at replacing a faulty or missing gene. So you need a carrier to get that gene into the body, and you want that gene to stay there. The problem with adenoviruses is you get such a potent immunogenic response against them. For The protein encoded by that gene, all the cells that pick up the gene will also pick up the adenovirus, by definition. They will get destroyed by the immune system. So that’s why adenoviruses for gene replacement therapy are not a very good idea. When early gene therapists started using AV as carriers, it wasn’t realized. By now, 10 years later, we know it was not the right way to go.”
Ertl is co-senior author of a paper in the March 2002 Journal of Virology. Its title: “Novel, chimpanzee serotype 68-based adenoviral vaccine carrier for induction of antibodies to a transgene product.” Her senior partner is pioneer gene therapist James Wilson, who directs the Institute for Gene Therapy at the University of Pennsylvania in Philadelphia. “Jim Wilson made the vectors,” Ertl commented. “I did the immunology.”
Count Chimp Adenovirus Advantages
“The reason we use those AV vaccines is because they have a couple of advantages. For one thing,” Ertl told BioWorld Today, “they are very good at inducing immune responses. So our reasoning was to find a nonhuman adenovirus that had the same advantages as the human serotypes. The one that’s being used doesn’t circulate in the human population so there is no pre-exposure, and humans are not immune to it. That’s why we took a virus from a chimpanzee, tested it and found it works just as fine as the human serotypes. It’s a simian adenovirus that’s naturally infecting chimpanzees. Most chimps have antibodies to it, but humans do not.”
Ertl allowed that “no one has done this before. The xenobiotic approach is actually a very old strategy. Remember, two centuries ago they immunized against smallpox virus using cowpox virus. So it’s not a new idea, but it doesn’t parallel this one, We are using a virus from a subhuman species to circumvent pre-existing immunity.”
The co-authors lined up two parallel AV vaccines one human, one simian directed against the pathogen of rabies. “First of all,” she recounted, “we took out a gene needed for replication of the virus. And that’s done in both constructs, for safety. What we are exploiting is the fact that it works, and we don’t have to be concerned about people already having antibodies to it.
“The chimp vaccine delivers a viral gene an antigen. In our experiment we used a rabies glycoprotein as target. We’ve done similar studies with antigens of human immunodeficiency virus HIV. We incorporate that into the genome of the virus so then the virus infects the cell; that genome is transcribed, translated and the protein is made. That protein then induces the immune response.
“Rabies infects nearly all mammals,” Ertl pointed out, “so it was easy for us to demonstrate whether our vaccine protects or not. So we vaccinated mice and then give them rabies virus, either intramuscularly or directly into the brain. We tried both. The virus was given in a fatal dose, so control mice died and the vaccinated ones survived. We gave the adenovirus vaccine into the muscle or intranasally. The intranasal route proved best because it presumably matched the adenovirus’ mucosal entry point.”
From Monkey Toxin To Weaponized Viruses
“We don’t know what kind of simian virus our chimpanzees harbor,” Ertl said. They may have some terrible Ebola-like viruses, and if we gave the vaccine to people it might cause, even in monkeys, something that’s really bad. So in order to avoid this what we are doing right now and it’s nearly done is making the virus as a molecular clone. Basically, we just take the gene, put it into a bacterial host, grow it up, recombine it in the bacteria with the gene we’re interested in and then grow it up in cells. We think we’ll have it in about a month. Any kind of contaminant we have in the monkeys we can get rid of. And that’s important for us, because we are crossing species, using a subhuman that is very related to us, and already has given us a couple of nasty viruses. For instance, HIV was clearly derived from chimpanzees in Africa.
“Obviously,” Ertl observed, “the beneficial use of this approach against bioterror viruses is something that’s very much on our minds. We clearly need vaccines for Ebola and Marburg viruses, and we need a better smallpox vaccine because what we have right now is pretty reactogenic that is, given to severe side effects. And we have only a limited number of vaccine carriers. This one is very good, so we’re clearly thinking about using it for poxvirus and Ebola-like pathogens.”