What with the AIDS virus laying waste to much of the African continent, it's a grim irony that the worldwide HIV infection came "out of Africa." Evolutionists suppose that sometime in the 1930s, a scant 70 years ago, the chimpanzee (Pan troglodytes) passed on its HIV infection to humans (Homo sapiens), who dwelled in the sub-Saharan African bush. What simplified this switch was the African people who devoured chimp flesh, which they call to this day "bush meat."
Of all the life forms on earth, the most closely related are humans and chimpanzees, which come within 2 percent of genomic identity. Little wonder that the chimp's native virus felt right at home infecting their human genomic cousins.
When immunologists set about contriving a vaccine against HIV, they ran into an unanticipated practical joke. Their preferred carrier molecule is the adenovirus (AV), which gives children and their elders sniffles and mild sore throats - not to mention minor gastrointestinal upsets. The immunological buzz saw that caught them short is the fact that nearly half of the world's population - 45 percent to be exact - carry neutralizing antibodies in their blood, which recognize adenoviruses. So any vaccine based on AV was scratched before it got going. But the vaccinologists haven't thrown in the towel.
Among the most recent and promising efforts being mounted is one by the Merck Research Laboratories in West Point, Pa. Instead of arming B cell-based antibodies aimed at the AIDS virus, they have weaponized cytotoxic killer T-cell lymphocytes, with HIV targets in their crosshairs. (See BioWorld Today, Jan. 17, 2002.)
Viral immunologist Hildegund Ertl, a professor at the Wistar Institute in Philadelphia, is senior author of a paper in the February issue of the Journal of Immunology. Its title: "A simian replication-defective adenoviral recombinant vaccine to HIV-1 gag."
"Merck's vaccine against HIV showed," Ertl told BioWorld Today, "that adenovirus are extremely efficacious in nonhuman primates - and then they started clinical trials. We used similar AV vectors but gave up on them for most humans who are immune against adenovirus of human strain 5. Many of us get it during childhood, and approximately 45 percent of the adult population carries detectable antibodies against this virus. If you use a vaccine that is based on the same serotype, that vaccine is neutralized, so it doesn't work."
Chimp-Virus Vaccine Guards Efficacy
"Based on that outlook," Ertl continued, "we decided to go and develop a fairly similar vaccine, but derived from a different species, the chimpanzee. That way, human vaccine recipients do not encounter those viruses naturally, and thus did not have neutralizing antibodies that could reduce our vaccine's efficacy. It doesn't matter what species the virus comes from that the immune system will recognize as foreign. We're not trying to make an immune response against adenovirus. We're trying to make an immune response against HIV, in which the adenovirus is just a carrier. It's basically a novel vaccine vector that is similar to the AV of the human serotype 5, which is used extensively, but it has the distinct advantage that there is no pre-existing immunity to it in humans.
"Basically, we're trying to make a vaccine to HIV, considering that right now the AV recombinant based on human serotype 5 looks the most promising. We think ours are even better, so that once we go on into macaque monkey studies early this spring - and from there, hopefully, soon into human trials - that we are the front-runner AIDS vaccine."
To build their vaccine construct, Ertl and her co-authors began by deleting the E1 protein out of a serotype derived from a chimpanzee. "We took out the E1 gene," she explained, "to make sure that virus can't replicate any more, and so can't cause disease. We replaced it with a sequence that encodes an antigen against which we wanted to induce an immune response. That was the gag epitope of HIV-1. Gag is the capsid protein that forms the shell of the virus.
"Before going into a nonhuman primate," Ertl recounted, "we obtained mouse models that mimic HIV, although not very closely. We had to make sure the vaccine works, so we went to mice for immunogenicity studies. We wanted to show that we could induce an immune response, and compare it to other kinds of vaccines that already have been established and tested on nonhuman primates. So that's what we did, and the immune response was very good.
"The upshot was that our new vaccine carrier was definitely better that a recombinant vaccine that has been tested in patients and abandoned because it didn't have the efficacy needed. And it's slightly more efficacious than the AV vector of human serotype 5, which Merck is developing. Our results show that this vaccine is capable of inducing the kind of powerful immune reaction that we and others believe will be critical for controlling HIV infection. Because the vaccine works well in a mouse model, it's hard to say that it will protect humans from HIV.
"Our next step is to go into a nonhuman primate model - macaque monkeys. So we are now in the process of making a vaccine that has a somewhat larger sequence, which is the one we will take into macaques, and also making additional carriers."
Macaque Monkeys In Wings For Key Test
"These macaque trials are going to be conducted at Harvard, not here," Ertl noted. "The immunogenicity studies will give us results in two to three months. Then we have to challenge the animals with HIV-1, and wait to see if they get sick. Altogether, it takes about a year to be sure that the vaccine is working. The moment we get the first monkey trials back," Ertl foresaw, "I would go and contact the FDA. That takes a long time to get things through. We have to conduct safety studies before we can go into human trials. That would be our next step."
Ertl summed up: "Obviously, we are also working on other pathogens. I think we have developed an entirely new vaccine platform that may not be useful just for HIV or rabies, but has applications for other infectious diseases, especially those vaccines that induce T cells They include vaccines for malaria, tuberculosis, poxviruses, Ebola and perhaps smallpox," Ertl concluded.