Novel Brazilian HIV vaccine strategy will be tested in monkeys
FAPESP AGENCY/DICYT Having obtained encouraging results last year in initial trials of a Brazilian HIV vaccine in monkeys, researchers at the University of São Paulo School of Medicine (FMUSP) and Heart Institute (INCOR-USP), as well as the Butantan Institute, will submit the vaccine to a new set of immunization experiments, also in monkeys.
The purpose of the tests will be to evaluate a novel strategy for administering the vaccine. Instead of being directly injected into monkeys, as was done in the previous trials, the antigen will be inserted into the genomes of attenuated smallpox viruses and chimpanzee adenoviruses to boost the immune system’s response. Attenuated viruses cannot cause infection.
No date has yet been determined for the new tests to start, however. First, a laboratory with a high biosafety level must be installed at the Butantan Institute. “A biosafety level 2 lab is required for testing of these viral vectors, especially in the case of chimpanzee adenovirus, which can’t replicate but could recombine with the wild adenovirus present in the monkey population that will participate in the experiments and then reactivate, becoming a replicative virus,” Edecio Cunha Neto, a professor at FMUSP, told Agência FAPESP.
“Hence the need for a high level of biosafety in the lab, including a number of measures to prevent attenuated viruses from escaping,” explained Cunha Neto, a lead investigator for the project, which is being conducted under the aegis of FMUSP’s Institute for Investigation in Immunology, one of the National Science & Technology Institutes (INCTs) supported by FAPESP and by the National Council for Scientific & Technological Development (CNPq).
The new lab, which has been designed by a US-based company, will consist of specially adapted containers in which to house the animals and conduct the experiments. Construction will start as soon as the budget is approved.
“It will take about six months to build and deliver the new facility. Then we can begin the tests,” Cunha Neto said.
Best combination
The main aim of the new tests will be to determine the best combination of the vaccine with the viral vectors, according to Cunha Neto.
To this end, the vaccine will be tested with each of the viral vectors separately and also with all of the vectors together.
After being immunized with the vaccine in combination with one or several viral vectors, the animals will also receive doses of another vaccine that is being developed by Brazilian immunologist Michel Nussenzweig’s group at Rockefeller University in New York. This vaccine uses gp140, a recombinant HIV envelope protein responsible for introducing the virus into cells.
“What we want to know from this test is whether prior immunization with our vaccine is capable of boosting both the cellular response to the vaccine’s components and the production of antibodies against gp140,” Cunha Neto said. “Anti-gp140 antibodies can bind to HIV and hinder its penetration of cells.”
After defining the best way to formulate the vaccine with viral vectors, the Brazilian researchers plan to work with colleagues at France’s Atomic & Alternative Energy Commission (CEA) to develop another vaccine with a similar design, but using antigens to the simian immunodeficiency (SIV), from which HIV is derived.
The researchers want to use this other vaccine to produce an infectious challenge that will enable them to evaluate the efficacies of the two vaccines in containing SIV infections in monkeys.
“The idea is to define the best protocol for administering the vaccine and then see whether this protocol effectively protects the animal,” Cunha Neto said. “If the results are successful, the vaccine will be ready for testing in a phase 1 clinical trial.” This will assess the vaccine’s safety and tolerability in humans, using a small group of patients.
All that is needed before a phase 1 clinical trial can begin is to complete the tests with viral vectors, he added.
The next phase, which will involve collaboration with CEA’s researchers, could be a preparation for a phase 3 clinical trial, for example, which would involve thousands of people and cost some US$100 million.
“A large-scale clinical trial like that can’t be performed unless we have evidence in an animal model that the candidate vaccine can work,” Cunha Neto said.
Differential
Candidate HIV vaccines are currently being tested in humans in some 30 clinical trials in the US and Europe, according to Cunha Neto. Most are phase 1 or phase 2, so they are ahead of the Brazilian vaccine.
One of the latter’s differentials, he said, is that it is the only candidate designed to induce a response by CD4 T-lymphocytes (TCD4), the most important cells in the immune system and the main target of HIV.
“There’s growing evidence that these cells are responsible for activating CD8 T-lymphocytes, which produce toxins that kill cells infected by HIV. In addition, they also activate B-lymphocytes, which produce antibodies,” he explained.
The 18 fragments of HIV DNA that compose the vaccine developed by the Brazilian researchers are easily recognized by TCD4 lymphocytes, which in turn help activate the immune system’s TCD8 lymphocytes.
The Rhesus monkeys that participated in the first experimental trial of the vaccine conducted last year, for example, displayed strong TCD4 responses, according to Cunha Neto.
“The results of the first test of the DNA vaccine in monkeys [in which HIV fragments were injected into the organism] were surprising because this type of vaccine doesn’t usually produce a strong response in primates or humans,” he said.
“We expected the response to be similar to the one we obtained in tests with mice, or even weaker. Surprisingly, the response in monkeys was five to ten times stronger.”