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Researchers are exploring a variety of novel ways to create a vaccine that will prevent HIV-1 infection and offer some therapeutic help to the millions who already are infected. "Now I think we’re at the most optimistic point we’ve ever been in," says Margaret I. Johnston, PhD, assistant director for AIDS Vaccines at the National Institutes of Allergy and Infectious Diseases (NIAID) in Bethesda, MD.
"That’s not to say we have the answer in hand, but it’s to say that for the first time we have an extremely healthy pipeline of product and more and more encouraging results from animal studies, along with enthusiasm for moving ahead to clinical trials," Johnston explains.
The vaccine pipeline has grown from a trickle to more than two dozen candidates, notes Ashley Haase, MD, regents’ professor and head of the Department of Microbiology at the University of Minnesota in Minneapolis. "From a pragmatic standpoint, pharmaceutical people have seen increasing hope and promise that something is going to work at least partially," Haase adds.
Researchers are exploring a variety of ways to enhance immune response through vaccines, and the studies are showing promise, says Larry O. Arthur, PhD, director of the AIDS Vaccine Program at the Scientific Applications International Corp. (SAIC), which does work for the National Cancer Institute - Frederick Cancer Research and Development Center of Frederick, MD. "Two years ago, I would have felt there was little or no chance of developing an AIDS vaccine," Arthur says. "Now I think we’re developing additional information about ways to get around CD4 cell help."
Some of the biggest obstacles to bringing an effective AIDS vaccine to market are the social and financial barriers, which hamper most efforts to develop a new vaccine, researchers say. "An AIDS vaccine has an incredible social value for me and you and for the taxes and health insurance we pay, but no one puts that into perspective, because if they did we’d be showered with money from all directions," says Donald P. Francis, MD, DSc, president and co-founder of VaxGen Inc. of Brisbane, CA. VaxGen has developed the only HIV vaccine that currently has made it to Phase III clinical trials. (See "AIDSVAX is safe, but efficacy question remains," in this issue.)
Even when the first vaccine is licensed, it may be decades before it’s used and available to everyone who is at risk for HIV infection, says David Gold, JD, vice president of policy and public sector support at the International AIDS Vaccine Initiative (IAVI) in New York City. "Experience with the hepatitis B vaccine shows us that there is still an average 20-year delay before vaccines licensed in industrialized countries are first introduced in developing countries," says Gold. He spoke about the need for a quick and decisive global response to developing an AIDS vaccine at the AIDS Vaccine 2001 Conference, held Sept. 5-8, 2001, in Philadelphia. IAVI recently announced plans to work with the Uganda Virus Research Institute to develop and test three AIDS vaccines based on HIV subtype A, which is the most common HIV strain in East Africa.
Another example is the smallpox vaccine, which finally did the trick of eliminating smallpox 140 years after its discovery, Francis notes. "Unless there’s something very shocking with HIV, we should be able to eliminate it," Francis says. "Unless I’m wrong, the issue is not going to be science; it’s going to be social commitment to make it and ultimately deliver it."
Gold says the international effort to develop and implement an AIDS vaccine requires these kinds of support:
Although the Bethesda, MD-based National Institutes of Health (NIH) has greatly increased vaccine research funding in recent years, with a projected budget of more than $350 million for fiscal year 2002, there has been very little government support for AIDSVAX, the front-running vaccine candidate, Francis says. "We have a great collaboration, but it’s not like everyone is anxious to put money into an AIDS vaccine," Francis says. "I don’t see it."
Part of the problem is that there are so many different approaches to creating an AIDS vaccine that it’s difficult for the NIH to choose which research to support, says Barney S. Graham, MD, PhD, chief of the Clinical Trials Core and Viral Pathogenesis Laboratory in The Vaccine Research Center of NIAID. "I think there’s a huge commitment, in particular from NIAID and NIH, to see a successful vaccine development process occur, so I don’t know so much that the level of funding is restricting what needs to be done," Graham says. "I think the agonizing part is choosing what’s the best thing to do rather than there being insufficient funds right now to get done what needs to be done."
One of the most important issues in AIDS vaccine development is safety, because licensed vaccines either contain whole killed versions of the disease-causing agent or have attenuated virus, Johnston says. "For HIV, we don’t want to make a vaccine that comes from HIV or causes AIDS because it’s uniformly deadly," Johnston says. That means AIDS vaccine research has explored ways to stimulate human immune responses against HIV without directly infecting cells with whole HIV, dead or alive.
All of the vaccines currently being evaluated are safe, so that is the good news about where the world is in developing an AIDS vaccine, Graham says. "The problem is not safety, but it’s immunogenicity and consensus-building about what type of immunogenicity it has and how much of it is needed to have any confidence that your vaccine might work," Graham adds. Some of the most convincing data in recent years suggest that a vaccine that elicits a strong cytotoxic T-lymphocyte (CTL) response in HIV-negative recipients may provide a good chance of preventing infection and, in some cases, controlling infection, Graham says. This strategy is being enthusiastically explored by investigators who are working with DNA-type vaccines, such as those based on recombinant DNA type and those that use vectors to deliver vaccine antigen, he adds.
For example, some of the new research presented at the recent vaccine conference involved using canarypox, which is lethal to birds, as a nonreplicating vector for delivering an AIDS vaccine. Investigators are focusing on using canarypox as a nonreplicating vector because it is safe, causes no disease in humans, and can accommodate large amounts of foreign DNA. "The canarypox is engineered to deliver HIV proteins into the cell, and that’s all it does," Johnston explains. "The human cell doesn’t have the necessary components to make a fully infectious canarypox particle."
One abstract presented data about use of a live genetically engineered recombinant canarypox vector, which expresses HIV subtype E env and B Gag/Pro. Made by Aventis Pasteur of Lyon, France, the canarypox vector (ALVAC-vCP1521) induces CTL activity against HIV Env and Gag vaccine antigens. The CTL activity occurs as early as after the second injection, prior to a protein boost, and researchers concluded that vCP1521 might be a potential phase III vaccine candidate.1 Another study of the use of canarypox as a vector found that ALVAC HIV-1 vectors produce anti-env and anti-gag CTL activity after multiple dose administration to normal participants.2
Graham says some other interesting research presented at the vaccine conference includes a study of immunization using an SIV replication-incompetent adenovirus vector that elicited a potent T-cell response in a trial involving rhesus macaques.3
Investigators at Merck Research Laboratories of West Point, PA, were involved with several other studies of immunization using DNA, DNA-adjuvant, and replication-defective adenovirus vectors. The Merck investigators concluded that the adenoviral vaccine provided the greatest degree of protection against the pathogenic SHIV89.6P virus, suggesting a direction for new vaccine candidates in human clinical trials.4
"The diversity of HIV is one of our greatest challenges," Johnston says. "The strategy is to design a vaccine that enables the immune response to recognize the parts of the virus that are the same."
SAIC vaccine research is focusing on developing an inactivated virus vaccine by manipulating the virus until it no longer is infectious, Arthur says. "It became clear to us that all targets for activation were internal to the virus, so we had the opportunity to inactivate the virus yet preserve the structural integrity and functional activity of the surface proteins," Arthur says. Using purified, inactivated virus, SAIC investigators are studying the effect of immunization on primates, Arthur adds. "We’ve immunized primates and challenged them with SIV, and in the first experiment we showed protection from the challenge," Arthur says. "Then we moved to the second experiment with a more rigorous challenge, and that’s ongoing."
The inactivated virus also has potential as a therapeutic vaccine, so SAIC researchers are looking at the monkey model to learn whether they can decrease the amount of SIV in the animals by treating with antiviral drugs and with the inactivated virus vaccine, Arthur says.
Another obstacle to developing an AIDS vaccine that will work in a majority of humans is related to how the virus can take advantage of its host’s pre-existing health problems. It’s taken five years for researchers to prove experimentally that HIV must make use of the cells it finds in order to continue infection, Haase explains. "In the first week of infection, in the resting T-cells, HIV replicates poorly in those cells, but keeps the embers glowing until it gets into the activated T-cells," Haase says. Haase spoke at the AIDS Vaccine 2001 Conference about how lessons from acute infection are relevant to vaccine development.
It’s been shown in primate studies that primates with pre-existing inflammatory conditions are rapidly infected when challenged with the virus, Haase says. "It’s my belief that in areas of the world like Thailand, where you have a high rate of heterosexual infection and underlying inflammatory condition, there won’t be any vaccine that will work," Haase says. "We need to deal with a virus that can very quickly establish infection when there’s a pre-existing inflammatory condition."
1. de Souza M, Karnasuta C, Cox J, et al. Cytotoxic T-lymphocyte responses in volunteers enrolled in a phase I/II HIV-1 prime-boost trial in Thailand. Abstract 322. Presented at the AIDS Vaccine 2001 Conference. Philadelphia: Sept. 5-8, 2001.
2. Dolin R, El Habib R, NIAID HIV Vaccine Trials Network. Immunogenicity of canarypox (ALVAC)-HIV-1 candidate vaccines in normal volunteers. Abstract 48. Presented at the AIDS Vaccine 2001 Conference. Philadelphia: Sept. 5-8, 2001.
3. Fu T-M, Trigona W, Davies M-E, et al. Replication-incompetent recombinant adenovirus vector expressing SIV gag elicits robust and effective cellular immune responses in rhesus macaques. Abstract 37. Presented at the AIDS Vaccine 2001 Conference. Philadelphia: Sept. 5-8, 2001.
4. Shiver J. Merck’s HIV vaccine program: Research approaches and critical issues. LB5. Presented at the AIDS Vaccine 2001 Conference. Philadelphia: Sept. 5-8, 2001.