How do vaccines work?

There are three ways to make a vaccine, but most strategies for an HIV/AIDS vaccine follow the third approach:

• A killed virus vaccine: The most well known of this type is Jonas Salk's polio vaccine. A pathogen (or disease-causing organism, such as a virus or bacteria) is killed using chemicals, light or heat, and then mixed with an adjuvant, which boosts the immune system. The vaccine is then injected into the body to induce an immune response. This approach has been unsuccessful in AIDS vaccine development.
• A live attenuated vaccine: The measles vaccine is an example of this type of vaccine, which is developed by weakening a live pathogen in order to reduce its ability to cause disease, but just enough to still allow it to raise immune responses inside the vaccine recipient. This approach has been sidelined in terms of developing an AIDS vaccine because it is too dangerous. As Dr. Emilio Emini, head of vaccine development at Wyeth, explains, "In the case of … live attenuated HIV, that virus never goes away because it becomes an integral part of the genetic information of the cells in that individual. Eventually it will cause disease."
• A genetically engineered vaccine: With this approach, scientists manipulate a pathogen's genetic material. They may insert it into a vehicle, such as a different nonlethal virus, to trigger the immune system -- an approach known as a viral vector or live vector vaccine. Or they could create a vaccine by injecting only certain elements of the virus, such as a portion of its DNA, or peptides, which are small, synthesized bits of protein. In this strategy, the immune system would recognize and respond to these viral components. Most current HIV/AIDS vaccine strategies are genetically engineered vaccines.

Why is it so hard to make a vaccine for AIDS?

Vaccine development has always been a long and arduous process (see chart below), but a number of elements make HIV a particularly challenging virus to inoculate against.

Developing Vaccines: How Long It Takes

Virus or Bacteria	Year cause discovered	Year vaccine licensed in U.S.	Years elapsed
Malaria	1893	none	-
Typhoid	1884	1989	105
Haemophilus Influenza	1889	1981	92
Pertussis	1906	1995	89
Polio	1908	1955	47
Measles	1953	1995	42
Hepatitis B	1965	1981	16
HIV	1983	none	-

Source: AIDS Vaccine Handbook 2nd Edition: Global Perspectives Patricia Kahn, ed. New York: AVAC, May 2005. Republished with permission.

 

The key problem facing vaccine developers is the astonishing nature of HIV: The virus not only evades the body's immune system response, it actually destroys the very immune system cells -- the CD4 T-cells -- that lead the body's response.

Upon penetrating the CD4 cells, HIV inserts its genetic material and hijacks the cell's mechanisms to create more viruses. By stimulating an immune response, a vaccine could actually spur further virus production.

In addition, HIV is a retrovirus, meaning it must convert its genetic code from RNA to DNA once inside the CD4 cell -- a process that is notoriously error-prone. The virus's high mutation rate would increase the chance that one or two mutations could escape the immune response stimulated by the vaccine, and that the vaccine-resistant virus could be transmitted to others.

Because of its high mutation rate, HIV has developed tremendous genetic diversity. The virus has two main strains: HIV-1, which is the dominant strain in the pandemic, and HIV-2, which is largely confined to West Africa. Within HIV-1 alone, there are at least 10 different subtypes (as well as recombinant viruses combining several subtypes), which are found in different parts of the globe. For example, subtype B is dominant in North America and Western Europe, while subtype C is prominent in the hardest-hit areas of sub-Saharan Africa. [See a global map showing the distribution.] Researchers must develop multiple vaccines or one that works broadly across multiple subtypes.

But perhaps the most discouraging problem facing vaccine researchers is that in the 25-plus years of the AIDS pandemic, not one individual has rid himself of the virus. As Dr. Anthony Fauci, head of the National Institute of Allergy and Infectious Diseases (NIAID), explains: "Of all the microbes we know of, this is the only one in which the body has proven itself completely incapable of eliminating the virus from the body once it gets infected. Even with the deadliest of diseases -- the viruses of smallpox, of polio, of measles -- you get infected, there's a certain mortality; then you clear the infection, the body gets an immune response, and it's unlikely you're going to get infected again. When you develop a vaccine, you look at the body and you say, 'This is what the body did to protect itself, and we're going to develop a vaccine that mimics what the body has done.' With HIV, the body has not been successful, so you don't have a framework to look and say, 'Ah, this is what we want to do.'"

What are the current strategies?

Because there are so many obstacles to an HIV/AIDS vaccine, researchers are pursuing multiple strategies. Some are looking at a preventative vaccine, which would block infection in people who are HIV negative. This is where the bulk of early vaccine research, which tried to encourage the immune system to produce antibodies that would block the virus from infecting cells, was concentrated. The antibody approach, while successful in lab experiments, has failed when mutated strains of HIV are introduced to the culture. According to the AIDS Vaccine Advocacy Coalition (AVAC), determining how to stimulate an antibody response is "a task that most researchers consider essential for an optimal vaccine but [one] that's proven impossible so far."

Most of the 30 vaccine candidates that are currently in trials are therapeutic vaccines, which try to stop the virus from progressing to AIDS in already-infected individuals and maybe even prevent an infected person from passing on the virus to an uninfected person. This approach tries to induce the immune system to produce more T-cells to fight HIV.

According to the U.S. Department of Health and Human Services, the answer may be that multiple vaccines may be necessary to prevent infection, in the same way that multiple drugs are necessary for treatment.

What are the predictions for developing an HIV/AIDS vaccine?

In September 2004, Richard Horton, editor of the scientific journal The Lancet, published a controversial article in The New York Review of Books in which he assessed the state of AIDS vaccine research and took some AIDS vaccine activists to task for making overly optimistic predictions and promises. "The sum total of our knowledge about the genetics, biology, and geographical distribution of HIV indicates that vaccine scientists may have met their match in this adaptable foe," he wrote. "The reality seems to be that a vaccine against AIDS is becoming little more than a pipe dream."

Not all scientists are as pessimistic -- but that doesn't mean they're necessarily optimistic either. Most agree that a successful vaccine is no closer than decades away. "When I'm asked about when we're going to have a vaccine, what I have said from ... 1986 ... to today is it's going to be at least 10 years," says Dr. David Baltimore, the Nobel Prize-winning virologist who co-discovered retroviruses. "That's never changed over the last 20 years, … because we haven't made any kind of progress that says it's going to be less than 10 years."

"Even if we come up with a cure or vaccine tomorrow, just think about the time that would be needed to implement all these measures widely throughout the world," adds Dr. David Ho, director and CEO of the Aaron Diamond AIDS Research Center. "And even with that optimal scenario, it would be decades before this fight is won, and we're certainly, unfortunately, not in that situation."

• Related Links
• How Are Vaccines Tested?
  An overview of the clinical trial process.
• AIDS Vaccine Advocacy Coalition (AVAC)
  AVAC publishes the AIDS Vaccine Handbook, a terrific overview of how vaccines work; the particular challenges facing scientists in developing an AIDS vaccine; how clinical trials work; and how the research affects HIV-positive populations around the world. AVAC also sponsors the AIDS Vaccine Clearinghouse, a gateway to information about vaccine research, development and advocacy.
• The International AIDS Vaccine Initiative (IAVI)
  The Web site for the International AIDS Vaccine Initiative includes an overview of the state of global research; a series of primers on issues surrounding vaccine research and development; a database of all the vaccines currently in clinical trials; and the archives of the IAVI Report, its bimonthly newsletter.
• The Global HIV/AIDS Vaccine Enterprise: Scientific Strategic Plan
  This document outlines the goals for a global AIDS vaccine initiative similar to the Human Genome Project: "The Global HIV/AIDS Vaccine Enterprise represents a novel paradigm to seek and identify international agreement on the critical roadblocks for developing an HIV vaccine and on creating a shared scientific plan that addresses these roadblocks. The Enterprise proposes to coordinate efforts at a global level, facilitate use of common tools and technologies, and help ensure access to optimized resources. Furthermore, the Enterprise approach is a way of behaving as a global community of problem-solvers, more openly sharing information, ensuring that the shared scientific plan is implemented, and basing decisions on evidence rather than advocacy." [Note: This is a pdf; Adobe Acrobat required]
• The End or the Beginning of the Drive to an HIV-Preventive Vaccine: A View From Over 20 Years
  Responding to Dr. Richard Horton's New York Review of Books article questioning the viability of an AIDS vaccine, virologist Dr. Robert Gallo wrote this article for The Lancet. He concludes: "It is not time to give up on HIV vaccines but to change the way we pursue them. HIV-preventive vaccine research should clearly ignore empirically driven approaches and rely exclusively on rational approaches that are based on solid knowledge of HIV biology. I suggest after years of wandering, we have only begun to travel this path." [Note: Free registration is required to access this article.]
• Rx for Survival: A Vaccine for AIDS?
  This video excerpt from the PBS series Rx for Survival explores the mystery of the natural immunity that some Kenyan prostitutes have to HIV and whether it could unlock the key to a vaccine.