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HIV Vaccine Primer: Basic Science and Concepts

By Warren Tong

May 13, 2013

Getting to zero new HIV infections is already possible with our current HIV prevention methods -- condom use, pre-exposure prophylaxis, education, testing and so forth. But the holy grail of getting to zero remains an HIV vaccine. With an effective vaccine, HIV could eventually be eradicated, as with smallpox.

Just to be clear: No HIV vaccine currently exists. But there are many ongoing efforts to develop one, and those efforts have been revived in recent years. Some experts say we are at least 10 years away from an HIV vaccine, while others say it may be much longer than that.

So why is it taking so long? What makes developing a vaccine for HIV so difficult? Some of the science behind HIV vaccines can be tricky, but here are the basics to help you better understand what goes on in the human body and how a successful vaccine may be developed.


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The Biggest Obstacle in Developing an HIV Vaccine

"The one biggest [obstacle] is HIV itself," as top researcher Nicole Frahm, Ph.D., puts it. "It's an extremely complicated bug because it basically infects the cells of the immune system that are supposed to help you prevent an infection in the first place. The fact that it infects CD4 cells makes it very hard to build a good immune response against it."

Not only does HIV infect and disable the very system that's supposed to fight against it, but by the time the immune system catches up and develops a response, HIV mutates. There are also different strains of the virus, each of which attacks the immune system slightly differently -- another reason why HIV is very good at evading our natural defenses.

Even when researchers create a potential vaccine that's ready for testing, the clinical trials required to test it take considerable time and aren't cheap, to say the least. There are three trial phases a vaccine candidate has to pass before it can be approved by an official authority, such as the U.S. Food and Drug Administration, for medical use in the general public. Each trial phase requires more time, money, vaccine product and study volunteers than the last.

This doesn't mean an HIV vaccine isn't possible. It will just take time and a considerable amount of investment.


What Is a Vaccine?

A preventive vaccine is a substance that, when introduced into the body, can protect a person against developing a particular infection or disease in the future. A vaccine prepares the body, particularly the immune system, to defend against a specific pathogen (a disease-causing microorganism, such as a virus, bacteria or parasite) by creating an immune response.

In general, vaccines are given to uninfected individuals who may be exposed to the pathogen in the future. "When HIV infects you, it's ahead of the game. It's got two weeks to a month while your immune system is gearing up and responding," explains Rick King, vice president of vaccine design at the International AIDS Vaccine Initiative (IAVI). "What we're trying to do is to get the immune system there in advance."

The vaccines that are currently available for other diseases save millions of lives every year. These include the polio, tetanus and measles vaccines. Like these vaccines, an HIV vaccine would prepare the body ahead of time, so that it's ready to fight HIV if exposed to it. An important thing to keep in mind: Vaccines don't have to be 100 percent effective to be approved, or to stop an outbreak in its tracks. Most licensed vaccines in the U.S. are 70 to 95 percent effective.

Vaccines can be given in many ways, including injections into the muscle, injections into or under the skin, as a patch applied onto the skin or inside the nose, or as a pill taken orally.

(In addition to preventive vaccines, there is some research going on to develop a therapeutic vaccine for people living with HIV. If effective, it would use the person's immune system to help control the HIV and delay disease progression. But we will focus on preventive vaccines in this article.)

For a more in-depth overview, watch "How an AIDS Vaccine Might Work" from IAVI:



Types of Vaccines

The most straightforward vaccine would be a live attenuated vaccine, which uses a weakened version of the pathogen. This is how the vaccines for measles and mumps work. However, live attenuated HIV is never used in HIV vaccine trials, in order to avoid any risk of HIV infection via the vaccine itself. Therefore, HIV vaccine trial participants are never actually exposed to HIV, and have no chance of becoming infected.

A whole-cell inactivated vaccine is made from whole viruses or bacteria whose ability to grow and reproduce has been eliminated. Currently, there is only one HIV vaccine trial testing an HIV vaccine candidate made from inactivated whole HIV that has been genetically modified. Phase 1 results demonstrated safety and tolerability, and the researchers are moving into phase 2.

A subunit vaccine uses purified pieces of the pathogen (known as antigens) to trigger a strong, protective immune response. This is how the vaccines for influenza and hepatitis B work. The first HIV vaccine candidate tested in humans (AIDSVAX) used this approach, but it failed to show protection. However, subunit vaccine approaches are still being researched.

A DNA vaccine is a vaccine that uses the genetic code of a pathogen inserted into a circular piece of DNA called a plasmid to invoke an immune response. With a DNA vaccine, trial participants cannot become infected because only those genes that code for the pathogen's antigens are used, never the whole pathogen. The genes are taken up by some cells in the body, which then produce the antigens that train the immune system to recognize the targeted pathogen. This approach has shown promising results, and trials are ongoing.

Perhaps the most common vaccine approach used in HIV research is a recombinant vector vaccine. This approach also uses genetic material from a pathogen to elicit an immune response, but inserts it into an attenuated bacterium or virus that acts as a carrier, or vector, to deliver the genetic material into the body. A common vector being used in HIV vaccine research is weakened adenovirus -- a virus that, when not weakened, can cause colds and sore throats. Many ongoing HIV trials use recombinant vector vaccine candidates in an attempt to trigger a protective immune response against HIV.

Vaccine trials often use a prime-boost approach to induce immunity. This means administering an initial vaccine dose (the "prime") to trigger an immune response. The prime may be coupled with an adjuvant, which is a substance used to improve the body's ability to fight disease or infection. Then a second type of vaccine (the "booster") is administered to sustain immunity. Finding the right combinations and order of vaccine doses can lead to better immune responses.


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Types of Immune Responses

A successful HIV vaccine should elicit two main immune responses that, in conjunction, can ward off the virus.

The first type of response is humoral immunity, meaning protection provided by antibodies against freely circulating pathogens. An antibody is an infection-fighting protein molecule made naturally by the immune system; it can tag or neutralize specific bacteria, viruses and other harmful toxins. Researchers are trying to improve the process by which antibodies identify an HIV so it can be destroyed by other cells of the immune system.

Because of HIV's ability to mutate, researchers are looking for ways to induce "broadly neutralizing" antibodies, which are antibodies that can identify many different strains and mutations of HIV. This would be the ideal form of humoral immunity to HIV.

The second type of immune response is cellular immunity, which protects against cancer cells and pathogens that hide within human cells. The most important immune cells involved in cellular immunity include killer T cells (activated CD8 T cells) and T helper cells (CD4 T cells).

Killer T cells can destroy cells that have been altered by infection by a pathogen or that have become cancerous. CD4 T cells stimulate the production of antibodies, activate CD8 T cells and make sure the immune system is running smoothly.

In addition to using CD4 and killer T cells to respond to pathogens, the immune system also gathers an army of memory B cells and memory T cells that can quickly detect and neutralize pathogens should they ever try to re-enter the body.

With an effective vaccine, all these components of the immune system would be able to work together to prevent HIV infection.


RV144: First Proof That an HIV Vaccine Can Work

In 2009, RV144, sometimes referred to as the "Thai prime-boost AIDS vaccine trial," was the first HIV vaccine study conducted in humans that showed some level of protection against HIV. More than 16,000 Thai men and women volunteered for the study, in which they took a prime-boost vaccine regimen consisting of an ALVAC vector followed by an AIDSVAX boost. The vaccine candidate was shown to reduce HIV infection by 31 percent overall. It wasn't enough to truly call the vaccine a success, but after many years of research in which candidates showed no protection at all, it was a watershed moment in HIV vaccine research.

Soon after the results were made public, researchers began setting up tests to identify what specific aspects of the RV144 vaccine made people more or less likely to be protected against HIV. In the analysis, researchers were able to identify a particular antibody that may be associated with vaccine-induced immunity. Further research is going on to better understand the response so that the vaccine can be improved. Some of the volunteers from RV144 have begun to be "re-boosted" to see if their immune responses to HIV can be improved. Meanwhile, three follow-up trials are planned.


HVTN 505 and Other Vaccine Trials

On April 25, HVTN 505, a large phase-2b HIV vaccine trial, was halted by the National Institute of Allergy and Infectious Diseases (NIAID) after it determined there was a lack of efficacy for the vaccine regimen being studied. At the time, HVTN 505 was the furthest along in terms of clinical progress and had 2,504 participants across 19 U.S. cities. The trial had used a prime-boost approach similar to RV144, administering a DNA-based vaccine as the prime and a recombinant vaccine as the boost.

The trial halting was certainly disappointing news, however, as Mitchell Warren, executive director of AVAC (AIDS Vaccine Advocacy Coalition) pointed out, "This trial has provided a clear, swift answer about a specific vaccine strategy. It's not the answer we hoped for, but the search doesn't end here. There are other approaches that must be pursued without delay, and this result will help to focus and guide research efforts."

While no new vaccinations will be given in HVTN 505, the researchers will continue to follow and collect data on the study participants. Moreover, there are still more than 30 ongoing HIV vaccine trials around the world, according to AVAC. They are still in early phases, but research continues.

Overall, we may still be years from developing an HIV vaccine that is considered successful enough to be used in the general public, but after a long period of time in which many started to believe HIV vaccine research was a dead end, hope now burns as brightly as ever that the "holy grail" of HIV prevention can still be found.

Warren Tong is the research editor for TheBody.com and TheBodyPRO.com.

Follow Warren on Twitter: @WarrenAtTheBody.


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