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Inching Toward a Vaccine

By Deirdre Grant

Fall 2012

inchworm on ruler

Recent advances in HIV prevention have many people optimistic about ending the AIDS epidemic. These advances include voluntary medical male circumcision in sub-Saharan Africa and the use of HIV meds for prevention in both HIV-positive and -negative people. These newer options have the potential to dramatically reduce new infections. Why then does the world still need an AIDS vaccine?

The history of disease control shows that trying to end an epidemic without one of the world's most powerful public health tools -- a vaccine -- is a tall order. This was underscored recently at the AIDS Vaccine 2012 Conference, where NIAID Director Anthony Fauci said we have the tools to control the epidemic but need a vaccine to maintain control and eventually end it.

There has been progress on many fronts in the search for an AIDS vaccine. In fact, evidence from a large-scale AIDS vaccine trial has shown that a protective vaccine is possible. Researchers are working to improve its effect while also looking into how it worked. Furthermore, the past two years have also seen amazing discoveries in antibody research. These combined efforts give hope that it may be possible to find an effective vaccine -- and make it important to sustain funding for this effort.


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A Knockout Punch?

Vaccines are designed to teach the body's immune system to fend off an attack from a particular disease or pathogen. One way to do this is through antibodies, which are produced by the immune system to block a pathogen. Scientists have studied antibodies against HIV for some time. Recently, however, they have identified many broadly neutralizing antibodies, or BNAbs, that are effective against a whole range of types of HIV (HIV is highly variable, and one of the challenges for an AIDS vaccine is developing a strategy that is effective against all HIV types.)

Antibodies bind to proteins on the coat of HIV and then either signal other cells to destroy the virus or disable the virus themselves. The great interest in HIV-specific BNAbs comes from the fact that most effective vaccines against other diseases induce a potent antibody response. BNAb activity against a broad range of HIV strains is also key.

For years, scientists were unsure if the human body could create BNAbs to fight HIV. But in September 2009, researchers announced the discovery of two very effective BNAbs. Since then, other BNabs have been identified that are even more effective and are capable of blocking over 90% of strains of HIV in lab tests. Using highly efficient robotic systems to analyze thousands of blood samples from people with HIV, scientists identified BNAbs in 15-20% of these samples.

People with HIV create HIV-specific antibodies that neutralize the virus. But the body's immune system is always playing "catch-up" with the ever-mutating virus. The neutralizing antibodies detectable in a person's blood are active against the virus that a person might have had in prior years, but not against the present genetic version. This is one of the reasons the body's natural response has not been enough to stop HIV. Researchers are now trying to work backwards to understand how a vaccine might teach the body to create BNAbs in HIV-negative people -- before they are exposed to the virus. A BNAb isn't born overnight. It goes through a set of specific alterations to get to its mature state. So the challenge for researchers is to design a vaccine that teaches the body to create mature, effective BNAbs that block HIV infection. As one researcher described it, "We want to use a series of vaccines to drive a shortened version of the body's journey to create broadly neutralizing antibodies." Steady progress is being made to understand the steps on this journey.

In addition, scientists are looking to "grow" BNAbs in the lab and give them directly to people as part of a process called "passive immunization." This could be a "proof of concept" that these antibodies work to prevent HIV in HIV-negative people. To date, BNAbs against HIV have been seen in people with HIV and studied in lab and animal studies. No trials have yet taken place in the HIV-negative population.


Ongoing Research

vaccine vials

There are over two dozen small-scale HIV vaccine trials currently under way (for a complete list visit avac.org/pxrd) and one large-scale efficacy trial: HVTN 505. This trial of a two-vaccine regimen is being tested in over 2,000 men who have sex with men (MSM) and transgender women in the U.S. Launched in 2009, the trial was originally designed to study only whether the vaccine regimen reduced viral load in people who were HIV negative when they received the vaccine but who later acquired HIV through sex or other risk behaviors. In 2011, the study was modified to study whether the vaccine regimen can also reduce the risk of HIV infection. Results are expected in late 2013.

HVTN 505 has had to evolve and adapt to the changing prevention landscape. Since the trial was launched, data from the iPrEx PrEP study showed that daily Truvada can reduce the risk of HIV infection in MSM and transgender women. Last July, the FDA approved its use as PrEP in adults -- the first time a drug has been approved to prevent HIV infection from sexual exposure.

Shortly after the iPrEx results were announced, HVTN 505 investigators amended the protocol to include counseling about PrEP and monitoring PrEP use by participants, given the positive iPrEx data and the fact that they could get a prescription for it from their personal physicians. Now that Truvada for PrEP is FDA-approved, trial sponsors are informing all trial participants about the regulatory approval and providing information about where it can be obtained.

Another area of research includes studying whether PrEP could provide protection long enough to allow a vaccine to assist the body in creating a protective immune response. This could close the "window of vulnerability" -- the time between HIV exposure and the body's protective immune response. HVTN 505 won't answer this question, so the field will have to wait for future trials.


The First Hope

man being given a shot

It has been three years since the RV144 study showed that a vaccine could reduce the risk of HIV. It studied a combination of two vaccines, ALVAC and AIDSVAX, in over 16,000 HIV-negative men and women in Thailand and showed a modest 31% reduction in HIV risk 3.5 years after the vaccines were given. But a later analysis suggested that the vaccines offered a 60% reduction in risk a year after they were given.

The first step in understanding this protection and why it waned over time, has been to study blood samples from trial participants to identify "correlates of risk." Scientists tested the samples and measured various immune responses to the vaccines and have been able to identify immune responses that were related to both lower and higher rates of infection in those who received the vaccine. The data currently available can't prove whether these responses had a direct role in protection from HIV infection. But they are important signals to follow in future trials.

Follow-up to the RV144 study is being organized by the Pox Protein Public-Private Partnership (the P5) to attempt to improve on the trial's results. One study is a specific follow-up of people who were in the trial. Additional studies are testing a vaccine regimen based on the one tested in RV144. These studies will focus on new groups, including MSM in Thailand and heterosexual men and women in South Africa. Yet another study will look at the effect of an additional booster vaccine along with a different adjuvant (a substance used to help enhance the immune response to the vaccine). The hope is that this combination will improve the durability and magnitude of the effect seen in RV144. Scientists are also studying the antibodies found in RV144 vaccine recipients that were linked to decreased risk of infection.

These studies are scheduled to begin in 2014-15 with results expected several years later. Based on the trial timelines presented by the P5 at AIDS 2012, this could lead to approval of the vaccine by 2022. Epidemiologists have tried to predict what the impact of a partially protective vaccine might be. In some scenarios, a vaccine that is 60% effective could lower HIV infection rates by up to 60% if annual booster shots were given.

New trial designs and an evolving standard of prevention will mean these trials will be some of the most complex yet. Careful planning and community engagement will be critical to their success.


Vaccines and HIV Prevention

At the AIDS Vaccine 2012 Conference, Global HIV Vaccine Enterprise Director Bill Snow acknowledged that the AIDS vaccine field may not be able to promise a vaccine by a certain date. But he did urge those in the field to keep working to ensure that the many intermediate questions are answered quickly.

In a conference plenary lecture, NIAID Director Fauci put AIDS vaccine research in the context of "combination HIV prevention" using proven and newer tools. This includes treatment as prevention, PrEP, microbicides, and voluntary medical male circumcision. He made a compelling case for the need to pursue an AIDS vaccine even as these other strategies help to reduce rates of new infections. He acknowledged that current and new prevention options may be enough to control the epidemic if implemented effectively. But Fauci reiterated that it will be virtually impossible to get to true control and elimination of HIV without a vaccine. He closed by answering a question he opened his talk with: Do we need a vaccine? -- and responded emphatically, "The answer is absolutely yes, but the HIV prevention strategy will in fact be a unique paradigm of non-vaccine combination prevention modalities together with a safe and effective vaccine, and then and only then, will we see a durable end of HIV/AIDS."

Deirdre Grant is a Senior Program Manager at AVAC: Global Advocacy for HIV Prevention.




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