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After the discovery of the HIV virus in 1984, many people both in and out of the medical community assumed that an effective vaccine would soon be developed. And yet, 30 years after its identification, that goal still seems far off. Despite the enormous amount of thought, effort and money that has been spent, many people are forced to wonder why we have not been able to develop a safe and effective vaccine against HIV.

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Most vaccines work by presenting the immune system with a weakened or partial form of an infectious germ before it is encountered naturally. This “trains” the immune system to rapidly recognize and respond to the germ, so it can be quickly be neutralized if it is encountered again. Protection from a given germ is generated either by producing antibodies that recognize parts of the pathogen, or by generating cells that remember the pathogen, or through a combination of both.

But HIV presents scientists with a variety of unique problems that have made developing a vaccine more challenging than initially expected. One of the biggest is that HIV copies itself very quickly — and with many small errors that cause mutations. Because of this, a patient’s immune system does not have time to completely neutralize the infecting strain before it has mutated enough to evade recognition.

To give this a sense of scale: HIV will mutate about 1 in every 18- 35 newly infected cells. With an estimated 100 million infected cells in an HIV positive individual at any one time: given that number, anywhere from 5 to 10 million cells will produce a slightly different variation of HIV. That means that the immune system — and vaccine developers — are always playing catch-up.

The rapid and widespread mutations of HIV also present a problem in developing a vaccine that will broadly neutralize the variety of strains that have taken hold in different parts of the world. An effective vaccine needs to generate a rapid and strong immune response that will broadly recognize and neutralize most if not all strains of HIV before they reach high levels of replication in the body.

Unfortunately, the emergence of viral variants is not the only obstacle to be overcome. During the past three decades of research, scientists themselves have disagreed on the kind of immune response that would most efficiently generate protective immunity. These professional disagreements stem from a variety of variations in scientific methods, which include the use of different animal models and virus strains in the development and testing of vaccine candidates. Such inconsistencies make it difficult to compare actual effectiveness across these different studies.

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Furthermore, each study has used different measures of effectiveness, different methods and sites of delivery, and varying vaccination schedules, which makes it even more difficult to compare and contrast results. Hence, we have a limited knowledge as to what a protective response might look like. While this was not a problem in the past — since most vaccines were developed with a limited knowledge of disease pathogenesis or how exactly the vaccine elicits protection — in the case of HIV, this lack of knowledge and consensus has led to the failure of most of the vaccines tested in humans so far.

And the failure to achieve a consensus on methodologies has caused more problems than just a delay in promising vaccines. One clinical trial conducted in Thailand by Merck in 2007 proved especially disastrous for the study volunteers. In this instance, vaccination actually caused people to become more susceptible to HIV infection. The trial was subsequently halted and led to the temporary suspension of all HIV vaccine trials — which, of course, led to further delays in vaccine development.

Researchers have, however, finally realized the necessity of a central agency to regulate the design, interpretation and execution all HIV vaccine trials in humans and established the HIV Vaccine Trials Network (HVTN). Combined with the efforts of the International AIDS Vaccine Initiative (IAVI), which oversees the design and development of vaccine candidates, the endeavor to develop and disseminate an effective HIV vaccine has become far more focused and cohesive.

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Recently, researchers from IAVI have made steps towards developing a vaccine by studying “elite controllers” — HIV positive patients who are able to control the virus without the use of antiretroviral therapy. This study identified two new broadly neutralizing antibodies, which were able to effectively neutralize most strains of HIV. Researchers hope that these antibodies hold the key to developing a vaccine that targets the region of HIV that is least susceptible to change. Currently, larger studies are planned to screen for more broadly neutralizing antibodies in the blood of elite controllers with the aim of finding even more possibilities for vaccine development.

In one promising trial conducted in 2009 by the US Military HIV Research Program (MHRP), one HIV vaccine was shown to effectively reduce HIV infection rates in humans by 30%. Even though researchers still do not fully understand the type of immune response that this vaccine generates, it is the first time that a vaccine has been shown to be effective in humans.

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While it has been a long and disheartening road for HIV vaccine development, there is a renewed optimism and focus amongst vaccine researchers that not only is an effective vaccine possible but that it may now be in sight. This newly found focus on cooperation and collaboration instead of competition leaves hope that vaccine research might yet help put an end to the AIDS epidemic in our lifetimes.

[Image via Roel Wijnants, Creative Commons licensed]

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