February 12, 2014

 

 

An HIV vaccine is one of the greatest challenges scientists have ever faced.

More than 30 years into the pandemic, we continue to work toward an effective vaccine. The difficulties stem in large part from HIV’s unusual characteristics – rapid replication, furious mutation, immune system evasion, and creation of viral reservoirs. As a result, typical vaccine approaches fail with HIV.

From the perspective of vaccine development, HIV is very different from other viruses against which today it seems routine to expect a vaccine. When viruses such as polio, smallpox, influenza, and measles infect the body, the immune system recognizes the viruses as foreign; white blood cells called B-lymphocytes differentiate into cells that produce antibodies specifically targeting the invading virus. This is why, if a person contracts a disease like measles or mumps, they may have long-term or even life-long immunity against subsequent infection. Effective vaccines prepare the body for infection in a similar way by raising a strong antibody response in advance that protects the individual from future infection.   

HIV turns this process upside-down. HIV hides from the immune system in two ways. In most patients HIV eludes the immune system, which fails to generate an effective antibody response to the infection. In the few patients that do generate HIV-specific antibodies, the antibodies are insufficient to limit the course of the disease. Second, HIV infects, disables, and kills the very cells that are critical to the healthy functioning of the immune system, which is why, as AIDS progresses, patients become increasingly vulnerable to life-threatening infections.

Soon after HIV enters the body, the virus disseminates and establishes a persistent infection in T-lymphocytes, turning them and other immune cells into hidden reservoirs from which it can strike again at any time. The opportunity for a vaccine-induced response to prevent infection or to control the initial, limited infection is therefore short-lived.  

To make the discovery of a vaccine even more difficult, HIV mutates rapidly; these changes in its genome lead to changes in the structure of proteins that would normally be the target of infection-controlling antibodies, further enabling HIV to evade elimination by the immune system. By comparison, the genetic variability of HIV in a single HIV-infected individual is about the same as the yearly genetic variation of the influenza virus across the population of the globe  

Also, some of the unique features of HIV make it harder to do experiments that would indicate whether a potential vaccine candidate might be able to invoke an effective immune response in humans. There are no animal models for HIV in which one can perform a challenge study. The closest researchers have come is to make a hybrid of simian and human immunodeficiency viruses that can be used to infect monkeys for evaluating potential treatments and preventive agents. Investigators have yet to find any “correlates of protection,” such as protein markers or antibody titers that can be measured to indicate the level of a protective immune response.

In short, the main barriers to HIV vaccine development include the global variability of HIV, lack of a validated animal model, lack of correlates of protective immunity, lack of natural protective immune responses against HIV, and the reservoir of infected cells conferred by integration of HIV’s genome into the host.  

Taken together, these are the challenges that have bedeviled scientists working to elicit specific, durable, and protective immune responses against HIV. In spite of these obstacles, researchers are optimistic that these hurdles can be overcome. In recent years, there have been major advances in developing broadly neutralizing antibodies against conserved regions of HIV envelope proteins, structure-based design of potent immunogens that induce broadly neutralizing antibodies, and success with multifaceted attacks on viral reservoirs. IAVI and its partners are pursuing an integrated scientific strategy that mixes basic scientific discovery with technological breakthroughs that we can expect to bring an HIV vaccine closer to realization. 

Read more about HIV vaccine basics in our VAX Report Primer series.