The Development of HIV Vaccines

CDC/C. Goldsmith, P. Feorino, E. L. Palmer, W. R. McManus, 1989

HIV virions (green)

101012

At a time when many infectious diseases were being brought or kept under control with global vaccination efforts in the 1990s, the human immunodeficiency virus (HIV), only identified in 1984, infected millions worldwide. From 1990 to 2000 the number of people living with HIV rose from 8 million to 27 million; since the beginning of the HIV/Acquired Immune Deficiency Syndrome (AIDS) epidemic, AIDS has claimed almost 30 million lives.[1]

HIV is a major public health concern not only because it can’t yet be prevented by vaccination, but also because those it infects are infected for life with a virus that wipes out their immune system - making them more prone to other infections. The virus kills immune T helper cells called CD4+ cells, which are the coordinators of the human immune system. This is where the “Acquired Immune Deficiency Syndrome” name comes from: when HIV kills enough CD4+ cells, the infected person’s immune system is unable to fight off infections it could ordinarily control. Patients are more susceptible to all infections, including those it could normally fight off, such as types of pneumonia, tuberculosis, and shingles, as well as certain cancers.[2] When the number of CD4+ cells drops below a certain point, a person is considered to have progressed from HIV infection to AIDS.

While antiretroviral treatments have drastically improved life expectancy and quality of life for HIV patients, preventing HIV infection is still a primary goal, especially for developing countries that are hardest hit by the pandemic and cannot afford treatments. Decades of effort have been spent, and continue to be made, toward developing an HIV vaccine.

This particular virus, however, poses unique challenges to vaccine development.

In general terms, all vaccines work the same way: they prime the immune system to recognize and attack a particular pathogen if it shows up in the body in the future. This can be done in a variety of ways: you can generate a vaccine by inactivating the pathogen (as in the injected polio vaccine) or weakening it (as in the measles vaccine), by using only part of it (pertussis), or by combining it with something else that helps it provoke an immune response (pneumococcal vaccine). Whichever method is used, the vaccine primes the immune system to respond quickly to the pathogen if it enters the body in the future.

HIV’s Unique Challenges 

In April 1984, US Health and Human Services Secretary Margaret Heckler made a hopeful statement about an HIV vaccine, based on a conversation she’d had with the virus’s co-discoverer, Robert Gallo: she said in a press conference that “We hope to have a vaccine ready for testing in about two years.”[3] Certainly, this prediction was overly optimistic, given that most vaccines take 10-20 years to develop. But nearly 30 years later, why is there no licensed vaccine?

HIV challenges the standard vaccine approaches first and foremost because, unlike diseases such as measles and chickenpox, no one naturally recovers from infection with HIV. If a person is infected with measles and survives, the immune response to the infection will usually be sufficient to prevent future infection with the measles. Researchers can use this naturally derived immunity as a model for the level of protection a successful vaccine should provide.

To date, however, no one has ever naturally recovered from HIV infection. This leaves researchers with no way to identify an immune response that would be effective against HIV, and makes vaccine development more difficult. (While no one has recovered from HIV infection, some individuals are naturally able to control the infection and prevent it from progressing to AIDS. Research into how these individuals, referred to as “elite controllers,” are able to control the infection offers another possible avenue toward vaccine development.)

A second challenge in developing a vaccine is that HIV mutates frequently. There are many subtypes, each of which is genetically distinct; it’s likely that additional subtypes will continue to emerge. This poses yet another challenge, as a vaccine that protects against one subtype may not provide protection against others. (The virus can even mutate within an individual, resulting in loss of immune system control over it.)

Finally, while animal models are an important aspect of most vaccine research, HIV vaccine tests in animals have not yet yielded accurate predictions of how the vaccines will work in humans. Researchers continue to perform trials testing vaccines against Simian Immunodeficiency Virus (SIV), the monkey virus from which HIV evolved, in hopes of using similar approaches against HIV.

Recent Cause for Optimism 

In 2009, the results of the largest HIV vaccine trial in history were announced. Referred to as “RV144” or “the Thai trial” (as it took place in Thailand), it had more than 16,000 participants and took six years to complete.

The trial used a “prime-boost” strategy with two experimental HIV vaccines. The first was a recombinant vaccine using a canarypox virus, with inserted genes that code for antigenic proteins from HIV subtypes B and E.[4][5] This vaccine was used as the “prime” and was intended to stimulate cell-mediated immunity (T cell responses). The “boost” vaccine was a composed of a genetically engineered antigenic surface protein from HIV, and was intended to stimulate antibody immune responses (that is, B cell responses).[6][7]

The prime vaccine had never been tested for efficacy against HIV in humans (although it had been through numerous safety trials). The boost vaccine had previously failed to show efficacy against HIV when tested. But when they were used in combination in the RV144 trial, the vaccines were about 31% effective in preventing HIV infection. That is, there were 31% fewer HIV infections in trial participants who got the prime-boost combination than among those who got a placebo.

A 31% level of efficacy is not high enough to warrant use of a vaccine outside a trial setting, especially for a disease as serious as HIV. Yet this was the first time an HIV vaccine efficacy trial actually showed evidence of protection against the virus, giving researchers hope that an effective HIV vaccine is possible.

Current Status of HIV Vaccine Development

The first priority in light of the positive results from the RV144 trial is for researchers to determine the “correlate of protection” from the prime-boost vaccine combination: that is, they must determine precisely how the prime-boost combination protected against infection with HIV. Researchers are studying whether antibodies were induced by the prime-boost combination (which could include multiple types of antibody responses); whether T-cell responses occurred; and whether the individual genetics of the study’s participants played a role in their responses to the vaccine combination. Currently, it appears that T-cell responses did not play a role in protecting against infection, and that the vaccine’s efficacy was related to an antibody response. However, the details of this response are not yet clear.

Additional studies are being planned to try to improve upon the immune response generated in the RV144 trial, even without specific details about the correlate of protection.

Researchers are also studying the methodology and administrative approaches of RV144, in hopes of applying the knowledge gleaned from the largest HIV vaccine trial in history to improve the design of future trials. The trial was a major international collaboration between non-profit groups, private companies, and the Thai and U.S. governments: the two vaccines had originally been developed by VaxGen and Sanofi Pasteur; trial funding was provided by the U.S. National Institutes of Allergy and Infectious Diseases and the U.S. Army Medical Research and Materiel Command; and the study’s execution was carried out through the efforts of numerous cooperating organizations, led by the Thai Ministry of Public Health. Vaccine developers believe that much can be learned by examining not just the outcomes of the RV144 trial, but the challenges that arose over its six years and how they were handled by the participating organizations.

Efforts and approaches completely separate from the RV144 trial are underway. Researchers are studying the previously mentioned “elite controllers” whose HIV infections never progress to AIDS, in hopes that whatever innate ability they have to control HIV might provide insights for vaccine development. Efforts are also being made to study individuals who never become infected with HIV despite being exposed to it repeatedly.

Many other vaccine candidates are in various stages of testing and development. In addition to the canarypox-based recombinant vaccine used as the “prime” in the RV144 trial, recombinant candidates have also been developed based on adenovirus. Other genetically engineered candidates consist of a protein administered with an adjuvant – an agent included to further stimulate the immune system.

Additionally, the positive results of a recent Simian Immunodeficiency Virus trial in rhesus macaque monkeys have raised the idea of using cytomegalovirus (CMV) as a vector in future HIV vaccine candidates. In this approach, T cells known as “killer T cells,” which can kill infected cells, provide the protection afforded by the vaccine. The SIV vaccine being tested used CMV as a vector, and resulted in longer-lasting immunity against SIV than all but one other SIV vaccine.*[8]

Researchers are now considering the possibility of a CMV-based HIV vaccine vector in hopes of generating long-lasting immunity against HIV. They are also advancing other vaccine approaches, such as candidates that stimulate immune responses in the mucosal surfaces of the gut – the same site of early HIV replication.

Finally, researchers are exploring ways of generating antibodies to HIV.  Antibodies are able to neutralize viruses before they are able to infect a person.  The results of collaborative work in the last two years shows that some humans are able to create antibodies capable of neutralizing a wide range of HIV strains.  These antibodies provide an excellent target for vaccine discovery by highlighting weaknesses on the surface of HIV. 

Many different groups are collaborating on these and other approaches to HIV vaccine development – perhaps more than for any vaccine development effort to date. Non-profit organizations, governments, pharmaceutical companies, philanthropic groups, and advocacy organizations are working together in what has become a truly global effort toward an HIV vaccine.

* The only other SIV vaccine to generate longer-lasting immunity than the CMV-based vector vaccine was one containing live, attenuated Simian Immunodeficiency Virus. This approach is not considered to be a possibility for humans, as a live HIV vaccine, even weakened, would be too dangerous for human testing.

Current Trials

The International AIDS Vaccine Initiative maintains a list of current and past AIDS vaccine trials, sorted by status, trial phase, and strategy. See the database here: 

http://www.iavireport.org/trials-db/Pages/default.aspx

Further Reading 

You can keep up to date with the latest news about HIV vaccine research via the following organizations:

• International AIDS Vaccine Initiative (iavi.org)
• U.S. Military HIV Vaccine Research Program (USMHRP)
• HIV Vaccine Trials Network (HVTN)