Understanding Live-Attenuated Vaccines

What can AIDS vaccine researchers learn from live-attenuated SIV vaccines?

Researchers have drawn on a number of different strategies in the pursuit of a safe and effective AIDS vaccine. Among the approaches that have been tested are using non-infectious viruses such as the cold virus as vectors to transport HIV fragments into cells to try to induce immune responses against HIV that will subsequently protect against infection. This was the strategy tested in Merck’s recently conducted STEP and Phambili trials.

But one approach used in many modern-day vaccines remains off limits to AIDS vaccine developers—using a weakened or attenuated version of HIV to stimulate protective immunity. This strategy has been used to develop several existing vaccines that are highly efficacious at preventing disease, including the measles and yellow fever vaccines. Although still a major killer of children in developing countries, measles deaths have dropped 91% in Africa and 68% globally, according to the World Health Organization, following introduction of the live-attenuated vaccine.

This strategy remains on the sidelines of AIDS vaccine development, however, because researchers are worried that live-attenuated HIV will revert to a disease-causing or pathogenic strain once inside the body, which could cause an HIV infection in the very people the vaccine is designed to protect.

Safety concerns

These safety concerns with live-attenuated HIV vaccines are not unfounded. A group of individuals in Australia were inadvertently infected with HIV after receiving tainted blood and, as researchers later discovered, the HIV they were exposed to was a live-attenuated version of the normally circulating virus. This group, which came to be known as the Sydney Blood Bank Cohort, was infected with HIV that lacked a critical gene known as nef that plays a key role in the virus’s ability to replicate in human cells. The nef gene is also responsible for shutting down a class of molecules that would normally summon the immune system’s killer T cells to attack and destroy HIV-infected cells. Despite being infected with an attenuated strain of HIV, several of the long-term survivors of this cohort have now developed damage to their immune systems. After living without any signs or symptoms for nearly two decades, three of the seven survivors now have declining CD4+ T-cell counts, the key marker for progression of HIV infection and development of AIDS.

Researchers believe the nef-deficient HIV strain, which infected the individuals in the Sydney cohort, mutated to regain its ability to replicate rapidly, and therefore became pathogenic. For this reason, live-attenuated HIV vaccines are considered by many to be unsafe for study in humans.

Protection by live-attenuated vaccines

Live-attenuated vaccines are prepared by purposely removing critical pieces of the virus’s genetic material that would normally allow them to wage war on their hosts. The attenuated virus strains are no longer pathogenic but they still pack enough punch to produce a strong immune response against the virus. Neutralizing antibodies, which bind to viruses and prevent them from infecting cells, are thought to be an important component of the protection generated by many of the currently available live-attenuated vaccines, including polio and measles.

In most situations where live-attenuated vaccines are employed, there is also ample evidence of natural immunity to support using an attenuated version of the actual disease-causing pathogen as a vaccine. Consider polio. Despite the recurring images of helpless victims in iron lungs, about 95% of people infected with polio either never get sick or display only mild symptoms. The live-attenuated polio vaccine merely replicated what occurred naturally. The opposite applies with HIV. Without treatment, over 95% of HIV-infected people will ultimately develop AIDS. An AIDS vaccine must therefore accomplish something that largely does not occur in natural infection.

Developing live-attenuated SIV vaccines

While safety concerns prevent the testing of live-attenuated HIV vaccines, the study of live-attenuated simian immunodeficiency virus (SIV) vaccines in nonhuman primates remains an important area of research. Although SIV is a different virus, nonhuman primate studies with SIV are the closest approximation researchers have for studying HIV. Experimental data collected from the study of SIV in non-human primate models can shed light on the development of future AIDS vaccine candidates.

To study the protection afforded by live-attenuated SIV vaccines in nonhuman primates researchers purposely handicap the virus by removing pieces of SIV’s genetic material. One strain of live-attenuated SIV is developed by removing part of the virus’s nef gene. There are also several other versions of live-attenuated SIV vaccines that are currently being studied in nonhuman primates. Generally, the virus becomes more compromised in its ability to replicate and cause an infection when more of its genetic material is removed. But as more genes or parts of genes are removed from SIV, the less effective the live-attenuated vaccine becomes at protecting against infection. Researchers must therefore develop an attenuated SIV strain that does not infect the animals, but is still close enough to the natural form to induce strong immune responses.

The crippled SIV strains are grown in a laboratory and are then used to vaccinate nonhuman primates. These animals are then purposely exposed to a naturally-circulating version of SIV so that researchers can see how well the immune responses induced by the vaccine are able to protect against infection.

Modeling protection

The live-attenuated SIV vaccine strategy has elicited some of the most impressive and consistent protection to date in nonhuman primate studies and can provide researchers with unique insights into the types of immune responses that might also provide some level of partial protection against HIV. Researchers are now developing a better understanding of how the spectrum of SIV-specific CD8+ T-cell, CD4+ T-cell, and antibody responses work together to provide protection against SIV.