Most licensed vaccines used to immunize people against viral diseases are live, attenuated vaccines. Examples include the oral polio vaccine and the combined vaccine against measles, mumps and rubella. Such vaccines use live viruses that have been weakened (by deleting genes, or selecting strains that only replicate under specific conditions) so they cannot cause illness but can still stimulate strong immune responses.
Because it closely resembles the intact virus, a live, attenuated virus vaccine evokes an immune response that closely resembles that seen during natural infection. Hence, it usually provides better protection against disease than other types of vaccines, for example, one made from just a piece of the virus. The trade-off to this benefit is the potential risk that the modified virus will maintain some degree of virulence and cause disease.
What is Known
Scientists have both identified naturally occurring and have genetically engineered attenuated strains of simian immunodeficiency virus (SIV), a virus similar to HIV that in its unweakened form causes an AIDS-like disease in monkeys. These attenuated SIV strains, which infect monkeys without causing disease, provide models for a live, attenuated human AIDS vaccine.
When used as vaccines, such attenuated viruses can protect monkeys against subsequent infection with the same and, to a lesser extent, different disease-causing strains of SIV.
In the SIV model, the level of attenuation can be altered by varying the number or location of genetically engineered deletions in the SIV genome. Preliminary results suggest that protective efficacy may vary inversely with the level of attenuation: with more deletions the vaccine becomes safer, but less effective.
Live, attenuated SIV vaccines can induce a diverse and persistent immune response against SIV. Most likely, the protective efficacy seen in monkeys is immune-mediated, since levels of antibodies and cellular immune responses increase over time, and the longer one waits to challenge vaccinated monkeys with a pathogenic SIV, the better the protection.
Scientists have identified a naturally occurring attenuated HIV strain that lacks HIV's nef gene. Among six Australians infected with this nef-deleted HIV through blood transfusions received between 1981 and 1984, none has developed HIV disease (although one has died of multiple complications, including immunodeficiency that has been attributed to systemic lupus erthematosis and steroid treatment). These individuals provide some information on the course of disease after infection with a naturally attenuated HIV strain.
These encouraging findings must be balanced against several potentially serious risks. These include:
A very small fraction of individuals receiving other attenuated viral vaccines do develop disease. An attenuated AIDS vaccine may still cause disease in some individuals.
An attenuated HIV might mutate and revert to a virulent form.
Other viruses used to make live, attenuated vaccines are cleared from the body. HIV, however, inserts itself into the genes of the body's cells and remains there for life.
Retroviruses like HIV integrate into an individual's DNA, and are known to cause cancer in animals. Chronic HIV infection might lead to the development of malignancies as well as other diseases apart from AIDS.
It may be possible for an attenuated HIV to be Transmitted to others, for example, perinatally or through sexual contact.
Recent research related to these safety concerns includes a study in rhesus macaque monkeys showing that an attenuated SIV vaccine protected adult females from SIV disease but was lethal in their newborns. Other research has demonstrated that some genetic changes made to attenuate SIV are quickly "repaired" after the modified SIV is inoculated into monkeys.
Areas of Research Contributing to the Potential Development of an Attenuated AIDS Vaccine for Humans
-The genetic and biological basis of attenuation.
-The mechanisms of attenuation conferred by deleting specific virus genes.
-The mechanisms by which live-attenuated SIV and HIV vaccines cause protection.
-Long-term safety studies in non-human primates that have received various attenuated model AIDS vaccines to study:
- what elements of the virus need to be included or deleted to ensure a safe yet immunogenic vaccine.
- the possibility of reversion of attenuated strains to disease-causing strains through recombination of attenuated SIV or HIV with either other viruses or with host genetic sequences.
- initiation of malignant transformation in infected cells.
The relationship, if any, between disease course and naturally attenuated HIV strains.
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