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Inactivated HIV vaccines
After live attenuated vaccines, the second classic technique, used in creating the world's first successful polio vaccine, is to create a vaccine based on 'killed' virus particles.
This technique is considered risky, especially by vaccine manufacturers. Should inactivation fail, vaccine recipients could be infected with HIV and compensation costs would be large, especially in the United States. The present tendency is therefore to think of these vaccines primarily as therapies for people already infected with HIV, rather than as preventive vaccines.
Early attempts to inactivate HIV and simian immunodeficiency viruses (SIVs) were beset by two problems. The first was the fragility of the viruses. Traditional methods of inactivating a virus, using heat or formalin treatment, are particularly disruptive to the envelope proteins gp120 and gp41, against which any neutralising antibody response would have to be directed. It now turns out that by careful selection of HIV strains, whole killed vaccines can be produced by traditional methods.
The second problem was the failure to recognise the importance of growing vaccine strains and challenge viruses in monkey cell cultures rather than in human ones. This seems to have damaged the credibility of the whole approach in the eyes of funders.
Despite these problems, Dr Jonas Salk, who developed the polio vaccine, devoted the last years of his life to developing a killed HIV vaccine or immunogen, now called Remune. This preparation is based on an African subtype G isolate of HIV and has the envelope protein gp120 removed. There is some evidence that it can induce cellular immune responses in people with HIV, which goes against much previous dogma, to the effect that killed viruses are only capable of inducing antibodies. However, despite claims from a Thai open-label study that Remune limited viral load and boosted CD4 cell counts when given to people with HIV with relatively well-preserved immunity, clinical development of the product has ceased (Chantratita 2004).
Preventive 'whole killed' vaccines
There is now some revival of interest in creating whole killed vaccines, using different chemicals to inactivate the virus. In particular, these are based on targeting the 'zinc fingers' of the structural ('nucleocapsid') HIV proteins.
The rationale for investigating this target was provided by observations that SIV containing a mutant nucleocapsid was found to be non-infectious in one macaque (Gorelick 1999). A substance called aldithriol-2 is able to modify the zinc fingers without disrupting other proteins. A study of its use to inactivate large quantities of concentrated SIV virus particles has recently been described by a United States National Cancer Institute team, headed by Dr Larry Arthur in Frederick, Maryland. They report that inactivated viral particles retain 'oligomeric' envelope proteins that are fully capable of fusing with cells.
A British research group led by Professor John Oxford at the Royal London Hospital has been working on inactivated HIV vaccines for a number of years, using two agents (β-propiolactone and binary ethylenimine). They have been unable to show protection in monkeys after applying their system of inactivation to SIV. However, an associated biotechnology company called Retroscreen has negotiated with the Medicines Control Agency to clarify the conditions to be met for trials of such a construct in people with HIV.
If vaccines made using this technology were proven to be effective in animals, the production of HIV vaccines, and human trials in people living with HIV, could follow quite rapidly. The question of whether, how, and where to test them as possible preventive vaccines might then become an issue.
Distinguishing vaccination with a whole inactivated HIV vaccine from natural infection with HIV could be a problem. Antibody tests might not be able to separate people who have been vaccinated from those with HIV. Alternative tests are more expensive and may be less reliable. There are also considerable problems in evaluating therapeutic uses of HIV vaccines since clinical endpoints, and not merely evidence of immune responses, would be essential for licensing them. As people would need to be provided with effective antiretroviral treatment throughout the trials, those trials would need to be very large and lengthy, and it would be expensive to arrive at conclusive results.