Understanding Therapeutic Vaccination

What is therapeutic vaccination and how are scientists using it today to develop new strategies against HIV?

By Regina McEnery

In the late 18th century, the British doctor Edward Jenner scratched some pus from a Cowpox sore into the arm of an eight-year-old boy to see whether exposure to the virus it contained—vaccinia variola—would subsequently protect the child from its far deadlier relative, the smallpox virus. The experiment might have been highly unethical by current standards, but its success revolutionized preventive medicine and established Jenner, in the eyes of many, as the founding father of immunology.
 
It also gave us the word “vaccine,” which is today used to describe a variety of substances administered to prevent disease—such as the live-attenuated or inactivated viruses contained in flu shots, or the molecular fragments of HIV that are used to make AIDS vaccine candidates. Though experimental and approved vaccines that fail to prevent infections might well dampen the severity of their targeted diseases, vaccination is generally associated more with the prevention of infection than its treatment (see VAX May 2009 Primer on Understanding How Partially Effective Vaccine Candidates are Evaluated).

But an entirely different sort of vaccine has lately become the focus of intense scientific research: the therapeutic vaccine. Such vaccines are currently being devised to harness the immune response to treat diseases ranging from cancer to multiple sclerosis. AIDS researchers too have sought to develop therapeutic vaccines in hopes of delaying or preventing the onset of AIDS in the HIV infected. The first person to try this was the French scientist Daniel Zagury, who in 1986 inoculated two HIV-infected women from Zaire (now the Democratic Republic of the Congo) with a genetically engineered version of an HIV protein. To deliver the HIV fragments, Zagury used a viral vector based on the vaccinia virus used in the smallpox vaccine. Soon after, Zagury tested the candidate in eight more HIV-infected individuals.

Zagury’s research, however, provoked controversy because his vaccine wasn’t adequately tested in preclinical studies, and because he did not obtain French regulatory approval for the trial. To make matters worse, three of the vaccinees died from severe, progressive necrosis that developed at the injection site, a reaction triggered by the recombinant vaccinia virus that was used as a vector. (The rare complication has also occurred in immune-compromised individuals vaccinated against smallpox.) This set back the pursuit of therapeutic vaccination, and the field languished for years.

The dawn of HAART

It took the introduction of highly active antiretroviral therapy (HAART) in 1996 to revive the field, and therapeutic vaccination is now being considered by some researchers as a potentially valuable component of investigational therapies to cure HIV infection.  The three or more drugs simultaneously used in HAART potently suppress viral replication in the blood, allowing the body to rebuild its immune system. But such regimens cannot by themselves cure HIV infection, since the virus weaves itself into the chromosomes of resting CD4+ T cells, creating a population of latently infected cells known as the viral reservoir. Because the virus in these T cells doesn’t replicate, it is unaffected by HAART.

While it is not entirely clear how these latent reservoirs form or are maintained, they have become the central focus of HIV cure research. Scientists believe that one way to cure HIV could be to locate and drain the reservoirs. In one recent clinical trial conducted in HIV-infected people on HAART who had undetectable viral loads, for example, a chemotherapy drug named vorinostat was used to roust HIV from latent cells in hopes of depleting such reservoirs and clearing the virus. More recent studies suggest, however, that single or multiple doses of this drug were unable to clear infected cells, suggesting that multiple strategies will likely be needed to do the job.

Scientists and pharmaceutical companies have also been evaluating other drug compounds to ferret out latent HIV and eradicate it or expose it to immune attack. The hope is that even if such approaches leave patients with a residual HIV infection, they will have suppressed the virus sufficiently to achieve what’s referred to as a functional cure.

So where does therapeutic vaccination enter into all of this? Scientists believe that the active recruitment of an immune cell known as the CD8+ T cell, which destroys virally infected cells, would help ensure that exposed cells of the viral reservoir are eliminated. Unfortunately, previous studies have found that the CD8+ T-cell responses induced in HIV-infected individuals were not sufficiently broad or potent to control the virus. Researchers are now trying to address this deficiency by boosting CD8+ T-cell responses through therapeutic vaccination.

The hope is that by first administering compounds to expose latent virus and then following up with therapeutic vaccination, it might be possible to suppress HIV indefinitely without relying on daily ARVs. Scientists are also evaluating therapeutic vaccine candidates as a single strategy for suppressing HIV after HAART is stopped. One candidate recently tested in a Phase I trial contained subsets of dendritic cells. These specialized immune cells act as first responders by detecting viruses and recruiting immune responses to target them. Unfortunately, this vaccine candidate, tested in a small group of individuals in Spain, did not work well enough to keep HIV-infected individuals off of HAART for very long (see VAX Jan. 2013 Global News).
 
Scientists have also shown in animal studies that therapeutic vaccination could further reduce and actively suppress the levels of residual virus following HAART. While the animals were on ARVs, the vaccine additionally lowered the average viral load of the monkeys to about 100 copies per ml of blood. When ARV treatment was stopped eight weeks after the final vaccination, the mean viral load did not rebound in the vaccinated animals.

Though they still have a long way to go, researchers hope that therapeutic vaccines may one day offer an alternative strategy to the daily grind of HAART for people infected with HIV.