By Regina McEnery

Mention Sendai and many people think of the 2011 earthquake and tsunami that devastated Japan. But Sendai is the name of an RNA virus that is being used as a viral vector in a recently launched Phase 1 AIDS vaccine trial. This is the first time Sendai is being used in an AIDS vaccine candidate. 

The vector carries an immunogen—the active ingredient of a vaccine—derived from the predominant subtype of HIV that circulates in East Africa, clade A HIV. But what distinguishes this vector is its ability to replicate within the body following delivery, and its replication within mucosal tissues. It is in such tissues, mainly in the gut, that HIV establishes a foothold in the early stages of infection. The Sendai candidate, researchers hope, might recruit targeted immune responses to mucosal tissues and provide an edge to the immune system when it is subsequently challenged by HIV.

The randomized, double-blind, placebo-controlled trial known as S001 began screening volunteers in Rwanda in March, is expected to start soon in the UK, and eventually Kenya. The trial is testing the safety and immunogenicity of a prime-boost regimen of the Sendai vector and another HIV vaccine candidate built from an inactivated strain of another virus, adenovirus serotype 35 (Ad35), a common virus that causes colds and respiratory infections. The two candidates will be given to volunteers four months apart.

The four-group study will enroll 64 healthy HIV-uninfected men and women ages 18-50. In the first part of the trial, vaccine recipients will receive a lower dose of the Sendai candidate containing the HIV subtype A gag gene, administered intranasally, followed by an intramuscular injection of the Ad35 viral vector vaccine candidate four months later. The Ad35 vaccine candidate contains four HIV genes: nef, reverse transcriptase, integrase, and gag. Volunteers in the next part of the trial will receive a higher dose of the Sendai candidate vaccine followed by the Ad35 vaccine candidate four months later in the second group, and the Ad35 vaccine candidate followed by the Sendai vaccine candidate in the third group. Vaccine recipients randomized to the fourth group will be given two intranasal administrations of the Sendai candidate.

The Sendai virus was isolated in 1952 in Japan. It is part of the Paramyxoviridae family of viruses, which includes measles, mumps, canine distemper, and human parainfluenza viruses. Though Sendai causes respiratory tract illness in rodents, it is not known to cause human disease. The Sendai viral vector was developed by the Japan-based DNAVEC Corporation and the Ad35 viral vector candidate was developed by IAVI, which is sponsoring the Phase 1 trial and supplying the vaccine candidate to the three clinical sites. 

Evidence suggests that replicating viral vectors might be able to elicit broader, more potent, and durable immune responses against the immunogens they carry (see VAX Dec. 2007 Primer on Understanding Replicating Viral Vectors).

Dagna Laufer, IAVI’s Senior Director for Medical Affairs, said one of the aims of the trial will be to see how well intranasal immunization alone or in a prime-boost regimen with the Ad35 viral vector vaccine candidate induces systemic and mucosal immune responses. While different vaccination routes elicit different mucosal responses, nasal immunization may not only stimulate an immune response in saliva, nasal secretions, and other parts of  the respiratory tract, but also in more distant mucosal sites, such as the vagina or rectum (see image below).

Routes of immunization. Oral immunization leads to an immune response in parts of the gut, as well as mammary and salivary glands, rectal immunization induces immune responses in the rectum, and vaginal immunization induces a vaginal immune response. A notable exception is nasal immunization, which not only stimulates an immune response in saliva, nasal secretions and in the respiratory tract, but can also elicit a strong vaginal mucosal immune response. In the diagram, the red shading indicates the strength of the response.

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.