First candidate HIV vaccine to employ Sendai vector poised for trials
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.