Candidate TB Booster Vaccine Shows Promise in Phase 1 Study

From Medscape Medical News

Megan Brooks

March 18, 2010 — In a phase 1 study, a booster vaccine against Mycobacterium tuberculosis had an acceptable safety profile and was immunogenic in healthy M tuberculosis–uninfected adults from South Africa who had been previously vaccinated with the only currently available tuberculosis (TB) vaccine, Bacille Calmette Guerin (BCG).

The vaccine, AERAS-402, developed by Aeras Global Tuberculosis Foundation and by Dutch biotechnology firm Crucell NV, induced a robust polyfunctional CD4 T cell response as well as a potent and durable CD8 T cell response, which appears "extremely promising," the study team reports in an article published online March 18 in the American Journal of Respiratory and Critical Care Medicine.

AERAS-402 is made up of a recombinant, replication-deficient adenovirus, serotype 35 (Ad35), expressing a fusion protein created from the mycobacterial antigens Ag85A, Ag85B, and TB10.4.

"This is the first clinical report of an Ad35 vectored vaccine given to humans in a heterologous prime-boost strategy," first author Brian Abel, PhD, from the University of Cape Town, South Africa, and colleagues note in their report. Ad35 is an attractive vector, they point out, because worldwide, the seroprevalence and levels of neutralizing antibody titers to this adenovirus are lower relative to other adenoviruses.

In the phase 1 safety and immunogenicity study conducted in South Africa, escalating doses of AERAS-402 were given intramuscularly to 3 groups of healthy, BCG-vaccinated adults not infected with M tuberculosis. A fourth group received 2 shots of the highest dose of the vaccine. Altogether, 29 participants received the AERAS-402 vaccine, and 11 received placebo. All were between 21 and 39 years old.

There were no serious vaccine-related adverse events, and increasing the vaccine dose did not result in an increase in adverse events, the investigators report. The majority of adverse events were mild (74%) or moderate (19%) in severity, of short duration, and resolved without sequelae.

AERAS-402 induced strong CD4 T cell responses dominated by polyfunctional cells coexpressing gamma interferon, alpha tumor necrosis factor, and interleukin 2, which are thought to be important for protection against intracellular pathogens such as M tuberculosis.

However, what was "most striking," the investigators say, was that the vaccine induced a potent CD8 T cell response, characterized by cells expressing gamma interferon and/or alpha tumor necrosis factor, which persisted throughout the study period.

"To date, most new TB vaccines have been reported to induce reasonable CD4 T cell responses, but relatively negligible CD8 T cell responses," Dr. Abel and colleagues note. Evidence is mounting, they add, that CD8 T cells mediate key roles in protective immunity against TB, leading them to hypothesize that the induction of robust vaccine-specific CD4 and CD8 T cell responses after AERAS-402 "would correlate with a more efficacious outcome."

The findings from this phase 1 study support further clinical trials assessing the efficacy of AERAS-402 as a TB booster vaccine, the investigators conclude.

The study was supported by the Aeras Global Tuberculosis Vaccine Foundation and by Crucell NV. The authors have disclosed no relevant financial relationships.

Am J Respir Crit Care Med. Published online March 18, 2010