Berkeley, California-based Dynavax announced April 17 that the FDA is requesting preclinical and clinical safety data on two investigational new drug applications for its hepatitis B vaccine, Heplisav, which combines an immunostimulatory sequence (ISS 1018) with hepatitis B antigen. Trials with Heplisav were halted last month in response to a serious adverse effect report from a phase 3 trial comparing Heplisav to a marketed hepatitis B vaccine, Engerix-B, sold by GlaxoSmithKline in London. (Merck, of Whitehead Station, New Jersey, which has the only other marketed hepatitis B vaccine, called Recombivax, is partnered with Dynavax on Heplisav.) After receiving two doses of Heplisav, one subject was preliminarily diagnosed with Wegener's granulomatosis, an autoimmune disease characterized by inflammation of the vasculature. Though dosing in that trial was complete, Dynavax halted a phase 2 trial of patients with end-stage renal disease. Early results for Heplisav had looked promising. A trial report in November 2006 that compared the product with Engerix-B showed that a larger percentage of recipients on Dynavex responded with what appeared to be a more robust response with fewer doses of vaccine (98.5% seroprotection versus 25% after two doses). It's not clear what caused the serious adverse effect, but immunostimulatory sequences—short oligodeoxynucleotides containing at least one internal unmethylated CpG—stimulate innate immunity by interacting with Toll-like receptors on immune cells, like the pathogen-associated molecular patterns they were designed to resemble. Immunomodulatory molecules sometimes raise safety concerns, owing to the possibility of inducing autoimmunity or causing the overproduction of inflammatory molecules, but this is the first serious adverse effect potentially related to Heplisav, 5,000 doses of which have been injected into 2,500 subjects in seven trials over the last ten years. In addition, at least 50 other clinical trials using immunostimulatory sequences have been reported to, ten using ISS 1018 in Heplisav. Eyal Raz, professor of medicine at University of California at San Diego, founder of Dynavax (though he no longer has ties to the company), says that although immunostimulatory sequences given to people with preclinical disease might “take it up a notch,” he feels this is unlikely, given that they have been used in humans for over a decade.