In a recent phase 2 trial, several different formulations of a bivalent norovirus vaccine candidate were well-tolerated and induced immune responses that persisted for 1 year after vaccination.
Following these promising results, one of the vaccine formulations has been selected to move forward in clinical development, according to Geert Leroux-Roels, MD, PhD, professor at Ghent University and University Hospital in Belgium, and colleagues.
Noroviruses are the most significant cause of nonbacterial gastroenteritis outbreaks worldwide, the researchers reported. The viruses are categorized into seven different genogroups and more than 40 genotypes. Those responsible for most human infections are in genogroups GI and GII.
“Norwalk virus was the first identified norovirus, the GI.1 genotype of the GI genogroup,” Leroux-Roels and colleagues wrote in The Journal of Infectious Diseases. “However, since the mid-1990s, the GII.4 genogroup has been the principal cause of human disease, and despite yearly drift of norovirus strains, GII.4 genotypes remain dominant and responsible for most outbreaks worldwide.”
The researchers conducted a phase 2, double-blind, randomized controlled trial to examine the safety and efficacy of an investigational bivalent norovirus vaccine (Takeda Pharmaceuticals) that is based on the Norwalk GI.1 strain and a consensus strain derived from three different GII.4 types known as GII.4c. Fourteen different formulations of the vaccine, administered intramuscularly, were assessed in 420 healthy adults. The participants were divided equally into two groups stratified by age (18 to 49 years and 50 to 64 years) and randomly assigned to a single-dose or two-dose regimen containing either 15 g, 50 g or 150 g of each virus-like particle and 167 g or 500 g of Al(OH) per 0.5-mL dose. Some participants received a regimen adjuvanted with either 15 g or 50 g of monophosphoryl lipid A (MPL). To maintain the blind randomization, participants who received only one dose of the norovirus vaccine were given a hepatitis A vaccine (Havrix, GlaxoSmithKline) as their second dose, spaced 28 days apart.
Fifty-six days after the first dose was administered, all formulations induced similar immune responses, which were measured by Pan-Ig and IgA antibodies, as well as histo-blood group binding antigen blocking titers (HBGA). The rate of seroresponse ranged across the study groups from 80% to 100% for GI.1 and 33.3% to 83.3% for GII.4c. Although immune responses waned by the end of the follow-up period at 393 days, they remained higher than baseline levels.
In a safety analysis, all vaccine formulations were well-tolerated, according to the researchers. The rate of systemic adverse events was similar among patients who received Havrix and those who received the second norovirus vaccine dose. The most common adverse events included headache, fatigue, diarrhea and myalgia.
The second dose of the norovirus vaccine did not increase the magnitude or longevity of the immune responses, and there was no evidence of an added benefit with MPL. Instead, MPL appeared to lower Pan-Ig and HBGA-blocking antibody responses to GI.1, according to the researchers. Further analysis showed that increasing GI.1 and GII.4c dosages incrementally increased immune responses. However, the higher GI.1 dosage had a refractory effect on the GII.4c response. Therefore, the researchers determined that the formulation containing 15 g of GI.1 and 50 g of GII.4c with 500 g of Al(OH) “elicited the best balance of immunogenicity.” The regimen will be further evaluated in clinical trials.
“Although generally self-limiting in healthy adults, norovirus illness can be serious and cause complications and even death in older adults and those with chronic medical conditions,” the researchers concluded. “It is encouraging to note that the younger and older age cohorts in this study displayed similar immune responses to the different formulations, although further studies will be required in elderly cohorts who will also present the opposing complications of immunosenescence and immune memory of related strains.” – by Stephanie Viguers
Disclosure: The study was sponsored by Takeda Vaccines, Inc.