Identification of Human Monoclonal Antibodies That Neutralize Pandemic GII.4 Noroviruses
Human monoclonal antibodies able to neutralize live human norovirus GII.4 Sydney 2012—the predominant strain responsible for recent outbreaks—are reported in the December issue of Gastroenterology. Researchers analyzed these antibodies and identified the neutralizing epitopes, providing insight into the human immune response to this deadly virus.
Inhibition of replication of GII.4 Sydney 2012 virus using selected IgGs, IgAs, and a nonspecific mAb, tested in the human intestinal enteroid system. Controlsfor each experiment were virus incubated without mAb. The IC50 value for each mAb is indicated on each graph. Data presented are an average of 2 independent experiments for NORO-263, -250B, -320, -273A, and -318 and a Dengue virus–specific control antibody 2D22.
Human noroviruses are the major cause of epidemic and sporadic acute gastroenteritis, due to their low infectious dose, environmental stability, high levels of shedding, and prolonged shedding even after symptoms have resolved. Noroviruses cause an average 19–21 million cases of infection and 570–800 deaths in children younger than 5 years each year in the United States, although they infect people of all ages. Even though infection is usually acute and self-limited, disease can become life threatening in young, old and immunocompromised people.
The extreme antigenic diversity of strains poses challenges to developing antibodies or vaccines to prevent noroviruses-associated disease. Noroviruses are classified into 7 different genogroups (genogroups [G] I–VII), and at least 41 different genotypes. Viruses from G1 and the rapidly evolving GII account for nearly all human infections. The human norovirus genome contains 3 open-reading frames (ORFs). ORF1 encodes nonstructural proteins, whereas ORF2 and ORF3 encode the major and minor capsid proteins, respectively.
Noroviruses could not previously be cultivated in cell culture, but the VP1 and VP2 protein sequences could be expressed using a baculovirus expression system to produce human noroviruses virus-like particles (VLPs). These VLP reagents have facilitated the study of norovirus evolution, antigenicity, and the emergence of strains.
In the journal Clinical Gastroenterology and Hepatology, Shintaro Sato et al report propagation of human norovirus (the the GII.3, GII.4, GII.6, and GII.17 genotypes) in human induced pluripotent stem cell-derived intestinal epithelial cells.
Since the mid-1990s, viruses from GII genotype 4 (GII.4) have caused most outbreaks, with new strains emerging every 2–3 years. In 2012, the GII.4 Sydney strain emerged and began spreading globally—it has continued to predominate among circulating strains. However, the molecular basis for antibody-mediated recognition of these strains and their mechanisms of action are not well characterized.
Dr. Kristine Novak is the science editor for Gastroenterology and Clinical Gastroenterology and Hepatology. She has worked as an editor at biomedical research journals and as a science writer for 15 years, covering advances in gastroenterology, hepatology, cancer, immunology, biotechnology, molecular genetics, and clinical trials. She has a PhD in cell biology and an interest in all areas of medical research.
