Serum Immunoglobulin A Cross-Strain Blockade of Human Noroviruses

Noroviruses (NoVs) are a leading cause of gastroenteritis outbreaks in all age groups, contributing to an estimated 21 million illnesses per year in the United States [1]. Although genogroup II (GII).4 NoV strains predominate worldwide, a large number of diverse NoV strains cocirculate at endemic levels. Genogroup I (GI) strain infections occur most frequently in children and the elderly [2, 3]. Norovirus disease is usually self-limiting in healthy individuals, but it can be severe in the very young, elderly, and immunocompromised [3–5]. A NoV vaccine would benefit these vulnerable groups as well as the military, food-handlers, and support-care workers. An understanding of the complex antigenic relationship between NoV strains will aid in vaccine development. Currently, a multivalent (GI.1/GII.4C) virus-like particle (VLP) vaccine is in phase I clinical trials [6]. Cross-strain reactive blockade Ab responses, a potential measure of strain cross-neutralization and a correlate to protective immunity in GI.1-challenged participants [7], were identified in serum samples collected during an initial reactogenicity trial of the vaccine [8]. These data support the hypothesis that some similar neutralizing antibody (Ab) epitopes might exist within both GI and GII NoV strains that could potentially provide targets for a broadly protective vaccine. Likewise, we have previously characterized Ab responses in humans after GI.1 NoV experimental infection [9], and we found that GI.1 infection induced blockade Ab cross-reactive within a panel of GI VLPs. In this follow-up study using the same serum samples, we extend these observations to identify serum immunoglobulin (Ig)A as a component of the cross-GI blockade Ab response, and we characterize the antigenic relationship between GI VLPs using a panel of monoclonal Abs (mAbs). These mAbs include the first reported human mAbs to GI NoV strains.