Abstract
Rotaviruses (RVs) and noroviruses (NoVs) are major causes of childhood acute gastroenteritis. During development of a combination vaccine based on NoV virus-like particles (VLP) and RV VP6 produced in baculovirus expression system in insect cells, a dual role of VP6 as a vaccine antigen and an adjuvant for NoV-specific immune responses was discovered. Here the VP6 adjuvant effect on bivalent GI.4 and GII.4-2006a NoV VLPs produced in Nicotiana benthamiana was investigated. BALB/c mice were immunized intradermally with suboptimal (0.3 µg) dose of each NoV VLP alone or combined with 10 µg of VP6, or equal doses of NoV VLPs and VP6 (1 µg/antigen). NoV-specific serum IgG antibodies and their blocking activity were analyzed using vaccine-homologous and heterologous NoV VLPs. Immunization with 0.3 µg NoV VLPs alone was insufficient to induce NoV-specific immune responses, but with co-administration of 10 µg of VP6, antibodies against vaccine-derived and heterologous NoV genotypes were generated. Furthermore, corresponding adjuvant effect of VP6 was observed with 1 µg dose. Efficient uptake and presentation of VP6 by dendritic cells was demonstrated in vitro. These results show that adjuvant effect of VP6 on bivalent NoV VLP vaccine is independent of the cell source used for vaccine production.
Highlights
Norovirus (NoV) infections are the most common cause of acute gastroenteritis worldwide across all age groups, causing estimated 685 million cases of acute gastroenteritis (AGE) each year and being responsible for 50,000 yearly deaths of children under five years of age [1,2]
During development of a combination vaccine based on NoV virus-like particles (VLP) and RV VP6 produced in baculovirus expression system in insect cells, a dual role of VP6 as a vaccine antigen and an adjuvant for NoV-specific immune responses was discovered
Efficient uptake and presentation of VP6 by dendritic cells was demonstrated in vitro. These results show that adjuvant effect of VP6 on bivalent NoV VLP vaccine is independent of the cell source used for vaccine production
Summary
Norovirus (NoV) infections are the most common cause of acute gastroenteritis worldwide across all age groups, causing estimated 685 million cases of acute gastroenteritis (AGE) each year and being responsible for 50,000 yearly deaths of children under five years of age [1,2]. We have developed a trivalent combination vaccine candidate children as a primary target group against NoV and RV AGE, consisting of two NoV virus-like particles (VLPs), GII.4-1999 and GI. and oligomeric RV VP6 [7,8]. Positive correlation of serum IgA targeted to RV VP6 following both RV infection and vaccination has been observed in humans [19,20,21] These characteristics make VP6 an ideal non-live RV vaccine candidate, but it has been demonstrated that RV VP6 has an adjuvant effect on co-delivered antigens such as NoV VLPs [7,22,23,24,25,26]. In vitro assays using mouse primary bone-marrow-derived dendritic cells (BMDCs) were performed to test plant-derived VP6 interaction with antigen-presenting cells (APC)
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