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Received Aug 31, 2017; Accepted Jan 16, 2018
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1. Introduction
The need for norovirus (NoV) vaccine is apparent, as NoV is the most common cause of acute viral gastroenteritis worldwide with approximately 200,000 annual deaths [1]. It infects humans of all ages, but children <5 years of age, the elderly, and immunocompromised individuals are at the highest risk. The most advanced NoV vaccine in phase II clinical trials is based on virus-like particles (VLPs) administered intramuscularly (IM) with aluminum hydroxide (Al(OH)3) [2] or a combination of Al(OH)3 and monophosphoryl lipid A (MPLA) [3–6]. Alternative intranasal (IN) administration of NoV VLPs has previously been evaluated as well [7, 8]. Despite the lack of the definite vaccine-associated correlate of protection for NoV, mucosal immunity is known to play a significant role in protection from infection and disease caused by enteric pathogens, including NoV [9–12].
At present, there are only a few adjuvants approved for human use, and none for mucosal delivery [13, 14]. Aluminum salts (Alum) and MPLA are adjuvants commonly included in the formulation of licensed protein subunit vaccines, such as VLP-based vaccines against human papilloma virus (Cervarix®, Gardasil®) and hepatitis B virus (Engerix-B®, Recombivax HB®). Alum, the first and predominant adjuvant in human vaccines, is employed to stabilize the vaccine antigen and also as a delivery system [13, 15]. MPLA, a new-generation toll-like receptor- (TLR-) based adjuvant, is a TLR4 agonist, which activates innate immunity [16, 17], thereby influencing the development of adaptive immunity. Recently, alum has been described to possess immunomodulatory features as well [18]. Both of these adjuvants stimulate systemic immune responses, when administered parenterally with the vaccine antigens. However, their effect on antigen-specific mucosal immunity is not known.
We have recently shown that NoV GII.4 VLPs induce protective IgA antibodies in mucosal lavages of mice immunized via intranasal (IN), but not IM, route [9]. Here, we investigated if IM delivery of NoV GII.4 VLPs formulated with commonly used adjuvants, Al(OH)3 or MPLA, has an effect on generation of NoV-specific mucosal immunity.
2. Materials and Methods
2.1. Recombinant NoV...