Rotavirus virus-like particles administered mucosally induce protective immunity

Abstract

We have evaluated the immunogenicity and protective efficacy of rotavirus subunit vaccines administered by mucosal routes. Virus-like particles (VLPs) produced by self-assembly of individual rotavirus structural proteins coexpressed by baculovirus recombinants in insect cells were the subunit vaccine tested. We first compared the immunogenicities and protective efficacies of VLPs containing VP2 and VP6 (2/6-VLPs) and G3 2/6/7-VLPs mixed with cholera toxin and administered by oral and intranasal routes in the adult mouse model of rotavirus infection. VLPs administered orally induced serum antibody and intestinal immunoglobulin A (IgA) and IgG. The highest oral dose (100 microg) of VLPs induced protection from rotavirus challenge (> or = 50% reduction in virus shedding) in 50% of the mice. VLPs administered intranasally induced higher serum and intestinal antibody responses than VLPs administered orally. All mice receiving VLPs intranasally were protected from challenge; no virus was shed after challenge. Since there was no difference in immunogenicity or protective efficacy between 2/6- and 2/6/7-VLPs, protection was achieved without inclusion of the neutralization antigens VP7 and VP4. We also tested the immunogenicities and protective efficacies of 2/6-VLPs administered intranasally without the addition of cholera toxin. 2/6-VLPs administered intranasally without cholera toxin induced lower serum and intestinal antibody titers than 2/6-VLPs administered with cholera toxin. The highest dose (100 microg) of 2/6-VLPs administered intranasally without cholera toxin resulted in a mean reduction in shedding of 38%. When cholera toxin was added, higher levels of protection were achieved with 10-fold less immunogen. VLPs administered mucosally offer a promising, safe, nonreplicating vaccine for rotavirus.

Induction of mucosal immune responses and protection against enteric viruses: rotavirus infection of gnotobiotic pigs as a model

“…or i.p.) induced complete or signi®cant partial protection against infection with or without adjuvants (Conner et al, 1993;McNeal et al, 1992McNeal et al, , 1998McNeal et al, , 1999aOf®t and Dudzik, 1989;O'Neal et al, 1997O'Neal et al, , 1998. We evaluated the immunogenicity and protective ef®cacy of non-replicating rotavirus vaccines in combination with different adjuvants, including inactivated Wa HRV given by the oral or i.m.…”

“…route has been shown to be more ef®cient for the induction of IgA antibody responses in the upper respiratory and genitourinary tract, and less ef®cient for the intestinal lamina propria in rodents and pigs (Brandtzaeg et al, 1999;McDermott and Bienenstock, 1979;VanCott et al, 1994), the i.n. vaccination route has been shown to be effective for induction of protective immunity against rotavirus infection in adult mice (O'Neal et al, 1997(O'Neal et al, , 1998McNeal et al, 1999b). In gnotobiotic pigs, double-layered 2/6-VLP vaccines derived from co-expression of the bovine RF core protein VP2 gene and the inner capsid protein VP6 gene of simian SA11 or human Wa rotavirus strains were evaluated using the i.n.…”

“…There are numerous reports of protective immunity against rotavirus infection in adult mice induced by different types of rotavirus antigens (e.g. live or inactivated, homologous or heterologous rotavirus (Feng et al, 1994;McNeal et al, 1992McNeal et al, , 1998McNeal et al, , 1999aOf®t and Dudzik, 1989); recombinant rotavirus proteins or VLPs Choi et al, 1999;O'Neal et al, 1997O'Neal et al, , 1998; and DNA plasmids (Chen et al, 1997(Chen et al, , 1998Herrmann et al, 1996)], using various routes of inoculation (oral, i.n., i.m., i.p., or i.d.). When comparing studies of mice, there are discrepancies in the protective ef®cacies of rotavirus vaccines possibly due to the use of different strains of in-or out-bred adult mice or murine rotaviruses.…”

Rotavirus Infection Enhances Lipopolysaccharide-Induced Intussusception in a Mouse Model

“…Viruses. A murine EC wt (P [17], G3) rotavirus stock was produced, and the 50% infectious does (ID 50 ) was determined in mice as described previously (68). The EDIM wt (P [17], G3) virus stock used was kindly characterized and supplied by Richard Ward (96).…”

“…Serum TNF-␣ and IFN-␥ levels were determined by enzyme-linked immunosorbent assay (ELISA; R&D Systems, Minneapolis, MN, and Endogen, Woburn, MA, respectively) according to the manufacturer's directions, except that the TNF-␣ coating antibody was used at 1.6 g/ml. Fecal rotavirus antigen shedding and total rotavirus-specific antibody titers were assessed in individual mice by using established ELISAs (68).…”