Comparison of mucosal and systemic humoral immune responses and subsequent protection in mice orally inoculated with a homologous or a heterologous rotavirus

Abstract

Rotaviruses are the single most important cause of severe diarrhea in young children worldwide, and vaccination is probably the most effective way to control the disease. Most current live virus vaccine candidates are based on the host range-restricted attenuation of heterologous animal rotaviruses in humans. The protective efficacy of these vaccine candidates has been variable. To better understand the nature of the heterologous rotavirus-induced active immune response, we compared the differences in the mucosal and systemic immune responses generated by heterologous (nonmurine) and homologous (murine) rotaviruses as well as the ability of these infections to produce subsequent protective immunity in a mouse model. Sucking mice were orally inoculated with a heterologous simian or bovine rotavirus (strain RRV or NCDV) or a homologous murine rotavirus (wild-type or tissue culture-adapted) strain EHP at various doses. Six weeks later, mice were challenged with a virulent murine rotavirus (wild-type strain ECW) and the shedding of viral antigen in feces was quantitated. Levels of rotavirus-specific serum immunoglobulin G (IgG) and fecal IgA prior to challenge were measured and correlated with subsequent viral shedding or protection. Heterologous rotavirus-induced active protection was highly dependent on the strain and dose of the virus tested. Mice inoculated with a high dose (107 PFU per mouse) of RRV were completely protected, while the protection was diminished in animals inoculated with NCDV or lower doses of RRV. The ability of a heterologous rotavirus to stimulate a detectable intestinal IgA response correlated with the ability of the virus to generate protective immunity. Serum IgG titer did not correlate with protection. Homologous rotavirus infection, on the other hand, was much more efficient at inducing both mucosal and systemic immune responses as well as protection regardless of the virulence of the virus strain or the size of the immunizing dose.

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

“…The protection rates from the virulent, AttHRV2Â, and AttHRV3Â inoculation groups were positively correlated with the magnitude of IgA ASC and memory B-cell responses in the intestinal lamina propria. A positive correlation between intestinal IgA antibody responses and protection was also shown in a study of mice comparing the differences in the mucosal and systemic immune responses generated by oral inoculation of mice with heterologous (non-murine) and homologous (murine) rotaviruses and the ability of these infections to produce protective immunity against subsequent reinfection upon challenge (Feng et al, 1994). Sucking mice were inoculated orally with live rhesus (RRV), bovine (NCDV), or murine (EHP) rotavirus and challenged at PID 42 with virulent murine rotavirus (ECW).…”

“…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.…”

Enteric Viral Infections of Pigs and Strategies for Induction of Mucosal Immunity

“…Similarly, in studies of natural rotavirus infections in children, higher fecal IgA antibody titers to rotavirus were associated with protection against infection and illness (Matson et al, 1993). Mouse studies of rotavirus-induced infection revealed similar findings: induction of intestinal IgA antibody responses were positively associated with protection against rotavirus shedding (Feng et al, 1994).…”

Ovine rotavirus strain LLR-85-based bovine rotavirus candidate vaccines: Construction, characterization and immunogenicity evaluation

“…Genotypic analyses of a major neutralization protein VP7 of a bovine rotavirus in diarrheal stools collected in different cattle populations throughout the world have shown that the majority of typeable rotavirus isolates belong to G genotypes 6 and 10 (Alfieri et al, 2004;Chang et al, 1996;Falcone et al, 1999;Garaicoechea et al, 2006;Monini et al, 2008;Parwani et al, 1993;Reidy et al, 2006;Snodgrass et al, 1990). Since the first licensed bovine rotavirus vaccine was a monovalent one, monovalent rotavirus vaccine cannot completely protect against heterologous rotavirus infection (Feng et al, 1994). We constructed a reassortant rotavirus strain R191 that contains a single VP7 gene encoding genotype G6 specificity of bovine rotavirus NCDV strain and the remaining 10 genes of ovine rotavirus strain LLR-85.…”

“…In China, our epidemiologic surveillance has shown that rotavirus diarrhea is one of the most important diseases of neonatal calves, and that G6 and G10 were also determined to be the most prevalent genotype of the bovine rotaviruses using nested RT-PCR and sequencing (Chang et al, 2008). Since monovalent rotavirus vaccine cannot completely protect against heterologous rotavirus infection (Feng et al, 1994), the multivalent rotavirus vaccine candidates are the most important research goal for the protective immunity of rotaviruses. In addition, the reassortant rotavirus vaccine approaches have been successfully employed to develop various human rotavirus candidate vaccines that include rhesus rotavirus based and bovine rotavirus based multivalent vaccines listed earlier (Hoshino et al, 2002(Hoshino et al, , 2003Midthun et al, 1985Midthun et al, , 1986.…”