Stimulation of Local Immunity and Protection in Mice by Intramuscular Immunization with Triple- or Double-Layered Rotavirus Particles and QS-21

Abstract

Based on studies in animal models, parenteral immunization has become recognized as a potential vaccination strategy against rotavirus. Using an adult mouse model, the effects of the saponin adjuvant QS-21 on protection against murine rotavirus (strain EDIM) infection was determined following two intramuscular (i.m.) immunizations with purified EDIM particles including triple-layered (tl) infectious particles, tl particles inactivated with psoralen/UV, and double-layered (dl) inactivated particles. All three particles stimulated large serum rotavirus IgG responses and small amounts of serum rotavirus IgA, but undetectable stool rotavirus IgA. Inclusion of QS-21 during immunization increased the serum responses approximately 2- to 10-fold and also stimulated low levels of stool rotavirus IgA. Protection based on reduced shedding of rotavirus following EDIM challenge was significant (P < 0.001) with each immunized group and was enhanced (P < 0.001) by inclusion of QS-21 during immunization. Mice immunized with either live or inactivated tl particles and QS-21 were almost fully protected. Furthermore, animals inoculated with dl particles and the adjuvant shed significantly (P = .02) less virus following challenge than mice immunized with inactivated tl particles even though the latter induced measurable titers of neutralizing antibody to EDIM. These results demonstrate significant protection against rotavirus following i.m. immunization with both dl and tl EDIM particles which is consistently enhanced with QS-21.

Intranasal Administration of 2/6-Rotavirus-Like Particles with MutantEscherichia coliHeat-Labile Toxin (LT-R192G) Induces Antibody-Secreting Cell Responses but Not Protective Immunity in Gnotobiotic Pigs

“…To induce consistent clinical responses in challenged pigs, generally a higher dose of heterologous virus than of homologous virus is required, similar to findings in mice (28,35). Also, the use of outbred gnotobiotic pigs (as for humans) is likely to result in responses more variable than those seen in studies using inbred mice strains (44,45,46,47). Additionally, from a clinical standpoint, children naturally infected with rotavirus shed massive amounts of rotavirus in stools, up to 10 10 to 10 11 particles per g of stool for 3 to 7 days, equating to 10 6 particles in 0.1 g of stool (19).…”

“…There are numerous reports of protective immunity against rotavirus infection in mice induced by various routes of inoculation using different forms of rotavirus antigen (e.g., live or inactivated, homologous or heterologous rotavirus [16,28,44,45,46,51]); recombinant rotaviral proteins or VLPs [12,53,54]; and DNA plasmids [8,9,31]). To date, the protective efficacy of the inactivated or 2/6-VLP rotavirus vaccines in the adult mouse model (protection against infection) did not predict the protective efficacy against rotavirus disease in the neonatal pig model.…”

Rectal Immunization with Rotavirus Virus-Like Particles Induces Systemic and Mucosal Humoral Immune Responses and Protects Mice against Rotavirus Infection

“…Parenteral immunization with RV VLP has been shown to induce immunogenicity and protection in animal models, particularly in the mouse model (7,11,30). However, RV is commonly transmitted via the fecal-oral route and infects intestinal epithelial cells.…”

Immunogenicity of a scalable inactivated rotavirus vaccine in mice

“…As the one of those, parenterally administered inactivated rotavirus vaccine (IRV) is a safer potential alternative strategy compared with oral live rotavirus vaccines. At first, the protective efficacy of IRV has been seen in some animal models, [19][20][21][22][23][24][25][26][27][28] which provides the experimental basis for development of IRV. If IRV had been developed, it is possible for the IRV to provide another choice to the prevention of rotavirus diarrhea and future enhance the efficacy of protection of current live rotavirus vaccines as a supplement.…”