Mice Develop Effective but Delayed Protective Immune Responses When Immunized as Neonates either Intranasally with Nonliving VP6/LT(R192G) or Orally with Live Rhesus Rotavirus Vaccine Candidates

Abstract

Rotavirus vaccines are delivered early in life, when the immune system is immature. To determine the effects of immaturity on responses to candidate vaccines, neonatal (7 days old) and adult mice were immunized with single doses of either Escherichia coli-expressed rotavirus VP6 protein and the adjuvant LT(R192G) or live rhesus rotavirus (RRV), and protection against fecal rotavirus shedding following challenge with the murine rotavirus strain EDIM was determined. Neonatal mice immunized intranasally with VP6/LT(R192G) were unprotected at 10 days postimmunization (dpi) and had no detectable rotavirus B-cell (antibody) or CD4

Qualitative and Quantitative Characteristics of Rotavirus-Specific CD8 T Cells Vary Depending on the Route of Infection

“…Second, the systemic immunoglobulin G antibody response following infection with RRV via each of the three routes was substantial (serum ELISA titer, 4,000 to 10,000), indicating that inoculation via all of the routes was quite immunogenic. Third, RRV infection induces protection against reinfection following murine rotavirus challenge (44). Finally, as mentioned above, when mice are administered a cocktail of neutralizing MAbs to both RRV surface proteins prior to direct enteric inoculation with RRV, they do not become infected.…”

Yersinia enterocoliticaPromotes Robust Mucosal Inflammatory T-Cell Immunity in Murine Neonates

“…ϩ cells (36,37,70). Altogether, it has become apparent that under the proper stimulation conditions, all arms of the neonatal adaptive immune system can be induced to generate adult-like responses.…”

“…Both of these approaches have shown dramatic improvements in CD4 ϩ and CD8 ϩ IFN-␥ production, mucosal IgA production, and systemic IgG1 and IgG2a antibodies to the delivered vaccine antigens. Recently, CD4 ϩ T h 17-mediated immunity has been studied in response to vaccination with rotavirus antigen in adjuvant (70) and to Mycobacterium tuberculosis antigens in the presence of non-CpG oligonucleotides (36) or cationic liposomes (37). These vaccines promoted interleukin-17A (IL-17A) levels of the same magnitude in neonatal and adult CD4…”

“…For example, bacterially derived products such as mutated Escherichia coli enterotoxins LT-R192G (70) and LT-K63 (11,14,27,34), CpG oligonucleotides (CpG) (8,29,31), and lyophilized bacterial extracts (12) have been described to markedly enhance neonatal vaccine responses. Another approach used to improve immune responses has been the delivery of specific antigens using live attenuated bacterial vectors such as Listeria monocytogenes (42,50) and Salmonella species (16,59).…”

Association of Gamma Interferon and Interleukin-17 Production in Intestinal CD4+T Cells with Protection against Rotavirus Shedding in Mice Intranasally Immunized with VP6 and the Adjuvant LT(R192G)

“…All steps involving the construction of a recombinant plasmid containing the coding sequence for the chimeric EDIM VP6::6XHis protein, the expression of the VP6::6XHis protein in E. coli, and the purification of this protein have been described elsewhere (47).…”