Possible Mechanisms of Protection Elicited by Candidate Rotavirus Vaccines as Determined with the Adult Mouse Model

Abstract

Rotaviruses cause extensive morbidity and mortality worldwide each year, supporting the need for a vaccine that is effective against rotavirus disease in all socioeconomic environments. Vaccines evaluated in clinical trials have all been live viruses that are delivered orally to mimic the excellent protection against severe rotavirus disease consistently observed after natural infection. The mechanisms by which either these vaccine candidates or natural rotavirus infections elicit protection are poorly understood. Therefore, it is not surprising that several of these candidate vaccines have provided little or no protection and have been discontinued. Two candidate vaccines are presently in phase III trials. These two were developed on the basis of very different views regarding the importance of one specific immune effector, that is, serotype-specific neutralizing antibody. One of these candidates (RotaTeq) is composed of five bovine/human reassortant rotavirus strains containing neutralization proteins representative of dominant human serotypes. The other candidate (Rotarix) is composed of only a single strain of human rotavirus. Very recent data obtained with Rotarix support the suggestion that factors other than neutralizing antibody can play important roles in protection against rotavirus disease after live rotavirus immunization. These results must be confirmed in subsequent studies in different locales with circulating rotaviruses belonging to a variety of serotypes in order to establish there overall applicability. Mechanisms by which rotavirus immunization with live viruses or other immunogens elicit protection have been most extensively examined in an adult mouse model and were reported to be multi-factorial. That is, CD8 and CD4 T cells as well as B cells were all found to play significant roles. The importance of each lymphocyte population as effectors of protection was found to be dependent on the immunogen and the route of immunization. The results of studies in the adult mouse model that appear to be most pertinent to the present vaccine candidates are presented and discussed.