Influence of Potential Protective Mechanisms on the Development of Live Rotavirus Vaccines

Abstract

Rotaviruses cause extensive morbidity and mortality worldwide, thus corroborating the need for a vaccine that is effective in all socioeconomic environments. Vaccines evaluated in clinical trials have all been live attenuated rotaviruses that are delivered orally to mimic the excellent protection observed after natural infection. The mechanisms by which these vaccine candidates or wild-type rotaviruses elicit protection are not fully understood. During the 1980s, several candidate vaccines provided little protection, particularly in developing countries, and were discontinued. Two, however, are in the process of being licensed worldwide, and several others are undergoing clinical trials. Development of live rotavirus vaccines has been highly influenced by views regarding the importance of serotype-specific neutralizing antibody. Development of several candidate vaccines is based on the concept that neutralizing antibody is the primary determinant of protection. These candidates, including 1 of the 2 being licensed worldwide (RotaTeq), are composed of multiple rotavirus strains representative of the major human rotavirus serotypes. The other group of candidates has been developed based on the theory that protection is not solely dependent on neutralizing antibody. These candidates are composed of single rotavirus strains and include the other vaccine being licensed worldwide (Rotarix). Studies that provide the basis for each approach will be presented and discussed.

Correlates of protection for rotavirus vaccines: Possible alternative trial endpoints, opportunities, and challenges

“…It is generally accepted that RV-NA against the infecting strain present in the intestine provides protection. 6,[43][44][45] In spite of this, protection following natural infection may not be solely correlated with the presence of type-specific RV-NA. Although quantitation of these antibodies in vaccinated individuals would probably be the best (mechanistic) CoP, it is impractical.…”

“…Two types of RV-NA have been described: homotypic (blocking only one RV serotype) or heterotypic (blocking 2 or more RV serotypes). 6,43,44 Studies evaluating associations between serum RV-serotype specific antibodies and protection are summarized in Table 1.…”

“…6,[43][44][45] Thus, if measurement of intestinal RV-NA were used as an endpoint in VE trials, it would probably be considered a true mechanistic CoP. However, in studies with adults experimentally challenged with homologous human RV, the relationship of pre-existing NA in intestinal fluid with protection was observed in one study (using a stepwise logistic regression, p D 0.01) 46 but not in another (using a 2-tailed Fisher exact test, p D 0.49, cut off 1:100).…”

“…Several reviews [3][4][5][6] have summarized multiple aspects of RV immunity and potential CoP for RV vaccines. Here, we will only concentrate on the issues most directly related to the 1.…”

Molecular characterization of rotavirus strains detected during a clinical trial of a human rotavirus vaccine in Blantyre, Malawi

“…Thus, Rotarix provides protection against severe disease caused by human rotaviruses irrespective of their outermost surface proteins, VP7 and VP4, and therefore does not solely rely on serotype-specific immunity. The mechanism responsible for this apparent cross-protection afforded by Rotarix is unknown, but could involve the internal or non-structural proteins shared by human rotavirus strains i.e., homologous immunity [37][38][39][40].…”