ReviewImmunity and correlates of protection for rotavirus vaccines
Introduction
Since their discovery in 1973 [1] rotaviruses (RVs) have been identified as the most common cause of severe, dehydrating diarrhea in children worldwide [2], [3]. RV immunity is not completely understood and issues like the relative role of serotype specific versus heterotypic immunity are controversial [4]. The role of serum antibodies in human immunity to RV has recently been reviewed [5]. Here, we will briefly review aspects of viral pathogenesis, serotype classification and epidemiology that shed light on RV immunity, followed by a discussion of the mechanisms of protection against RV in selected animal models (with emphasis on our results from the adult mouse model), and the correlates of protection associated with natural infection or vaccination in humans. We will emphasize total serum RV IgA and RV serum neutralizing antibodies as possible correlates of protection against disease.
Section snippets
Pathogenesis, serotype classification and epidemiology
RVs have characteristics that make them highly infectious pathogens very well adapted to their host (Table 1). RV belong to a large group of pathogens that will never be eradicated because they do not generate sterilizing immunity and because RV can infect animal hosts. Thus, reasonable goals of vaccination are probably to decrease or eliminate severe disease in children but not to prevent infection. The physiopathological mechanisms of RV induced diarrhea are multiple and not yet completely
Mechanisms of protection in animal models
Animal models have been instrumental for our understanding of immunity to RV. A comprehensive review of the literature of this subject is not intended, and with few exceptions, we will only refer to selected papers of the murine and the neonatal gnotobiotic pig models, that have been the most frequently used models. Each animal model offers certain advantages and disadvantages. For example, the adult mouse model is an infection only model [24], while in the pig model, protection against
Future studies to better understand immunity to RV and obtain better correlates of protection
From the above discussion, it is clear that we need a better understanding of immunity to RV in children. The nature of human cross-reactive antibodies against VP4, or VP7, is poorly understood. A recent study of human monoclonal neutralizing antibodies showed that cross-reactive neutralization epitopes recognized by humans may be distinct from those of mice. Moreover, the two human monoclonal antibodies evaluated were cross-reactive for at least two P genotypes [51]. Hence, humans, like mice,
Conclusions
- a.
Intestinal IgA is probably the most important mechanism for long-term protection against RV.
- b.
Total serum RV IgA measured shortly after infection generally reflects intestinal IgA levels, and may be the best (but imperfect) available marker that correlates with protection against RV. Total serum RV IgA can probably be used as a correlate of protection for many of the vaccines in development and in use.
- c.
Correlates of protection after vaccination may vary depending on the type (homologous versus
Acknowledgments
This work was supported by funds from the Pontificia Universidad Javeriana, Colciencias Grants 1203-04-12638 and 1203-04-16466, FIRCA Grants TWO5647-01 and TW005647-04 and by NIH Grants R01 AI21362-20 and Digestive Disease Center Grant DK56339 and a VA Merit Review Grant.
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