In praise of birth cohorts: norovirus infection, disease, and immunity.

Noroviruses are the most common cause of diarrheal disease in the community for all ages [1] and the most common cause of foodborne disease outbreaks in the United States [2]. Despite this ubiquity and high disease burden, there remains substantial uncertainty about some basic features of norovirus infection, epidemiology, and immunity. This knowledge gap partly results from a lack of studies with appropriate designs to examine this rather complicated virus. Birth cohort studies can be vital for understanding the acquisition of protective immunity against a pathogen. Such studies have led to fundamental improvements in understanding rotavirus, for example, and, in turn, have supported the development of vaccination strategies. In a classic study of a birth cohort in Mexico, Velazquez and colleagues showed that severe disease is restricted to the first 2 infections, that each infection reduces future disease risk, and that homotypic protection comes earlier than protection against other genogroups [3]. The implications for vaccines were clear. Fifteen years after the publication of the Velazquez et al study, rotavirus vaccines are in widespread use and have led to remarkable declines in diarrheal disease in the United States and elsewhere. This is not to say that the Velazquez study single-handedly brought about this chain of events, but rather that it provided insights that were indispensable for the course of subsequent developments. With the publication of this study by Saito et al in the current issue of Clinical Infectious Diseases, in which a birth cohort in a Lima, Peru, shantytown was followed for 2 years, we finally have an analogous study on norovirus. The study is packed full of insights for understanding norovirus disease and immunity, with clear implications for vaccines, but, as always seems to be the case with these viruses, the picture is more complex than with other agents of viral gastroenteritis and requires careful interpretation. First and foremost among the findings is the quantification of the tremendous incidence of norovirus-associated diarrhea, with a per capita rate of >0.5 per year (our recalculations), over the first 2 years of life. Basic incidence estimates are fundamental for assessing the burden of a disease, and this is one of the precious few for norovirus in a developing country, or indeed, any setting. Cohort studies are resourceintensive to conduct, but for a virus that commonly infects and reinfects, sometime subclinically, longitudinal data may be the only way to understand the relationship between primary, secondary, and subsequent infections and development of disease. Even the most meticulously conducted case-control studies that compare norovirus prevalence in cases to that in healthy controls can generate data that are hard to interpret. For example, the seminal Global Enterics Multi-Center Study found norovirus to be generally as common among cases of moderate to severe diarrhea as in healthy controls, and concluded that norovirus is largely not a cause of moderate to severe diarrhea [4]. Saito et al’s longitudinal study demonstrates a more complicated and nuanced pattern. Among these children in a Peruvian shantytown, detection of norovirus in nondiarrhea specimens was exceedingly common, and indeed, at similar levels in diarrhea specimens in the first 6 months of life, suggesting that maternal antibody confers some degree of protection against disease early in life. From age 6 months to 2 years, however, the association of norovirus infection with diarrhea became clear. Why were Saito and colleagues able to find a clear association of norovirus with Received and accepted 22 November 2013; electronically published 2 December 2013. Correspondence: Ben Lopman, PhD, National Center for Immunization and Respiratory Diseases, Centers for Disease Control and Prevention, 1600 Clifton Rd, MS-G04, Atlanta, GA 30333 ([email protected]). Clinical Infectious Diseases 2014;58(4):492–4 Published by Oxford University Press on behalf of the Infectious Diseases Society of America 2013. This work is written by (a) US Government employee(s) and is in the public domain in the US. DOI: 10.1093/cid/cit785