Norovirus surveillance comes of age: the impact of NoroNet

Noroviruses are associated with a staggering number of illnesses worldwide annually.¹ The typical clinical case is an acute and self-limiting gastroenteritis that can be managed by rehydration therapy. However, illness can become life-threatening in the young and old and in patients with underlying disease, supporting the need for vaccines.² Vaccine design has been challenging, in part, because of the genotypic diversity of norovirus strains.³ Findings presented by Janko van Beek and colleagues⁴ in The Lancet Infectious Diseases show the importance of global norovirus surveillance to the development of vaccines and for sustaining successful immunisation programmes.

Researchers and public health teams in Europe, Asia, Oceania, and Africa have systematically tracked the molecular epidemiology of noroviruses from 2005 to 2016 by contributing to the NoroNet surveillance system.⁵ This voluntary collaboration has grown to include 22 nations across four continents. A collection of norovirus polymerase and capsid genotypes⁶ was analysed along with epidemiological meta-data collected from 16 635 sporadic and outbreak-associated illnesses, making this dataset the most extensive continuous surveillance information available for noroviruses.

van Beek and colleagues⁴ identified several consistent trends in norovirus epidemiology that are relevant to vaccines. Each continent seems to have repeated seasonal patterns of infection, with sequence submissions peaking most often in the cooler months of the year. The most common route of transmission reported overall was person to person, with food-borne transmission second. Genogroup (G) II human noroviruses predominated over GI and GIV, comprising 15 256 (91·7%) of 16 635 cases reported, and genotype GII.4 was the predominant capsid genotype overall, accounting for 4184 (65·1%) of 6423 cases (although the dominant genotype varied over time and across regions). Within one region at any given time, a genotypically diverse population of noroviruses circulated in addition to the dominant genotype. Finally, 477 (46%) of 1047 noroviruses tested were identified as recombinants with various polymerase and capsid genotype combinations.

NoroNet tracked the prevalence of four major GII.4 norovirus variants (known as Hunter 2004, Den Haag 2006, New Orleans 2009, and Sydney 2012) during the surveillance period between 2005 and 2016, which is an important analysis considering the possible inclusion of GII.4 immunogens in vaccines.⁷ The surveillance data from van Beek and colleagues showed the substantial and rapid expansion of each new GII.4 variant into the human population as it replaced an old variant. Of note, most new GII.4 variants were detected at low numbers in the 2–5 years before their emergence. Further analysis of these so-called pre-pandemic strains might yield useful insight into how these viruses emerge, and whether pandemic strains can be predicted. Selective pressure of vaccines on GII.4 strains and other genotypes will be important to monitor.

The NoroNet analysis⁴ also included a survey of different polymerase genotypes and their association with various capsids. One polymerase genotype, GII. P16, was found in combination with several different capsid genotypes during the surveillance period, but its pairing with a slightly different form of the GII.4 Sydney 2012 capsid created a GII.4 strain that spread rapidly within and outside the NoroNet countries.^8,9 Of note, the GII.P16 polymerase paired also with a GII.2 capsid that has now spread globally.¹⁰ Recombination is a poorly understood driving force in norovirus evolution, but from this analysis⁴ and other studies,⁸ it is clear that recombination must be monitored in any global surveillance effort.

The coordinated data sharing experience of NoroNet illustrates both the challenges and promises for norovirus surveillance. The dual genotyping system that allows tracking of recombinant strains⁶ should be used by laboratories doing sequence-based identification. Full-length genome sequencing would be ideal for this analysis, but at a minimum sequencing of both polymerase and capsid gene regions with standardised protocols would improve data quality and help control costs. Sequencing data should be generated as quickly as possible after stool collection so that viruses can be tracked in real-time. Additionally, NoroNet should be expanded with more uniform coverage of countries within the network and by adding new partners. A true global network would be ideal, but would require additional infrastructure and one or several strong coordinators. Until then, other norovirus surveillance networks (often established for internal regional public health work), such as the GatVirusWeb in Japan, the Australian and New Zealand Norovirus Surveillance Network, and CaliciNet in the USA, have enhanced global data sharing with a unified genotyping nomenclature⁶ that is publically accessible.¹¹ Finally, the work of norovirus surveillance must be recognised as essential by public health agencies and sponsoring partners, as norovirus research, in general, has been underfunded.¹² Epidemiological surveillance and vaccines are integral for the control of human pathogens, and the elegant work of the NoroNet collaboration shows that a framework for global surveillance and evaluation of norovirus vaccines is now possible.