CamboJEv

Japanese encephalitis virus (JEV, genus Orthoflavivirus, family Flaviviridae) is transmitted in an enzootic cycle between Culex mosquitoes and vertebrate hosts, mainly pigs (main amplifying host) and aquatic birds (natural reservoir). Humans are an occasional host and epidemiological dead-end. JEV infection is the main cause of viral encephalitis in Asia. In endemic countries, JE mainly affects children, reflecting long term post-infection immunity. The case fatality rate historically described was as high as 30%, with 30-50% of survivors suffering neurological or psychiatric sequelae. These figures apply to symptomatic forms leading to diagnosis, and do not take into account the large proportion of a- or pauci-symptomatic cases, or the recent evolution in a complex context that combines vaccination campaigns, immunity against dengue, reduced poverty, an increase in urban populations and improved health standards. The WHO estimates that 68,000 cases of JE are reported worldwide each year. Due to difficulty of diagnosis and limited surveillance in certain endemic regions, this figure is probably underestimated. Tsai et al. estimated the number of cases at 175,000 in 1994, and Quan et al. at 100,000 in 2015, despite vaccination programs in most of the countries at risk. The WHO has identified 24 countries in South-East Asia and Oceania at risk of JEV transmission, including Australia with outbreaks in 2021 and 2022. JEV is common in rural and peri-urban areas, where transmission of dengue virus (DENV) frequently overlaps. Circulation of the four DENV serotypes has expanded massively over the last few decades in South-East Asia, but the epidemiological interactions resulting from cross-immunity between DENV and JEV are poorly documented. In addition, the geographical distribution of JEV is steadily increasing, possibly due in part to climate change, which favors the spread of mosquito vectors, to the expansion of rice-growing, source of JEV vector species, and pig-breeding areas, JEV reservoir. In Cambodia, JEV infection is the main cause of encephalitis in children. The live attenuated SA14-14-2 vaccine manufactured in China, which provides good protection even with a single dose and was prequalified by the WHO in October 2013 has been most widely used in Cambodia during vaccination campaigns for children since 2009. Inactivated vaccines prepared in cell culture (JEEV) or the chimeric live vaccine (IMOJEV, a recombinant between the SA14-14-2 strain and the 17D strain of yellow fever) have also been licensed and prequalified by the WHO and are available in Cambodia. In 2014, the GAVI alliance launched a support program for the introduction and roll-out of JE vaccination from which Cambodia has benefited. Despite the introduction of vaccination into the national program in 2015, pediatric JE remains frequent and little data on vaccination coverage, which is probably suboptimal, is available. Pandemic preparedness and prevention plans plead for regular surveillance to rapidly detect emerging zoonoses. Recent epidemics (Zika, COVID-19, etc.) show the importance of clinical cohorts for real-time assessment of the clinical impact of epidemics and the rapid deployment of diagnostic and treatment tools. Accordingly ambitious multidisciplinary projects now include clinical cohorts, as in the ZIKAlliance project (https://zikalliance.tghn.org/). Furthermore, effectivity of pandemic preparedness plans requires the ongoing maintenance of technical and human resources in the field. Experience shows that this requires co-construction of integrated approaches with local communities and institutions and clear identification of needs (e.g. here, the surveillance, diagnosis, prevention and management of JE). One of the cohort of children that we will set up in this study will be structured and managed in such a way that it can be redirected to address other emerging issues.
We propose to study two groups of pediatric participants in Cambodia: 1) a group of 2000 non febrile children at inclusion, and, 2) a group of 2000 children hospitalized for febrile neurological syndrome (FNS). First, a crosssectional study will analyze the seropositivity rate among the 4000 children and the factors associated with seropositivity, and clinical and biological factors of JE. Second, to estimate JEV incidence rate and assess factors associated with a-pauci-symptomatic infections, Cohort 1 (2000 non-NFS children) will be followed over 2 years. To estimate JEV severity rate and associated individual clinical and biological factors, Cohort 2, including the JEV positive NFS children, will be followed over 1 year.