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CamboJEv

Pediatric cohorts on Japanese encephalitis in Cambodia

Primary objective :
To quantify the clinical burden of JE and the asymptomatic circulation of JEV based on two groups of children
living in Cambodia: (i) prospectively followed children, non-febrile at recruitment (cohort 1) and (ii) children
hospitalized for febrile neurological syndrome (FNS) with JE (cohort 2).

Secondary objectives:

  • To estimate anti-JEV seropositivity rate in children attending Kantha Popha hospitals for different age groups (all
    children, initial cross-sectional study).
  • To identify individual risk-factors and living conditions associated with JEV seropositivity (all children, initial crosssectional
    study) and new infection (cohort 1).
  • To identify prognostic factors for severity of JEV infection within the cohort 2 studied (which could support
    recommendations for vaccine prioritization).
  • To describe the influence of dengue immunity on the epidemiological, clinical and biological characteristics of JEV
    infection (cohorts 1 and 2).
  • To model anti-JEV antibody kinetics over time following natural infection and vaccination (cohorts 1 and 2).
    To study the involvement of deficiencies in the IFN response in the development of severe JEV infection (cohort
    2).
  • To identify potential clinical and biological profile associated to treatable etiology or to severity in patients with FNS
    to guide hospital care (all FNS children).
  • To evaluate different diagnostic approaches and methodologies and transfer the most effective techniques and
    algorithms for routine hospital use in Cambodia for FNS children.
  • To build capacity at the University of Health Science (UHS) for laboratory and clinical investigation of JE and for
    establishment of prospective pediatric cohort that can be redirected to address other emerging issues (cohorts 1
    and 2).
Période du projet :
-
Investigateur principal :

Xavier De Lamballerie

Membre(s) SESSTIM du projet :
Membre(s) hors SESSTIM du projet :

Bory Sothavireak, Saphonn Vonthanak, Phoeng Chan-Leakhena, Seang Kennarey, Sebastien Boyer, Audery Dubot-Peres

Commanditaires :

ANRS-MIE

Partenaires :

UMR UVE (AMU, INSERM, IRD)

Problématique:

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.

Méthode :

This project has been designed following the findings of the SEAe project which has shown the importance of JE in hospitalized children in Cambodia and because, in the context of JEV vaccination expansion and endemicity of other flaviviruses, past understanding of JE epidemiology can be called into question. The strengths of this project lie in the strong expertise of Kantha Bopha hospitals and UHS in conducting clinical research and the multidisciplinary approach provided by the collaboration with recognized experts: UVE in virology of emerging viruses, SESSTIM and UHS in epidemiology and health geography, GHMI in immunogenetic, Institut Pasteur Cambodia in entomology, SynatAc in auto-immune disease, MMMI in mathematical modeling of infectious diseases.
This project is an observatory prospective study including two pediatric cohorts. Study sites for both groups will be Kantha Bopha hospitals at Siem Reap and Phnom Penh. Children from groups 1 and 2 will be included in the initial cross-sectional study. Group 1 will include children 2-14 yo, presenting at hospital for another reason than suspicion of infectious disease. During the first year of the project, 1000 children will be recruited at each study site (total 2000), in the trauma unit. Children will be followed-up at one year and two years post inclusion. Group 2 will include children 2-14 yo hospitalized with febrile neurological syndrome (FNS). The recruitment will be done three days per week, aiming at including 15 participants per week (800 per year). The total number of children included is expected to be 2000 over a 2,5 year period. Only the children with laboratory evidence of JEV infection will be part of Cohort 2 and will be followed-up at one month, 3 months, 6 months and one year post inclusion. Based on the results from the SEAe study, we expect to have 600 participants in Cohort 2 (30% of recruited FNS children with confirmed JEV infection).

Resultats:

The cross-sectional analysis of the baseline data collected from FNS patients and cohort 1 will provide important information to guide public health policy in Cambodia. Identification of high risk areas for JEV circulation and risk factors for JE will permit recommendation for JEV vaccination priority target population. The description of the importance of treatable FNS etiologies as well as clinical and biological profile, including auto-immune diseases which are rarely investigated in hospitalized children in Cambodia, will be included in guidelines for hospital care of FNS.
Capacity building will be an important outcome of the project, with improvement of the UHS laboratory for the screen of FNS samples for a large panel of pathogens which could be made available for other hospitals and also redirected for the investigation of other syndromes. The project will also lead to the improvement of knowledge of hospital staff and students in meningo-encephalitis etiology and adapted hospital care in Cambodia. In addition to those direct public health impacts, the project will fill important gaps of knowledge on JEV infection as the impact of dengue status and of the interaction between anti-DENV and anti-JEV antibodies on the course of JEV infection. Proportion of severe JE and sequelae has been described in the literature, but little is known on the factor associated with severity, and the implication of IFN pathway has never been investigated for JEV infection.