Viral clade is associated with severity of symptomatic genotype 3 hepatitis E virus infections in Belgium, 2010-2018.

BACKGROUND & AIMS: HEV genotype (gt) 3 infections are prevalent in high-income countries and display a wide spectrum of clinical presentations. Host - but not viral - factors are reported to be associated with worse clinical outcomes. METHODS: Demographic, clinical, and biochemical data laboratory-confirmed HEV infections (by PCR and/or a combination of IgM and IgG serology) at the Belgian National Reference Centre between January 2010 and June 2018 were collected using standardised case report forms. Genotyping was based on HEV open reading frame 2 sequences. Serum CXCL10 levels were measured by a magnetic bead-based assay. H&E staining was performed on liver biopsies. RESULTS: A total of 274 HEV-infected individuals were included. Subtype assignment was possible for 179/218 viraemic cases, confirming gt3 as dominant with an almost equal representation of clades abchijklm and efg. An increased hospitalisation rate and higher peak serum levels of alanine aminotransferase, bilirubin, and alkaline phosphatase were found in clade efg-infected individuals in univariate analyses. In multivariable analyses, clade efg infections remained more strongly associated with severe disease presentation than any of the previously identified host risk factors, being associated with a 2.1-fold higher risk of hospitalisation (95% CI 1.1-4.4, p = 0.034) and a 68.2% higher peak of bilirubin levels (95% CI 13.3-149.9, p = 0.010), independently of other factors included in the model. In addition, acute clade efg infections were characterised by higher serum CXCL10 levels (p = 0.0005) and a more pronounced liver necro-inflammatory activity (p = 0.022). CONCLUSIONS: In symptomatic HEV gt3 infections, clade efg is associated with a more severe disease presentation, higher serum CXCL10 levels, and liver necro-inflammatory activity, irrespective of known host risk factors. CLINICAL TRIAL REGISTRATION: The protocol was submitted to clinicaltrials.gov (NCT04670419). IMPACT AND IMPLICATIONS: HEV genotype (gt) 3 infections display a wide spectrum of clinical presentations currently ascribed to host factors. Here we examined the role of viral factors on liver disease outcomes by combining viral phylogeny with clinical, biochemical, cytokine, and histological data from 274 Belgian adults infected with HEV presenting between 2010 and 2018. HEV gt 3 clade efg infections were associated with a more severe disease presentation, higher serum CXCL10 levels and liver necro-inflammatory activity, irrespective of known host risk factors. HEV gt3 clade-dependent clinical outcomes call for broad HEV gt3 subtyping in clinical practice and research to help identify those at higher risk for worse outcomes and to further unravel underlying virus-host interactions.

Stable HEV IgG seroprevalence in Belgium between 2006 and 2014.

Recent European studies suggest an emergence of hepatitis E virus (HEV) infection. We evaluated trends in birth cohort-specific HEV seroprevalence and regional differences in Belgium. HEV IgG seroprevalence was analysed on national serum banks (1579 and 2087 samples for 2006 and 2014, respectively. Hepatitis E virus antigen was tested on positive samples. Observed data were modelled using a generalized additive model with a complementary log-log link. No significant differences between birth cohorts or sexes were found. Modelling identified the individual's age and province as relevant factors. The probability of HEV seropositivity increases significantly with age. An estimated total of 434 819 (yearly rate of 54,352) (sero-)infections were found between 2006 and 2014. Overall, HEV IgG seroprevalences were 4.1% (64/1579, 95% CI 3.1-5.1) and 5.8% (121/2087, CI 4.8-6.9) in 2006 and 2014, respectively. Observed HEV antigen seroprevalence was 0.027% (1/3666) for the entire cohort. These results show stable HEV IgG seroprevalence in Belgium.

Identifying immunity gaps for measles using Belgian serial serology data.

Vaccine-preventable diseases, such as measles, have been re-emerging in countries with moderate to high vaccine uptake. It is increasingly important to identify and close immunity gaps and increase coverage of routine childhood vaccinations, including two doses of the measles-mumps-rubella vaccine (MMR). Here, we present a simple cohort model relying on a Bayesian approach to evaluate the evolution of measles seroprevalence in Belgium using the three most recent cross-sectional serological survey data collections (2002, 2006 and 2013) and information regarding vaccine properties. We find measles seroprevalence profiles to be similar for the different regions in Belgium. These profiles exhibit a drop in seroprevalence in birth cohorts that were offered vaccination at suboptimal coverages in the first years after routine vaccination has been started up. This immunity gap is observed across all cross-sectional survey years, although it is more pronounced in survey year 2013. At present, the COVID-19 pandemic could negatively impact the immunization coverage worldwide, thereby increasing the need for additional immunization programs in groups of children that are impacted by this. Therefore, it is now even more important to identify existing immunity gaps and to sustain and reach vaccine-derived measles immunity goals.

Immunogenicity and persistence of trivalent measles, mumps, and rubella vaccines: a systematic review and meta-analysis.

BACKGROUND: Despite the universal use of the two-dose trivalent measles-mumps-rubella (MMR) vaccine in the past two decades, outbreaks of these diseases still occur in countries with high vaccine uptake, giving rise to concerns about primary and secondary failure of MMR vaccine components. We aimed to provide seroconversion and waning rate estimates for the measles, mumps, and rubella components of MMR vaccines. METHODS: In this systematic review and meta-analysis we searched PubMed (including MEDLINE), Web of Science, and Embase for randomised controlled trials, cohort studies, or longitudinal studies reporting the immunogenicity and persistence of MMR vaccines, published in English from database inception to Dec 31, 2019. Studies were included if they investigated vaccine-induced immunity in healthy individuals who received a trivalent MMR vaccine, including different dosages and timepoints of vaccine administration. Studies featuring coadministration of MMR with other vaccines, maternal immunity to the MMR vaccine, or non-trivalent formulations of the vaccine were excluded. Pooled seroconversion and waning rates were estimated by random-effects meta-analyses. This study is registered with PROSPERO, CRD42019116705. FINDINGS: We identified 3615 unique studies, 62 (1·7%) of which were eligible for analysis. Estimated overall seroconversion rates were 96·0% (95% CI 94·5-97·4; I2=91·1%) for measles, 93·3% (91·1-95·2; I2=94·9%) for mumps when excluding the Rubini strain, 91·1% (87·4-94·1; I2=96·6%) for mumps when including the Rubini strain, and 98·3% (97·3-99·2; I2=93·0%) for rubella. Estimated overall annual waning rates were 0·009 (95% CI 0·005-0·016; I2=85·2%) for measles, 0·024 (0·016-0·039; I2=94·7%) for mumps, and 0·012 (0·010-0·014; I2=93·3%) for rubella. INTERPRETATION: Our meta-analysis provides estimates of primary and secondary vaccine failure, which are essential to improve the accuracy of mathematical and statistical modelling to understand and predict the occurrence of future measles, mumps, and rubella outbreaks in countries with high vaccine uptake. FUNDING: European Research Council.

Placental circadian pathway methylation and in utero exposure to fine particle air pollution.

In mammals, a central clock maintains the daily rhythm in accordance with the external environment. At the molecular level, the circadian rhythm is maintained by epigenetic regulation of the Circadian pathway. Here, we tested the role of particulate matter with an aerodynamic diameter ≤ 2.5 µm (PM2.5) exposure during gestational life on human placental Circadian pathway methylation, as an important molecular target for healthy development. In 407 newborns, we quantified placental methylation of CpG sites within the promoter regions of the following genes: CLOCK, BMAL1, NPAS2, CRY1-2 and PER1-3 using bisulfite-PCR-pyrosequencing. Daily PM2.5 exposure levels were estimated for each mother's residence, using a spatiotemporal interpolation model. We applied mixed-effects models to study the methylation status of the Circadian pathway genes and in utero PM2.5 exposure, while adjusting for a priori chosen covariates. In a multi-gene model, placental Circadian pathway methylation was positively and significantly (p < 0.0001) associated with 3rd trimester PM2.5 exposure. Consequently, the single-gene models showed relative methylation differences [Log(fold change)] in placental NPAS2 (+0.16; p = 0.001), CRY1 (+0.59; p = 0.0023), PER2 (+0.36; p = 0.0005), and PER3 (+0.42; p = 0.0008) for an IQR increase (8.9 µg/m3) in 3rd trimester PM2.5 exposure. PM2.5 air pollution, an environmental risk factor leading to a pro-inflammatory state of the mother and foetus, is associated with the methylation pattern of genes in the Circadian pathway. The observed alterations in the placental CLOCK epigenetic signature might form a relevant molecular mechanism through which fine particle air pollution exposure might affect placental processes and foetal development.