Spatiotemporal Heterogeneity in the Distribution of Chikungunya and Zika Virus Case Incidences and Risk Factors During Their Epidemics in Barranquilla, Colombia, between 2014 and 2016: An Ecological Study

Chikungunya virus (CHIKV) and Zika virus (ZIKV) have recently emerged as global infections with consequential disability adjusted life years (DALYs) and economic burden. This study aimed to explore the spatiotemporal heterogeneity in the occurrence of CHIKV and ZIKV outbreaks throughout Barranquilla, Colombia during 2014 and 2016 and explored the potential for clustering. Incidence data were fitted using multiple Bayesian Poisson models based on a suite of explanatory variables as potential risk factors and multiple options for random effects. A best fit model was used to analyse the case incidence risk for both epidemics to identify any risk factors during their epidemics. Neighbourhoods in the northern region of Barranquilla were hotspots for the outbreaks of both CHIKV and ZIKV. Additional hotspots occurred in the south-western and central regions of the CHIKV and ZIKV outbreaks, respectively. Multivariate conditional autoregressive models strongly identified higher socioeconomic strata (SES) and residing in detached houses as risk factors for ZIKV case incidences. These novel findings challenge the belief that these infections are driven by social vulnerability and merits further study both in Barranquilla and throughout the tropical and subtropical regions of the world.&amp;nbsp;</jats:p

Potency and Breadth of Human Primary ZIKV Immune Sera shows that Zika Viruses Cluster Antigenically as a Single Serotype

The recent emergence of Zika virus as an important human pathogen has raised questions about the durability and breadth of Zika virus immunity following natural infection in humans. While global epidemic patterns suggest that Zika infection elicits a protective immune response that is likely to offer long-term protection against repeat infection by other Zika viruses, only one study to date has formally examined the ability of human Zika immune sera to neutralize different Zika viruses. That study was limited because it evaluated human immune sera no more than 13 weeks after Zika virus infection and tested a relatively small number of Zika viruses. In this study, we examine twelve human Zika immune sera as far as 3 years after infection and test the sera against a total of eleven Zika virus isolates. Our results confirm the earlier study and epidemic patterns that suggest Zika virus exists in nature as a single serotype, and infection with one Zika virus can be expected to elicit protective immunity against repeat infection by any Zika virus for years to decades after the first infection

Potency and breadth of human primary ZIKV immune sera shows that Zika viruses cluster antigenically as a single serotype.

Zika virus (ZIKV) emerged as a global public health threat throughout the Americas since 2014. Phylogenetically, the virus is composed of three main lineages, an African, Asian, and American lineage. The recent emergence and spread of ZIKV has raised questions regarding the breadth and potency of human primary ZIKV immune sera against antigenically diverse ZIKV. Although ZIKV is thought to compose a single antigenic serotype, in-depth evaluation of the antigenic relatedness of ZIKV across genetic variants has been limited to a relatively small series of early convalescent human immune sera (4-12 weeks) against a limited number (3) of genetic variants. Using virus neutralization assays, we characterize the potency and breadth of twelve primary ZIKV immune sera from adults infected 5 to 38 months previously against a panel of 11 ZIKV isolates from the African, Asian and American lineages. We assess the variability of neutralization potency of immune sera from these subjects and the variability of susceptibility to neutralization for each virus isolate. Overall, we found all sera neutralized all viruses at FRNT50 ranging from 1:271 to 1:4271, a 15.8-fold range, with only small differences between subject geometric mean titers (GMT) against all viruses and small differences between each ZIKV isolate and sensitivity to neutralization by all sera: when pooled, African strains were 1.3-fold more sensitive to neutralization by subject immune sera compared to pooled American strains. Finally, we subjected our data to analysis using antigenic cartography, finding that ZIKV are highly antigenically similar, with only a ~4-fold range across all antigenic distances between viruses, consistent with a single serotype

Targeted Gene Sequencing in Children with Crohn’s Disease and Their Parents: Implications for Missing Heritability

Crohn’s disease is a complex genetic trait characterized by chronic relapsing intestinal inflammation. Genome wide association studies (GWAS) have identified more than 170 loci associated with the disease, accounting for ∼14% of the disease variance. We hypothesized that rare genetic variation in GWAS positional candidates also contribute to disease pathogenesis. We performed targeted, massively-parallel sequencing of 101 genes in 205 children with Crohn’s disease, including 179 parent-child trios and 200 controls, both of European ancestry. We used the gene burden test implemented in VAAST and estimated effect sizes using logistic regression and meta-analyses. We identified three genes with nominally significant p-values: NOD2, RTKN2, and MGAT3. Only NOD2 was significant after correcting for multiple comparisons. We identified eight novel rare variants in NOD2 that are likely disease-associated. Incorporation of rare variation and compound heterozygosity nominally increased the proportion of variance explained from 0.074 to 0.089. We estimated the population attributable risk and total heritability of variation in NOD2 to be 32.9% and 3.4%, respectively, with 3.7% and 0.25% accounted for by rare putatively functional variants. Sequencing probands (as opposed to genotyping) to identify rare variants and incorporating phase by sequencing parents can recover a portion of the missing heritability of Crohn’s disease

Spatiotemporal Heterogeneity in the Distribution of Chikungunya and Zika Virus Case Incidences during their 2014 to 2016 Epidemics in Barranquilla, Colombia

Chikungunya virus (CHIKV) and Zika virus (ZIKV) have recently emerged as globally important infections. This study aimed to explore the spatiotemporal heterogeneity in the occurrence of CHIKV and ZIKV outbreaks throughout the major international seaport city of Barranquilla, Colombia in 2014 and 2016 and the potential for clustering. Incidence data were fitted using multiple Bayesian Poisson models based on multiple explanatory variables as potential risk factors identified from other studies and options for random effects. A best fit model was used to analyse their case incidence risks and identify any risk factors during their epidemics. Neighbourhoods in the northern region were hotspots for both CHIKV and ZIKV outbreaks. Additional hotspots occurred in the southwestern and some eastern/southeastern areas during their outbreaks containing part of, or immediately adjacent to, the major circular city road with its import/export cargo warehouses and harbour area. Multivariate conditional autoregressive models strongly identified higher socioeconomic strata and living in a neighbourhood near a major road as risk factors for ZIKV case incidences. These findings will help to appropriately focus vector control efforts but also challenge the belief that these infections are driven by social vulnerability and merit further study both in Barranquilla and throughout the world’s tropical and subtropical regions

Infection with chikungunya virus confers heterotypic cross-neutralizing antibodies and memory B-cells against other arthritogenic alphaviruses predominantly through the B domain of the E2 glycoprotein.

Infections with Chikungunya virus, a mosquito-borne alphavirus, cause an acute febrile syndrome often followed by chronic arthritis that persists for months to years post-infection. Neutralizing antibodies are the primary immune correlate of protection elicited by infection, and the major goal of vaccinations in development. Using convalescent blood samples collected from both endemic and non-endemic human subjects at multiple timepoints following suspected or confirmed chikungunya infection, we identified antibodies with broad neutralizing properties against other alphaviruses within the Semliki Forest complex. Cross-neutralization generally did not extend to the Venezuelan Equine Encephalitis virus (VEEV) complex, although some subjects had low levels of VEEV-neutralizing antibodies. This suggests that broadly neutralizing antibodies elicited following natural infection are largely complex restricted. In addition to serology, we also performed memory B-cell analysis, finding chikungunya-specific memory B-cells in all subjects in this study as remotely as 24 years post-infection. We functionally assessed the ability of memory B-cell derived antibodies to bind to chikungunya virus, and related Mayaro virus, as well as the highly conserved B domain of the E2 glycoprotein thought to contribute to cross-reactivity between related Old-World alphaviruses. To specifically assess the role of the E2 B domain in cross-neutralization, we depleted Mayaro and Chikungunya virus E2 B domain specific antibodies from convalescent sera, finding E2B depletion significantly decreases Mayaro virus specific cross-neutralizing antibody titers with no significant effect on chikungunya virus neutralization, indicating that the E2 B domain is a key target of cross-neutralizing and potentially cross-protective neutralizing antibodies

Supplemental Material for Chen et al., 2018

<div>Table S1 lists 101 targeted genes.</div><div>Table S2 lists 63 testable genes for multiple test correction.</div><div>Table S3 shows VAAST results for genes with p-value less than 0.05.</div><div>Tables S4, S5 and S6 contain the resources and data used for meta-analyses.</div><div>Figure S1 contains clinical characteristics of cases.</div><div>Figure S2 shows a PCA plot of cases and controls superimposed on HapMap samples.</div