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Dengue virus (DENV) infection is widespread and its disease burden has increased in past decades. However, little is known about the epidemiology of dengue in the Middle East and North Africa (MENA). Following Cochrane Collaboration guidelines and reporting our findings following PRISMA guidelines, we systematically reviewed available records across MENA describing dengue occurrence in humans (prevalence studies, incidence studies, and outbreak reports), occurrence of suitable vectors (Aedes aegypti and Aedes albopictus), and DENV vector infection rates. We identified 105 human prevalence measures in 13 of 24 MENA countries; 81 outbreaks reported from 9 countries from 1941-2015; and reports of Ae. aegypti and/or Ae. albopictus occurrence in 15 countries. The majority of seroprevalence studies were reported from the Red Sea region and Pakistan, with multiple studies indicating >20% DENV seroprevalence in general populations (median 25%, range 0-62%) in these subregions. Fifty percent of these studies were conducted prior to 1990. Multiple studies utilized assays susceptible to serologic cross-reactions and 5% of seroprevalence studies utilized viral neutralization testing. There was considerable heterogeneity in study design and outbreak reporting, as well as variability in subregional study coverage, study populations, and laboratory methods used for diagnosis. DENV seroprevalence in the MENA is high among some populations in the Red Sea region and Pakistan, while recent outbreaks in these subregions suggest increasing incidence of DENV which may be driven by a variety of ecologic and social factors. However, there is insufficient study coverage to draw conclusions about Aedes or DENV presence in multiple MENA countries. These findings illustrate the epidemiology of DENV in the MENA while revealing priorities for DENV surveillance and Aedes control.

Arboviruses represent a significant burden to public health and local economies due to their ability to cause unpredictable and widespread epidemics. To maximize early detection of arbovirus emergence in non-endemic areas, surveillance efforts should target areas where circulation is most likely. However, identifying such hotspots of potential emergence is a major challenge. The ecological conditions leading to arbovirus outbreaks are shaped by complex interactions between the virus, its vertebrate hosts, arthropod vector, and abiotic environment that are often poorly understood. Here, we systematically review the ecological risk factors associated with the circulation of six arboviruses that are of considerable concern to northwestern Europe. These include three mosquito-borne viruses (Japanese encephalitis virus, West Nile virus, Rift Valley fever virus) and three tick-borne viruses (Crimean-Congo hemorrhagic fever virus, tick-borne encephalitis virus, and louping-ill virus). We consider both intrinsic (e.g. vector and reservoir host competence) and extrinsic (e.g. temperature, precipitation, host densities, land use) risk factors, identify current knowledge gaps, and discuss future directions. Our systematic review provides baseline information for the identification of regions and habitats that have suitable ecological conditions for endemic circulation, and therefore may be used to target early warning surveillance programs aimed at detecting multi-virus and/or arbovirus emergence.

Given the emergence of the SARS-CoV-2 Omicron BA.1 and BA.2 variants and the roll-out of booster COVID-19 vaccination, evidence is needed on protection conferred by primary vaccination, booster vaccination and previous SARS-CoV-2 infection by variant. We employed a test-negative design on S-gene target failure data from community PCR testing in the Netherlands from 22 November 2021 to 31 March 2022 (n = 671,763). Previous infection, primary vaccination or both protected well against Delta infection. Protection against Omicron BA.1 infection was much lower compared to Delta. Protection was similar against Omicron BA.1 compared to BA.2 infection after previous infection, primary and booster vaccination. Higher protection was observed against all variants in individuals with both vaccination and previous infection compared with either one. Protection against all variants decreased over time since last vaccination or infection. We found that primary vaccination with current COVID-19 vaccines and previous SARS-CoV-2 infections offered low protection against Omicron BA.1 and BA.2 infection. Booster vaccination considerably increased protection against Omicron infection, but decreased rapidly after vaccination. The protection of COVID-19 vaccines against emerging variants needs to be monitored. Here, the authors use community testing data from the Netherlands and find that protection against infection by Omicron subvariants BA.1 and 2 is low and that booster vaccines considerably but temporarily increase protection.

Usutu virus (USUV) is an emerging flavivirus that is maintained in an enzootic cycle with mosquitoes as vectors and birds as amplifying hosts. In Europe, the virus has caused mass mortality of wild birds, mainly among Common Blackbird ( Turdus merula ) populations. While mosquitoes are the primary vectors for USUV, Common Blackbirds and other avian species are exposed to other arthropod ectoparasites, such as ticks. It is unknown, however, if ticks can maintain and transmit USUV. We addressed this question using in vitro and in vivo experiments and field collected data. USUV replicated in IRE/CTVM19 Ixodes ricinus tick cells and in injected ticks. Moreover, I . ricinus nymphs acquired the virus via artificial membrane blood-feeding and maintained the virus for at least 70 days. Transstadial transmission of USUV from nymphs to adults was confirmed in 4.9% of the ticks. USUV disseminated from the midgut to the haemocoel, and was transmitted via the saliva of the tick during artificial membrane blood-feeding. We further explored the role of ticks by monitoring USUV in questing ticks and in ticks feeding on wild birds in the Netherlands between 2016 and 2019. In total, 622 wild birds and the Ixodes ticks they carried were tested for USUV RNA. Of these birds, 48 (7.7%) carried USUV-positive ticks. The presence of negative-sense USUV RNA in ticks, as confirmed via small RNA-sequencing, showed active virus replication. In contrast, we did not detect USUV in 15,381 questing ticks collected in 2017 and 2019. We conclude that I . ricinus can be infected with USUV and can transstadially and horizontally transmit USUV. However, in comparison to mosquito-borne transmission, the role of I . ricinus ticks in the epidemiology of USUV is expected to be minor.

The world is combating an ongoing COVID-19 pandemic with health-care systems, society and economies impacted in an unprecedented way. It is unclear how many people have contracted the causative coronavirus (SARS-CoV-2) unknowingly and are asymptomatic. Therefore, reported COVID-19 cases do not reflect the true scale of outbreak. Here we present the prevalence and distribution of antibodies to SARS-CoV-2 in a healthy adult population of the Netherlands, which is a highly affected country, using a high-performance immunoassay. Our results indicate that one month into the outbreak (i) the seroprevalence in the Netherlands was 2.7% with substantial regional variation, (ii) the hardest-hit areas showed a seroprevalence of up to 9.5%, (iii) the seroprevalence was sex-independent throughout age groups (18–72 years), and (iv) antibodies were significantly more often present in younger people (18–30 years). Our study provides vital information on the extent of exposure to SARS-CoV-2 in a country where social distancing is in place. The Netherlands is a country highly affected by the COVID-19 pandemic. In this study, Slot, Hogema and colleagues report a low SARS-CoV-2 seroprevalence one month into the outbreak and provide insights into virus exposure by region and age group when widespread non-pharmaceutical interventions are in place.

Tick-borne encephalitis virus (TBEV) may cause tick-borne encephalitis (TBE), a potential life-threatening infection of the central nervous system in humans. Phylogenetically, TBEVs can be subdivided into three main subtypes, which differ in endemic region and pathogenic potential. In 2016, TBEV was first detected in the Netherlands. One of two detected strains, referred to as Salland, belonged to the TBEV-Eu subtype, yet diverged ≥ 2% on amino acid level from other members of this subtype. Here, we report the successful rescue of this strain using infectious subgenomic amplicons and its subsequent in vitro characterization by comparison to two well-characterized TBEV-Eu strains; Neudoerfl and Hypr. In the human alveolar epithelial cell line A549, growth kinetics of Salland were comparable to the high pathogenicity TBEV-Eu strain Hypr, and both strains grew considerably faster than the mildly pathogenic strain Neudoerfl. In the human neuroblastoma cell line SK-N-SH, Salland replicated faster and to higher infectious titers than both reference strains. All three TBEV strains infected primary human monocyte-derived dendritic cells to a similar extent and interacted with the type I interferon system in a similar manner. The current study serves as the first in vitro characterization of the novel, divergent TBEV-Eu strain Salland.

The Usutu virus (USUV) is a mosquito-borne zoonotic flavivirus. Despite its continuous circulation in Europe, knowledge on the pathology, cellular and tissue tropism and pathogenetic potential of different circulating viral lineages is still fragmentary. Here, macroscopic and microscopic evaluations are performed in association with the study of cell and tissue tropism and comparison of lesion severity of two circulating virus lineages (Europe 3; Africa 3) in 160 Eurasian blackbirds (Turdus merula) in the Netherlands. Results confirm hepatosplenomegaly, coagulative necrosis and lymphoplasmacytic inflammation as major patterns of lesions and, for the first time, vasculitis as a novel virus-associated lesion. A USUV and Plasmodium spp. co-infection was commonly identified. The virus was associated with lesions by immunohistochemistry and was reported most commonly in endothelial cells and blood circulating and tissue mononucleated cells, suggesting them as a major route of entry and spread. A tropism for mononuclear phagocytes cells was further supported by viral labeling in multinucleated giant cells. The involvement of ganglionic neurons and epithelial cells of the gastrointestinal tract suggests a possible role of oral transmission, while the involvement of feather follicle shafts and bulbs suggests their use as a diagnostic sample for live bird testing. Finally, results suggest similar pathogenicity for the two circulating lineages.

The epidemiology of Chikungunya virus (CHIKV) in the Middle East and North Africa (MENA) is not well characterized despite increasing recognition of its expanding infection and disease burden in recent years. Following Cochrane Collaboration guidelines and reporting our findings following PRISMA guidelines, we systematically reviewed records describing the human prevalence and incidence, CHIKV prevalence/infection rates in vectors, outbreaks, and reported cases for CHIKV across the MENA region. We identified 29 human seroprevalence measures, one human incidence study, one study reporting CHIKV infection rates in Aedes, and nine outbreaks and case reports/series reported in the MENA from 1970-2015. Overall, anti-CHIKV antibody or reports of autochthonous transmission were identified from 10 of 23 countries in the MENA region (Djibouti, Egypt, Iraq, Iran, Kuwait, Pakistan, Saudi Arabia, Somalia, Sudan, and Yemen), with seroprevalence measures among general populations (median 1.0%, range 0-43%) and acute febrile illness populations (median 9.8%, range 0-30%). Sudan reported the highest number of studies (n = 11) and the highest seroprevalence among general populations (median 12%, range 0-43%) and undifferentiated acute febrile illness populations (median 18%, range 10-23%). CHIKV outbreaks were reported from Djibouti, Pakistan, Sudan, and Yemen. Seroprevalence studies and outbreak reports suggest endemic transmission of urban cycle CHIKV in at least the Red Sea region and Pakistan. However, indications of seroprevalence despite a low quantity of CHIKV epidemiologic research from the region suggests that CHIKV transmission is currently underrecognized.

The Crimean–Congo hemorrhagic fever virus (CCHFV) is considered to be a major emerging infectious threat, according to the WHO R&D blueprint. A wide range of CCHFV molecular assays have been developed, employing varied primer/probe combinations. The high genetic variability of CCHFV often hampers the efficacy of available molecular tests and can affect their diagnostic potential. Recently, increasing numbers of complete CCHFV genomic sequences have become available, allowing a better appreciation of the genomic evolution of this virus. We summarized the current knowledge on molecular methods and developed a new bioinformatics tool to evaluate the existing assays for CCHFV detection, with a special focus on strains circulating in different geographical areas. Twenty-two molecular methods and 181 sequences of CCHFV were collected, respectively, from PubMed and GenBank databases. Up to 28 mismatches between primers and probes of each assay and CCHFV strains were detected through in-silico PCR analysis. Combinations of up to three molecular methods markedly decreased the number of mismatches within most geographic areas. These results supported the good practice of CCHFV detection of performing more than one assay, aimed for different sequence targets. The choice of the most appropriate tests must take into account patient’s travel history and geographic distribution of the different CCHFV strains.

The Asian bush mosquito Aedes japonicus is invading Europe and was first discovered in Lelystad, the Netherlands in 2013, where it has established a permanent population. In this study, we investigated the vector competence of Ae. japonicus from the Netherlands for the emerging Zika virus (ZIKV) and zoonotic Usutu virus (USUV). ZIKV causes severe congenital microcephaly and Guillain-Barré syndrome in humans. USUV is closely related to West Nile virus, has recently spread throughout Europe and is causing mass mortality of birds. USUV infection in humans can result in clinical manifestations ranging from mild disease to severe neurological impairments. In our study, field-collected Ae. japonicus females received an infectious blood meal with ZIKV or USUV by droplet feeding. After 14 days at 28°C, 3% of the ZIKV-blood fed mosquitoes and 13% of the USUV-blood fed mosquitoes showed virus-positive saliva, indicating that Ae. japonicus can transmit both viruses. To investigate the effect of the mosquito midgut barrier on virus transmission, female mosquitoes were intrathoracically injected with ZIKV or USUV. Of the injected mosquitoes, 96% (ZIKV) and 88% (USUV) showed virus-positive saliva after 14 days at 28°C. This indicates that ZIKV and USUV can efficiently replicate in Ae. japonicus but that a strong midgut barrier is normally restricting virus dissemination. Small RNA deep sequencing of orally infected mosquitoes confirmed active replication of ZIKV and USUV, as demonstrated by potent small interfering RNA responses against both viruses. Additionally, de novo small RNA assembly revealed the presence of a novel narnavirus in Ae. japonicus. Given that Ae. japonicus can experimentally transmit arthropod-borne viruses (arboviruses) like ZIKV and USUV and is currently expanding its territories, we should consider this mosquito as a potential vector for arboviral diseases in Europe.