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Of individuals who develop West Nile neuroinvasive disease (WNND), ~10% will die and >40% will develop long-term complications. Current treatment recommendations solely focus on supportive care; therefore, we urgently need to identify novel and effective therapeutic options. We observed a correlation between substance P (SP), a key player in neuroinflammation, and its receptor Neurokinin-1 (NK1R). Our study in a wild-type BL6 mouse model found that SP is upregulated in the brain during infection, which correlated with neuroinvasion and damage to the blood–brain barrier. Blocking the SP/NK1R interaction beginning at disease onset modestly improved survival and prolonged time to death in a small pilot study. Although SP is significantly increased in the brain of untreated WNND mice when compared to mock-infected animals, levels of WNV are unchanged, indicating that SP likely does not play a role in viral replication but may mediate the immune response to infection. Additional studies are necessary to define if SP plays a mechanistic role or if it represents other mechanistic pathways. [ABSTRACT FROM AUTHOR]

Aim: This study investigated the stability of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on 16 common environmental surface materials. Background: SARS-CoV-2 is the causative agent of severe coronavirus disease, a significant public health concern that quickly led to a pandemic. Contamination of environmental surface materials is of concern, with previous studies identifying long-term detection of infectious particles on surfaces. These contaminated surfaces create an increased risk for contact transmission. Methods: Surface materials were inoculated with 10,000 plaque forming units and samples were collected 4, 8, 12, 24, 30, 48, and 168 hours post infection (hpi). Viral titers were determined for each sample and time point using plaque assays. Nonparametric modeling utilized the Turnbull algorithm for interval-censored data. Maximum likelihood estimates for the survival curve were calculated. Parametric proportional hazards regression models for interval censored data were used to explore survival time across the surface materials. Results: There was a sharp decline in recoverable virus after 4 hpi for all tested surfaces. By 12 hpi, infectious SARS-CoV-2 was recoverable from only four surfaces; and by 30 hr, the virus was recoverable from only one surface. There were differences in survival curves based on the materials although some groups of materials are similar, both statistically and practically. Conclusions: While very low amounts of infectious SARS-CoV-2 are recoverable over time, there remains a risk of viral transmission by surface contamination in indoor environments. Individuals and institutions must follow appropriate procedures to decontaminate indoor environment and increase diligence for hand hygiene and personal protective equipment. [ABSTRACT FROM AUTHOR]

After the unexpected arrival of West Nile virus (WNV) in the United States in 1999, the mosquito-borne virus quickly spread throughout North America. Over the past 20 years, WNV has become endemic, with sporadic epizootics. Concerns about the economic impact of infection in horses lead to the licensure of an equine vaccine as early as 2005, but few advances regarding human vaccines or treatments have since been made. There is a high level of virus transmission in hot/humid, subtropical climates, and high morbidity that may disproportionately affect vulnerable populations including the homeless, elderly, and those with underlying health conditions. Although WNV continues to cause significant morbidity and mortality at great cost, funding and research have declined in recent years. These factors, combined with neglect by policy makers and amenability of control measures, indicate that WNV has become a neglected tropical disease. [ABSTRACT FROM AUTHOR]

Using reported case data from ArboNET and previous seroprevalence data stratified by age and sex, we conservatively estimate that ≈7 million persons in the United States have been infected with West Nile virus since its introduction in 1999. Our data support the need for public health interventions and improved surveillance. [ABSTRACT FROM AUTHOR]

West Nile virus (WNV) is a mosquito-borne pathogen that can lead to encephalitis and death in susceptible hosts. Cytokines play a critical role in inflammation and immunity in response to WNV infection. Murine models provide evidence that some cytokines offer protection against acute WNV infection and assist with viral clearance, while others play a multifaceted role WNV neuropathogenesis and immune-mediated tissue damage. This article aims to provide an up-to-date review of cytokine expression patterns in human and experimental animal models of WNV infections. Here, we outline the interleukins, chemokines, and tumor necrosis factor superfamily ligands associated with WNV infection and pathogenesis and describe the complex roles they play in mediating both protection and pathology of the central nervous system during or after virus clearance. By understanding of the role of these cytokines during WNV neuroinvasive infection, we can develop treatment options aimed at modulating these immune molecules in order to reduce neuroinflammation and improve patient outcomes. [ABSTRACT FROM AUTHOR]

COVID-19, caused by the SARS-CoV-2 virus, is a highly pathogenic emerging infectious disease. Healthcare personnel (HCP) are presumably at higher risk of acquiring emerging infections because of occupational exposure. The prevalence of COVID-19 in HCP is unknown, particularly in low- to middle-income countries like El Salvador. The goal of this study was to determine the seroprevalence of anti-SARS-CoV-2 antibodies among HCP in El Salvador just prior to vaccine rollout in March 2021. We evaluated 2176 participants from a nationally representative sample of national healthcare institutions. We found 40.4% (n = 880) of the study participants were seropositive for anti-spike protein antibodies. Significant factors associated with infection included younger age; living within the central, more populated zone of the country; living in a larger household (≥7 members); household members with COVID-19 or compatible symptoms; and those who worked in auxiliary services (i.e., housekeeping and food services). These findings provide insight into opportunities to mitigate SARS-CoV-2 risk and other emerging respiratory pathogens in HCP in El Salvador. [ABSTRACT FROM AUTHOR]

West Nile virus (WNV) is an arbovirus with important public health implications globally. This study characterizes a viral isolate, 2004Hou3, in comparison with the NY99 strain from the original WNV outbreak in New York, USA. NextGen sequencing was used to compare the viral isolates genetically, while wild-type C57/BL6 mice were used to compare pathogenicity and viral persistence. Significant differences in survival and clinical presentations were noted, with minor genetic variations between the two strains potentially offering an explanation. One notable difference is that 5 of 35 mice infected with the 2004Hou3 strain developed hind limb flaccid paralysis, suggesting its possible use as a small animal pathogenesis model for this clinical characteristic often observed in human WN neuroinvasive disease patients but not reported in other animal models of infection. Overall, this study suggests that 2004Hou3 is a less pathogenic strain with potential for use in long-term outcome studies using small animal models. [ABSTRACT FROM AUTHOR]

Chagas disease is a leading cause of non-ischemic cardiomyopathy in endemic regions of Central and South America. In Belize, Triatoma dimidiata sensu lato has been identified as the predominate taxon but vectorial transmission of Chagas disease is considered to be rare in the country. We recently identified an acute case of vector-borne Chagas disease in the northern region of Belize. Here we present a subsequent investigation of triatomines collected around the case-patient's home. We identified yet undescribed species, closely related to Triatoma huehuetenanguensis vector by molecular systematics methods occurring in the peridomestic environment. The identification of a T. cruzi-positive, novel species of Triatoma in Belize indicates an increased risk of transmission to humans in the region and warrants expanded surveillance and further investigation. [ABSTRACT FROM AUTHOR]

Previous interim data from a phase I study of AKS-452, a subunit vaccine comprising an Fc fusion of the respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein receptor binding domain (SP/RBD) emulsified in the water-in-oil adjuvant, Montanide™ ISA 720, suggested a good safety and immunogenicity profile in healthy adults. This phase I study was completed and two dosing regimens were further evaluated in this phase II study. This phase II randomized, open-labelled, parallel group study was conducted at a single site in The Netherlands with 52 healthy adults (18 – 72 years) receiving AKS-452 subcutaneously at one 90 µg dose (cohort 1, 26 subjects) or two 45 µg doses 28 days apart (cohort 2, 26 subjects). Serum samples were collected at the first dose (day 0) and at days 28, 56, 90, and 180. Safety and immunogenicity endpoints were assessed, along with induction of IgG isotypes, cross-reactive immunity against viral variants, and IFN-γ T cell responses. All AEs were mild/moderate (grades 1 or 2), and no SAEs were attributable to AKS-452. Seroconversion rates reached 100% in both cohorts, although cohort 2 showed greater geometric mean IgG titers that were stable through day 180 and associated with enhanced potencies of SP/RBD-ACE2 binding inhibition and live virus neutralization. AKS-452-induced IgG titers strongly bound mutant SP/RBD from several SARS-CoV-2 variants (including Omicrons) that were predominantly of the favorable IgG1/3 isotype and IFN-γ-producing T cell phenotype. These favorable safety and immunogenicity profiles of the candidate vaccine as demonstrated in this phase II study are consistent with those of the phase I study (ClinicalTrials.gov: NCT04681092) and suggest that a total of 90 µg received in 2 doses may offer a greater duration of cross-reactive neutralizing titers than when given in a single dose. [ABSTRACT FROM AUTHOR]

The Acute Febrile Illness (AFI) Surveillance Network in Belize is a country-wide active surveillance program aimed at diagnosing vector-borne, respiratory, and enteric pathogens among patients presenting to 11 participating hospitals and clinics with new onset fever. This study describes the epidemiology of dengue virus (DENV) infections in Belize diagnosed through AFI surveillance in 2020. Of the 894 patients enrolled and PCR-tested for DENV in this period, 44 DENV-positive cases (5%) were identified. All four DENV serotypes were detected, with two cases testing positive for DENV serotype 4, which is the first report of this serotype in Belize since 2004. The majority of DENV cases (66%) were diagnosed in the Belize District, which contains the largest urban center in the country (Belize City). Positive cases were detected between January 2020 and September 2020, with the majority (89%) diagnosed during the dry season between January and April, unlike years prior when cases were more often diagnosed during the wet season. Clinical signs and symptoms varied slightly between DENV serotypes. Active surveillance of DENV among AFI cases provides insight into the epidemiologic and clinical characteristics of DENV in Belize. This information is important for informing public health interventions to mitigate DENV transmission. [ABSTRACT FROM AUTHOR]

To address the coronavirus disease 2019 (COVID-19) pandemic caused by infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a recombinant subunit vaccine, AKS-452, is being developed comprising an Fc fusion protein of the SARS-CoV-2 viral spike protein receptor binding domain (SP/RBD) antigen and human IgG1 Fc emulsified in the water-in-oil adjuvant, Montanide™ ISA 720. A single-center, open-label, phase I dose-finding and safety study was conducted with 60 healthy adults (18–65 years) receiving one or two doses 28 days apart of 22.5 µg, 45 µg, or 90 µg of AKS-452 (i.e. , six cohorts, N = 10 subjects per cohort). Primary endpoints were safety and reactogenicity and secondary endpoints were immunogenicity assessments. No AEs ≥ 3, no SAEs attributable to AKS-452, and no SARS-CoV-2 viral infections occurred during the study. Seroconversion rates of anti-SARS-CoV-2 SP/RBD IgG titers in the 22.5, 45, and 90 µg cohorts at day 28 were 70%, 90%, and 100%, respectively, which all increased to 100% at day 56 (except 89% for the single-dose 22.5 µg cohort). All IgG titers were Th1-isotype skewed and efficiently bound mutant SP/RBD from several SARS-CoV-2 variants with strong neutralization potencies of live virus infection of cells (including alpha and delta variants). The favorable safety and immunogenicity profiles of this phase I study (ClinicalTrials.gov: NCT04681092) support phase II initiation of this room-temperature stable vaccine that can be rapidly and inexpensively manufactured to serve vaccination at a global scale without the need of a complex distribution or cold chain. [ABSTRACT FROM AUTHOR]

AKS-452 is a biologically-engineered vaccine comprising an Fc fusion protein of the SARS-CoV-2 viral spike protein receptor binding domain antigen (Ag) and human IgG1 Fc (SP/RBD-Fc) in clinical development for the induction and augmentation of neutralizing IgG titers against SARS-CoV-2 viral infection to address the COVID-19 pandemic. The Fc moiety is designed to enhance immunogenicity by increasing uptake via Fc-receptors (FcγR) on Ag-presenting cells (APCs) and prolonging exposure due to neonatal Fc receptor (FcRn) recycling. AKS-452 induced approximately 20-fold greater neutralizing IgG titers in mice relative to those induced by SP/RBD without the Fc moiety and induced comparable long-term neutralizing titers with a single dose vs. two doses. To further enhance immunogenicity, AKS-452 was evaluated in formulations containing a panel of adjuvants in which the water-in-oil adjuvant, Montanide™ ISA 720, enhanced neutralizing IgG titers by approximately 7-fold after one and two doses in mice, including the neutralization of live SARS-CoV-2 virus infection of VERO-E6 cells. Furthermore, ISA 720-adjuvanted AKS-452 was immunogenic in rabbits and non-human primates (NHPs) and protected from infection and clinical symptoms with live SARS-CoV-2 virus in NHPs (USA-WA1/2020 viral strain) and the K18 human ACE2-trangenic (K18-huACE2-Tg) mouse (South African B.1.351 viral variant). These preclinical studies support the initiation of Phase I clinical studies with adjuvanted AKS-452 with the expectation that this room-temperature stable, Fc-fusion subunit vaccine can be rapidly and inexpensively manufactured to provide billions of doses per year especially in regions where the cold-chain is difficult to maintain. [ABSTRACT FROM AUTHOR]

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has killed more than 4 million humans globally, but there is no bona fide Food and Drug Administration-approved drug-like molecule to impede the COVID-19 pandemic. The sluggish pace of traditional therapeutic discovery is poorly suited to producing targeted treatments against rapidly evolving viruses. Here, we used an affinity-based screen of 4 billion DNA-encoded molecules en masse to identify a potent class of virus-specific inhibitors of the SARS-CoV-2 main protease (Mpro) without extensive and time-consuming medicinal chemistry. CDD-1714, the initial three-building-block screening hit (molecular weight [MW] = 542.5 g/mol), was a potent inhibitor (inhibition constant [Ki] = 20 nM). CDD-1713, a smaller two-building-block analog (MW = 353.3 g/mol) of CDD-1714, is a reversible covalent inhibitor of Mpro (Ki = 45 nM) that binds in the protease pocket, has specificity over human proteases, and shows in vitro efficacy in a SARS-CoV-2 infectivity model. Subsequently, key regions of CDD-1713 that were necessary for inhibitory activity were identified and a potent (Ki = 37 nM), smaller (MW = 323.4 g/mol), and metabolically more stable analog (CDD-1976) was generated. Thus, screening of DNA-encoded chemical libraries can accelerate the discovery of efficacious drug-like inhibitors of emerging viral disease targets. [ABSTRACT FROM AUTHOR]

West Nile virus (WNV), a mosquito-borne arbovirus, remains a major global health concern. In this study, we optimized PCR methods then assessed serially-collected whole blood (WB), urine (UR), saliva, and semen specimens from a large cohort of WNV-positive participants to evaluate the natural history of infection and persistent shedding of WNV RNA. Viral RNA extraction protocols for frozen WB and UR specimens were optimized and validated through spiking experiments to maximize recovery of viral RNA from archived specimens and to assess the degradation of WNV RNA in stored UR specimens. The resultant procedures were used in conjunction with PCR detection to identify WNV-positive specimens and to quantify their viral loads. A total of 59 of 352 WB, 10 of 38 UR, and 2 of 34 saliva specimens tested positive for WNV RNA. Although a single semen specimen was positive 22 days post onset, we could not definitively confirm the presence of WNV RNA in the remaining specimens. WNV RNA-positive UR specimens exhibited profound loss of viral RNA during storage, highlighting the need for optimal preservation pre-storage. This study provides optimized methods for WNV RNA detection among different fluid types and offers alternative options for diagnostic testing during the acute stages of WNV. [ABSTRACT FROM AUTHOR]

Background: Chagas disease is a chronic parasitic infection that progresses to dilated cardiomyopathy in 30% of human cases. Public health efforts target diagnosing asymptomatic cases, as therapeutic efficacy diminishes as irreversible tissue damage progresses. Physician diagnosis of Chagas disease cases in the United States is low, partially due to lack of awareness of the potential burden in the United States. Methodology/Principal findings: The current study tested a patient cohort of 1,196 Starr County, Texas residents using the Hemagen Chagas ELISA Kit as a preliminary screening assay. Samples testing positive using the Hemagen test were subjected to additional confirmatory tests. Two patients (0.17%) without previous Chagas disease diagnosis were identified; both had evidence of acquiring disease in the United States or along the Texas-Mexico border. Conclusions/Significance: The Texas-Mexico border is a foci of Chagas disease human cases, with a local disease burden potentially twice the national estimate of Hispanic populations. It is imperative that physicians consider persons with residential histories along the Texas-Mexico border for Chagas disease testing. [ABSTRACT FROM AUTHOR]

Anti- N -methyl- d -aspartate receptor autoimmune encephalitis (NMDAR AE) is an antibody-mediated neurological disorder that may be caused by post-herpes simplex virus-1 meningoencephalitis (HSV ME) and ovarian teratomas, although most pediatric cases are idiopathic. We sought to evaluate if other infections precede NMDAR AE by conducting a single-center, retrospective, case-control study of 86 pediatric cases presenting to Texas Children's Hospital between 2006 and 2022. HSV ME (HSV-1 and HSV-2) was a significantly more common preceding infection in the experimental group compared to control patients with idiopathic intracranial hypertension, while there was no difference in remote HSV infection between the two groups. Recent Epstein-Barr virus infection was evident in 8/42 (19%) tested experimental patients in comparison to 1/25 (4%) tested control patients which provided evidence for a genuine measure of effect but was not statistically significant due to small sample size (p = 0.07). The other 25 infectious etiologies were not different among the two groups and not all variables were clinically indicated or obtained in every subject, highlighting the need for future standardized, multi-institutional studies on underlying infectious precursors of autoimmune encephalitis. • In addition to HSV- 1, HSV- 2 meningoencephalitis is a likely precipitant of anti-NMDAR encephalitis. • Other Herpesviridae like EBV may predispose to NMDAR AE greater than previously appreciated, requiring further study. • Frequently detected concomitant infections with NMDAR AE like common respiratory viruses are less likely triggers of NMDAR AE. [ABSTRACT FROM AUTHOR]

The article discusses the vector control and pest management at the U.S. Dept. of Defense for the health of military personnel. It cites on the government program to control the vector-borne diseases (VBD) while balancing pesticide exposure risk and environmental risk. The article also discusses the susceptibility of military personnel to VBD during outdoor training exercises, military missions and occupational-specific exposures.

West Nile virus (WNV) is a widespread and devastating disease, especially in those who develop neuroinvasive disease. A growing body of evidence describes sequelae years after infection, including neurological complications and chronic kidney disease (CKD). Eighty-nine out of 373 WNV-positive cases were followed for approximately two years and compared to 127 WNV-negative controls with and without CKD. Adjusted risk ratios (aRRs) were calculated via a log binomial regression to determine the impact of WNV exposure and other possible confounders on the likelihood of developing CKD. Cytokine profiles of WNV patients and controls were evaluated to characterize differences and describe potential underlying pathophysiological mechanisms. The associated risk for developing CKD was significantly associated with history of WNV infection (aRR = 1.91, 95% CI 1.13–3.25). Additionally, five distinct cytokines were found to be significantly associated with WNV infection (eotaxin, IL-8, IL-12p70, IP-10, and TNFα) after the p-value was adjusted to <0.0019 due to the Bonferroni correction. These data support that WNV infection is an independent risk factor for CKD, even after accounting for confounding comorbidities. WNV participants who developed CKD had high activity of proinflammatory markers, indicating underlying inflammatory disease. This study provides new insights into CKD resultant of WNV infection. [ABSTRACT FROM AUTHOR]