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Routine entomological monitoring data are used to quantify the abundance of Ae. aegypti. The public health utility of these indicators is based on the assumption that greater mosquito abundance increases the risk of human DENV transmission, and therefore reducing exposure to the vector decreases incidence of infection. Entomological survey data from two longitudinal cohort studies in Iquitos, Peru, linked with 8,153 paired serological samples taken approximately six months apart were analyzed. Indicators of Ae. aegypti density were calculated from cross-sectional and longitudinal entomological data collected over a 12-month period for larval, pupal and adult Ae. aegypti. Log binomial models were used to estimate risk ratios (RR) to measure the association between Ae. aegypti abundance and the six-month risk of DENV seroconversion. RRs estimated using cross-sectional entomological data were compared to RRs estimated using longitudinal data. Higher cross-sectional Ae. aegypti densities were not associated with an increased risk of DENV seroconversion. Use of longitudinal entomological data resulted in RRs ranging from 1.01 (95% CI: 1.01, 1.02) to 1.30 (95% CI: 1.17, 1.46) for adult stage density estimates and RRs ranging from 1.21 (95% CI: 1.07, 1.37) to 1.75 (95% CI: 1.23, 2.5) for categorical immature indices. Ae. aegypti densities calculated from longitudinal entomological data were associated with DENV seroconversion, whereas those measured cross-sectionally were not. Ae. aegypti indicators calculated from cross-sectional surveillance, as is common practice, have limited public health utility in detecting areas or populations at high risk of DENV infection.

Yellow fever virus, family Orthoflaviviridae, is the causative agent of yellow fever – a lethal mosquito-borne disease endemic to South America and Africa. Recent advances in understanding the mechanism of orthoflavivirus pathogenesis, particularly for dengue (DENV), demonstrate a role for the secreted viral non-structural protein 1 (NS1) in both animal and human models. The NS1 protein’s most well described pathogenic mechanism is its ability to induce vascular endothelial permeability in a tissue organ specific manner, contributing to orthoflavivirus disease severity. Surprisingly, there is minimal research published on the role of NS1 in YFV pathogenesis, despite the clear and present danger of YFV outbreaks in endemic countries. Understanding the role of NS1 in YFV pathogenesis is critical for the development of therapeutic interventions. Notably, while vaccination efforts for orthoflaviviruses have been historically difficult, the live attenuated vaccine (YFV-17D) against YFV has been hailed as not only the most successful orthoflavivirus vaccine but is among the most successful live virus vaccines ever created. Despite YFV-17D’s widespread use since its introduction in the 1930’s, the best described mechanism of protection is the vaccine’s potent neutralizing antibodies. Our knowledge of NS1 pathogenic mechanisms has expanded since the development of YFV-17D, but how vaccine mediated immunity may interact with NS1 during natural YFV infection is not well described. In this review we describe the current knowledge of YFV NS1 mediated pathogenesis and adaptive immunity directed against YFV NS1 in a variety of animal and human models. Graphical Abstract

Flaviviridae: A growing family of human pathogens Among the major contributors to the positive-strand RNA virus global disease burden are the flaviviruses, a genus of enveloped viruses that includes Yellow fever virus (YFV), Zika virus (ZIKV), Dengue virus (DENV), and West Nile virus (WNV) and is closely related to Hepatitis C virus (HCV) [2]. Cer, ceramide; Chol, cholesterol; DAG, diacylglycerol; ER, endoplasmic reticulum; FFA, free fatty acids; GalCer, galactosylceramide; GlcCer, glucosylceramide; GSPL, complex glycosphingolipids; mTOR, mammalian target of rapamycin; NS, nonstructural; PC, phosphatidylcholine; PE, phosphatidylethanolamine; PIP2, phosphatidylinositol-(4,5)-bisphosphate; PI, phosphatidylinositol; PIP3, phosphatidylinositol-(3,4,5)-trisphosphate; PM, plasma membrane; PS, phosphatidylserine; S1P, sphingosine-1-phosphate; SM, sphingomyelin; TAG, triacylglycerol; Ve, invaginated vesicles. https://doi.org/10.1371/journal.ppat.1006952.g001 Replication complex assembly remakes the host lipid landscape Inducing the negative membrane curvature required for vesicle formation is a thermodynamically unfavorable process [16]. [...]LD lipids may be required for multiple aspects of flavivirus infection and pathogenesis, from providing the raw materials and energy for replication to supporting efficient encapsidation and assembly of viral particles. Fatty acid synthesis is regulated by sterol regulatory element-binding proteins (SREBPs), a family of membrane-bound transcription factors also responsible for controlling cholesterol biosynthesis [30].

SARS-CoV-2 and its variants continue to infect hundreds of thousands every day despite the rollout of effective vaccines. Therefore, it is essential to understand the levels of protection that these vaccines provide in the face of emerging variants. Here, we report two demographically balanced cohorts of BNT162b2 vaccine recipients and COVID-19 patients, from which we evaluate neutralizing antibody titers against SARS-CoV-2 as well as the B.1.1.7 (alpha) and B.1.351 (beta) variants. We show that both B.1.1.7 and B.1.351 are less well neutralized by serum from vaccinated individuals, and that B.1.351, but not B.1.1.7, is less well neutralized by convalescent serum. We also find that the levels of variant-specific anti-spike antibodies are proportional to neutralizing activities. Together, our results demonstrate the escape of the emerging SARS-CoV-2 variants from neutralization by serum antibodies, which may lead to reduced protection from re-infection or increased risk of vaccine breakthrough. Here, the authors show that neutralization of human sera from both BNT162b2 vaccine recipients and from convalescent COVID-19 patients is less efficient against SARS- CoV-2 variants B.1.1.7 and B.1.351 and negatively associated with patient age.

Access to fast and reliable nucleic acid testing continues to play a key role in controlling the COVID-19 pandemic, especially in the context of increased vaccine break-through risks due to new variants. We report a rapid, low-cost (~ 2 USD), simple-to-use nucleic acid test kit for self-administered at-home testing without lab instrumentation. The entire sample-to-answer workflow takes < 60 min, including noninvasive sample collection, one-step RNA preparation, reverse-transcription loop-mediated isothermal amplification (RT-LAMP) in a thermos, and direct visual inspection of a colorimetric test result. To facilitate long-term storage without cold-chain, a fast one-pot lyophilization protocol was developed to preserve all required biochemical reagents of the colorimetric RT-LAMP test in a single microtube. Notably, the lyophilized RT-LAMP assay demonstrated reduced false positives as well as enhanced tolerance to a wider range of incubation temperatures compared to solution-based RT-LAMP reactions. We validated our RT-LAMP assay using simulated infected samples, and detected a panel of SARS-CoV-2 variants with successful detection of all variants that were available to us at the time. With a simple change of the primer set, our lyophilized RT-LAMP home test can be easily adapted as a low-cost surveillance platform for other pathogens and infectious diseases of global public health importance.

Zika virus (ZIKV), an arbovirus of global concern, remodels intracellular membranes to form replication sites. How ZIKV dysregulates lipid networks to allow this, and consequences for disease, is poorly understood. Here, we perform comprehensive lipidomics to create a lipid network map during ZIKV infection. We find that ZIKV significantly alters host lipid composition, with the most striking changes seen within subclasses of sphingolipids. Ectopic expression of ZIKV NS4B protein results in similar changes, demonstrating a role for NS4B in modulating sphingolipid pathways. Disruption of sphingolipid biosynthesis in various cell types, including human neural progenitor cells, blocks ZIKV infection. Additionally, the sphingolipid ceramide redistributes to ZIKV replication sites, and increasing ceramide levels by multiple pathways sensitizes cells to ZIKV infection. Thus, we identify a sphingolipid metabolic network with a critical role in ZIKV replication and show that ceramide flux is a key mediator of ZIKV infection. Zika virus (ZIKV) remodels intracellular membranes for replication, but the role of different lipid types for infection and disease is unclear. Here, the authors perform lipidomics, show perturbation of the lipid network during ZIKV infection and show that ceramides are important for ZIKV infection.

Humans who experience a primary dengue virus (DENV) infection develop antibodies that preferentially neutralize the homologous serotype responsible for infection. Affected individuals also generate cross-reactive antibodies against heterologous DENV serotypes, which are non-neutralizing. Dengue cross-reactive, non-neutralizing antibodies can enhance infection of Fc receptor bearing cells and, potentially, exacerbate disease. The actual binding sites of human antibody on the DENV particle are not well defined. We characterized the specificity and neutralization potency of polyclonal serum antibodies and memory B-cell derived monoclonal antibodies (hMAbs) from 2 individuals exposed to primary DENV infections. Most DENV-specific hMAbs were serotype cross-reactive and weakly neutralizing. Moreover, many hMAbs bound to the viral pre-membrane protein and other sites on the virus that were not preserved when the viral envelope protein was produced as a soluble, recombinant antigen (rE protein). Nonetheless, by modifying the screening procedure to detect rare antibodies that bound to rE, we were able to isolate and map human antibodies that strongly neutralized the homologous serotype of DENV. Our MAbs results indicate that, in these two individuals exposed to primary DENV infections, a small fraction of the total antibody response was responsible for virus neutralization.

Dengue is a mosquito-borne flavivirus that is spreading at an unprecedented rate and has developed into a major health and economic burden in over 50 countries. Even though infected individuals develop potent and long-lasting serotype-specific neutralizing antibodies (Abs), the epitopes engaged by human neutralizing Abs have not been identified. Here, we demonstrate that the dengue virus (DENV)-specific serum Ab response in humans consists of a large fraction of cross-reactive, poorly neutralizing Abs and a small fraction of serotype-specific, potently inhibitory Abs. Although many mouse-generated, strongly neutralizing monoclonal antibodies (mAbs) recognize epitopes that are present on recombinant DENV envelope (E) proteins, unexpectedly, the majority of neutralizing Abs in human immune sera bound to intact virions but not to the ectodomain of purified soluble E proteins. These conclusions with polyclonal Abs were confirmed with newly generated human mAbs derived from DENV-immune individuals. Two of three strongly neutralizing human mAbs bound to E protein epitopes that were preserved on the virion but not on recombinant E (rE) protein. We propose that humans produce Abs that neutralize DENV infection by binding a complex, quaternary structure epitope that is expressed only when E proteins are assembled on a virus particle. Mapping studies indicate that this epitope has a footprint that spans adjacent E protein dimers and includes residues at the hinge between domains I and II of E protein. These results have significant implications for the DENV Ab and vaccine field.

BACKGROUNDVaccination is typically administered without regard to site of prior vaccination, but this factor may substantially affect downstream immune responses.METHODSWe assessed serological responses to initial COVID-19 vaccination in baseline seronegative adults who received second-dose boosters in the ipsilateral or contralateral arm relative to initial vaccination. We measured serum SARS-CoV-2 spike-specific Ig, receptor-binding domain-specific (RBD-specific) IgG, SARS-CoV-2 nucleocapsid-specific IgG, and neutralizing antibody titers against SARS-CoV-2.D614G (early strain) and SARS-CoV-2.B.1.1.529 (Omicron) at approximately 0.6, 8, and 14 months after boosting.RESULTSIn 947 individuals, contralateral boosting was associated with higher spike-specific serum Ig, and this effect increased over time, from a 1.1-fold to a 1.4-fold increase by 14 months (P < 0.001). A similar pattern was seen for RBD-specific IgG. Among 54 pairs matched for age, sex, and relevant time intervals, arm groups had similar antibody levels at study visit 2 (W2), but contralateral boosting resulted in significantly higher binding and neutralizing antibody titers at W3 and W4, with progressive increase over time, ranging from 1.3-fold (total Ig, P = 0.007) to 4.0-fold (pseudovirus neutralization to B.1.1.529, P < 0.001).CONCLUSIONSIn previously unexposed adults receiving an initial vaccine series with the BNT162b2 mRNA COVID-19 vaccine, contralateral boosting substantially increases antibody magnitude and breadth at times beyond 3 weeks after vaccination. This effect should be considered during arm selection in the context of multidose vaccine regimens.FUNDINGM.J. Murdock Charitable Trust, OHSU Foundation, NIH.

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.