Development of a hydrogen peroxide-inactivated vaccine that protects against viscerotropic yellow fever in a non-human primate model.

Yellow fever virus (YFV) is endemic in >40 countries and causes viscerotropic disease with up to 20%-60% mortality. Successful live-attenuated yellow fever (YF) vaccines were developed in the mid-1930s, but their use is restricted or formally contraindicated in vulnerable populations including infants, the elderly, and people with compromised immune systems. In these studies, we describe the development of a next-generation hydrogen peroxide-inactivated YF vaccine and determine immune correlates of protection based on log neutralizing index (LNI) and neutralizing titer-50% (NT50) studies. In addition, we compare neutralizing antibody responses and protective efficacy of hydrogen peroxide-inactivated YF vaccine candidates to live-attenuated YFV-17D (YF-VAX) in a rhesus macaque model of viscerotropic YF. Our results indicate that an optimized, inactivated YF vaccine elicits protective antibody responses that prevent viral dissemination and lethal infection in rhesus macaques and may be a suitable alternative for vaccinating vulnerable populations who are not eligible to receive replicating live-attenuated YF vaccines.

Molecular identification and GC-MS analysis of a newly isolated novel bacterium (Lysinibacillus sp. VCRC B655) for mosquito control.

BACKGROUND: Mosquitoes are widespread globally and have contributed to transmitting pathogens to humans and the burden of vector-borne diseases. They are effectively controlled at their larval stages by biocontrol agents. Unravelling natural sources for microbial agents can lead us to novel potential candidates for managing mosquito-borne diseases. In the present study, an attempt was made to isolate a novel bacterium from the field-collected agricultural soil for larvicidal activity and promising bacterial metabolites for human healthcare. METHODS AND RESULTS: Field-collected soil samples from the Union territory of Puducherry, India, have been used as the source of bacteria. Isolate VCRC B655 belonging to the genus Lysinibacillus was identified by 16S rRNA gene sequencing and exhibited promising larvicidal activity against different mosquito species, including Culex (Cx.) quinquefasciatus, Anopheles (An.) stephensi, and Aedes (Ae.) aegypti. The lethal concentration (LC) of Lysinibacillus sp. VCRCB655 was observed to be high for Cx. quiquefasciatus: LC50 at 0.047 mg/l, LC90 at 0.086 mg/l, followed by An. stephensi and Ae. aegypti (LC50: 0.6952 mg/l and 0.795 mg/l) respectively. Additionally, metabolic profiling of the culture supernatant was carried out through Gas chromatography and Mass spectrophotometry (GC/MS) and identified 15 major secondary metabolites of different metabolic classes. Diketopiperazine (DKPs), notably pyro lo [1, 2-a] pyrazine1, 4-dione, are the abundant compounds reported for antioxidant activity, and an insecticide compound benzeneacetic acid was also identified. CONCLUSIONS: A new bacterial isolate, Lysinibacillus sp. VCRC B655 has been identified with significant larvicidal activity against mosquito larvae with no observed in non-target organisms. GC-MS analysis revealed diverse bioactive compounds with substantial biological applications. In conclusion, Lysinibacillus sp. VCRC B655 showed promise as an alternative biocontrol agent for mosquito vector control, with additional biological applications further enhancing its significance.

Hydroxychloroquine is associated with lower seroconversion upon 17DD-Yellow fever primovaccination in patients with primary Sjögren's syndrome.

The present study aimed at investigating whether the hydroxychloroquine (HCQ) treatment would impact the neutralizing antibody production, viremia levels and the kinetics of serum soluble mediators upon planned 17DD-Yellow Fever (YF) primovaccination (Bio-Manguinhos-FIOCRUZ) of primary Sjögren's syndrome (pSS). A total of 34 pSS patients and 23 healthy controls (HC) were enrolled. The pSS group was further categorized according to the use of HCQ (HCQ and Non-HCQ). The YF-plaque reduction neutralization test (PRNT ≥1:50), YF viremia (RNAnemia) and serum biomarkers analyses were performed at baseline and subsequent time-points (Day0/Day3-4/Day5-6/Day7/Day14-D28). The pSS group showed PRNT titers and seropositivity rates similar to those observed for HC (GeoMean = 238 vs 440, p = .11; 82% vs 96%, p = .13). However, the HCQ subgroup exhibited lower seroconversion rates as compared to HC (GeoMean = 161 vs 440, p = .04; 69% vs 96%, p = .02) and Non-HQC (GeoMean = 161 vs 337, p = .582; 69% vs 94%, p = .049). No differences in YF viremia were observed amongst subgroups. Serum biomarkers analyses demonstrated that HCQ subgroup exhibited increased levels of CCL2, CXL10, IL-6, IFN-γ, IL1-Ra, IL-9, IL-10, and IL-2 at baseline and displayed a consistent increase of several biomarkers along the kinetics timeline up to D14-28. These results indicated that HCQ subgroup exhibited a deficiency in assembling YF-specific immune response elicited by 17DD-YF primovaccination as compared to Non-HCQ subgroup. Our findings suggested that hydroxychloroquine is associated with a decrease in the humoral immune response after 17DD-YF primovaccination.

Imidazolium salt's toxic effects in larvae and cells of Aedes aegypti and Aedes albopictus (Diptera: Culicidae).

Aedes aegypti and Aedes albopictus are the main vectors of arboviruses such as Dengue, Chikungunya and Zika, causing a major impact on global economic and public health. The main way to prevent these diseases is vector control, which is carried out through physical and biological methods, in addition to environmental management. Although chemical insecticides are the most effective strategy, they present some problems such as vector resistance and ecotoxicity. Recent research highlights the potential of the imidazolium salt "1-methyl-3-octadecylimidazolium chloride" (C18MImCl) as an innovative and environmentally friendly solution against Ae. aegypti. Despite its promising larvicidal activity, the mode of action of C18MImCl in mosquito cells and tissues remains unknown. This study aimed to investigate its impacts on Ae. aegypti larvae and three cell lines of Ae. aegypti and Ae. albopictus, comparing the cellular effects with those on human cells. Cell viability assays and histopathological analyses of treated larvae were conducted. Results revealed the imidazolium salt's high selectivity (> 254) for mosquito cells over human cells. After salt ingestion, the mechanism of larval death involves toxic effects on midgut cells. This research marks the first description of an imidazolium salt's action on mosquito cells and midgut tissues, showcasing its potential for the development of a selective and sustainable strategy for vector control.

Exploring fine-scale urban landscapes using satellite data to predict the distribution of Aedes mosquito breeding sites.

BACKGROUND: The spread of mosquito-transmitted diseases such as dengue is a major public health issue worldwide. The Aedes aegypti mosquito, a primary vector for dengue, thrives in urban environments and breeds mainly in artificial or natural water containers. While the relationship between urban landscapes and potential breeding sites remains poorly understood, such a knowledge could help mitigate the risks associated with these diseases. This study aimed to analyze the relationships between urban landscape characteristics and potential breeding site abundance and type in cities of French Guiana (South America), and to evaluate the potential of such variables to be used in predictive models. METHODS: We use Multifactorial Analysis to explore the relationship between urban landscape characteristics derived from very high resolution satellite imagery, and potential breeding sites recorded from in-situ surveys. We then applied Random Forest models with different sets of urban variables to predict the number of potential breeding sites where entomological data are not available. RESULTS: Landscape analyses applied to satellite images showed that urban types can be clearly identified using texture indices. The Multiple Factor Analysis helped identify variables related to the distribution of potential breeding sites, such as buildings class area, landscape shape index, building number, and the first component of texture indices. Models predicting the number of potential breeding sites using the entire dataset provided an R² of 0.90, possibly influenced by overfitting, but allowing the prediction over all the study sites. Predictions of potential breeding sites varied highly depending on their type, with better results on breeding sites types commonly found in urban landscapes, such as containers of less than 200 L, large volumes and barrels. The study also outlined the limitation offered by the entomological data, whose sampling was not specifically designed for this study. Model outputs could be used as input to a mosquito dynamics model when no accurate field data are available. CONCLUSION: This study offers a first use of routinely collected data on potential breeding sites in a research study. It highlights the potential benefits of including satellite-based characterizations of the urban environment to improve vector control strategies.

Guía de mensajes sobre cómo cuidar en casa a niños con dengue

El dengue se transmite por la picadura de un mosquito infectado con uno de los cuatro serotipos del virus del dengue. Es una enfermedad febril que afecta a lactantes, niños y adultos y puede evolucionar a un dengue grave, caracterizado por choque, dificultad para respirar, sangrado grave y/o complicaciones graves de los órganos. La prevención y el control del dengue debe ser intersectorial e involucrar a la familia y la comunidad. Ante la sospecha de síntomas de dengue en el niño, llevarlo al médico o a la unidad de salud más cercana. Si el médico considera que puede ser cuidado en casa, se deben seguir las recomendaciones establecidas en este documento. En el caso de niños pequeños no pueden hablar o expresar cómo se sienten. Por eso, es importante observar al niño y si aparece alguno de los signos de alarma, llevarlo inmediatamente a la unidad de salud más cercana, ya que su vida corre peligro. La información presentada a continuación es sobre aspectos generales del cuidado en casa de niños con dengue. El presente documento está dirigido a los comunicadores de los ministerios de Salud de los Estados Miembros de la OPS, para que, junto a sus equipos nacionales adapten la información según las necesidades propias de cada país y el público al cual se dirigirá.

Exploring community needs in combating aedes mosquitoes and dengue fever: a study with urban community in the recurrent hotspot area.

BACKGROUND: Aedes mosquitoes are the main vector of dengue infection, a global health threat affecting millions of people annually. Conventional prevention and control methods against dengue outbreaks have only achieved marginal success. Recognizing the complex issue at hand, a multilevel participatory approach is crucial. Thus, alternative strategies that involve community engagement are increasingly being considered and attempted. While community-based vector control programs have been conducted, sustaining behavioral changes among the population remains a challenge. This study aimed to identify the specific community needs in combating Aedes mosquitoes and dengue fever as a basis to guide the development of community-driven initiatives and foster a deeper sense of ownership in the fight against dengue. METHODS: Between 1 August 2022 and 30 November 2022, we conducted a study in Hulu Langat district, Selangor, using a mixed-method design. All participants consented to the study, which comprised 27 participants (FGDs) and 15 participants (IDIs). The IDIs included two participants with a history of dengue fever, one community leader, one faith leader, seven local authorities, and four district health officers. Semi-structured interviews and discussions were performed among stakeholders and community members recruited via purposive and snowball sampling techniques. All interviews were audio-recorded before being analyzed using reflexive thematic analysis. RESULTS: These results derived from qualitative data explored the perspectives and needs of communities in combating Aedes mosquitoes and dengue fever. Interviews were conducted with various stakeholders, including community members, leaders, and health officers. The study identified the necessity of decisive actions by authorities to address the impact of the dengue epidemic, the importance of community engagement through partnerships and participatory approaches, the potential benefits of incentives and rewards to enhance community participation, and the need for sustained community engagement and education, especially via the involvement of young people in prevention efforts. These findings provide valuable insights into the design of effective strategies against Aedes mosquitoes and dengue fever. CONCLUSIONS: In short, there is an urgent need for a comprehensive approach involving multiple stakeholders in the fight against Aedes mosquitoes and dengue fever. The approach should incorporate efforts to raise awareness, provide practical resources, and foster community responsibility. The active involvement of teenagers as volunteers can contribute to long-term prevention efforts. Collaboration, resource allocation, and community engagement are crucial for effective dengue control and a healthier environment.

Update to: Assessing the efficacy of male Wolbachia-infected mosquito deployments to reduce dengue incidence in Singapore.

BACKGROUND: This trial is a parallel, two-arm, non-blinded cluster randomised controlled trial that is under way in Singapore, with the aim of measuring the efficacy of male Wolbachia-infected Aedes aegypti deployments in reducing dengue incidence in an endemic setting with all four dengue serotypes in circulation. The trial commenced in July 2022 and is expected to conclude in September 2024. The original study protocol was published in December 2022. Here, we describe amendments that have been made to the study protocol since commencement of the trial. METHODS: The key protocol amendments are (1) addition of an explicit definition of Wolbachia exposure for residents residing in intervention sites based on the duration of Wolbachia exposure at point of testing, (2) incorporation of a high-dimensional set of anthropogenic and environmental characteristics in the analysis plan to adjust for baseline risk factors of dengue transmission, and (3) addition of alternative statistical analyses for endpoints to control for post hoc imbalance in cluster-based environmental and anthropogenic characteristics. DISCUSSION: The findings from this study will provide the first experimental evidence for the efficacy of releasing male-Wolbachia infected mosquitoes to reduce dengue incidence in a cluster-randomised controlled trial. The trial will conclude in 2024 and results will be reported shortly thereafter. TRIAL REGISTRATION: ClinicalTrials.gov, identifier: NCT05505682. Registered on 16 August 2022. Retrospectively registered. Last updated 11 November 2023.

Wolbachia mediates crosstalk between miRNA and Toll pathways to enhance resistance to dengue virus in Aedes aegypti.

The obligate endosymbiont Wolbachia induces pathogen interference in the primary disease vector Aedes aegypti, facilitating the utilization of Wolbachia-based mosquito control for arbovirus prevention, particularly against dengue virus (DENV). However, the mechanisms underlying Wolbachia-mediated virus blockade have not been fully elucidated. Here, we report that Wolbachia activates the host cytoplasmic miRNA biogenesis pathway to suppress DENV infection. Through the suppression of the long noncoding RNA aae-lnc-2268 by Wolbachia wAlbB, aae-miR-34-3p, a miRNA upregulated by the Wolbachia strains wAlbB and wMelPop, promoted the expression of the antiviral effector defensin and cecropin genes through the Toll pathway regulator MyD88. Notably, anti-DENV resistance induced by Wolbachia can be further enhanced, with the potential to achieve complete virus blockade by increasing the expression of aae-miR-34-3p in Ae. aegypti. Furthermore, the downregulation of aae-miR-34-3p compromised Wolbachia-mediated virus blockade. These findings reveal a novel mechanism by which Wolbachia establishes crosstalk between the cytoplasmic miRNA pathway and the Toll pathway via aae-miR-34-3p to strengthen antiviral immune responses against DENV. Our results will aid in the advancement of Wolbachia for arbovirus control by enhancing its virus-blocking efficiency.

Inactivation of yellow fever virus by WHO-recommended hand rub formulations and surface disinfectants.

Despite continued outbreaks of yellow fever virus (YFV) in endemic regions, data on its environmental stability or guidelines for its effective inactivation is limited. Here, we evaluated the susceptibility of the YFV 17D vaccine strain to inactivation by ethanol, 2-propanol, World Health Organization (WHO)-recommended hand rub formulations I and II, as well as surface disinfectants. In addition, two pathogenic strains were tested to compare inactivation kinetics by WHO-recommended hand rub formulations I and II. Furthermore, environmental stability of the vaccine strain was assessed. YFV 17D particles displayed infectivity half-life decay profiles of ~13 days at room temperature. Despite this extended environmental stability, YFV was efficiently inactivated by alcohols, WHO-recommended hand formulations, and four out of five tested surface disinfectants. These results are useful in defining disinfection protocols to prevent non-vector borne YFV transmission.

Sofosbuvir Off-label Treatment of Yellow Fever Patients During an Outbreak in Brazil, 2018: A Cohort Study.

We enrolled 21 patients with laboratory-confirmed yellow fever (YF), hospitalized at Eduardo de Menezes Hospital, Brazil, to be treated with sofosbuvir, a drug approved for hepatitis C. Given the absence of specific YF antiviral treatments, the off-label nonrandomized sofosbuvir treatment aimed to address high disease severity and the risk of fatal outcomes. Patients received a daily dose of 400 mg sofosbuvir from 4 to 10 days post-symptom onset. YF viral load (VL) comparisons were made between treated and nontreated patients who either survived or died. The genomic VL for the treated group steadily decreased after day 7 post-symptom onset, suggesting that sofosbuvir might reduce YF VL. This study underscores the urgent need for YF antiviral therapies, advocating for randomized clinical trials to further explore sofosbuvir's role in YF treatment.

Effectiveness of repellent from patchouli (Pogestemon cablin) varieties of Southeast Sulawesi against Aedes aegypti.

BACKGROUND OBJECTIVES: The incidence of Dengue Hemorrhagic Fever (DHF) continues to increase over time in the world, including Indonesia. One of the prevention efforts against dengue virus transmission is to avoid vector mosquito bites by the use of repellants. Using repellents can reduce exposure to mosquito bites that may cause infection with the dengue virus. This study aimed to determine the effectiveness of repellent lotion composed of patchouli batik extract (Pogostemon cablin) from Southeast Sulawesi varieties against Aedes aegypti mosquitoes. METHODS: The research subjects were Aedes aegypti adult mosquitoes. The research consisted of three stages. The first stage was a phytochemical test (qualitative method), the second stage was the analysis of patchouli essential oil (GC-MS method) and the third stage was a test of the effectiveness of lotions made from patchouli extract in lotion preparations against Aedes aegypti. RESULTS: The results of the effectiveness test of patchouli leaf repellent (Pogestemon cablin) lotion preparations were as follows: for a concentration of 2.5%, protective power 81.5%; concentration 5%, protection power 83.67%; concentration 7.5%, protection power 88.64 %; the concentration of 10%, protection power 90.44%, and the concentration of 12.5% had protection power 90.89%. Probit analysis and linear regression showed the value of ProbitLc 50 was 6.631. INTERPRETATION CONCLUSION: The results of the effectiveness test of Pogestemon cablin repellent lotion preparations with the most effective concentrations were 10% and 12.5%. The results of ANOVA test indicated there was no difference in the average value of the protection power in patchouli leaves.

Bamboo stumps that are artificially in use put pressure on dengue and chikungunya vector control in Dhaka city, Bangladesh.

BACKGROUND OBJECTIVES: Aedes aegypti and Ae. albopictus mosquitoes breed in natural and artificial containers, and they transmit dengue and chikungunya. A study was conducted to identify the contribution of bamboo stumps to these disease vectors that were used in the flower garden as pillars to hold the bamboo flex fence. METHODS: Two sizes of whole bamboo were used to hold fences around gardens at Dhaka University, Bangladesh, and were painted red and green. Mosquito larvae and pupae were collected from bamboo stumps between July and August, and vectors were identified up to the species level. The data were analyzed using the STATA/MP 14.2 version. RESULTS: 83.5% and 0.2% were Ae. albopictus and Ae. aegypti, respectively, and the remaining were Culex and Ar-migeres species. Ae. albopictus, Ae. aegypti, and both species-positive bamboo stumps were 46.9, 0.7, and 47.1%, respectively. 54.5% of the bamboo stumps had at least one mosquito species. The average stump depth for Aedes positive stumps (mean=11.7 cm, SE = 0.5) was significantly (p <0.001) higher than the Aedes negative stumps (mean = 9.5 cm, SE = 0.4). 53.8% and 38.0% stumps were found Aedes positive on the ground and upper sides of fences, respectively, and found significant (p<0.01) differences between both sides. A zero-inflated negative binomial count model is significant at a 5% level of significance, χ2(4) = 11.8, p = 0.019 (<0.05) for Ae. albopictus. Stump depth is found to have a significant positive effect on the number of Aedes-positive stumps. INTERPRETATION CONCLUSION: Artificially used natural containers are adding pressure to current mosquito control activities as mosquitoes are breeding on them, which needs additional attention.

Duration of post-vaccination immunity to yellow fever in volunteers ten years after a dose-response study - A complementary study.

A single dose of standard yellow fever (YF) vaccine is considered to provide life-long protection. In this study, we evaluate the seropositivity conferred by lower doses 10 years post-vaccination. In 2009, Bio-Manguinhos/Fiocruz performed a dose-response study with the 17DD yellow fever vaccine, administering the vaccine in the usual mean dose of 27.476 IU and in decreasing doses (10.447 IU, 3.013 IU, 587 IU, 158 IU and 31 IU), with the usual volume and route (0,5 ml subcutaneous). The decreasing doses were obtained by dilution in the laboratory of the manufacturer and the lots in test had standard quality control and were produced by good manufacturing practices (GMP). Around 30 days after the vaccination, doses down to 587 IU had similar immunogenicity and the 158 IU and 31 IU were inferior to the full dose. The seropositivity was maintained for 10 months, except on the 31 IU group. Eight years after, 85 % of 318 participants evaluated in a follow-up, maintained seropositivity that was similar across groups. Consistently, antibody titers in the reduced-dose groups were also comparable to those of the full-dose group. The current study, 10 years later, showed similarity between the vaccine groups (six arms who received the YF vaccine in decreasing doses: 27.476 IU, 10.447 IU, 3.013 IU, 587 IU, 158 IU, 31 IU) both in relation of seropositivity and in the evaluation of the geometric mean titers. The seropositivity rates across subgroups were 83,1%, 90 %, 87 %, 93 %, 83,8% and 85 %, correspondingly. These findings provides further support to the long-term immunogenicity of lower doses. Clinical trial registry: NCT04416477.

Applicability of Traps for Collecting Mosquito Immatures (Diptera: Culicidae) for Entomological Surveillance of Arbovirus Vectors in a Remnant of the Atlantic Forest, Rio de Janeiro State, Brazil.

Diverse larval habitats significantly influence female mosquito oviposition. Utilizing traps that simulate these habitats is helpful in the study of the bioecology and characteristics of pathogen-transmitting species during oviposition. This study evaluated the feasibility of different traps in natural environments by comparing sampling methods and detecting the oviposition of epidemiologically important mosquitoes, with emphasis on Haemagogus species, in a fragment of the Atlantic Forest in Silva Jardim, Rio de Janeiro State, Brazil. Monthly collections were conducted from March 2021 to October 2023 using four types of traps: plastic containers, tires, bamboo, and sapucaia. Immatures were collected from these traps using a pipette, placed in plastic bags, and transported to the laboratory. Tire was the most efficient trap, showing the highest mosquito abundance (n = 1239) and number of species (S = 11). Conversely, the plastic container trap exhibited the lowest diversity (H = 0.43), with only two species and a low mosquito abundance (n = 26). The bamboo trap captured six species and recorded the second-highest diversity index (H = 1.04), while the sapucaia trap captured five species and had the third-highest diversity index (H = 0.91). Of the total immatures collected, 1817 reached adulthood, comprising 13 species, two of which are vectors of the sylvatic yellow fever virus: Haemagogus leucocelaenus and Haemagogus janthinomys. In conclusion, detecting key vectors of the sylvatic yellow fever virus in Brazil highlights the need for ongoing entomological and epidemiological surveillance in the study area and its vicinity. These efforts are crucial for monitoring vector presence and activity, identifying potential transmission hotspots, and devising effective control and prevention strategies.

Mechanisms of Flavivirus Cross-Protection against Yellow Fever in a Mouse Model.

The complete lack of yellow fever virus (YFV) in Asia, and the lack of urban YFV transmission in South America, despite the abundance of the peridomestic mosquito vector Aedes (Stegomyia.) aegypti is an enigma. An immunologically naïve population of over 2 billion resides in Asia, with most regions infested with the urban YF vector. One hypothesis for the lack of Asian YF, and absence of urban YF in the Americas for over 80 years, is that prior immunity to related flaviviruses like dengue (DENV) or Zika virus (ZIKV) modulates YFV infection and transmission dynamics. Here we utilized an interferon α/ß receptor knock-out mouse model to determine the role of pre-existing dengue-2 (DENV-2) and Zika virus (ZIKV) immunity in YF virus infection, and to determine mechanisms of cross-protection. We utilized African and Brazilian YF strains and found that DENV-2 and ZIKV immunity significantly suppresses YFV viremia in mice, but may or may not protect relative to disease outcomes. Cross-protection appears to be mediated mainly by humoral immune responses. These studies underscore the importance of re-assessing the risks associated with YF outbreak while accounting for prior immunity from flaviviruses that are endemic.

Impact of HIV-Related Immune Impairment of Yellow Fever Vaccine Immunogenicity in People Living with HIV-ANRS 12403.

The yellow fever (YF) vaccine is one of the safest and most effective vaccines currently available. Still, its administration in people living with HIV (PLWH) is limited due to safety concerns and a lack of consensus regarding decreased immunogenicity and long-lasting protection for this population. The mechanisms associated with impaired YF vaccine immunogenicity in PLWH are not fully understood, but the general immune deregulation during HIV infection may play an important role. To assess if HIV infection impacts YF vaccine immunogenicity and if markers of immune deregulation could predict lower immunogenicity, we evaluated the association of YF neutralization antibody (NAb) titers with the pre-vaccination frequency of activated and exhausted T cells, levels of pro-inflammatory cytokines, and frequency of T cells, B cells, and monocyte subsets in PLWH and HIV-negative controls. We observed impaired YF vaccine immunogenicity in PLWH with lower titers of YF-NAbs 30 days after vaccination, mainly in individuals with CD4 count <350 cells/mm3. At the baseline, those individuals were characterized by having a higher frequency of activated and exhausted T cells and tissue-like memory B cells. Elevated levels of those markers were also observed in individuals with CD4 count between 500 and 350 cells/mm3. We observed a negative correlation between the pre-vaccination level of CD8+ T cell exhaustion and CD4+ T cell activation with YF-NAb titers at D365 and the pre-vaccination level of IP-10 with YF-NAb titers at D30 and D365. Our results emphasize the impact of immune activation, exhaustion, and inflammation in YF vaccine immunogenicity in PLWH.

Spatial and temporal analysis on the impact of ultra-low volume indoor insecticide spraying on Aedes aegypti household density.

BACKGROUND: Aedes aegypti is the primary mosquito vector for several arboviruses, such as dengue, chikungunya and Zika viruses, which cause frequent outbreaks of human disease in tropical and subtropical regions. Control of these outbreaks relies on vector control, commonly in the form of insecticide sprays that target adult female mosquitoes. However, the spatial coverage and frequency of sprays needed to optimize effectiveness are unclear. In this study, we characterize the effect of ultra-low-volume (ULV) indoor spraying of pyrethroid insecticides on Ae. aegypti abundance within households. We also evaluate the effects of spray events during recent time periods or in neighboring households. Improved understanding of the duration and distance of the impact of a spray intervention on Ae. aegypti populations can inform vector control interventions, in addition to modeling efforts that contrast vector control strategies. METHODS: This project analyzes data from two large-scale experiments that involved six cycles of indoor pyrethroid spray applications in 2 years in the Amazonian city of Iquitos, Peru. We developed spatial multi-level models to disentangle the reduction in Ae. aegypti abundance that resulted from (i) recent ULV treatment within households and (ii) ULV treatment of adjacent or nearby households. We compared fits of models across a range of candidate weighting schemes for the spray effect, based on different temporal and spatial decay functions to understand lagged ULV effects. RESULTS: Our results suggested that the reduction of Ae. aegypti in a household was mainly due to spray events occurring within the same household, with no additional effect of sprays that occurred in neighboring households. Effectiveness of a spray intervention should be measured based on time since the most recent spray event, as we found no cumulative effect of sequential sprays. Based on our model, we estimated the spray effect is reduced by 50% approximately 28 days after the spray event. CONCLUSIONS: The reduction of Ae. aegypti in a household was mainly determined by the number of days since the last spray intervention in that same household, highlighting the importance of spray coverage in high-risk areas with a spray frequency determined by local viral transmission dynamics.

Modelling mosquito population suppression based on competition system with strong and weak Allee effect.

Mosquito-borne diseases are threatening half of the world's population. To prevent the spread of malaria, dengue fever, or other mosquito-borne diseases, a new disease control strategy is to reduce or eradicate the wild mosquito population by releasing sterile mosquitoes. To study the effects of sterile insect technique on mosquito populations, we developed a mathematical model of constant release of sterile Aedes aegypti mosquitoes with strong and weak Allee effect and considered interspecific competition with Anopheles mosquitoes. We calculated multiple release thresholds and investigated the dynamical behavior of this model. In order to get closer to reality, an impulsive differential equation model was also introduced to study mosquito suppression dynamics under the strategy of releasing $ c $ sterile male mosquitoes at each interval time $ T $. Finally, the relationship between the releasing amount or the waiting period and the number of days required to suppress mosquitoes was illustrated by numerical simulations.

Bloodmeals fuel dengue virus replication in the female mosquito Aedes aegypti.

Vector competence defines the ability of a vector to acquire, host, and transmit a pathogen. Understanding the molecular determinants of the mosquitos' competence to host dengue virus (DENV) holds promise to prevent its transmission. To this end, we employed RNA-seq to profile mRNA transcripts of the female Aedes aegypti mosquitos feeding on naïve vs viremic mouse. While most transcripts (12,634) did not change their abundances, 360 transcripts showed decreases. Biological pathway analysis revealed representatives of the decreased transcripts involved in the wnt signaling pathway and hippo signaling pathway. One thousand three hundred fourteen transcripts showed increases in abundance and participate in 21 biological pathways including amino acid metabolism, carbon metabolism, fatty acid metabolism, and oxidative phosphorylation. Inhibition of oxidative phosphorylation with antimycin A reduced oxidative phosphorylation activity and ATP concentration associated with reduced DENV replication in the Aedes aegypti cells. Antimycin A did not affect the amounts of the non-structural proteins 3 and 5, two major components of the replication complex. Ribavirin, an agent that reduces GTP concentration, recapitulated the effects of reduced ATP concentration on DENV replication. Knocking down one of the oxidative phosphorylation components, ATP synthase subunit ß, reduced DENV replication in the mosquitos. In summary, our results suggest that DENV enhances metabolic pathways in the female Aedes aegypti mosquitos to supply nutrients and energy for virus replication. ATP synthase subunit ß knockdown might be exploited to reduce the mosquitos' competence to host and transmit DENV. IMPORTANCE: Through evolution, the mosquito-borne viruses have adapted to the blood-feeding behaviors of their opportunist hosts to fulfill a complete lifecycle in humans and mosquitos. Disruption in the mosquitos' ability to host these viruses offers strategies to prevent diseases caused by them. With the advent of genomic tools, we discovered that dengue virus (DENV) benefited from the female mosquitos' bloodmeals for metabolic and energetic supplies for replication. Chemical or genetic disruption in these supplies reduced DENV replication in the female mosquitos. Our discovery can be exploited to produce genetically modified mosquitos, in which DENV infection leads to disruption in the supplies and thereby reduces replication and transmission. Our discovery might be extrapolated to prevent mosquito-borne virus transmission and the diseases they cause.