Publications by authors named "Eva Harris"

300 Publications

An immune correlate of SARS-CoV-2 infection and severity of reinfections.

medRxiv 2021 Nov 24. Epub 2021 Nov 24.

Background: An immune correlate of protection from SARS-CoV-2 infection is urgently needed.

Methods: We used an ongoing household cohort with an embedded transmission study that closely monitors participants regardless of symptom status. Real-time reverse-transcription polymerase chain reaction (RT-PCR) and Enzyme-linked immunosorbent assays (ELISAs) were used to measure infections and seropositivity. Sequencing was performed to determine circulating strains of SARS-CoV-2. We investigated the protection associated with seropositivity resulting from prior infection, the anti-spike antibody titers needed for protection, and we compared the severity of first and second infections.

Results: In March 2021, 62.3% of the cohort was seropositive. After March 2021, gamma and delta variants predominated. Seropositivity was associated with 69.2% protection from any infection (95% CI: 60.7%-75.9%), with higher protection against moderate or severe infection (79.4%, 95% CI: 64.9%-87.9%). Anti-spike titers of 327 and 2,551 were associated with 50% and 80% protection from any infection; titers of 284 and 656 were sufficient for protection against moderate or severe disease. Second infections were less severe than first infections (Relative Risk (RR) of moderated or severe disease: 0.6, 95% CI: 0.38-0.98; RR of subclinical disease:1.9, 95% CI: 1.33-2.73).

Conclusions: Prior infection-induced immunity is protective against infection when predominantly gamma and delta SARS-CoV-2 circulated. The protective antibody titers presented may be useful for vaccine policy and control measures. While second infections were somewhat less severe, they were not as mild as ideal. A strategy involving vaccination will be needed to ease the burden of the SARS-CoV-2 pandemic.
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http://dx.doi.org/10.1101/2021.11.23.21266767DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8629202PMC
November 2021

DengueChat: A Social and Software Platform for Community-based Arbovirus Vector Control.

Am J Trop Med Hyg 2021 Oct 11. Epub 2021 Oct 11.

Sustainable Sciences Institute, Managua, Nicaragua.

The mosquito Aedes aegypti transmits arboviral diseases at extraordinary rates. Dengue alone afflicts 50 to 100 million people each year, with more than 3 billion at risk globally. This indicates that current approaches to prevention and control are inadequate, and that a paradigm shift from one that largely promotes vertical chemical-based control and vaccine development to one that also concentrates on eliminating the mosquito through actions by the communities it plagues is necessary. We have developed a new social and software platform, DengueChat (denguechat.org), to advance community interventions in arbovirus vector control. It is an interactive platform combining open-source digital communication technologies with face-to-face assemblies. It promotes resident participation in evidence collection, reporting, and analysis, and it incorporates pedagogic information, key messaging, and game concepts to motivate communities to implement vector reduction strategies. Using DengueChat, we conducted a 19-month pilot study in five neighborhoods of Managua, Nicaragua. The results strongly suggest that using the software produced value-added features that enhance community engagement. We measured the entomological and behavioral impacts at different time points and relative risk reduction of entomological indices at the end of the study. The entomological results showed significant risk reductions in disease transmission: Ae. aegypti larvae and pupae indices were reduced by approximately 44% in neighborhoods using DengueChat during one epidemic year, whereas control neighborhoods experienced an increase of more than 500%. A cluster permutation test determined that the probability of household positivity was significantly reduced in neighborhoods that participated in DengueChat compared with the reference neighborhoods (P = 0.0265). Therefore, DengueChat is a promising resource for vector control.
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http://dx.doi.org/10.4269/ajtmh.20-0808DOI Listing
October 2021

Viral genome-based Zika virus transmission dynamics in a paediatric cohort during the 2016 Nicaragua epidemic.

EBioMedicine 2021 Oct 7;72:103596. Epub 2021 Oct 7.

Saw Swee Hock School of Public Health, National University of Singapore and National University Health System, Singapore; Duke-NUS Medical School, Singapore, Singapore; Department of Pharmacy, National University of Singapore, Singapore. Electronic address:

Background: Nicaragua experienced a large Zika epidemic in 2016, with up to 50% of the population in Managua infected. With the domesticated Aedes aegypti mosquito as its vector, it is widely assumed that Zika virus transmission occurs within the household and/or via human mobility. We investigated these assumptions by using viral genomes to trace Zika transmission spatially.

Methods: We analysed serum samples from 119 paediatric Zika cases participating in the long-standing Paediatric Dengue Cohort Study in Managua, which was expanded to include Zika in 2015. An optimal spanning directed tree was constructed by minimizing the differences in viral sequence diversity composition between patient nodes, where low-frequency variants were used to increase the resolution of the inferred Zika outbreak dynamics.

Findings: Out of the 18 houses where pairwise difference in sample collection dates among all the household members was within 30 days, we only found two where viruses from individuals within the same household were up to 10-most closely linked to each other genetically. We also identified a substantial number of transmission events involving long geographical distances (n=30), as well as potential super-spreading events in the estimated transmission tree.

Interpretation: Our finding highlights that community transmission, often involving long geographical distances, played a much more important role in epidemic spread than within-household transmission.

Funding: This study was supported by an NUS startup grant (OMS) and grants R01 AI099631 (AB), P01 AI106695 (EH), P01 AI106695-03S1 (FB), and U19 AI118610 (EH) from the US National Institutes of Health.
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http://dx.doi.org/10.1016/j.ebiom.2021.103596DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8511802PMC
October 2021

A step towards therapeutics for dengue.

Nature 2021 10;598(7881):420-421

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http://dx.doi.org/10.1038/d41586-021-02638-9DOI Listing
October 2021

Risk Factors Associated With SARS-CoV-2 Infection Among Farmworkers in Monterey County, California.

JAMA Netw Open 2021 09 1;4(9):e2124116. Epub 2021 Sep 1.

Center for Environmental Research and Children's Health, School of Public Health, University of California, Berkeley.

Importance: Essential workers in agriculture and food production have been severely affected by the ongoing COVID-19 pandemic.

Objective: To identify risk factors associated with SARS-CoV-2 infection among farmworkers in California.

Design, Setting, And Participants: This cross-sectional study invited farmworkers in California's Salinas Valley (Monterey County) receiving transcription-mediated amplification (TMA) tests for SARS-CoV-2 infection at federally qualified community clinics and community sites to participate. Individuals were eligible if they were not pregnant, were 18 years or older, had conducted farmwork since the pandemic started, and were proficient in English or Spanish. Survey data were collected and SARS-CoV-2 tests were conducted among participants from July 16 to November 30, 2020.

Exposures: Sociodemographic, household, community, and workplace characteristics.

Main Outcomes And Measures: TMA- and immunoglobulin G (IgG)-positive SARS-CoV-2 infection.

Results: A total of 1107 farmworkers (581 [52.5%] women; mean [SD] age, 39.7 [12.6] years) were included in these analyses. Most participants were born in Mexico (922 [83.3%]), were married or living with a partner (697 [63.0%]), and worked in the fields (825 [74.5%]). Overall, 118 of 911 (13.0%) had a positive result on their TMA test for SARS-CoV-2 infection, whereas 201 of 1058 (19.0%) had antibody evidence of infection. In multivariable analyses accounting for recruitment venue and enrollment period, the incidence of TMA-positive SARS-CoV-2 infection was higher among those with lower than primary school-level education (adjusted relative risk [aRR], 1.32; 95% CI, 0.99-1.76; non-statistically significant finding), who spoke an Indigenous language at home (aRR, 1.30; 95% CI, 0.97-1.73; non-statistically significant finding), who worked in the fields (aRR, 1.60; 95% CI, 1.03-2.50), and who were exposed to a known or suspected COVID-19 case at home (aRR, 2.98; 95% CI, 2.06-4.32) or in the workplace (aRR, 1.59; 95% CI, 1.18-2.14). Positive results on IgG tests for SARS-CoV-2 infection were more common among those who lived in crowded housing (aRR, 1.23; 95% CI, 0.98-1.53; non-statistically significant finding), with children aged 5 years or younger (aRR, 1.40; 95% CI, 1.11-1.76), with unrelated roommates (aRR, 1.40; 95% CI, 1.19-1.64), and with an individual with known or suspected COVID-19 (aRR, 1.59; 95% CI, 1.13-2.24). The risk of IgG positivity was also higher among those with body mass index of 30 or greater (aRR, 1.65; 95% CI, 1.01-2.70) or diabetes (aRR, 1.31; 95% CI, 0.98-1.75; non-statistically significant finding).

Conclusions And Relevance: In this cross-sectional study of farmworkers in California, both residential and workplace exposures were associated with SARS-CoV-2 infection. Urgent distribution of COVID-19 vaccines and intervention on modifiable risk factors are warranted given this population's increased risk of infection and the essential nature of their work.
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http://dx.doi.org/10.1001/jamanetworkopen.2021.24116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8444020PMC
September 2021

The Compound SBI-0090799 Inhibits Zika Virus Infection by Blocking Formation of the Membranous Replication Compartment.

J Virol 2021 Oct 1;95(22):e0099621. Epub 2021 Sep 1.

Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California, USA.

Zika virus (ZIKV) is a mosquito-borne pathogen classified by the World Health Organization (WHO) as a public health emergency of international concern in 2016, and it is still identified as a priority disease. Although most infected individuals are asymptomatic or show mild symptoms, a risk of neurologic complications is associated with infection in adults. Additionally, infection during pregnancy is directly linked to microcephaly and other congenital malformations. Since there are no currently available vaccines or approved therapeutics for this virus, there is a critical unmet need in developing treatments to prevent future ZIKV outbreaks. Toward this end, we performed a large-scale cell-based high-content screen of 51,520 chemical compounds to identify potential antiviral drug candidates. The compound (2E)-N-benzyl-3-(4-butoxyphenyl)prop-2-enamide (SBI-0090799) was found to inhibit replication of multiple ZIKV strains and in different cell systems. SBI-0090799 did not affect viral entry or RNA translation but suppressed RNA replication by preventing the formation of the membranous replication compartment. Selection of drug-resistant viruses identified single-amino-acid substitutions in the N-terminal region of nonstructural protein NS4A, arguing this is the likely drug target. These resistance mutations rescued viral RNA replication and restored the formation of the membranous replication compartment. This mechanism of action is similar to clinically approved NS5A inhibitors for hepatitis C virus (HCV). Taken together, SBI-0090799 represents a promising lead candidate for the development of an antiviral treatment against ZIKV infection for the mitigation of severe complications and potential resurgent outbreaks of the virus. This study describes the elucidation of (2E)-N-benzyl-3-(4-butoxyphenyl)prop-2-enamide (SBI-0090799) as a selective and potent inhibitor of Zika virus (ZIKV) replication using a high-throughput screening approach. Mapping and resistance studies, supported by electron microscopy observations, indicate that the small molecule is functioning through inhibition of NS4A-mediated formation of ZIKV replication compartments in the endoplasmic reticulum (ER). Intriguingly, this defines a novel nonenzymatic target and chemical matter for the development of a new class of ZIKV antivirals. Moreover, chemical modulation affecting this nonstructural protein mirrors the identification and development of hepatitis C virus (HCV) NS5A inhibitor daclatasvir and its derivatives, similarly interfering with the formation of the viral replication compartment and also targeting a protein with no enzymatic activity, which have been part of a curative strategy for HCV.
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http://dx.doi.org/10.1128/JVI.00996-21DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8549497PMC
October 2021

Interferon receptor-deficient mice are susceptible to eschar-associated rickettsiosis.

Elife 2021 08 23;10. Epub 2021 Aug 23.

Molecular and Cell Biology, University of California, Berkeley, Berkeley, United States.

Arthropod-borne rickettsial pathogens cause mild and severe human disease worldwide. The tick-borne pathogen elicits skin lesions (eschars) and disseminated disease in humans; however, inbred mice are generally resistant to infection. We report that intradermal infection of mice lacking both interferon receptors () with as few as 10 . elicits eschar formation and disseminated, lethal disease. Similar to human infection, eschars exhibited necrosis and inflammation, with bacteria primarily found in leukocytes. Using this model, we find that the actin-based motility factor Sca2 is required for dissemination from the skin to internal organs, and the outer membrane protein OmpB contributes to eschar formation. Immunizing mice with and mutant protects against rechallenge, revealing live-attenuated vaccine candidates. Thus, mice are a tractable model to investigate rickettsiosis, virulence factors, and immunity. Our results further suggest that discrepancies between mouse and human susceptibility may be due to differences in interferon signaling.
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http://dx.doi.org/10.7554/eLife.67029DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8428839PMC
August 2021

Clinical spectrum of SARS-CoV-2 infection and protection from symptomatic re-infection.

Clin Infect Dis 2021 Aug 19. Epub 2021 Aug 19.

Department of Epidemiology, School of Public Health, University of Michigan in Ann Arbor, Michigan, USA.

Background: There are few data on the full spectrum of disease caused by SARS-CoV-2 infection across the lifespan from community-based or non-clinical settings.

Methods: We followed 2,338 people in Managua, Nicaragua, aged 0 to 94 years old from March 2020 through March 2021. SARS-CoV-2 infection was identified through real-time reverse transcription polymerase chain reaction (RT-PCR) or through enzyme-linked immunosorbent assay (ELISA). Disease presentation was assessed at the time of infection or retrospectively by survey at the time of blood collection.

Results: There was a large epidemic that peaked between March-August 2020. In total, 129 RT-PCR-positive infections were detected, for an overall incidence rate of 5.3 infections per 100 person-years (95% CI: 4.4-6.3). Seroprevalence was 56.7% (95%CI: 53.5%-60.1%) and was consistent from age 11 through adulthood but was lower in children aged ≤10 years. Overall, 31.0% of the infections were symptomatic, with 54.7% mild, 41.6% moderate, and 3.7% severe. There were two deaths that were likely due to SARS-CoV-2 infection, yielding an infection fatality rate of 0.2%. Antibody titers exhibited a J-shaped curve with respect to age, with the lowest titers observed among older children and young adults and the highest among older adults. When compared to SARS-CoV-2 seronegative individuals, SARS-CoV-2 seropositivity at the midyear sample was associated with 93.6% protection from symptomatic re-infection (95%CI: 51.1-99.2%).

Conclusions: This population exhibited a very high SARS-CoV-2 seropositivity with lower-than-expected severity, and immunity from natural infection was protective against symptomatic re-infection.
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http://dx.doi.org/10.1093/cid/ciab717DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8499752PMC
August 2021

Adapting Rapid Diagnostic Tests to Detect Historical Dengue Virus Infections.

Front Immunol 2021 23;12:703887. Epub 2021 Jul 23.

Viral Epidemiology and Immunity Unit, Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, United States.

The only licensed dengue vaccine, Dengvaxia, increases risk of severe dengue when given to individuals without prior dengue virus (DENV) infection but is protective against future disease in those with prior DENV immunity. The World Health Organization has recommended using rapid diagnostic tests (RDT) to determine history of prior DENV infection and suitability for vaccination. Dengue experts recommend that these assays be highly specific (≥98%) to avoid erroneously vaccinating individuals without prior DENV infection, as well as be sensitive enough (≥95%) to detect individuals with a single prior DENV infection. We evaluated one existing and two newly developed anti-flavivirus RDTs using samples collected >6 months post-infection from individuals in non-endemic and DENV and ZIKV endemic areas. We first evaluated the IgG component of the SD BIOLINE Dengue IgG/IgM RDT, which was developed to assist in confirming acute/recent DENV infections (n=93 samples). When evaluated following the manufacturer's instructions, the SD BIOLINE Dengue RDT had 100% specificity for both non-endemic and endemic samples but low sensitivity for detecting DENV seropositivity (0% non-endemic, 41% endemic). Sensitivity increased (53% non-endemic, 98% endemic) when tests were allowed to run beyond manufacturer recommendations (0.5 up to 3 hours), but specificity decreased in endemic samples (36%). When tests were evaluated using a quantitative reader, optimal specificity could be achieved (≥98%) while still retaining sensitivity at earlier timepoints in non-endemic (44-88%) and endemic samples (31-55%). We next evaluated novel dengue and Zika RDTs developed by Excivion to detect prior DENV or ZIKV infections and reduce cross-flavivirus reactivity (n=207 samples). When evaluated visually, the Excivion Dengue RDT had sensitivity and specificity values of 79%, but when evaluated with a quantitative reader, optimal specificity could be achieved (≥98%) while still maintaining moderate sensitivity (48-75%). The Excivion Zika RDT had high specificity (>98%) and sensitivity (>93%) when evaluated quantitatively, suggesting it may be used alongside dengue RDTs to minimize misclassification due to cross-reactivity. Our findings demonstrate the potential of RDTs to be used for dengue pre-vaccination screening to reduce vaccine-induced priming for severe dengue and show how assay design adaptations as well quantitative evaluation can further improve RDTs for this purpose.
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http://dx.doi.org/10.3389/fimmu.2021.703887DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8344047PMC
July 2021

Levels of Circulating NS1 Impact West Nile Virus Spread to the Brain.

J Virol 2021 09 4;95(20):e0084421. Epub 2021 Aug 4.

Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri, USA.

Dengue virus (DENV) and West Nile virus (WNV) are arthropod-transmitted flaviviruses that cause systemic vascular leakage and encephalitis syndromes, respectively, in humans. However, the viral factors contributing to these specific clinical disorders are not completely understood. Flavivirus nonstructural protein 1 (NS1) is required for replication, expressed on the cell surface, and secreted as a soluble glycoprotein, reaching high levels in the blood of infected individuals. Extracellular DENV NS1 and WNV NS1 interact with host proteins and cells, have immune evasion functions, and promote endothelial dysfunction in a tissue-specific manner. To characterize how differences in DENV NS1 and WNV NS1 might function in pathogenesis, we generated WNV NS1 variants with substitutions corresponding to residues found in DENV NS1. We discovered that the substitution NS1-P101K led to reduced WNV infectivity in the brain and attenuated lethality in infected mice, although the virus replicated efficiently in cell culture and peripheral organs and bound at wild-type levels to brain endothelial cells and complement components. The P101K substitution resulted in reduced NS1 antigenemia in mice, and this was associated with reduced WNV spread to the brain. Because exogenous administration of NS1 protein rescued WNV brain infectivity in mice, we conclude that circulating WNV NS1 facilitates viral dissemination into the central nervous system and impacts disease outcomes. Flavivirus NS1 serves as an essential scaffolding molecule during virus replication but also is expressed on the cell surface and is secreted as a soluble glycoprotein that circulates in the blood of infected individuals. Although extracellular forms of NS1 are implicated in immune modulation and in promoting endothelial dysfunction at blood-tissue barriers, it has been challenging to study specific effects of NS1 on pathogenesis without disrupting its key role in virus replication. Here, we assessed WNV NS1 variants that do not affect virus replication and evaluated their effects on pathogenesis in mice. Our characterization of WNV NS1-P101K suggests that the levels of NS1 in the circulation facilitate WNV dissemination to the brain and affect disease outcomes. Our findings facilitate understanding of the role of NS1 during flavivirus infection and support antiviral strategies for targeting circulating forms of NS1.
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http://dx.doi.org/10.1128/JVI.00844-21DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8475509PMC
September 2021

Epidemics of chikungunya, Zika, and COVID-19 reveal bias in case-based mapping.

medRxiv 2021 Jul 26. Epub 2021 Jul 26.

Explosive epidemics of chikungunya, Zika, and COVID-19 have recently occurred worldwide, all of which featured large proportions of subclinical infections. Spatial studies of infectious disease epidemics typically use symptomatic infections (cases) to estimate incidence rates (cases/total population), often misinterpreting them as infection risks (infections/total population) or disease risks (cases/infected population). We examined these three measures in a pediatric cohort (N≈3,000) over two chikungunya epidemics and one Zika epidemic and in a household cohort (N=1,793) over one COVID-19 epidemic in Nicaragua. Across different analyses and all epidemics, case incidence rates considerably underestimated both risk-based measures. Spatial infection risk differed from spatial disease risk, and typical case-only approaches precluded a full understanding of the spatial seroprevalence patterns. For epidemics of pathogens that cause many subclinical infections, relying on case-only datasets and misinterpreting incidence rates, as is common, results in substantial bias, a general finding applicable to many pathogens of high human concern.
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http://dx.doi.org/10.1101/2021.07.23.21261038DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8328077PMC
July 2021

Previous exposure to dengue virus is associated with increased Zika virus burden at the maternal-fetal interface in rhesus macaques.

PLoS Negl Trop Dis 2021 07 30;15(7):e0009641. Epub 2021 Jul 30.

Department of Pediatrics, University of Wisconsin-Madison, Madison, Wisconsin, United States of America.

Concerns have arisen that pre-existing immunity to dengue virus (DENV) could enhance Zika virus (ZIKV) disease, due to the homology between ZIKV and DENV and the observation of antibody-dependent enhancement (ADE) among DENV serotypes. To date, no study has examined the impact of pre-existing DENV immunity on ZIKV pathogenesis during pregnancy in a translational non-human primate model. Here we show that macaques with a prior DENV-2 exposure had a higher burden of ZIKV vRNA in maternal-fetal interface tissues as compared to DENV-naive macaques. However, pre-existing DENV immunity had no detectable impact on ZIKV replication kinetics in maternal plasma, and all pregnancies progressed to term without adverse outcomes or gross fetal abnormalities detectable at delivery. Understanding the risks of ADE to pregnant women worldwide is critical as vaccines against DENV and ZIKV are developed and licensed and as DENV and ZIKV continue to circulate.
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http://dx.doi.org/10.1371/journal.pntd.0009641DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8357128PMC
July 2021

Knowledge gaps in the epidemiology of severe dengue impede vaccine evaluation.

Lancet Infect Dis 2021 Jul 12. Epub 2021 Jul 12.

Dengue Branch, Centers for Disease Control and Prevention, San Juan, PR, USA; United States Public Health Service, Silver Springs, MD, USA.

The most severe consequences of dengue virus infection include shock, haemorrhage, and major organ failure; however, the frequency of these manifestations varies, and the relative contribution of pre-existing anti-dengue virus antibodies, virus characteristics, and host factors (including age and comorbidities) are not well understood. Reliable characterisation of the epidemiology of severe dengue first depends on the use of consistent definitions of disease severity. As vaccine trials have shown, severe dengue is a crucial interventional endpoint, yet the infrequency of its occurrence necessitates the inclusion of thousands of study participants to appropriately compare its frequency among participants who have and have not been vaccinated. Hospital admission is frequently used as a proxy for severe dengue; however, lack of specificity and variability in clinical practices limit the reliability of this approach. Although previous infection with a dengue virus is the best characterised risk factor for developing severe dengue, the influence of the timing between dengue virus infections and the sequence of dengue virus infections on disease severity is only beginning to be elucidated. To improve our understanding of the diverse factors that shape the clinical spectrum of disease resulting from dengue virus infection, prospective, community-based and clinic-based immunological, virological, genetic, and clinical studies across a range of ages and geographical regions are needed.
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http://dx.doi.org/10.1016/S1473-3099(20)30871-9DOI Listing
July 2021

Identification of Anti-Premembrane Antibody as a Serocomplex-Specific Marker To Discriminate Zika, Dengue, and West Nile Virus Infections.

J Virol 2021 09 9;95(19):e0061921. Epub 2021 Sep 9.

Department of Tropical Medicine, Medical Microbiology and Pharmacology, John A. Burns School of Medicine, University of Hawaii at Manoa, Honolulu, Hawaii, USA.

Although transmission of Zika virus (ZIKV) in the Americas has greatly declined since late 2017, recent reports of reduced risks of symptomatic Zika by prior dengue virus (DENV) infection and increased risks of severe dengue disease by previous ZIKV or DENV infection underscore a critical need for serological tests that can discriminate past ZIKV, DENV, and/or other flavivirus infections and improve our understanding of the immune interactions between these viruses and vaccine strategy in endemic regions. As serological tests for ZIKV primarily focus on envelope (E) and nonstructural protein 1 (NS1), antibodies to other ZIKV proteins have not been explored. Here, we employed Western blot analysis using antigens of 6 flaviviruses from 3 serocomplexes to investigate antibody responses following reverse transcription-PCR (RT-PCR)-confirmed ZIKV infection. Panels of 20 primary ZIKV and 20 ZIKV with previous DENV infection recognized E proteins of all 6 flaviviruses and the NS1 protein of ZIKV with some cross-reactivity to DENV. While the primary ZIKV panel recognized only the premembrane (prM) protein of ZIKV, the ZIKV with previous DENV panel recognized both ZIKV and DENV prM proteins. Analysis of antibody responses following 42 DENV and 18 West Nile virus infections revealed similar patterns of recognition by anti-E and anti-NS1 antibodies, whereas both panels recognized the prM protein of the homologous serocomplex but not others. The specificity was further supported by analysis of sequential samples. Together, these findings suggest that anti-prM antibody is a flavivirus serocomplex-specific marker and can be used to delineate current and past flavivirus infections in endemic areas. Despite a decline in Zika virus (ZIKV) transmission since late 2017, questions regarding its surveillance, potential reemergence, and interactions with other flaviviruses in regions where it is endemic remain unanswered. Recent studies have reported reduced risks of symptomatic Zika by prior dengue virus (DENV) infection and increased risks of severe dengue disease by previous ZIKV or DENV infection, highlighting a need for better serological tests to discriminate past ZIKV, DENV, and/or other flavivirus infections and improved understanding of the immune interactions and vaccine strategy for these viruses. As most serological tests for ZIKV focused on envelope and nonstructural protein 1, antibodies to other ZIKV proteins, including potentially specific antibodies, remain understudied. We employed Western blot analysis using antigens of 6 flaviviruses to study antibody responses following well-documented ZIKV, DENV, and West Nile virus infections and identified anti-premembrane antibody as a flavivirus serocomplex-specific marker to delineate current and past flavivirus infections in areas where flaviviruses are endemic.
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http://dx.doi.org/10.1128/JVI.00619-21DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8428386PMC
September 2021

CyTOF Profiling of Zika and Dengue Virus-Infected Human Peripheral Blood Mononuclear Cells Identifies Phenotypic Signatures of Monotype Subsets and Upregulation of the Interferon-Inducible Protein CD169.

mSphere 2021 06 23;6(3):e0050521. Epub 2021 Jun 23.

Department of Microbiology, Icahn School of Medicine at Mount Sinaigrid.59734.3c, New York, New York, USA.

Zika and dengue virus (ZIKV and DENV) are two flaviviruses responsible for important vector-borne emerging infectious diseases. While there have been multiple DENV epidemics in the last decades, there have been fewer documented epidemics caused by ZIKV until recent years. Thus, our current knowledge about the biology of ZIKV, the disease, and the immune responses in humans is limited. Here, we used mass cytometry (CyTOF) to perform a detailed characterization of the innate immune responses elicited by ZIKV and DENV in human peripheral blood mononuclear cells (PBMCs) from healthy donors infected . We found that ZIKV and DENV exposure of human PBMCs induces global phenotypic changes in myeloid cells, characterized mainly by upregulation of costimulatory molecules (CD86 and CD40), CD38, and the type I interferon-inducible protein CD169, a marker for phagocytic function and cross-priming potential in myeloid cells. We also found that ZIKV induces expansion of nonclassical monocytes in cell culture. The analysis of the phenotype of the three monocyte subtypes (classical, intermediate, and nonclassical) at the single-cell level identified differences in their expression of CD86, CD38, CXCL8, and CXCL10 during ZIKV and DENV infection. Overall, using CyTOF, we found that infections of PBMCs with ZIKV and DENV reproduced many aspects of the profile found in blood from patients in previously described cohort studies, which highlights the suitability of this system for the study of the human host responses to these viruses. Zika and dengue viruses are emergent arboviruses of great public health impact. Both viruses are responsible for important diseases, yet there is currently no vaccine or specific treatment available. Immune cells play critical roles in the virus cycle as well as in the innate and adaptive immune response elicited in the host; therefore, it is critical to understand the changes induced by virus infection in peripheral blood mononuclear cells (PBMCs). In this study, we used a model of infection of PBMCs and CyTOF technology to profile the early innate immune changes induced by Zika virus and dengue virus in blood.
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http://dx.doi.org/10.1128/mSphere.00505-21DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8265667PMC
June 2021

Studying the Endothelial Glycocalyx : What Is Missing?

Front Cardiovasc Med 2021 14;8:647086. Epub 2021 Apr 14.

Critical Care Research Group, The Prince Charles Hospital, Chermside, QLD, Australia.

All human cells are coated by a surface layer of proteoglycans, glycosaminoglycans (GAGs) and plasma proteins, called the glycocalyx. The glycocalyx transmits shear stress to the cytoskeleton of endothelial cells, maintains a selective permeability barrier, and modulates adhesion of blood leukocytes and platelets. Major components of the glycocalyx, including syndecans, heparan sulfate, and hyaluronan, are shed from the endothelial surface layer during conditions including ischaemia and hypoxia, sepsis, atherosclerosis, diabetes, renal disease, and some viral infections. Studying mechanisms of glycocalyx damage can be challenging due to the complexity of immuno-inflammatory responses which are inextricably involved. Previously, both static as well as perfused models have studied the glycocalyx, and have reported either imaging data, assessment of barrier function, or interactions of blood components with the endothelial monolayer. To date, no model has simultaneously incorporated all these features at once, however such a model would arguably enhance the study of vasculopathic processes. This review compiles a series of current models described in the literature that have targeted the glycocalyx layer, their limitations, and potential opportunities for further developments in this field.
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http://dx.doi.org/10.3389/fcvm.2021.647086DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8079726PMC
April 2021

Persistence of Anti-ZIKV-IgG over Time Is Not a Useful Congenital Infection Marker in Infants Born to ZIKV-Infected Mothers: The NATZIG Cohort.

Viruses 2021 04 20;13(4). Epub 2021 Apr 20.

Department of Pediatrics, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto 14049-900, SP, Brazil.

Confirming ZIKV congenital infection is challenging because viral RNA is infrequently detected. We compared the presence of anti-ZIKV-IgM and the persistence of anti-ZIKV-IgG antibodies over 18 months in two cohorts of infants born to ZIKV-infected mothers: Cohort one: 30 infants with typical microcephaly or major brain abnormalities (Congenital Zika Syndrome-CZS); Cohort two: 123 asymptomatic infants. Serum samples obtained within 6 months of age were tested for anti-ZIKV-IgM. Anti-ZIKV-IgG was quantified in sequential samples collected at birth, 3-6 weeks, 3, 6, 12, and 18 months. ZIKV-RNA was never detected postnatally. Anti-ZIKV-IgM antibodies were detected at least once in 15/25 (60.0%; 95%CI: 38.7-78.9) infants with CZS and in 2/115 (1.7%; 95%CI: 0.2-6.1) asymptomatic infants. Although anti-ZIKV-IgG was always positive within 3-6 weeks of age, IgG levels decreased similarly over time in both cohorts. IgG levels decreased similarly in ZIKV-IgM-positive and ZIKV-IgM-negative CZS infants. Differently from other congenital infections, IgM would fail to diagnose 40% of severely symptomatic infants, and the persistence of IgG is not a useful marker for discriminating congenital infection among infants exposed to maternal ZIKV infection.
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http://dx.doi.org/10.3390/v13040711DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8074187PMC
April 2021

Boosting can explain patterns of fluctuations of ratios of inapparent to symptomatic dengue virus infections.

Proc Natl Acad Sci U S A 2021 04;118(14)

Integrative Biology, University of California, Berkeley, CA 94720;

Dengue is the most prevalent arboviral disease worldwide, and the four dengue virus (DENV) serotypes circulate endemically in many tropical and subtropical regions. Numerous studies have shown that the majority of DENV infections are inapparent, and that the ratio of inapparent to symptomatic infections (I/S) fluctuates substantially year-to-year. For example, in the ongoing Pediatric Dengue Cohort Study (PDCS) in Nicaragua, which was established in 2004, the I/S ratio has varied from 16.5:1 in 2006-2007 to 1.2:1 in 2009-2010. However, the mechanisms explaining these large fluctuations are not well understood. We hypothesized that in dengue-endemic areas, frequent boosting (i.e., exposures to DENV that do not lead to extensive viremia and result in a less than fourfold rise in antibody titers) of the immune response can be protective against symptomatic disease, and this can explain fluctuating I/S ratios. We formulate mechanistic epidemiologic models to examine the epidemiologic effects of protective homologous and heterologous boosting of the antibody response in preventing subsequent symptomatic DENV infection. We show that models that include frequent boosts that protect against symptomatic disease can recover the fluctuations in the I/S ratio that we observe, whereas a classic model without boosting cannot. Furthermore, we show that a boosting model can recover the inverse relationship between the number of symptomatic cases and the I/S ratio observed in the PDCS. These results highlight the importance of robust dengue control efforts, as intermediate dengue control may have the potential to decrease the protective effects of boosting.
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http://dx.doi.org/10.1073/pnas.2013941118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8040803PMC
April 2021

Pre-existing T Cell Memory against Zika Virus.

J Virol 2021 05 24;95(12). Epub 2021 May 24.

Center for Infectious Disease and Vaccine Research, La Jolla Institute for Immunology, La Jolla, California, USA

The mosquito-borne Zika virus (ZIKV) has spread rapidly into regions where dengue virus (DENV) is endemic, and flavivirus cross-reactive T cell responses have been observed repeatedly in animal models and in humans. Preexisting cellular immunity to DENV is thought to contribute to protection in subsequent ZIKV infection, but the epitope targets of cross-reactive T cell responses have not been comprehensively identified. Using human blood samples from the regions of Nicaragua and Sri Lanka where DENV is endemic that were collected before the global spread of ZIKV in 2016, we employed an expansion strategy to map ZIKV T cell epitopes in ZIKV-unexposed, DENV-seropositive donors. We identified 93 epitopes across the ZIKV proteome, and we observed patterns of immunodominance that were dependent on antigen size and sequence identity to DENV. We confirmed the immunogenicity of these epitopes through a computational HLA binding analysis, and we showed that cross-reactive T cells specifically recognize ZIKV peptides homologous to DENV sequences. We also found that these CD4 responses were derived from the memory T cell compartment. These data have implications for understanding the dynamics of flavivirus-specific T cell immunity in areas of endemicity. Multiple flaviviruses, including Zika virus (ZIKV) and the four serotypes of dengue virus (DENV), are prevalent in the same large tropical and equatorial areas, which are inhabited by hundreds of millions of people. The interplay of DENV and ZIKV infection is especially relevant, as these two viruses are endemic in largely overlapping regions, have significant sequence similarity, and share the same arthropod vector. Here, we define the targets of preexisting immunity to ZIKV in unexposed subjects in areas where dengue is endemic. We demonstrate that preexisting immunity to DENV could shape ZIKV-specific responses, and DENV-ZIKV cross-reactive T cell populations can be expanded by stimulation with ZIKV peptides. The issue of potential ZIKV and DENV cross-reactivity is of relevance for understanding patterns of natural immunity, as well as for the development of diagnostic tests and vaccines.
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http://dx.doi.org/10.1128/JVI.00132-21DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8316092PMC
May 2021

Prevalence and Clinical Profile of Severe Acute Respiratory Syndrome Coronavirus 2 Infection among Farmworkers, California, USA, June-November 2020.

Emerg Infect Dis 2021 May 3;27(5):1330-1342. Epub 2021 Mar 3.

During the ongoing coronavirus disease (COVID-19) pandemic, farmworkers in the United States are considered essential personnel and continue in-person work. We conducted prospective surveillance for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and antibody prevalence among farmworkers in Salinas Valley, California, during June 15-November 30, 2020. We observed 22.1% (1,514/6,864) positivity for SARS-CoV-2 infection among farmworkers compared with 17.2% (1,255/7,305) among other adults from the same communities (risk ratio 1.29, 95% CI 1.20-1.37). In a nested study enrolling 1,115 farmworkers, prevalence of current infection was 27.7% among farmworkers reporting >1 COVID-19 symptom and 7.2% among farmworkers without symptoms (adjusted odds ratio 4.16, 95% CI 2.85-6.06). Prevalence of SARS-CoV-2 antibodies increased from 10.5% (95% CI 6.0%-18.4%) during July 16-August 31 to 21.2% (95% CI 16.6%-27.4%) during November 1-30. High SARS-CoV-2 infection prevalence among farmworkers underscores the need for vaccination and other preventive interventions.
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http://dx.doi.org/10.3201/eid2705.204949DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8084509PMC
May 2021

Developmental outcomes in children exposed to Zika virus in utero from a Brazilian urban slum cohort study.

PLoS Negl Trop Dis 2021 02 5;15(2):e0009162. Epub 2021 Feb 5.

Instituto de Saúde Coletiva, Universidade Federal da Bahia, Salvador, Brazil.

Background: The prevalence of developmental alterations associated with in-utero Zika virus (ZIKV) exposure in children is not well understood. Furthermore, estimation of the Population Attributable Fraction (PAF) of developmental alterations attributed to ZIKV has not been performed due to lack of population-based cohorts with data on symptomatic and asymptomatic ZIKV exposures and an appropriate control group. The aim of this study was to characterize neurodevelopmental outcomes of children at 11 to 32 months of age with intrauterine ZIKV exposure and estimate the PAF of alterations secondary to ZIKV exposure.

Methodology/principal Findings: We performed a cohort of biannual community-based prospective serosurveys in a slum community in Salvador, Brazil. We recruited women participating in our cohort, with a documented pregnancy from January 2015 to December 2016 and children born to those mothers. Children were classified as ZIKV exposed in utero (born from women with ZIKV seroconversion during pregnancy) or unexposed (born from women without ZIKV seroconversion or that seroconverted before/after pregnancy) by using an IgG monoclonal antibody blockade-of-binding (BoB). We interviewed mothers and performed anthropometric, audiometric, ophthalmological, neurologic, and neurodevelopmental evaluations of their children at 11 to 32 months of age. Among the 655 women participating in the cohort, 66 (10%) were pregnant during the study period. 46 (70%) of them completed follow-up, of whom ZIKV seroconversion occurred before, during, and after pregnancy in 25 (54%), 13 (28%), and 1 (2%), respectively. The rest of women, 7 (21.2%), did not present ZIKV seroconversion. At 11 to 32 months of life, the 13 ZIKV-exposed children had increased risk of mild cognitive delay (RR 5.1; 95%CI 1.1-24.4) compared with the 33 children unexposed, with a PAF of 53.5%. Exposed children also had increased risk of altered auditory behavior (RR 6.0; 95%CI 1.3-26.9), with a PAF of 59.5%.

Conclusions: A significant proportion of children exposed in utero to ZIKV developed mild cognitive delay and auditory behavioral abnormalities even in the absence of gross birth defects such as microcephaly and other neurodevelopmental domains. Furthermore, our findings suggest that over half of these abnormalities could be attributed to intrauterine ZIKV exposure.
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http://dx.doi.org/10.1371/journal.pntd.0009162DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7891708PMC
February 2021

Structural basis for antibody inhibition of flavivirus NS1-triggered endothelial dysfunction.

Science 2021 01;371(6525):194-200

Division of Infectious Diseases and Vaccinology, School of Public Health, University of California, Berkeley, Berkeley, CA 94720-3370, USA.

Medically important flaviviruses cause diverse disease pathologies and collectively are responsible for a major global disease burden. A contributing factor to pathogenesis is secreted flavivirus nonstructural protein 1 (NS1). Despite demonstrated protection by NS1-specific antibodies against lethal flavivirus challenge, the structural and mechanistic basis remains unknown. Here, we present three crystal structures of full-length dengue virus NS1 complexed with a flavivirus-cross-reactive, NS1-specific monoclonal antibody, 2B7, at resolutions between 2.89 and 3.96 angstroms. These structures reveal a protective mechanism by which two domains of NS1 are antagonized simultaneously. The NS1 wing domain mediates cell binding, whereas the β-ladder triggers downstream events, both of which are required for dengue, Zika, and West Nile virus NS1-mediated endothelial dysfunction. These observations provide a mechanistic explanation for 2B7 protection against NS1-induced pathology and demonstrate the potential of one antibody to treat infections by multiple flaviviruses.
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http://dx.doi.org/10.1126/science.abc0476DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8000976PMC
January 2021

Rapid, point-of-care molecular diagnostics with Cas13.

medRxiv 2021 Apr 5. Epub 2021 Apr 5.

Innovative Genomics Institute, University of California, Berkeley, Berkeley, CA, USA.

Rapid nucleic acid testing is a critical component of a robust infrastructure for increased disease surveillance. Here, we report a microfluidic platform for point-of-care, CRISPR-based molecular diagnostics. We first developed a nucleic acid test which pairs distinct mechanisms of DNA and RNA amplification optimized for high sensitivity and rapid kinetics, linked to Cas13 detection for specificity. We combined this workflow with an extraction-free sample lysis protocol using shelf-stable reagents that are widely available at low cost, and a multiplexed human gene control for calling negative test results. As a proof-of-concept, we demonstrate sensitivity down to 40 copies/μL of SARS-CoV-2 in unextracted saliva within 35 minutes, and validated the test on total RNA extracted from patient nasal swabs with a range of qPCR Ct values from 13-35. To enable sample-to-answer testing, we integrated this diagnostic reaction with a single-use, gravity-driven microfluidic cartridge followed by real-time fluorescent detection in a compact companion instrument. We envision this approach for Diagnostics with Coronavirus Enzymatic Reporting (DISCoVER) will incentivize frequent, fast, and easy testing.
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http://dx.doi.org/10.1101/2020.12.14.20247874DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7755151PMC
April 2021

Pneumonia Following Symptomatic Influenza Infection Among Nicaraguan Children Before and After Introduction of the Pneumococcal Conjugate Vaccine.

J Infect Dis 2021 08;224(4):643-647

Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, Michigan, USA.

Influenza is associated with primary viral and secondary bacterial pneumonias; however, the dynamics of this relationship in populations with varied levels of pneumococcal vaccination remain unclear. We conducted nested matched case-control studies in 2 prospective cohorts of Nicaraguan children aged 2-14 years: 1 before pneumococcal conjugate vaccine introduction (2008-2010) and 1 following introduction and near universal adoption (2011-2018). The association between influenza and pneumonia was similar in both cohorts. Participants with influenza (across types/subtypes) had higher odds of developing pneumonia in the month following influenza infection. These findings underscore the importance of considering influenza in interventions to reduce global pneumonia burden.
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http://dx.doi.org/10.1093/infdis/jiaa776DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8499702PMC
August 2021

Evolution and epidemiologic dynamics of dengue virus in Nicaragua during the emergence of chikungunya and Zika viruses.

Infect Genet Evol 2021 08 14;92:104680. Epub 2020 Dec 14.

Institute for Biodiversity Science and Sustainability, California Academy of Sciences, 55 Music Concourse Dr, San Francisco, CA 94118, USA. Electronic address:

Arthropod-borne viruses (arboviruses) comprise a significant and ongoing threat to human health, infecting hundreds of millions annually. Three such arboviruses include circumtropical dengue, Zika, and chikungunya viruses, exhibiting continuous emergence primarily via Aedes mosquito vectors. Nicaragua has experienced endemic dengue virus (DENV) transmission involving multiple serotypes since 1985, with chikungunya virus (CHIKV) reported in 2014-2015, followed by Zika virus (ZIKV) first reported in 2016. In order to identify patterns of genetic variation and selection pressures shaping the evolution of co-circulating DENV serotypes in light of the arrival of CHIKV and ZIKV, we employed whole-genome sequencing on an Illumina MiSeq platform of random-amplified total RNA libraries to characterize 42 DENV low-passage isolates, derived from viremic patients in Nicaragua between 2013 and 2016. Our approach also revealed clinically undetected co-infections with CHIKV. Of the three DENV serotypes (1, 2, and 3) co-circulating during our study, we uncovered distinct patterns of evolution using comparative phylogenetic inference. DENV-1 genetic variation was structured into two distinct co-circulating lineages with no evidence of positive selection in the origins of either lineage, suggesting they are equally fit. In contrast, the evolutionary history of DENV-2 was marked by positive selection, and a unique, divergent lineage correlated with high epidemic potential emerged in 2015 to drive an outbreak in 2016. DENV-3 genetic variation remained unstructured into lineages throughout the period of study. Thus, this study reveals insights into evolutionary and epidemiologic trends exhibited during the circulation of multiple arboviruses in Nicaragua.
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http://dx.doi.org/10.1016/j.meegid.2020.104680DOI Listing
August 2021

Utility of entomological indices for predicting transmission of dengue virus: secondary analysis of data from the Camino Verde trial in Mexico and Nicaragua.

PLoS Negl Trop Dis 2020 10 26;14(10):e0008768. Epub 2020 Oct 26.

Department of Family Medicine, McGill University, Montreal, Canada.

Dengue vector entomological indices are widely used to monitor vector density and disease control activities. But the value of these indices as predictors of dengue infection is not established. We used data from the impact assessment of a trial of community mobilization for dengue prevention (Camino Verde) to examine the associations between vector indices and evidence of dengue infection and their value for predicting dengue infection levels. In 150 clusters in Mexico and Nicaragua, two entomological surveys, three months apart, allowed calculation of the mean Container Index, Breteau index, Pupae per Household Index, and Pupae per Container Index across the two surveys. We measured recent dengue virus infection in children, indicated by a doubling of dengue antibodies in paired saliva samples over the three-month period. We examined the associations between each of the vector indices and evidence of dengue infection at household level and at cluster level, accounting for trial intervention status. To examine the predictive value for dengue infection, we constructed receiver operating characteristic (ROC) curves at household and cluster level, considering the four vector indices as continuous variables, and calculated the positive and negative likelihood ratios for different levels of the indices. None of the vector indices was associated with recent dengue infection at household level. The Breteau Index was associated with recent infection at cluster level (Odds ratio 1.36, 95% confidence interval 1.14-1.61). The ROC curve confirmed the weak predictive value for dengue infection of the Breteau Index at cluster level. Other indices showed no predictive value. Conventional vector indices were not useful in predicting dengue infection in Mexico and Nicaragua. The findings are compatible with the idea of sources of infection outside the household which were tackled by community action in the Camino Verde trial.
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http://dx.doi.org/10.1371/journal.pntd.0008768DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7588090PMC
October 2020

Protective and enhancing interactions among dengue viruses 1-4 and Zika virus.

Curr Opin Virol 2020 08 24;43:59-70. Epub 2020 Sep 24.

Division of Infectious Diseases and Vaccinology, School of Public Health, University of California, Berkeley, 185 Li Ka Shing Center, 1951 Oxford Street, Berkeley, CA 94720-3370, United States. Electronic address:

Dengue viruses 1-4 (DENV 1-4) and Zika virus (ZIKV) are closely related flaviviruses transmitted by Aedes mosquitoes that co-circulate in Asia, the Americas, Africa, and Oceania. Here, we review recent and historical literature on in vitro experiments, animal models, and clinical and epidemiological studies to describe how the sequence of DENV 1-4 and ZIKV infections modulates subsequent dengue and Zika disease outcome. Overall, we find these interactions are asymmetric. Immunity from a prior DENV infection or a prior ZIKV infection can enhance future severe dengue disease for some DENV serotypes while protecting against other serotypes. Further, prior DENV immunity has not been shown to enhance future uncomplicated or severe Zika and instead appears to be protective. Interestingly, secondary ZIKV infection induces type-specific ZIKV immunity but only generates weakly cross-neutralizing anti-DENV/ZIKV immunity, consistent with risk of future dengue disease. In contrast, secondary DENV infection induces strongly cross-neutralizing antibodies that protect against subsequent severe dengue disease. These immunologic interactions may be explained by differences in virion structure between DENV 1-4 and ZIKV, which modulate thermostability, susceptibility to neutralization, and cell infectivity. Overall, these observations are important for the understanding and prediction of epidemics and the development and evaluation of dengue and Zika vaccines.
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http://dx.doi.org/10.1016/j.coviro.2020.08.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7655628PMC
August 2020

Avian anti-NS1 IgY antibodies neutralize dengue virus infection and protect against lethal dengue virus challenge.

Antiviral Res 2020 11 23;183:104923. Epub 2020 Sep 23.

Department of Biomedical Sciences, University of North Dakota, School of Medicine and Health Sciences, Grand Forks, ND, 58202, USA. Electronic address:

Dengue is the most prevalent arboviral disease in humans and a continually increasing global public health burden. To date, there are no approved antiviral therapies against dengue virus (DENV) and the only licensed vaccine, Dengvaxia, is exclusively indicated for individuals with prior DENV infection. Endothelial hyperpermeability and vascular leak, pathogenic hallmarks of severe dengue disease, can be directly triggered by DENV non-structural protein 1 (NS1). As such, anti-NS1 antibodies can prevent NS1-triggered endothelial dysfunction in vitro and pathogenesis in vivo. Recently, goose-derived anti-DENV immunoglobulin Y (IgY) antibodies were shown to neutralize DENV and Zika virus (ZIKV) infection without adverse effects, such as antibody-dependent enhancement (ADE). In this study, we used egg yolks from DENV-immunized geese to purify IgY antibodies specific to DENV NS1 epitopes. We determined that 2 anti-NS1 IgY antibodies, NS1-1 and NS1-8, were capable of neutralizing DENV infection in vitro. In addition, these antibodies did not cross-react with the DENV Envelope (E) protein nor enhance DENV or ZIKV infection in vitro. Intriguingly, NS1-8, but not NS1-1, partially blocked NS1-induced endothelial dysfunction in vitro while neither antibody blocked binding of soluble NS1 to cells. Finally, prophylactic treatment of mice with NS1-8 conferred significant protection against lethal DENV challenge. Although further research is needed to define the mechanism of action of these antibodies, our findings highlight the potential of anti-NS1 IgY as a promising prophylactic approach against DENV infection.
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http://dx.doi.org/10.1016/j.antiviral.2020.104923DOI Listing
November 2020

Zika virus infection enhances future risk of severe dengue disease.

Science 2020 08;369(6507):1123-1128

Division of Infectious Diseases and Vaccinology, School of Public Health, University of California, Berkeley, Berkeley, CA, USA.

The Zika pandemic sparked intense interest in whether immune interactions among dengue virus serotypes 1 to 4 (DENV1 to -4) extend to the closely related Zika virus (ZIKV). We investigated prospective pediatric cohorts in Nicaragua that experienced sequential DENV1 to -3 (2004 to 2015), Zika (2016 to 2017), and DENV2 (2018 to 2020) epidemics. Risk of symptomatic DENV2 infection and severe disease was elevated by one prior ZIKV infection, one prior DENV infection, or one prior DENV infection followed by one ZIKV infection, compared with being flavivirus-naïve. By contrast, multiple prior DENV infections reduced dengue risk. Further, although high preexisting anti-DENV antibody titers protected against DENV1, DENV3, and ZIKV disease, intermediate titers induced by previous ZIKV or DENV infection enhanced future risk of DENV2 disease and severity, as well as DENV3 severity. The observation that prior ZIKV infection can modulate dengue disease severity like a DENV serotype poses challenges to development of dengue and Zika vaccines.
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http://dx.doi.org/10.1126/science.abb6143DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8274975PMC
August 2020
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