Publications by authors named "Scott C Weaver"

360 Publications

Designing multivalent immunogens for alphavirus vaccine optimization.

Virology 2021 Feb 5. Epub 2021 Feb 5.

Department of Biochemistry and Molecular Biology, University of Texas Medical Branch at Galveston, 301 University Boulevard, Galveston, TX, 77555, USA; Institute for Human Infections and Immunity (IHII), University of Texas Medical Branch at Galveston, 301 University Boulevard, Galveston, TX, 77555, USA. Electronic address:

There is a pressing need for vaccines against mosquito-borne alphaviruses such as Venezualen and eastern equine encephalitis viruses (VEEV, EEEV). We demonstrate an approach to vaccine development based on physicochemical properties (PCP) of amino acids to design a PCP-consensus sequence of the epitope-rich B domain of the VEEV major antigenic E2 protein. The consensus "spike" domain was incorporated into a live-attenuated VEEV vaccine candidate (ZPC/IRESv1). Mice inoculated with either ZPC/IRESv1 or the same virus containing the consensus E2 protein fragment (VEEVconE2) were protected against lethal challenge with VEEV strains ZPC-738 and 3908, and Mucambo virus (MUCV, related to VEEV), and had comparable neutralizing antibody titers against each virus. Both vaccines induced partial protection against Madariaga virus (MADV), a close relative of EEEV, lowering mortality from 60% to 20%. Thus PCP-consensus sequences can be integrated into a replicating virus that could, with further optimization, provide a broad-spectrum vaccine against encephalitic alphaviruses.
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http://dx.doi.org/10.1016/j.virol.2020.11.010DOI Listing
February 2021

The variant gambit: COVID-19's next move.

Cell Host Microbe 2021 Mar 1. Epub 2021 Mar 1.

Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX, USA; World Reference Center for Emerging Viruses and Arboviruses, University of Texas Medical Branch, Galveston, TX, USA; Institute for Human Infections and Immunity, University of Texas Medical Branch, Galveston, TX, USA. Electronic address:

More than a year after its emergence, COVID-19, the disease caused by SARS-CoV-2, continues to plague the world and dominate our daily lives. Even with the development of effective vaccines, this coronavirus pandemic continues to cause a fervor with the identification of major new variants hailing from the United Kingdom, South Africa, Brazil, and California. Coupled with worries over a distinct mink strain that has caused human infections and potential for further mutations, SARS-CoV-2 variants bring concerns for increased spread and escape from both vaccine and natural infection immunity. Here, we outline factors driving SARS-CoV-2 variant evolution, explore the potential impact of specific mutations, examine the risk of further mutations, and consider the experimental studies needed to understand the threat these variants pose. In this review, Plante et al. examine SARS-CoV-2 variants including B.1.1.7 (UK), B.1.351 (RSA), P.1 (Brazil), and B.1.429 (California). They focus on what factors contribute to variant emergence, mutations in and outside the spike protein, and studies needed to understand the impact of variants on infection, transmission, and vaccine efficacy.
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http://dx.doi.org/10.1016/j.chom.2021.02.020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7919536PMC
March 2021

Tiled-ClickSeq for targeted sequencing of complete coronavirus genomes with simultaneous capture of RNA recombination and minority variants.

bioRxiv 2021 Mar 11. Epub 2021 Mar 11.

High-throughput genomics of SARS-CoV-2 is essential to characterize virus evolution and to identify adaptations that affect pathogenicity or transmission. While single-nucleotide variations (SNVs) are commonly considered as driving virus adaption, RNA recombination events that delete or insert nucleic acid sequences are also critical. Whole genome targeting sequencing of SARS-CoV-2 is typically achieved using pairs of primers to generate cDNA amplicons suitable for Next-Generation Sequencing (NGS). However, paired-primer approaches impose constraints on where primers can be designed, how many amplicons are synthesized and requires multiple PCR reactions with non-overlapping primer pools. This imparts sensitivity to underlying SNVs and fails to resolve RNA recombination junctions that are not flanked by primer pairs. To address these limitations, we have designed an approach called ' '. Tiled-ClickSeq uses hundreds of tiled-primers spaced evenly along the virus genome in a single reverse-transcription reaction. The other end of the cDNA amplicon is generated by azido-nucleotides that stochastically terminate cDNA synthesis, obviating the need for a paired-primer. A sequencing adaptor containing a Unique Molecular Identifier (UMI) is appended using click-chemistry and a PCR reaction using Illumina adaptors generates a final NGS library. Tiled-ClickSeq provides complete genome coverage, including the 5'UTR, at high depth and specificity to virus on both Illumina and Nanopore NGS platforms. Here, we analyze multiple SARS-CoV-2 isolates and simultaneously characterize minority variants, sub-genomic mRNAs (sgmRNAs), structural variants (SVs) and D-RNAs. Tiled-ClickSeq therefore provides a convenient and robust platform for SARS-CoV-2 genomics that captures the full range of RNA species in a single, simple assay.
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http://dx.doi.org/10.1101/2021.03.10.434828DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7987005PMC
March 2021

The N501Y spike substitution enhances SARS-CoV-2 transmission.

bioRxiv 2021 Mar 9. Epub 2021 Mar 9.

Beginning in the summer of 2020, a variant of SARS-CoV-2, the cause of the COVID-19 pandemic, emerged in the United Kingdom (UK). This B.1.1.7 variant increased rapidly in prevalence among sequenced strains, attributed to an increase in infection and/or transmission efficiency. The UK variant has 19 nonsynonymous mutations across its viral genome including 8 substitutions or deletions in the spike protein, which interacts with cellular receptors to mediate infection and tropism. Here, using a reverse genetics approach, we show that, of the 8 individual spike protein substitutions, only N501Y exhibited consistent fitness gains for replication in the upper airway in the hamster model as well as primary human airway epithelial cells. The N501Y substitution recapitulated the phenotype of enhanced viral transmission seen with the combined 8 UK spike mutations, suggesting it is a major determinant responsible for increased transmission of this variant. Mechanistically, the N501Y substitution improved the affinity of the viral spike protein for cellular receptors. As suggested by its convergent evolution in Brazil and South Africa, our results indicate that N501Y substitution is a major adaptive spike mutation of major concern.
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http://dx.doi.org/10.1101/2021.03.08.434499DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7986995PMC
March 2021

Outbreak of coronavirus disease 2019 (COVID-19) among operating room staff of a tertiary referral center: An epidemiologic and environmental investigation.

Infect Control Hosp Epidemiol 2021 Mar 19:1-7. Epub 2021 Mar 19.

Department of Infection Control and Healthcare Epidemiology, University of Texas Medical Branch, Galveston, Texas.

Objective: Investigate an outbreak of coronavirus disease 2019 (COVID-19) among operating room staff utilizing contact tracing, mass testing for severe acute respiratory coronavirus virus 2 (SARS-CoV-2), and environmental sampling.

Design: Outbreak investigation.

Setting: University-affiliated tertiary-care referral center.

Patients: Operating room staff with positive SARS-CoV-2 molecular testing.

Methods: Epidemiologic and environmental investigations were conducted including contact tracing, environmental surveys, and sampling and review of the operating room schedule for staff-to-staff, staff-to-patient, and patient-to-staff SARS-CoV-2 transmission.

Results: In total, 24 healthcare personnel (HCP) tested positive for SARS-CoV-2, including nurses (29%), surgical technologists (25%), and surgical residents (16%). Moreover, 19 HCP (79%) reported having used a communal area, most commonly break rooms (75%). Overall, 20 HCP (83%) reported symptomatic disease. In total, 72 environmental samples were collected from communal areas for SARS-CoV-2 genomic testing; none was positive. Furthermore, 236 surgical cases were reviewed for transmission: 213 (90%) had negative preoperative SARS-CoV-2 testing, 21 (9%) had a positive test on or before the date of surgery, and 2 (<1%) did not have a preoperative test performed. In addition, 40 patients underwent postoperative testing (mean, 13 days to postoperative testing), and 2 returned positive results. Neither of these 2 cases was linked to our outbreak.

Conclusions: Complacency in infection control practices among staff during peak community transmission of SARS-CoV-2 is believed to have driven staff-to-staff transmission. Prompt identification of the outbreak led to rapid interventions, ultimately allowing for uninterrupted surgical service.
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http://dx.doi.org/10.1017/ice.2021.116DOI Listing
March 2021

Antiviral activity of oleandrin and a defined extract of Nerium oleander against SARS-CoV-2.

Biomed Pharmacother 2021 Mar 3;138:111457. Epub 2021 Mar 3.

Department of Experimental Therapeutics, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Phoenix Biotechnology, Inc., San Antonio, TX 78217, USA. Electronic address:

With continued expansion of the coronavirus disease (COVID-19) pandemic, caused by severe acute respiratory syndrome 2 (SARS-CoV-2), both antiviral drugs as well as effective vaccines are desperately needed to treat patients at high risk of life-threatening disease. Here, we present in vitro evidence for significant inhibition of SARS-CoV-2 by oleandrin and a defined extract of N. oleander (designated as PBI-06150). Using Vero cells, we found that prophylactic (pre-infection) oleandrin (as either the pure compound or as the active principal ingredient in PBI-06150) administration at concentrations as low as 0.05 µg/ml exhibited potent antiviral activity against SARS-CoV-2, with an 800-fold reduction in virus production, and a 0.1 µg/ml concentration resulted in a greater than 3000-fold reduction in infectious virus production. The half maximal effective concentration (EC) values were 11.98 ng/ml when virus output was measured at 24 h post-infection, and 7.07 ng/ml measured at 48 h post-infection. Therapeutic (post-infection) treatment up to 24 h after SARS-CoV-2 infection of Vero cells also reduced viral titers, with 0.1 µg/ml and 0.05 µg/ml concentrations causing greater than 100-fold reduction as measured at 48 h, and the 0.05 µg/ml concentration resulting in a 78-fold reduction. Concentrations of oleandrin up to 10 µg/ml were well tolerated in Vero cells. We also present in vivo evidence of the safety and efficacy of defined N. oleander extract (PBI-06150), which was administered to golden Syrian hamsters in a preparation containing as high as 130 µg/ml of oleandrin. In comparison to administration of control vehicle, PBI-06150 provided a statistically significant reduction of the viral titer in the nasal turbinates (nasal conchae). The potent prophylactic and therapeutic antiviral activities demonstrated here, together with initial evidence of its safety and efficacy in a relevant hamster model of COVID-19, support the further development of oleandrin and/or defined extracts containing this molecule for the treatment of SARS-CoV-2 and associated COVID-19 disease and potentially also for reduction of virus spread by persons diagnosed early after infection.
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http://dx.doi.org/10.1016/j.biopha.2021.111457DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7927596PMC
March 2021

A trans-complementation system for SARS-CoV-2 recapitulates authentic viral replication without virulence.

Cell 2021 Feb 23. Epub 2021 Feb 23.

Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, TX, USA; Institute for Human Infections and Immunity, University of Texas Medical Branch, Galveston, TX, USA; Sealy Institute for Vaccine Sciences, University of Texas Medical Branch, Galveston, TX, USA; Sealy Center for Structural Biology & Molecular Biophysics, University of Texas Medical Branch, Galveston, TX, USA. Electronic address:

The biosafety level 3 (BSL-3) requirement to culture severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a bottleneck for research. Here, we report a trans-complementation system that produces single-round infectious SARS-CoV-2 that recapitulates authentic viral replication. We demonstrate that the single-round infectious SARS-CoV-2 can be used at BSL-2 laboratories for high-throughput neutralization and antiviral testing. The trans-complementation system consists of two components: a genomic viral RNA containing ORF3 and envelope gene deletions, as well as mutated transcriptional regulator sequences, and a producer cell line expressing the two deleted genes. Trans-complementation of the two components generates virions that can infect naive cells for only one round but does not produce wild-type SARS-CoV-2. Hamsters and K18-hACE2 transgenic mice inoculated with the complementation-derived virions exhibited no detectable disease, even after intracranial inoculation with the highest possible dose. Thus, the trans-complementation platform can be safely used at BSL-2 laboratories for research and countermeasure development.
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http://dx.doi.org/10.1016/j.cell.2021.02.044DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7901297PMC
February 2021

Inhibition of innate immune response ameliorates Zika virus-induced neurogenesis deficit in human neural stem cells.

PLoS Negl Trop Dis 2021 Mar 3;15(3):e0009183. Epub 2021 Mar 3.

Department of Neuroscience, Cell Biology and Anatomy, University of Texas Medical Branch, Galveston, Texas, United States of America.

Global Zika virus (ZIKV) outbreaks and their strong link to microcephaly have raised major public health concerns. ZIKV has been reported to affect the innate immune responses in neural stem/progenitor cells (NS/PCs). However, it is unclear how these immune factors affect neurogenesis. In this study, we used Asian-American lineage ZIKV strain PRVABC59 to infect primary human NS/PCs originally derived from fetal brains. We found that ZIKV overactivated key molecules in the innate immune pathways to impair neurogenesis in a cell stage-dependent manner. Inhibiting the overactivated innate immune responses ameliorated ZIKV-induced neurogenesis reduction. This study thus suggests that orchestrating the host innate immune responses in NS/PCs after ZIKV infection could be promising therapeutic approach to attenuate ZIKV-associated neuropathology.
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http://dx.doi.org/10.1371/journal.pntd.0009183DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7959377PMC
March 2021

Neutralization of SARS-CoV-2 spike 69/70 deletion, E484K and N501Y variants by BNT162b2 vaccine-elicited sera.

Nat Med 2021 Feb 8. Epub 2021 Feb 8.

Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, TX, USA.

We engineered three severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viruses containing key spike mutations from the newly emerged United Kingdom (UK) and South African (SA) variants: N501Y from UK and SA; 69/70-deletion + N501Y + D614G from UK; and E484K + N501Y + D614G from SA. Neutralization geometric mean titers (GMTs) of 20 BTN162b2 vaccine-elicited human sera against the three mutant viruses were 0.81- to 1.46-fold of the GMTs against parental virus, indicating small effects of these mutations on neutralization by sera elicited by two BNT162b2 doses.
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http://dx.doi.org/10.1038/s41591-021-01270-4DOI Listing
February 2021

Optimized production and immunogenicity of an insect virus-based chikungunya virus candidate vaccine in cell culture and animal models.

Emerg Microbes Infect 2021 Dec;10(1):305-316

Department of Microbiology & Immunology, University of Texas Medical Branch, Galveston, TX, USA.

A chimeric Eilat/ Chikungunya virus (EILV/CHIKV) was previously reported to replicate only in mosquito cells but capable of inducing robust adaptive immunity in animals. Here, we initially selected C7/10 cells to optimize the production of the chimeric virus. A two-step procedure produced highly purified virus stocks, which was shown to not cause hypersensitive reactions in a mouse sensitization study. We further optimized the dose and characterized the kinetics of EILV/CHIKV-induced immunity. A single dose of 10 PFU was sufficient for induction of high levels of CHIKV-specific IgM and IgG antibodies, memory B cell and CD8 T cell responses. Compared to the live-attenuated CHIKV vaccine 181/25, EILV/CHIKV induced similar levels of CHIKV-specific memory B cells, but higher CD8 T cell responses at day 28. It also induced stronger CD8, but lower CD4 T cell responses than another live-attenuated CHIKV strain (CHIKV/IRES) at day 55 post-vaccination. Lastly, the purified EILV/CHIKV triggered antiviral cytokine responses and activation of antigen presenting cell (APC)s but did not induce APCs alone upon exposure. Overall, our results demonstrate that the EILV/CHIKV vaccine candidate is safe, inexpensive to produce and a potent inducer of both innate and adaptive immunity in mice.
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http://dx.doi.org/10.1080/22221751.2021.1886598DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7919884PMC
December 2021

A -complementation system for SARS-CoV-2.

bioRxiv 2021 Jan 19. Epub 2021 Jan 19.

The biosafety level-3 (BSL-3) requirement to culture severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a bottleneck for research and countermeasure development. Here we report a -complementation system that produces single-round infectious SARS-CoV-2 that recapitulates authentic viral replication. We demonstrate that the single-round infectious SARS-CoV-2 can be used at BSL-2 laboratories for high-throughput neutralization and antiviral testing. The -complementation system consists of two components: a genomic viral RNA containing a deletion of ORF3 and envelope gene, and a producer cell line expressing the two deleted genes. complementation of the two components generates virions that can infect naive cells for only one round, but does not produce wild-type SARS-CoV-2. Hamsters and K18-hACE2 transgenic mice inoculated with the complementation-derived virions exhibited no detectable disease, even after intracranial inoculation with the highest possible dose. The results suggest that the -complementation platform can be safely used at BSL-2 laboratories for research and countermeasure development.
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http://dx.doi.org/10.1101/2021.01.16.426970DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7836106PMC
January 2021

Role of mutational reversions and fitness restoration in Zika virus spread to the Americas.

Nat Commun 2021 01 26;12(1):595. Epub 2021 Jan 26.

World Reference Center for Emerging Viruses and Arboviruses, Institute for Human Infections and Immunity, and Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX, 77555, USA.

Zika virus (ZIKV) emerged from obscurity in 2013 to spread from Asia to the South Pacific and the Americas, where millions of people were infected, accompanied by severe disease including microcephaly following congenital infections. Phylogenetic studies have shown that ZIKV evolved in Africa and later spread to Asia, and that the Asian lineage is responsible for the recent epidemics in the South Pacific and Americas. However, the reasons for the sudden emergence of ZIKV remain enigmatic. Here we report evolutionary analyses that revealed four mutations, which occurred just before ZIKV introduction to the Americas, represent direct reversions of previous mutations that accompanied earlier spread from Africa to Asia and early circulation there. Our experimental infections of Aedes aegypti mosquitoes, human cells, and mice using ZIKV strains with and without these mutations demonstrate that the original mutations reduced fitness for urban, human-amplifed transmission, while the reversions restored fitness, increasing epidemic risk. These findings include characterization of three transmission-adaptive ZIKV mutations, and demonstration that these and one identified previously restored fitness for epidemic transmission soon before introduction into the Americas. The initial mutations may have followed founder effects and/or drift when the virus was introduced decades ago into Asia.
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http://dx.doi.org/10.1038/s41467-020-20747-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7838395PMC
January 2021

Loss of furin cleavage site attenuates SARS-CoV-2 pathogenesis.

Nature 2021 03 25;591(7849):293-299. Epub 2021 Jan 25.

Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX, USA.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-a new coronavirus that has led to a worldwide pandemic-has a furin cleavage site (PRRAR) in its spike protein that is absent in other group-2B coronaviruses. To explore whether the furin cleavage site contributes to infection and pathogenesis in this virus, we generated a mutant SARS-CoV-2 that lacks the furin cleavage site (ΔPRRA). Here we report that replicates of ΔPRRA SARS-CoV-2 had faster kinetics, improved fitness in Vero E6 cells and reduced spike protein processing, as compared to parental SARS-CoV-2. However, the ΔPRRA mutant had reduced replication in a human respiratory cell line and was attenuated in both hamster and K18-hACE2 transgenic mouse models of SARS-CoV-2 pathogenesis. Despite reduced disease, the ΔPRRA mutant conferred protection against rechallenge with the parental SARS-CoV-2. Importantly, the neutralization values of sera from patients with coronavirus disease 2019 (COVID-19) and monoclonal antibodies against the receptor-binding domain of SARS-CoV-2 were lower against the ΔPRRA mutant than against parental SARS-CoV-2, probably owing to an increased ratio of particles to plaque-forming units in infections with the former. Together, our results demonstrate a critical role for the furin cleavage site in infection with SARS-CoV-2 and highlight the importance of this site for evaluating the neutralization activities of antibodies.
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http://dx.doi.org/10.1038/s41586-021-03237-4DOI Listing
March 2021

Population bottlenecks and founder effects: implications for mosquito-borne arboviral emergence.

Nat Rev Microbiol 2021 03 11;19(3):184-195. Epub 2021 Jan 11.

World Reference Center for Emerging Viruses and Arboviruses, University of Texas Medical Branch, Galveston, TX, USA.

Transmission of arthropod-borne viruses (arboviruses) involves infection and replication in both arthropod vectors and vertebrate hosts. Nearly all arboviruses are RNA viruses with high mutation frequencies, which leaves them vulnerable to genetic drift and fitness losses owing to population bottlenecks during vector infection, dissemination from the midgut to the salivary glands and transmission to the vertebrate host. However, despite these bottlenecks, they seem to avoid fitness declines that can result from Muller's ratchet. In addition, founder effects that occur during the geographic introductions of human-amplified arboviruses, including chikungunya virus and Zika virus, can affect epidemic and endemic circulation, as well as virulence. In this Review, we discuss the role of genetic drift following population bottlenecks and founder effects in arboviral evolution and spread, and the emergence of human disease.
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http://dx.doi.org/10.1038/s41579-020-00482-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7798019PMC
March 2021

The first laboratory-confirmed imported infections of SARS-CoV-2 in Sudan.

Trans R Soc Trop Med Hyg 2021 01;115(1):103-109

World Reference Center for Emerging Viruses and Arboviruses, University of Texas, Medical Branch, Galveston, TX 77550, USA.

Background: The rapidly growing pandemic of coronavirus disease 2019 (COVID-19) has challenged health systems globally. Here we report the first identified infections of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2; aetiology of COVID-19) among recent international arrivals to Sudan and their contacts.

Methods: Suspected cases were identified clinically and/or epidemiologically. Samples from suspected cases and their contacts were tested in the National Influenza Centre following World Health Organization protocols. Two real-time reverse transcription quantitative polymerase chain reaction assays were used to detect and confirm SARS-CoV-2 infection.

Results: Seven cases of COVID-19, including two deaths, were confirmed in Sudan between 27 February and 30 March 2020. Suspected cases were identified and tested. As of 30 March, no local transmission was yet reported in the country. Fifty-nine percent of the suspected cases were international travellers coming from areas with current COVID-19 epidemics. Cough and fever were the major symptoms, presented by 65% and 60% of the suspected cases, respectively. By early April, an additional seven cases were confirmed through limited contact tracing that identified the first locally acquired infections in recent contact with imported cases.

Conclusions: The high mortality rate of COVID-19 cases in Sudan might be due to limitations in test and trace and case management services. Unfortunately, infections have spread further into other states and the country has no capacity for mass community screening to better estimate disease prevalence. Therefore external support is urgently needed to improve the healthcare and surveillance systems.
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http://dx.doi.org/10.1093/trstmh/traa151DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7788291PMC
January 2021

Unique Outbreak of Rift Valley Fever in Sudan, 2019.

Emerg Infect Dis 2020 12;26(12):3030-3033

We report a unique outbreak of Rift Valley fever in the Eldamar area, Sudan, May-July 2019, that resulted in 1,129 case-patients and 19 (1.7%) deaths. Patients exhibited clinical signs including fever (100%), headache (79%), and bleeding (4%). Most (98%) patients also reported death and abortions among their livestock.
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http://dx.doi.org/10.3201/eid2612.201599DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7706939PMC
December 2020

Changes in the dynamics of dengue incidence in South and Central America are possibly due to cross-population immunity after Zika virus epidemics.

Trop Med Int Health 2021 Mar 30;26(3):272-280. Epub 2020 Nov 30.

Instituto Gonçalo Moniz, Fundação Oswaldo Cruz, Ministério da Saúde, Salvador, BA, Brazil.

Objective: We tested the hypothesis that Zika virus (ZIKV) immunity may protect against dengue virus (DENV) infection, disease severity or human amplification, based on analysis of epidemiological data from our long-term surveillance study (2009-2016) in the city of Salvador, Brazil, that indicated a substantial reduction in the frequency of laboratory-confirmed dengue cases following the Zika outbreak. To assess whether similar patterns were observed across the Americas, we did a broader explorative investigation of historical series (2004 to 2019) of suspected cases of dengue fever, covering 20 DENV-endemic South and Central American countries.

Methods: We used segmented linear regressions of single group interrupted time series (ITS) analysis to evaluate whether the Zika epidemic had a statistical effect on the trends of annual dengue incidence.

Results: We observed in our 16-year historical series that in all countries, the incidence of dengue exhibited periodic oscillations over time, with a general trend of statistically significant increase during the pre-Zika period overall and for 11 of the 20 countries. Following the peak of the first population exposure to ZIKV in the Americas, in 2016, the overall rate of reported dengue cases in 2017 and 2018 in the countries under study sharply dropped (P < 0.05) and was the lowest reported since 2005. Individually in each country, a statistically significant reduction in the annual dengue incidence beginning in 2016 or in 2017-2018 occurred in 13 of the 20 studied countries. However, in 2019, reports of suspected dengue cases increased across the Americas. In Brazil, Dominican Republic, Guatemala and Honduras, dengue incidence was >5 times higher in 2019 than in 2017 and 2018, and, in 2019, they had the greater dengue incidence than in all previous years throughout the historical series.

Conclusions: The widespread decline in suspected dengue cases recorded in 2017 and 2018 lends further support to our previous epidemiological hypothesis of ZIKV-induced cross-species immunity to DENV. However, the cross-protection appears to be transient (around 2 years). Long-term, prospective follow-ups of dengue reports are needed to confirm (or refute) these findings, which could have significant public health implications, in particular regarding DENV vaccine development and application.
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http://dx.doi.org/10.1111/tmi.13526DOI Listing
March 2021

Acute Respiratory Distress in Aged, SARS-CoV-2-Infected African Green Monkeys but Not Rhesus Macaques.

Am J Pathol 2021 02 7;191(2):274-282. Epub 2020 Nov 7.

Tulane National Primate Research Center, Covington, Louisiana; Department of Microbiology and Immunology, Tulane University School of Medicine, New Orleans, Louisiana.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) induces a wide range of disease severity, ranging from asymptomatic infection to a life-threating illness, particularly in the elderly population and individuals with comorbid conditions. Among individuals with serious coronavirus 2019 (COVID-19) disease, acute respiratory distress syndrome (ARDS) is a common and often fatal presentation. Animal models of SARS-CoV-2 infection that manifest severe disease are needed to investigate the pathogenesis of COVID-19-induced ARDS and evaluate therapeutic strategies. We report two cases of ARDS in two aged African green monkeys (AGMs) infected with SARS-CoV-2 that had pathological lesions and disease similar to severe COVID-19 in humans. We also report a comparatively mild COVID-19 phenotype characterized by minor clinical, radiographic, and histopathologic changes in the two surviving, aged AGMs and four rhesus macaques (RMs) infected with SARS-CoV-2. Notable increases in circulating cytokines were observed in three of four infected, aged AGMs but not in infected RMs. All the AGMs had increased levels of plasma IL-6 compared with baseline, a predictive marker and presumptive therapeutic target in humans infected with SARS-CoV-2. Together, our results indicate that both RMs and AGMs are capable of modeling SARS-CoV-2 infection and suggest that aged AGMs may be useful for modeling severe disease manifestations, including ARDS.
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http://dx.doi.org/10.1016/j.ajpath.2020.10.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7648506PMC
February 2021

Arthritogenic alphaviruses: epidemiological and clinical perspective on emerging arboviruses.

Lancet Infect Dis 2020 Nov 5. Epub 2020 Nov 5.

Emerging Viruses, Inflammation, and Therapeutics Group, Menzies Health Institute Queensland, Griffith University, Gold Coast, QLD, Australia. Electronic address:

Mosquito-borne viruses, or arboviruses, have been part of the infectious disease landscape for centuries, and are often, but not exclusively, endemic to equatorial and subtropical regions of the world. The past two decades saw the re-emergence of arthritogenic alphaviruses, a genus of arboviruses that includes several members that cause severe arthritic disease. Recent outbreaks further highlight the substantial public health burden caused by these viruses. Arthritogenic alphaviruses are often reported in the context of focused outbreaks in specific regions (eg, Caribbean, southeast Asia, and Indian Ocean) and cause debilitating acute disease that can extend to chronic manifestations for years after infection. These viruses are classified among several antigenic complexes, span a range of hosts and mosquito vectors, and can be distributed along specific geographical locations. In this Review, we highlight key features of alphaviruses that are known to cause arthritic disease in humans and outline the present findings pertaining to classification, immunogenicity, pathogenesis, and experimental approaches aimed at limiting disease manifestations. Although the most prominent alphavirus outbreaks in the past 15 years featured chikungunya virus, and a large body of work has been dedicated to understanding chikungunya disease mechanisms, this Review will instead focus on other arthritogenic alphaviruses that have been identified globally and provide a comprehensive appraisal of present and future research directions.
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http://dx.doi.org/10.1016/S1473-3099(20)30491-6DOI Listing
November 2020

Endemic and Epidemic Human Alphavirus Infections in Eastern Panama: An Analysis of Population-Based Cross-Sectional Surveys.

Am J Trop Med Hyg 2020 12 22;103(6):2429-2437. Epub 2020 Oct 22.

Department of Statistics, University of Oxford, Oxford, United Kingdom.

Madariaga virus (MADV) has recently been associated with severe human disease in Panama, where the closely related Venezuelan equine encephalitis virus (VEEV) also circulates. In June 2017, a fatal MADV infection was confirmed in a community of Darien Province. We conducted a cross-sectional outbreak investigation with human and mosquito collections in July 2017, where sera were tested for alphavirus antibodies and viral RNA. In addition, by applying a catalytic, force-of-infection (FOI) statistical model to two serosurveys from Darien Province in 2012 and 2017, we investigated whether endemic or epidemic alphavirus transmission occurred historically. In 2017, MADV and VEEV IgM seroprevalences were 1.6% and 4.4%, respectively; IgG antibody prevalences were MADV: 13.2%, VEEV: 16.8%, Una virus (UNAV): 16.0%, and Mayaro virus: 1.1%. Active viral circulation was not detected. Evidence of MADV and UNAV infection was found near households, raising questions about its vectors and enzootic transmission cycles. Insomnia was associated with MADV and VEEV infections, depression symptoms were associated with MADV, and dizziness with VEEV and UNAV. Force-of-infection analyses suggest endemic alphavirus transmission historically, with recent increased human exposure to MADV and VEEV in Aruza and Mercadeo, respectively. The lack of additional neurological cases suggests that severe MADV and VEEV infections occur only rarely. Our results indicate that over the past five decades, alphavirus infections have occurred at low levels in eastern Panama, but that MADV and VEEV infections have recently increased-potentially during the past decade. Endemic infections and outbreaks of MADV and VEEV appear to differ spatially in some locations of eastern Panama.
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http://dx.doi.org/10.4269/ajtmh.20-0408DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7695115PMC
December 2020

Spike mutation D614G alters SARS-CoV-2 fitness.

Nature 2021 04 26;592(7852):116-121. Epub 2020 Oct 26.

Institute for Human Infections and Immunity, University of Texas Medical Branch, Galveston, TX, USA.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein substitution D614G became dominant during the coronavirus disease 2019 (COVID-19) pandemic. However, the effect of this variant on viral spread and vaccine efficacy remains to be defined. Here we engineered the spike D614G substitution in the USA-WA1/2020 SARS-CoV-2 strain, and found that it enhances viral replication in human lung epithelial cells and primary human airway tissues by increasing the infectivity and stability of virions. Hamsters infected with SARS-CoV-2 expressing spike(D614G) (G614 virus) produced higher infectious titres in nasal washes and the trachea, but not in the lungs, supporting clinical evidence showing that the mutation enhances viral loads in the upper respiratory tract of COVID-19 patients and may increase transmission. Sera from hamsters infected with D614 virus exhibit modestly higher neutralization titres against G614 virus than against D614 virus, suggesting that the mutation is unlikely to reduce the ability of vaccines in clinical trials to protect against COVID-19, and that therapeutic antibodies should be tested against the circulating G614 virus. Together with clinical findings, our work underscores the importance of this variant in viral spread and its implications for vaccine efficacy and antibody therapy.
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http://dx.doi.org/10.1038/s41586-020-2895-3DOI Listing
April 2021

Pharmacological approaches to the treatment of COVID-19 patients.

J Transl Sci 2020 Dec 17;6(6). Epub 2020 Apr 17.

Department of Family Medicine, University of Texas Medical Branch, Galveston, Texas.

The current COVID-19 pandemic has presented unprecedented challenges to the world community. No effective therapies or vaccines have yet been established. Upon the basis of homologies to similar coronaviruses, several potential drug targets have been identified and are the focus of both laboratory and clinical investigation. The rationale for several of these drug candidates is presented in this review. Emerging clinical data has revealed that severe COVID-19 disease is associated with heightened inflammatory responses and a procoagulant state, suggesting that patient treatment strategies must extend beyond antiviral agents. Effective approaches to the treatment of vulnerable patients with comorbidities will render COVID-19 substantially more manageable.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7543691PMC
December 2020

Clinical and Serological Findings of Madariaga and Venezuelan Equine Encephalitis Viral Infections: A Follow-up Study 5 Years After an Outbreak in Panama.

Open Forum Infect Dis 2020 Sep 20;7(9):ofaa359. Epub 2020 Aug 20.

Division of Infectious Disease and Global Medicine, Department of Medicine, University of Florida, Gainesville, Florida, USA.

Background: Human cases of Madariaga virus (MADV) infection were first detected during an outbreak in 2010 in eastern Panama, where Venezuelan equine encephalitis virus (VEEV) also circulates. Little is known about the long-term consequences of either alphavirus infection.

Methods: A follow-up study of the 2010 outbreak was undertaken in 2015. An additional survey was carried out 2 weeks after a separate 2017 alphavirus outbreak in a neighboring population in eastern Panama. Serological studies and statistical analyses were undertaken in both populations.

Results: Among the originally alphavirus-seronegative participants (n = 35 of 65), seroconversion was observed at a rate of 14.3% (95% CI, 4.8%-30.3%) for MADV and 8.6% (95% CI, 1.8%-23.1%) for VEEV over 5 years. Among the originally MADV-seropositive participants (n = 14 of 65), VEEV seroconversion occurred in 35.7% (95% CI, 12.8%-64.9%). In the VEEV-seropositive participants (n = 16 of 65), MADV seroconversion occurred in 6.3% (95% CI, 0.2%-30.2%). MADV seroreversion was observed in 14.3% (95% CI, 1.8%-42.8%) of those who were originally seropositive in 2010. VEEV seroconversion in the baseline MADV-seropositive participants was significantly higher than in alphavirus-negative participants. In the population sampled in 2017, MADV and VEEV seroprevalence was 13.2% and 16.8%, respectively. Memory loss, insomnia, irritability, and seizures were reported significantly more frequently in alphavirus-seropositive participants than in seronegative participants.

Conclusions: High rates of seroconversion to MADV and VEEV over 5 years suggest frequent circulation of both viruses in Panama. Enhanced susceptibility to VEEV infection may be conferred by MADV infection. We provide evidence of persistent neurologic symptoms up to 5 years following MADV and VEEV exposure.
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http://dx.doi.org/10.1093/ofid/ofaa359DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7518370PMC
September 2020

Decontamination of SARS-CoV-2 and Other RNA Viruses from N95 Level Meltblown Polypropylene Fabric Using Heat under Different Humidities.

ACS Nano 2020 10 29;14(10):14017-14025. Epub 2020 Sep 29.

Department of Materials Science and Engineering, Stanford University, Stanford, California 94305, United States.

In March of 2020, the World Health Organization declared a pandemic of coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The pandemic led to a shortage of N95-grade filtering facepiece respirators (FFRs), especially surgical-grade N95 FFRs for protection of healthcare professionals against airborne transmission of SARS-CoV-2. We and others have previously reported promising decontamination methods that may be applied to the recycling and reuse of FFRs. In this study we tested disinfection of three viruses, including SARS-CoV-2, dried on a piece of meltblown fabric, the principal component responsible for filtering of fine particles in N95-level FFRs, under a range of temperatures (60-95 °C) at ambient or 100% relative humidity (RH) in conjunction with filtration efficiency testing. We found that heat treatments of 75 °C for 30 min or 85 °C for 20 min at 100% RH resulted in efficient decontamination from the fabric of SARS-CoV-2, human coronavirus NL63 (HCoV-NL63), and another enveloped RNA virus, chikungunya virus vaccine strain 181/25 (CHIKV-181/25), without lowering the meltblown fabric's filtration efficiency.
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http://dx.doi.org/10.1021/acsnano.0c06565DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7526332PMC
October 2020

Spike mutation D614G alters SARS-CoV-2 fitness and neutralization susceptibility.

bioRxiv 2020 Sep 2. Epub 2020 Sep 2.

Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston TX, USA.

A spike protein mutation D614G became dominant in SARS-CoV-2 during the COVID-19 pandemic. However, the mutational impact on viral spread and vaccine efficacy remains to be defined. Here we engineer the D614G mutation in the SARS-CoV-2 USA-WA1/2020 strain and characterize its effect on viral replication, pathogenesis, and antibody neutralization. The D614G mutation significantly enhances SARS-CoV-2 replication on human lung epithelial cells and primary human airway tissues, through an improved infectivity of virions with the spike receptor-binding domain in an "up" conformation for binding to ACE2 receptor. Hamsters infected with D614 or G614 variants developed similar levels of weight loss. However, the G614 virus produced higher infectious titers in the nasal washes and trachea, but not lungs, than the D614 virus. The hamster results confirm clinical evidence that the D614G mutation enhances viral loads in the upper respiratory tract of COVID-19 patients and may increases transmission. For antibody neutralization, sera from D614 virus-infected hamsters consistently exhibit higher neutralization titers against G614 virus than those against D614 virus, indicating that (i) the mutation may not reduce the ability of vaccines in clinical trials to protect against COVID-19 and (ii) therapeutic antibodies should be tested against the circulating G614 virus before clinical development.

Importance: Understanding the evolution of SARS-CoV-2 during the COVID-19 pandemic is essential for disease control and prevention. A spike protein mutation D614G emerged and became dominant soon after the pandemic started. By engineering the D614G mutation into an authentic wild-type SARS-CoV-2 strain, we demonstrate the importance of this mutation to (i) enhanced viral replication on human lung epithelial cells and primary human airway tissues, (ii) improved viral fitness in the upper airway of infected hamsters, and (iii) increased susceptibility to neutralization. Together with clinical findings, our work underscores the importance of this mutation in viral spread, vaccine efficacy, and antibody therapy.
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http://dx.doi.org/10.1101/2020.09.01.278689DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7480025PMC
September 2020

Microbial interactions in the mosquito gut determine Serratia colonization and blood-feeding propensity.

ISME J 2021 Jan 7;15(1):93-108. Epub 2020 Sep 7.

Departments of Vector Biology and Tropical Disease Biology, Centre for Neglected Tropical Disease, Liverpool School of Tropical Medicine, Liverpool, UK.

How microbe-microbe interactions dictate microbial complexity in the mosquito gut is unclear. Previously we found that, Serratia, a gut symbiont that alters vector competence and is being considered for vector control, poorly colonized Aedes aegypti yet was abundant in Culex quinquefasciatus reared under identical conditions. To investigate the incompatibility between Serratia and Ae. aegypti, we characterized two distinct strains of Serratia marcescens from Cx. quinquefasciatus and examined their ability to infect Ae. aegypti. Both Serratia strains poorly infected Ae. aegypti, but when microbiome homeostasis was disrupted, the prevalence and titers of Serratia were similar to the infection in its native host. Examination of multiple genetically diverse Ae. aegypti lines found microbial interference to S. marcescens was commonplace, however, one line of Ae. aegypti was susceptible to infection. Microbiome analysis of resistant and susceptible lines indicated an inverse correlation between Enterobacteriaceae bacteria and Serratia, and experimental co-infections in a gnotobiotic system recapitulated the interference phenotype. Furthermore, we observed an effect on host behavior; Serratia exposure to Ae. aegypti disrupted their feeding behavior, and this phenotype was also reliant on interactions with their native microbiota. Our work highlights the complexity of host-microbe interactions and provides evidence that microbial interactions influence mosquito behavior.
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http://dx.doi.org/10.1038/s41396-020-00763-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7852612PMC
January 2021

Rationally Attenuated Vaccines for Venezuelan Equine Encephalitis Protect Against Epidemic Strains with a Single Dose.

Vaccines (Basel) 2020 Sep 2;8(3). Epub 2020 Sep 2.

World Reference Center for Emerging Viruses and Arboviruses, University of Texas Medical Branch, Galveston, TX 77555, USA.

Venezuelan equine encephalitis virus (VEEV) is a re-emerging virus of human, agriculture, and bioweapon threat importance. No FDA-approved treatment is available to combat Venezuelan equine encephalitis in humans, prompting the need to create a vaccine that is safe, efficacious, and cannot be replicated in the mosquito vector. Here we describe the use of a serotype ID VEEV (ZPC-738) vaccine with an internal ribosome entry site (IRES) to alter gene expression patterns. This ZPC/IRES vaccine was genetically engineered in two ways based on the position of the IRES insertion to create a vaccine that is safe and efficacious. After a single dose, both versions of the ZPC/IRES vaccine elicited neutralizing antibody responses in mice and non-human primates after a single dose, with more robust responses produced by version 2. Further, all mice and primates were protected from viremia following VEEV challenge. These vaccines were also safer in neonatal mice than the current investigational new drug vaccine, TC-83. These results show that IRES-based attenuation of alphavirus genomes consistently produce promising vaccine candidates, with VEEV/IRES version 2 showing promise for further development.
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http://dx.doi.org/10.3390/vaccines8030497DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7563393PMC
September 2020