Analysis of humoral immune responses in #chikungunya virus (CHIKV) infected patients and individuals vaccinated with a candidate CHIKV #vaccine (J Infect Dis., abstract)

[Source: Journal of Infectious Diseases, full page: (LINK). Abstract, edited.]

Analysis of humoral immune responses in chikungunya virus (CHIKV) infected patients and individuals vaccinated with a candidate CHIKV vaccine

Lisa Henss, Constanze Yue, Christine von Rhein, Roland Tschismarov, Lia Laura Lewis-Ximenez, Albert Dölle, Sally A Baylis, Barbara S Schnierle

The Journal of Infectious Diseases, jiz658, https://doi.org/10.1093/infdis/jiz658

Published: 12 December 2019

 

Abstract

Background

Chikungunya virus (CHIKV) is a mosquito-transmitted alphavirus that causes severe flu like symptoms. The acute symptoms disappear after one week, but chronic arthralgia can persist for years. Here, humoral immune responses in CHIKV-infected patients and vaccinees were analyzed.

Methods

Alphavirus neutralization activity was analyzed with pseudotyped lentiviral vectors and antibody epitope mapping was performed with a peptide array.

Results

Greatest CHIKV neutralization activity was observed 60-92 days after onset of symptoms. The amount of CHIKV-specific antibodies, their binding avidity and cross-reactivity with other alphaviruses increased over time. CHIKV and o’nyong-nyong virus (ONNV) were both neutralized to a similar extent. Linear antibody binding epitopes were mainly found in E2 domain B and the acid-sensitive regions (ASRs). In addition, serum samples from healthy volunteers vaccinated with a measles-vectored chikungunya vaccine candidate, MV-CHIK, were analyzed. Neutralization activity in the samples from the vaccine cohort was 2–6-fold lower than in samples from CHIKV-infected patients. In contrast to infection, vaccination only induced cross-neutralization with ONNV and the E2 ASR1 was the major antibody target.

Conclusion

These data could assist vaccine design and enable the identification of correlates of protection necessary for vaccine efficacy.

alphavirus, chikungunya, antibody, neutralization

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This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model)

Keywords: Chikungunya fever; Alphavirus; o’nyong-nyong virus; Vaccines.

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Eastern Equine #Encephalitis Virus [#EEEV] — Another Emergent #Arbovirus in the #US (N Engl J Med., summary)

[Source: The New England Journal of Medicine, full page: (LINK). Summary, edited.]

Eastern Equine Encephalitis Virus — Another Emergent Arbovirus in the United States

David M. Morens, M.D., Gregory K. Folkers, M.S., M.P.H., and Anthony S. Fauci, M.D.

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Humans have always lived in intimate association with arthropods that transmit pathogens between humans or from animals to humans. About 700,000 deaths due to vectorborne diseases occur globally each year, according to World Health Organization estimates. In the summer and fall of 2019, nine U.S. states have reported 36 human cases (14 of them fatal) of one of the deadliest of these diseases: eastern equine encephalitis (EEE), an arthropod-borne viral (arboviral) disease transmitted by mosquitoes. In recent years, the Americas have witnessed a steady stream of other emerging or reemerging arboviruses, such as dengue, West Nile, chikungunya, Zika, and Powassan, as well as increasing numbers of travel-related cases of various other arboviral infections. This year’s EEE outbreaks may thus be a harbinger of a new era of arboviral emergences.

(…)

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Disclosure forms provided by the authors are available at NEJM.org.

Author Affiliations: From the Office of the Director, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD.

Keywords: Arbovirus; Alphavirus; Eastern Equine Encephalitis Virus; USA; Moquitoes.

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#Host #nutritional status affects #alphavirus #virulence, #transmission, and #evolution (PLOS Pathog., abstract)

[Source: PLoS Pathogens, full page: (LINK). Abstract, edited.]

OPEN ACCESS /  PEER-REVIEWED / RESEARCH ARTICLE

Host nutritional status affects alphavirus virulence, transmission, and evolution

James Weger-Lucarelli , Lucia Carrau, Laura I. Levi, Veronica Rezelj, Thomas Vallet, Hervé Blanc, Jérémy Boussier, Daniela Megrian, Sheryl Coutermarsh-Ott, Tanya LeRoith, Marco Vignuzzi

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Published: November 11, 2019 / DOI: https://doi.org/10.1371/journal.ppat.1008089 / This is an uncorrected proof.

 

Abstract

Malnourishment, specifically overweight/obesity and undernourishment, affects more than 2.5 billion people worldwide, with the number affected ever-increasing. Concurrently, emerging viral diseases, particularly those that are mosquito-borne, have spread dramatically in the past several decades, culminating in outbreaks of several viruses worldwide. Both forms of malnourishment are known to lead to an aberrant immune response, which can worsen disease outcomes and reduce vaccination efficacy for viral pathogens such as influenza and measles. Given the increasing rates of malnutrition and spread of arthropod-borne viruses (arboviruses), there is an urgent need to understand the role of host nutrition on the infection, virulence, and transmission of these viruses. To address this gap in knowledge, we infected lean, obese, and undernourished mice with arthritogenic arboviruses from the genus Alphavirus and assessed morbidity, virus replication, transmission, and evolution. Obesity and undernourishment did not consistently influence virus replication in the blood of infected animals except for reductions in virus in obese mice late in infection. However, morbidity was increased in obese mice under all conditions. Using Mayaro virus (MAYV) as a model arthritogenic alphavirus, we determined that both obese and undernourished mice transmit virus less efficiently to mosquitoes than control (lean) mice. In addition, viral genetic diversity and replicative fitness were reduced in virus isolated from obese compared to lean controls. Taken together, nutrition appears to alter the course of alphavirus infection and should be considered as a critical environmental factor during outbreaks.

 

Author summary

Over- and undernutrition, collectively known as malnutrition, affect over 2.5 billion people worldwide. Associations between malnutrition and mosquito-borne virus infection and resulting disease have been identified in epidemiological studies but have not been explored in controlled studies. Here, we infect obese or undernourished mice with different arthritis inducing viruses in the genus Alphavirus and measure disease symptoms, viral replication, transmission, and evolution. We found that markers of disease, namely weight loss and footpad swelling, were increased in obese mice. We also found that replication differences between mice fed different diets were minimal except late in infection for obese mice when levels of virus dropped significantly. When mosquitoes were allowed to feed on mice fed different diets, we observed reduced infection and transmission rates, depending on the diet. Finally, we found reduced genetic diversity and replicative fitness of virus isolated from obese mice. This study provides insights into the influence of nutrition on alphavirus pathogenesis and evolution.

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Citation: Weger-Lucarelli J, Carrau L, Levi LI, Rezelj V, Vallet T, Blanc H, et al. (2019) Host nutritional status affects alphavirus virulence, transmission, and evolution. PLoS Pathog 15(11): e1008089. https://doi.org/10.1371/journal.ppat.1008089

Editor: Richard J. Kuhn, Purdue University, UNITED STATES

Received: June 23, 2019; Accepted: September 17, 2019; Published: November 11, 2019

Copyright: © 2019 Weger-Lucarelli et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Data Availability: All next-generation sequencing files are uploaded to the small read archive (SRA) under accession number PRJNA573904.

Funding: This work was partially funded by the DARPA program PREventing EMerging Pathogenic Threats (PREEMPT) awarded to MV and JWL. Partial funding was also provided by a faculty start-up package at Virginia Tech awarded to JWL. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript

Competing interests: The authors have declared that no competing interests exist.

Keywords: Arbovirus; Alphavirus; Mosquitoes; Animal models.

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#Chikungunya and O’nyong-nyong Viruses in #Uganda: Implications for Diagnostics (Open Forum Infect Dis., abstract)

[Source: US National Library of Medicine, full page: (LINK). Abstract, edited.]

Open Forum Infect Dis. 2019 Jan 3;6(3):ofz001. doi: 10.1093/ofid/ofz001. eCollection 2019 Mar.

Chikungunya and O’nyong-nyong Viruses in Uganda: Implications for Diagnostics.

Clements TL1, Rossi CA1, Irish AK2, Kibuuka H3, Eller LA3, Robb ML4, Kataaha P5, Michael NL6, Hensley LE7, Schoepp RJ1.

Author information: 1 US Army Medical Research Institute of Infectious Diseases, Fort Detrick, Frederick, Maryland. 2 College of Public Health, University of Iowa, Iowa City, Iowa. 3 Makerere University Walter Reed Project, Kampala, Uganda. 4 Henry M. Jackson Foundation, Rockville, Maryland. 5 Nakasero Blood Bank, Kampala, Uganda. 6 Walter Reed Army Institute of Research, Rockville, Maryland. 7 National Institute of Allergy and Infectious Diseases-Integrated Research Facility, Frederick, Maryland.

 

Abstract

BACKGROUND:

A serosurvey of healthy blood donors provided evidence of hemorrhagic fever and arthropod-borne virus infections in Uganda.

METHODS:

Antibody prevalence to arthropod-borne and hemorrhagic fever viruses in human sera was determined using enzyme-linked immunosorbent assay (ELISA) and plaque reduction neutralization test (PRNT).

RESULTS:

The greatest antibody prevalence determined by ELISA was to chikungunya virus (CHIKV) followed in descending order by West Nile virus (WNV), Crimean-Congo hemorrhagic fever virus (CCHFV), Ebola virus (EBOV), dengue virus (DEN), yellow fever virus (YFV), Rift Valley fever virus (RVFV), Marburg virus (MARV), and Lassa virus (LASV). Further investigation of CHIKV-positive sera demonstrated that the majority of antibody responses may likely be the result of exposure to the closely related alphavirus o’nyong-nyong virus (ONNV).

CONCLUSIONS:

As the use of highly specific and sensitive polymerase chain reaction-based assays becomes the diagnostic standard without the corresponding use of the less sensitive but more broadly reactive immunological-based assays, emerging and re-emerging outbreaks will be initially missed, illustrating the need for an orthogonal system for the detection and identification of viruses causing disease.

Published by Oxford University Press on behalf of Infectious Diseases Society of America 2019.

KEYWORDS: CHIKV; ONNV; Uganda; chikungunya; diagnostics; o’nyong-nyong; serosurvey

PMID: 31660384 PMCID: PMC6411207 [Available on 2020-01-03] DOI: 10.1093/ofid/ofz001

Keywords: Alphavirus; Chikungunya fever; O’nyong-nyong virus; Serosurvey; Uganda.

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Neutralizing #antibodies against #Mayaro virus require Fc effector functions for protective activity (J Exp Med., abstract)

[Source: Journal of Experimental Medicine, full page: (LINK). Abstract, edited.]

Neutralizing antibodies against Mayaro virus require Fc effector functions for protective activity

James T. Earnest, Katherine Basore, Vicky Roy, Adam L. Bailey, David Wang, Galit Alter, Daved H. Fremont, Michael S. Diamond

DOI: 10.1084/jem.20190736 | Published July 23, 201

 

Abstract

Despite causing outbreaks of fever and arthritis in multiple countries, no countermeasures exist against Mayaro virus (MAYV), an emerging mosquito-transmitted alphavirus. We generated 18 neutralizing mAbs against MAYV, 11 of which had “elite” activity that inhibited infection with EC50values of <10 ng/ml. Antibodies with the greatest inhibitory capacity in cell culture mapped to epitopes near the fusion peptide of E1 and in domain B of the E2 glycoproteins. Unexpectedly, many of the elite neutralizing mAbs failed to prevent MAYV infection and disease in vivo. Instead, the most protective mAbs bound viral antigen on the cell surface with high avidity and promoted specific Fc effector functions, including phagocytosis by neutrophils and monocytes. In subclass switching studies, murine IgG2a and humanized IgG1 mAb variants controlled infection better than murine IgG1 and humanized IgG1-N297Q variants. An optimally protective antibody response to MAYV and possibly other alphaviruses may require tandem virus neutralization by the Fab moiety and effector functions of the Fc region.

Submitted: 24 April 2019 – Revision received 11 June 2019 – Accepted: 20 June 2019

This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms/). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 4.0 International license, as described at https://creativecommons.org/licenses/by-nc-sa/4.0/).

Keywords: Alphavirus; Mayaro virus; Monoclonal antibodies.

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Infectious #cDNA #clones of two #strains of #Mayaro virus for studies on viral #pathogenesis and #vaccine development (Virology, abstract)

[Source: US National Library of Medicine, full page: (LINK). Abstract, edited.]

Virology. 2019 Jul 14;535:227-231. doi: 10.1016/j.virol.2019.07.013. [Epub ahead of print]

Infectious cDNA clones of two strains of Mayaro virus for studies on viral pathogenesis and vaccine development.

Chuong C1, Bates TA1, Weger-Lucarelli J2.

Author information: 1 Department of Biomedical Sciences and Pathobiology, Virginia Tech, VA-MD Regional College of Veterinary Medicine, Blacksburg, VA, USA. 2 Department of Biomedical Sciences and Pathobiology, Virginia Tech, VA-MD Regional College of Veterinary Medicine, Blacksburg, VA, USA. Electronic address: weger@vt.edu.

 

Abstract

Mayaro virus (MAYV; family Togaviridae, genus Alphavirus) is an emerging global threat that can cause severe clinical manifestations similar to Zika, dengue, and chikungunya viruses. Currently, there is a lack of molecular tools to enable a better understanding of the transmission and pathogenesis of MAYV. Here, we detail the development and characterization of infectious clones of two strains of MAYV that produce infectious virus and replicate in mammalian and mosquito cells similarly to wild-type virus. Additionally, clone-derived viruses produced identical infection rates and phenotypes in CD-1 mice compared to the parental strains. This infectious clone system will provide a resource to the research community to analyze MAYV genetic determinants of virulence, determine vector competence, and develop vaccines.

Copyright © 2019 Elsevier Inc. All rights reserved.

KEYWORDS: Alphavirus; Infectious clones; Mayaro virus

PMID: 31325837 DOI: 10.1016/j.virol.2019.07.013

Keywords: Alphavirus; Togavirus; Mayaro virus; Viral pathogenesis.

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#Chikungunya virus #vaccine candidates with decreased mutational robustness are attenuated in vivo and have compromised transmissibility (J Virol., abstract)

[Source: Journal of Virology, full page: (LINK). Abstract, edited.]

Chikungunya virus vaccine candidates with decreased mutational robustness are attenuated in vivo and have compromised transmissibility.

Lucía Carrau, Veronica V. Rezelj, María G. Noval, Laura I. Levi, Daniela Megrian, Herve Blanc, James Weger-Lucarelli, Gonzalo Moratorio, Kenneth Stapleford, Marco Vignuzzi

DOI: 10.1128/JVI.00775-19

 

ABSTRACT

Chikungunya virus (CHIKV) is a re-emerged arbovirus, member of the Togaviridae family. It circulates through mosquito vectors mainly of the Aedes family and a mammalian host. CHIKV causes chikungunya fever, a mild to severe disease characterized by arthralgia, with some fatal outcomes described. In the past years, several outbreaks mainly caused by enhanced adaptation of the virus to the vector and ineffective control of the contacts between infected mosquito populations and the human host have been reported. Vaccines represent the best solution for the control of insect-borne viruses, including CHIKV, but are often unavailable. We designed live attenuated CHIKV by applying a rational genomic design based on multiple replacements of synonymous codons. In doing so, the virus mutational robustness (capacity to maintain phenotype despite introduction of mutations to genotype) is decreased, driving the viral population towards deleterious evolutionary trajectories. When tested in the insect and mammalian hosts, we observed overall strong attenuation in both and greatly diminished signs of disease. Moreover, we found the vaccine candidates elicited protective immunity, related to the production of neutralizing antibodies after a single dose. During an experimental transmission cycle between mosquitoes and naïve mice, vaccine candidates could be transmitted by mosquito bite leading to asymptomatic infection in mice with compromised dissemination. Using deep sequencing technology we observed an increase in detrimental (stop) codons, which confirmed the effectiveness of this genomic design. Because the approach involves hundreds of synonymous modifications to the genome, the reversion risk is significantly reduced, rendering them promising vaccine candidates.

 

IMPORTANCE

Chikungunya fever is a debilitating disease that causes severe pain to the joints, which can compromise the patient’s lifestyle for several months and even in some grave cases lead to death. The etiological agent is chikungunya virus, an alphavirus transmitted by mosquito bite. Currently there are no approved vaccines or treatments against the disease. In our research, we developed novel live attenuated vaccine candidates against chikungunya virus by applying an innovative genomic design. When tested in the insect and mammalian host, the vaccine candidates did not cause disease, elicited strong protection against further infection and had low risk of reversion to pathogenic phenotypes.

Copyright © 2019 Carrau et al. This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license.

Keywords: Alphavirus; Togavirus; Chikungunya fever; Vaccines.

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