Evaluation of candidate vaccine approaches for MERS-CoV

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Abstract

The emergence of Middle East respiratory syndrome coronavirus (MERS-CoV) as a cause of severe respiratory disease highlights the need for effective approaches to CoV vaccine development. Efforts focused solely on the receptor-binding domain (RBD) of the viral Spike (S) glycoprotein may not optimize neutralizing antibody (NAb) responses. Here we show that immunogens based on full-length S DNA and S1 subunit protein elicit robust serum-neutralizing activity against several MERS-CoV strains in mice and non-human primates. Serological analysis and isolation of murine monoclonal antibodies revealed that immunization elicits NAbs to RBD and, non-RBD portions of S1 and S2 subunit. Multiple neutralization mechanisms were demonstrated by solving the atomic structure of a NAb-RBD complex, through sequencing of neutralization escape viruses and by constructing MERS-CoV S variants for serological assays. Immunization of rhesus macaques confers protection against MERS-CoV-induced radiographic pneumonia, as assessed using computerized tomography, supporting this strategy as a promising approach for MERS-CoV vaccine development.

Abstract

Unmet need exists for a vaccine against Middle East respiratory syndrome coronavirus (MERS-CoV). Here the authors report the establishment and evaluation, in mice and primates, of a series of MERS-CoV immunogens and show that they can serve as promising leads for vaccine development.

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Epidemiological, demographic, and clinical characteristics of 47 cases of Middle East respiratory syndrome coronavirus disease from Saudi Arabia: a descriptive study

Abdullah Assiri, Jaffar Al-Tawfiq, Abdullah A Al-Rabeeah … (2013)

Summary Background Middle East respiratory syndrome (MERS) is a new human disease caused by a novel coronavirus (CoV). Clinical data on MERS-CoV infections are scarce. We report epidemiological, demographic, clinical, and laboratory characteristics of 47 cases of MERS-CoV infections, identify knowledge gaps, and define research priorities. Methods We abstracted and analysed epidemiological, demographic, clinical, and laboratory data from confirmed cases of sporadic, household, community, and health-care-associated MERS-CoV infections reported from Saudi Arabia between Sept 1, 2012, and June 15, 2013. Cases were confirmed as having MERS-CoV by real-time RT-PCR. Findings 47 individuals (46 adults, one child) with laboratory-confirmed MERS-CoV disease were identified; 36 (77%) were male (male:female ratio 3·3:1). 28 patients died, a 60% case-fatality rate. The case-fatality rate rose with increasing age. Only two of the 47 cases were previously healthy; most patients (45 [96%]) had underlying comorbid medical disorders, including diabetes (32 [68%]), hypertension (16 [34%]), chronic cardiac disease (13 [28%]), and chronic renal disease (23 [49%]). Common symptoms at presentation were fever (46 [98%]), fever with chills or rigors (41 [87%]), cough (39 [83%]), shortness of breath (34 [72%]), and myalgia (15 [32%]). Gastrointestinal symptoms were also frequent, including diarrhoea (12 [26%]), vomiting (ten [21%]), and abdominal pain (eight [17%]). All patients had abnormal findings on chest radiography, ranging from subtle to extensive unilateral and bilateral abnormalities. Laboratory analyses showed raised concentrations of lactate dehydrogenase (23 [49%]) and aspartate aminotransferase (seven [15%]) and thrombocytopenia (17 [36%]) and lymphopenia (16 [34%]). Interpretation Disease caused by MERS-CoV presents with a wide range of clinical manifestations and is associated with substantial mortality in admitted patients who have medical comorbidities. Major gaps in our knowledge of the epidemiology, community prevalence, and clinical spectrum of infection and disease need urgent definition. Funding None.

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A decade after SARS: strategies for controlling emerging coronaviruses

Rachel Graham, Eric F. Donaldson, Ralph Baric (2013)

Key Points Two highly pathogenic human coronaviruses, severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome coronavirus (MERS-CoV), have emerged in the past decade. The lack of any clinically approved antiviral treatments or vaccines for either virus emphasizes the importance of the design of effective therapeutics and preventives. Bats have been implicated as reservoirs of both SARS-CoV and MERS-CoV as well as related viruses and other human coronaviruses (HCoVs), such as HCoV-229E and HCoV-NL63. The dispersion of bat species over much of the globe probably enhances their potential to act as reservoirs for pathogens, some of which are extremely virulent and potentially lethal to other animals and humans. Multiple animal models for SARS-CoV infection exist, although mouse models have been the most thoroughly characterized. Mouse-adapted SARS-CoV is capable of causing pathology that is representative of human infections in both young and aged animals. Small animal models for MERS-CoV infection have not yet been reported, although the possibility of further ongoing selection in the receptor-binding sequence in the spike protein or other sequences that are important for host specificity might contribute to this limitation. A mild disease phenotype that can include either localized or widespread pneumonia is observed in inoculated macaques. Multiple vaccine strategies have been attempted with coronaviruses, mostly (but not exclusively) targeting the spike glycoprotein. Successful live-attenuated vaccines have utilized reverse genetic strategies to delete the envelope protein or inactivate the exonuclease activity of non-structural protein 14 (nsp14) . MERS-CoV, similarly to SARS-CoV in 2003, has the potential to have a profound impact on the human population; however, its low penetrance thus far suggests that the virus might either ultimately fail to develop a niche in humans or it might still be adapting to human hosts and that the worst of its effects are yet to come. Coronavirus phylogeny shows an incredible diversity in antigenic variants, which leads to limited cross-protection against infection with different strains, even within a phylogenetic subcluster. Consequently, the risk of introducing novel coronaviruses into naive human and animal populations remains high. Supplementary information The online version of this article (doi:10.1038/nrmicro3143) contains supplementary material, which is available to authorized users.

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Refinement of severely incomplete structures with maximum likelihood in BUSTER-TNT.

E Blanc, P Roversi, C Vonrhein … (2004)

BUSTER-TNT is a maximum-likelihood macromolecular refinement package. BUSTER assembles the structural model, scales observed and calculated structure-factor amplitudes and computes the model likelihood, whilst TNT handles the stereochemistry and NCS restraints/constraints and shifts the atomic coordinates, B factors and occupancies. In real space, in addition to the traditional atomic and bulk-solvent models, BUSTER models the parts of the structure for which an atomic model is not yet available ('missing structure') as low-resolution probability distributions for the random positions of the missing atoms. In reciprocal space, the BUSTER structure-factor distribution in the complex plane is a two-dimensional Gaussian centred around the structure factor calculated from the atomic, bulk-solvent and missing-structure models. The errors associated with these three structural components are added to compute the overall spread of the Gaussian. When the atomic model is very incomplete, modelling of the missing structure and the consistency of the BUSTER statistical model help structure building and completion because (i) the accuracy of the overall scale factors is increased, (ii) the bias affecting atomic model refinement is reduced by accounting for some of the scattering from the missing structure, (iii) the addition of a spatial definition to the source of incompleteness improves on traditional Luzzati and sigmaA-based error models and (iv) the program can perform selective density modification in the regions of unbuilt structure alone.

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Author and article information

Journal

Journal ID (nlm-ta): Nat Commun

Journal ID (iso-abbrev): Nat Commun

Title: Nature Communications

Publisher: Nature Pub. Group

ISSN (Electronic): 2041-1723

Publication date (Electronic): 28 July 2015

Publication date Collection: 2015

Volume: 6

Electronic Location Identifier: 7712

Affiliations

[1 ]Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health , Bethesda, Maryland 20892, USA

[2 ]U.S. Military HIV Research Program, Walter Reed Army Institute of Research , Silver Spring, Maryland 20910, USA

[3 ]Henry M. Jackson Foundation for the Advancement of Military Medicine , Bethesda, Maryland 20817, USA

[4 ]Sanofi-Aventis, 270 Albany Street , Cambridge, Massachusetts 02139, USA

[5 ]Department of Pediatrics, Vanderbilt University Medical Center , Nashville, Tennessee 37232, USA

[6 ]Emerging Respiratory Viruses Section, Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health , Bethesda, Maryland 20892, USA

[7 ]Integrated Research Facility, National Institute of Allergy and Infectious Diseases, National Institutes of Health , Frederick, Maryland,21702, USA

[8 ]Center for Infectious Disease Imaging, Department of Radiology and Imaging Sciences, National Institutes of Health , Bethesda, Maryland 20892, USA

[9 ]Center for Research in Computer Vision (CRCV), University of Central Florida , Orlando, Florida 32816, USA

[10 ]Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center , Nashville, Tennessee 37232, USA

Author notes

[a ] wkong@ 123456niaid.nih.gov

[b ] bgraham@ 123456nih.gov

[*]

These authors contributed equally to this work

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Publisher Item ID: ncomms8712

DOI: 10.1038/ncomms8712

PMC ID: 4525294

PubMed ID: 26218507

SO-VID: 04ca2a8e-1bd5-4bb1-a598-3bdc2d32bbcb

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Evaluation of candidate vaccine approaches for MERS-CoV

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Malaria vaccine development

Most cited references 29

Epidemiological, demographic, and clinical characteristics of 47 cases of Middle East respiratory syndrome coronavirus disease from Saudi Arabia: a descriptive study

A decade after SARS: strategies for controlling emerging coronaviruses

Refinement of severely incomplete structures with maximum likelihood in BUSTER-TNT.

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