Single-Dose, Intranasal Immunization with Recombinant Parainfluenza Virus 5 Expressing Middle East Respiratory Syndrome Coronavirus (MERS-CoV) Spike Protein Protects Mice from Fatal MERS-CoV Infection

ABSTRACT Middle East respiratory syndrome coronavirus (MERS-CoV) can cause severe and fatal acute respiratory disease in humans and remains endemic in the Middle East since first being identified in 2012. There are currently no approved vaccines or therapies available for MERS-CoV. In this study, we evaluated parainfluenza virus 5 (PIV5)-based vaccine expressing the MERS-CoV envelope spike protein (PIV5/MERS-S) in a human DPP4 knockin C57BL/6 congenic mouse model (hDPP4 KI). Following a single-dose intranasal immunization, PIV5-MERS-S induced neutralizing antibody and robust T cell responses in hDPP4 KI mice. A single intranasal administration of 104 PFU PIV5-MERS-S provided complete protection against a lethal challenge with mouse-adapted MERS-CoV (MERSMA6.1.2) and improved virus clearance in the lung. In comparison, single-dose intramuscular immunization with 106 PFU UV-inactivated MERSMA6.1.2 mixed with Imject alum provided protection to only 25% of immunized mice. Intriguingly, an influx of eosinophils was observed only in the lungs of mice immunized with inactivated MERS-CoV, suggestive of a hypersensitivity-type response. Overall, our study indicated that PIV5-MERS-S is a promising effective vaccine candidate against MERS-CoV infection. IMPORTANCE MERS-CoV causes lethal infection in humans, and there is no vaccine. Our work demonstrates that PIV5 is a promising vector for developing a MERS vaccine. Furthermore, success of PIV5-based MERS vaccine can be employed to develop a vaccine for emerging CoVs such as SARS-CoV-2, which causes COVID-19.

Download Full-text

Superior immune responses induced by intranasal immunization with recombinant adenovirus-based vaccine expressing full-length Spike protein of Middle East respiratory syndrome coronavirus

PLoS ONE ◽

10.1371/journal.pone.0220196 ◽

2019 ◽

Vol 14 (7) ◽

pp. e0220196 ◽

Cited By ~ 19

Author(s):

Myung Hee Kim ◽

Hyun Jik Kim ◽

Jun Chang

Keyword(s):

Middle East ◽

Immune Responses ◽

Recombinant Adenovirus ◽

Middle East Respiratory Syndrome ◽

Full Length ◽

Spike Protein ◽

Intranasal Immunization

Download Full-text

Intranasal immunization with a vaccinia virus vaccine vector expressing pre-fusion stabilized SARS-CoV-2 spike fully protected mice against lethal challenge with the heavily mutated mouse-adapted SARS2-N501YMA30 strain of SARS-CoV-2

10.1101/2021.12.06.471483 ◽

2021 ◽

Author(s):

Karen V Kibler ◽

Mateusz Szczerba ◽

Douglas F. Lake ◽

Alexa J Roeder ◽

Masmudur Rahman ◽

...

Keyword(s):

Vaccinia Virus ◽

Virus Vaccine ◽

Neutralizing Antibodies ◽

Neutralizing Antibody ◽

Vaccine Vector ◽

Spike Protein ◽

Lethal Challenge ◽

Intranasal Immunization ◽

Parenteral Injection ◽

Mild Disease

The Omicron SARS-CoV-2 variant has been designated a variant of concern because its spike protein is heavily mutated. In particular, Omicron spike is mutated at 5 positions (K417, N440, E484, Q493 and N501) that have been associated with escape from neutralizing antibodies induced by either infection with or immunization against the early Washington strain of SARS-CoV-2. The mouse-adapted strain of SARS-CoV-2, SARS2-N501YMA30, contains a spike that is also heavily mutated, with mutations at 4 of the 5 positions in Omicron spike associated with neutralizing antibody escape (K417, E484, Q493 and N501). In this manuscript we show that intranasal immunization with a pre-fusion stabilized Washington strain spike, expressed from a highly attenuated, replication-competent vaccinia virus construct, NYVAC-KC, fully protected mice against disease and death from SARS2-N501YMA30. Similarly, immunization by scarification on the skin fully protected against death, but not from mild disease. This data demonstrates that Washington strain spike, when expressed from a highly attenuated, replication-competent poxvirus, administered without parenteral injection can fully protect against the heavily mutated mouse-adapted SARS2-N501YMA30.

Download Full-text

Single-dose treatment with a humanized neutralizing antibody affords full protection of a human transgenic mouse model from lethal Middle East respiratory syndrome (MERS)-coronavirus infection

Antiviral Research ◽

10.1016/j.antiviral.2016.06.003 ◽

2016 ◽

Vol 132 ◽

pp. 141-148 ◽

Cited By ~ 35

Author(s):

Hongjie Qiu ◽

Shihui Sun ◽

He Xiao ◽

Jiannan Feng ◽

Yan Guo ◽

...

Keyword(s):

Single Dose ◽

Middle East ◽

Mouse Model ◽

Transgenic Mouse ◽

Neutralizing Antibody ◽

Transgenic Mouse Model ◽

Middle East Respiratory Syndrome ◽

Coronavirus Infection ◽

Single Dose Treatment ◽

Full Protection

Download Full-text

Middle East respiratory syndrome coronavirus (MERS-CoV) entry inhibitors targeting spike protein

Virus Research ◽

10.1016/j.virusres.2014.10.007 ◽

2014 ◽

Vol 194 ◽

pp. 200-210 ◽

Cited By ~ 49

Author(s):

Shuai Xia ◽

Qi Liu ◽

Qian Wang ◽

Zhiwu Sun ◽

Shan Su ◽

...

Keyword(s):

Middle East ◽

Middle East Respiratory Syndrome ◽

Spike Protein ◽

Entry Inhibitors

Download Full-text

Peptide-Protein Interaction Studies of Antimicrobial Peptides Targeting Middle East Respiratory Syndrome Coronavirus Spike Protein: An In Silico Approach

Advances in Bioinformatics ◽

10.1155/2019/6815105 ◽

2019 ◽

Vol 2019 ◽

pp. 1-16 ◽

Cited By ~ 5

Author(s):

Sabeena Mustafa ◽

Hanan Balkhy ◽

Musa Gabere

Keyword(s):

Middle East ◽

Antimicrobial Peptides ◽

Protein Interactions ◽

In Silico ◽

Therapeutic Option ◽

Binding Mode ◽

Middle East Respiratory Syndrome ◽

Spike Protein ◽

In Silico Docking ◽

Peptide Database

There is no effective therapeutic or vaccine for Middle East Respiratory Syndrome and this study attempts to find therapy using peptide by establishing a basis for the peptide-protein interactions through in silico docking studies for the spike protein of MERS-CoV. The antimicrobial peptides (AMPs) were retrieved from the antimicrobial peptide database (APD3) and shortlisted based on certain important physicochemical properties. The binding mode of the shortlisted peptides was measured based on the number of clusters which forms in a protein-peptide docking using Piper. As a result, we identified a list of putative AMPs which binds to the spike protein of MERS-CoV, which may be crucial in providing the inhibitory action. It is observed that seven putative peptides have good binding score based on cluster size cutoff of 208. We conclude that seven peptides, namely, AP00225, AP00180, AP00549, AP00744, AP00729, AP00764, and AP00223, could possibly have binding with the active site of the MERS-CoV spike protein. These seven AMPs could serve as a therapeutic option for MERS and enhance its treatment outcome.

Download Full-text

Blocking transmission of Middle East respiratory syndrome coronavirus (MERS-CoV) in llamas by vaccination with a recombinant spike protein

Emerging Microbes & Infections ◽

10.1080/22221751.2019.1685912 ◽

2019 ◽

Vol 8 (1) ◽

pp. 1593-1603 ◽

Cited By ~ 7

Author(s):

Jordi Rodon ◽

Nisreen M. A. Okba ◽

Nigeer Te ◽

Brenda van Dieren ◽

Berend-Jan Bosch ◽

...

Keyword(s):

Middle East ◽

Middle East Respiratory Syndrome ◽

Spike Protein

Download Full-text

Conjugation of Human β-Defensin 2 to Spike Protein Receptor-Binding Domain Induces Antigen-Specific Protective Immunity against Middle East Respiratory Syndrome Coronavirus Infection in Human Dipeptidyl Peptidase 4 Transgenic Mice

Vaccines ◽

10.3390/vaccines8040635 ◽

2020 ◽

Vol 8 (4) ◽

pp. 635

Author(s):

Ju Kim ◽

Ye Lin Yang ◽

Yongsu Jeong ◽

Yong-Suk Jang

Keyword(s):

Middle East ◽

Immune Responses ◽

Receptor Binding ◽

Dipeptidyl Peptidase ◽

Binding Domain ◽

Middle East Respiratory Syndrome ◽

Spike Protein ◽

Receptor Binding Domain ◽

Dipeptidyl Peptidase 4 ◽

Protein Receptor

Middle East respiratory syndrome coronavirus (MERS-CoV) causes severe acute respiratory symptoms. Due to the lack of medical countermeasures, effective and safe vaccines against MERS-CoV infection are urgently required. Although different types of candidate vaccines have been developed, their immunogenicity is limited, and the dose and administration route need optimization to achieve optimal protection. We here investigated the potential use of human β-defensin 2 (HBD 2) as an adjuvant to enhance the protection provided by MERS-CoV vaccination. We found that immunization of human dipeptidyl peptidase 4 (hDPP4)-transgenic (hDPP4-Tg) mice with spike protein receptor-binding domain (S RBD) conjugated with HBD 2 (S RBD-HBD 2) induced potent antigen (Ag)-specific adaptive immune responses and protected against MERS-CoV infection. In addition, immunization with S RBD-HBD 2 alleviated progressive pulmonary fibrosis in the lungs of MERS-CoV-infected hDPP4-Tg mice and suppressed endoplasmic reticulum stress signaling activation upon viral infection. Compared to intramuscular administration, intranasal administration of S RBD-HBD 2 induced more potent mucosal IgA responses and was more effective for protecting against intranasal MERS-CoV infection. In conclusion, our findings suggest that HBD 2 potentiates Ag-specific immune responses against viral Ag and can be used as an adjuvant enhancing the immunogenicity of subunit vaccine candidates against MERS-CoV.

Download Full-text