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A Highly Immunogenic, Protective, and Safe Adenovirus-Based Vaccine Expressing Middle East Respiratory Syndrome Coronavirus S1-CD40L Fusion Protein in a Transgenic Human Dipeptidyl Peptidase 4 Mouse Model.
J Infect Dis. 2019 10 08; 220(10):1558-1567.JI

Abstract

BACKGROUND

Infection control measures have played a major role in limiting human/camel-to-human transmission of Middle East respiratory syndrome coronavirus (MERS-CoV); however, development of effective and safe human or camel vaccines is warranted.

METHODS

We extended and optimized our previous recombinant adenovirus 5 (rAd5)-based vaccine platform characterized by in vivo amplified and CD40-mediated specific responses to generate MERS-CoV S1 subunit-based vaccine. We generated rAd5 constructs expressing CD40-targeted S1 fusion protein (rAd5-S1/F/CD40L), untargeted S1 (rAd5-S1), and Green Fluorescent Protein (rAd5-GFP), and evaluated their efficacy and safety in human dipeptidyl peptidase 4 transgenic (hDPP4 Tg+) mice.

RESULTS

Immunization of hDPP4 Tg+ mice with a single dose of rAd5-S1/F/CD40L elicited as robust and significant specific immunoglobulin G and neutralizing antibodies as those induced with 2 doses of rAd5-S1. After MERS-CoV challenge, both vaccines conferred complete protection against morbidity and mortality, as evidenced by significantly undetectable/reduced pulmonary viral loads compared to the control group. However, rAd5-S1- but not rAd5-S1/F/CD40L-immunized mice exhibited marked pulmonary perivascular hemorrhage post-MERS-CoV challenge despite the observed protection.

CONCLUSIONS

Incorporation of CD40L into rAd5-based MERS-CoV S1 vaccine targeting molecule and molecular adjuvants not only enhances immunogenicity and efficacy but also prevents inadvertent pulmonary pathology after viral challenge, thereby offering a promising strategy to enhance safety and potency of vaccines.

Authors+Show Affiliations

Department of Medical Microbiology and Parasitology, Faculty of Medicine. Vaccines and Immunotherapy Unit, King Fahd Medical Research Center, Saudi Arabia. Special Infectious Agents Unit, King Fahd Medical Research Center, King Abdulaziz University, Jeddah, Saudi Arabia.Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston. Department of Medical Laboratories Technology, College of Applied Medical Sciences, Jazan University.Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston.Vaccines and Immunotherapy Unit, King Fahd Medical Research Center, Saudi Arabia. Special Infectious Agents Unit, King Fahd Medical Research Center, King Abdulaziz University, Jeddah, Saudi Arabia.Vaccines and Immunotherapy Unit, King Fahd Medical Research Center, Saudi Arabia. Special Infectious Agents Unit, King Fahd Medical Research Center, King Abdulaziz University, Jeddah, Saudi Arabia. Department of Medical Laboratory Technology, Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah.Special Infectious Agents Unit, King Fahd Medical Research Center, King Abdulaziz University, Jeddah, Saudi Arabia.Department of Infectious Disease Research, King Abdullah International Medical Research Center, Riyadh, Saudi Arabia.Department of Infectious Disease Research, King Abdullah International Medical Research Center, Riyadh, Saudi Arabia.Department of Neurosciences, Cell Biology, and Anatomy, University of Texas Medical Branch, Galveston.Center for Vaccine Evaluation, Biologics and Genetic Therapies Directorate, Health Canada, Ottawa, Ontario.Center for Vaccine Evaluation, Biologics and Genetic Therapies Directorate, Health Canada, Ottawa, Ontario.Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston. Center of Biodefense and Emerging Disease, University of Texas Medical Branch, Galveston.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

30911758

Citation

Hashem, Anwar M., et al. "A Highly Immunogenic, Protective, and Safe Adenovirus-Based Vaccine Expressing Middle East Respiratory Syndrome Coronavirus S1-CD40L Fusion Protein in a Transgenic Human Dipeptidyl Peptidase 4 Mouse Model." The Journal of Infectious Diseases, vol. 220, no. 10, 2019, pp. 1558-1567.
Hashem AM, Algaissi A, Agrawal AS, et al. A Highly Immunogenic, Protective, and Safe Adenovirus-Based Vaccine Expressing Middle East Respiratory Syndrome Coronavirus S1-CD40L Fusion Protein in a Transgenic Human Dipeptidyl Peptidase 4 Mouse Model. J Infect Dis. 2019;220(10):1558-1567.
Hashem, A. M., Algaissi, A., Agrawal, A. S., Al-Amri, S. S., Alhabbab, R. Y., Sohrab, S. S., S Almasoud, A., Alharbi, N. K., Peng, B. H., Russell, M., Li, X., & Tseng, C. K. (2019). A Highly Immunogenic, Protective, and Safe Adenovirus-Based Vaccine Expressing Middle East Respiratory Syndrome Coronavirus S1-CD40L Fusion Protein in a Transgenic Human Dipeptidyl Peptidase 4 Mouse Model. The Journal of Infectious Diseases, 220(10), 1558-1567. https://doi.org/10.1093/infdis/jiz137
Hashem AM, et al. A Highly Immunogenic, Protective, and Safe Adenovirus-Based Vaccine Expressing Middle East Respiratory Syndrome Coronavirus S1-CD40L Fusion Protein in a Transgenic Human Dipeptidyl Peptidase 4 Mouse Model. J Infect Dis. 2019 10 8;220(10):1558-1567. PubMed PMID: 30911758.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - A Highly Immunogenic, Protective, and Safe Adenovirus-Based Vaccine Expressing Middle East Respiratory Syndrome Coronavirus S1-CD40L Fusion Protein in a Transgenic Human Dipeptidyl Peptidase 4 Mouse Model. AU - Hashem,Anwar M, AU - Algaissi,Abdullah, AU - Agrawal,Anurodh Shankar, AU - Al-Amri,Sawsan S, AU - Alhabbab,Rowa Y, AU - Sohrab,Sayed S, AU - S Almasoud,Abdulrahman, AU - Alharbi,Naif Khalaf, AU - Peng,Bi-Hung, AU - Russell,Marsha, AU - Li,Xuguang, AU - Tseng,Chien-Te K, PY - 2019/01/08/received PY - 2019/03/21/accepted PY - 2019/3/27/pubmed PY - 2020/5/21/medline PY - 2019/3/27/entrez KW - CD40L KW - MERS-CoV KW - adenovirus KW - immunopathology KW - vaccine SP - 1558 EP - 1567 JF - The Journal of infectious diseases JO - J Infect Dis VL - 220 IS - 10 N2 - BACKGROUND: Infection control measures have played a major role in limiting human/camel-to-human transmission of Middle East respiratory syndrome coronavirus (MERS-CoV); however, development of effective and safe human or camel vaccines is warranted. METHODS: We extended and optimized our previous recombinant adenovirus 5 (rAd5)-based vaccine platform characterized by in vivo amplified and CD40-mediated specific responses to generate MERS-CoV S1 subunit-based vaccine. We generated rAd5 constructs expressing CD40-targeted S1 fusion protein (rAd5-S1/F/CD40L), untargeted S1 (rAd5-S1), and Green Fluorescent Protein (rAd5-GFP), and evaluated their efficacy and safety in human dipeptidyl peptidase 4 transgenic (hDPP4 Tg+) mice. RESULTS: Immunization of hDPP4 Tg+ mice with a single dose of rAd5-S1/F/CD40L elicited as robust and significant specific immunoglobulin G and neutralizing antibodies as those induced with 2 doses of rAd5-S1. After MERS-CoV challenge, both vaccines conferred complete protection against morbidity and mortality, as evidenced by significantly undetectable/reduced pulmonary viral loads compared to the control group. However, rAd5-S1- but not rAd5-S1/F/CD40L-immunized mice exhibited marked pulmonary perivascular hemorrhage post-MERS-CoV challenge despite the observed protection. CONCLUSIONS: Incorporation of CD40L into rAd5-based MERS-CoV S1 vaccine targeting molecule and molecular adjuvants not only enhances immunogenicity and efficacy but also prevents inadvertent pulmonary pathology after viral challenge, thereby offering a promising strategy to enhance safety and potency of vaccines. SN - 1537-6613 UR - https://www.unboundmedicine.com/medline/citation/30911758/A_Highly_Immunogenic_Protective_and_Safe_Adenovirus_Based_Vaccine_Expressing_Middle_East_Respiratory_Syndrome_Coronavirus_S1_CD40L_Fusion_Protein_in_a_Transgenic_Human_Dipeptidyl_Peptidase_4_Mouse_Model_ L2 - https://academic.oup.com/jid/article-lookup/doi/10.1093/infdis/jiz137 DB - PRIME DP - Unbound Medicine ER -