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

Anwar M. Hashem, Abdullah Algaissi, Anurodh Shankar Agrawal, Sawsan S. Al-Amri, Rowa Y. Alhabbab, Sayed S. Sohrab, Abdulrahman S. Almasoud, Naif Khalaf Alharbi, Bi Hung Peng, Marsha Russell, Xuguang Li, Chien Te K. Tseng

Research output: Contribution to journalArticle

3 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)1558-1567
Number of pages10
JournalJournal of Infectious Diseases
Volume220
Issue number10
DOIs
StatePublished - Oct 8 2019

Fingerprint

Adenovirus Vaccines
Dipeptidyl Peptidase 4
CD40 Ligand
Adenoviridae
Proteins
Vaccines
Camelus
Lung
Vaccine Potency
Recombinant Fusion Proteins
Safety
Middle East Respiratory Syndrome Coronavirus
Subunit Vaccines
Infection Control
Green Fluorescent Proteins
Neutralizing Antibodies
Viral Load
Immunization
Immunoglobulin G

Keywords

  • adenovirus
  • CD40L
  • immunopathology
  • MERS-CoV
  • vaccine

ASJC Scopus subject areas

  • Immunology and Allergy
  • Infectious Diseases

Cite this

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. / Hashem, Anwar M.; Algaissi, Abdullah; Agrawal, Anurodh Shankar; Al-Amri, Sawsan S.; Alhabbab, Rowa Y.; Sohrab, Sayed S.; Almasoud, Abdulrahman S.; Alharbi, Naif Khalaf; Peng, Bi Hung; Russell, Marsha; Li, Xuguang; Tseng, Chien Te K.

In: Journal of Infectious Diseases, Vol. 220, No. 10, 08.10.2019, p. 1558-1567.

Research output: Contribution to journalArticle

Hashem, Anwar M. ; Algaissi, Abdullah ; Agrawal, Anurodh Shankar ; Al-Amri, Sawsan S. ; Alhabbab, Rowa Y. ; Sohrab, Sayed S. ; Almasoud, Abdulrahman S. ; Alharbi, Naif Khalaf ; Peng, Bi Hung ; Russell, Marsha ; Li, Xuguang ; Tseng, Chien Te K. / 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. In: Journal of Infectious Diseases. 2019 ; Vol. 220, No. 10. pp. 1558-1567.
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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.",
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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 - Almasoud, Abdulrahman S.

AU - Alharbi, Naif Khalaf

AU - Peng, Bi Hung

AU - Russell, Marsha

AU - Li, Xuguang

AU - Tseng, Chien Te K.

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AB - 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.

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