Abstract
Abstract Middle East respiratory syndrome coronavirus (MERS-CoV) is a highly pathogenic respiratory virus that emerged in 2012. While infection control measures have played a major role in limiting human/camel-to-human transmissions, development of safe and effective human or camel vaccines is warranted. Here, we extended and optimized our previous 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 GFP (rAd5-GFP), and evaluated their efficacy and safety in human DPP4 transgenic (hDPP4 Tg+) mice. Immunization of hDPP4 Tg+ mice showed that a single dose of rAd5-S1/F/CD40L elicited robust and significant specific IgG and neutralizing antibody responses as those induced in mice immunized with two-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 as compared to 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. Collectively, these data indicate that incorporating CD40L into this Ad5-based MERS-CoV S1 subunit vaccine as targeting molecule and molecular adjuvant can not only enhance immunogenicity and efficacy but also prevents induction of inadvertent pulmonary pathology in immunized and challenged mice, thereby offering a promising strategy to enhance the safety and potency of antigen-specific immune responses.