Evaluation of candidate vaccine approaches for MERS-CoV

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.

A novel neutralizing monoclonal antibody targeting the N-terminal domain of the MERS-CoV spike protein

“…27, 28, 29, 30, 31, 32 The MERS-CoV RBD maps to a 200–300 residue region spanning residues 358–588, 367–588, 367–606, 377–588 and 377–662, which are located in the S1 subunit C-terminal domain. 16, 17, 33, 34, 35, 36, 37, 38, 39, 40 The specific interaction between MERS-CoV RBD and its receptor DPP4 (also known as CD26) has also been revealed at the atomic level by structural analysis.…”

Rapid development of a DNA vaccine for Zika virus

“…Mice were immunized intramuscularly once with 50 μg of DNA in the quadriceps using electroporation as previously described (21). Serum was evaluated for binding to ZIKV SVPs (fig.…”

Middle East respiratory syndrome: current status and future prospects for vaccine development

“…In addition to the DNA-only strategy, DNA-priming and protein-boosting could be an alternative vaccine approach for MERS-CoV. It is revealed that full-length S DNA priming and S1 subunit protein boosting immunization of mice and NHPs induced robust neutralizing antibody responses against several MERS-CoV strains, protecting NHPs from MERS-CoV challenge [27]. …”

“…In the presence of suitable adjuvants, this type of vaccine is generally able to induce higher titers of neutralizing antibody responses than those elicited by other vaccine types, and they can be easily injected via different pathways, including intramuscular injection, an adopted route for human vaccines. Importantly, some of these MERS subunit vaccines are shown to be protective against MERS-CoV infection in challenged mouse and/or NHP models [23,27], demonstrating their ability for further scale-up and/or human clinical trials.…”

“…This should not be a problem for RBD-based vaccines because RBD contains several conformational neutralizing epitopes, and thus mutation(s) in one epitope may not significantly affect the neutralizing activity of antibodies elicited by other epitopes. For example, the RBD-specific mAb F11 could not neutralize the Bisha1 strain of MERS-CoV, whose RBD contains 509 mutation, but susceptible to neutralization of D12, another MERS-CoV RBD-specific mAb [27]. Previous studies have demonstrated that RBD of SARS-CoV Tor2 strain, which contains six different conformational neutralizing epitopes, induces antibodies in the vaccinated animals with neutralizing activity against all SARS-CoV strains tested, including those caused by the early SARS outbreaks (e.g., GD03 strain) and late SARS pandemics (e.g., Urbani strain), as well as the SARS-like CoV strain from civets (SZ strain) [40].…”