Searching for an ideal vaccine candidate among different MERS coronavirus receptor-binding fragments-The importance of immunofocusing in subunit vaccine design

Cuiqing Ma, Lili Wang, Xinrong Tao, Naru Zhang, Yang Yang, Chien-Te Tseng, Fang Li, Yusen Zhou, Shibo Jiang, Lanying Du

Research output: Contribution to journalArticle

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Abstract

The newly emerged Middle East respiratory syndrome coronavirus (MERS-CoV) is currently spreading among humans, making development of effective MERS vaccines a high priority. A defined receptor-binding domain (RBD) in MERS-CoV spike protein can potentially serve as a subunit vaccine candidate against MERS-CoV infections. To identify an ideal vaccine candidate, we have constructed five different versions of RBD fragments, S350-588-Fc, S358-588-Fc, S367-588-Fc, S367-606-Fc, and S377-588-Fc (their names indicate their residue range in the spike protein and their C-terminal Fc tag), and further investigated their receptor binding affinity, antigenicity, immunogenicity, and neutralizing potential. The results showed that S377-588-Fc is among the RBD fragments that demonstrated the highest DPP4-binding affinity and induced the highest-titer IgG antibodies in mice. In addition, S377-588-Fc elicited higher-titer neutralizing antibodies than all the other RBD fragments in mice, and also induced high-titer neutralizing antibodies in immunized rabbits. Structural analysis suggests that S377-588-Fc contains the stably folded RBD structure, the full receptor-binding site, and major neutralizing epitopes, such that additional structures to this fragment introduce non-neutralizing epitopes and may also alter the tertiary structure of the RBD. Taken together, our data suggest that the RBD fragment encompassing spike residues 377-588 is a critical neutralizing receptor-binding fragment and an ideal candidate for development of effective MERS vaccines, and that adding non-neutralizing structures to this RBD fragment diminishes its neutralizing potential. Therefore, in viral vaccine design, it is important to identify the most stable and neutralizing viral RBD fragment, while eliminating unnecessary and non-neutralizing structures, as a means of "immunofocusing".

Original languageEnglish (US)
Pages (from-to)6170-6176
Number of pages7
JournalVaccine
Volume32
Issue number46
DOIs
StatePublished - Oct 21 2014

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Subunit Vaccines
Coronavirinae
subunit vaccines
Vaccines
vaccines
Neutralizing Antibodies
receptors
Epitopes
Coronavirus Spike Glycoproteins
Coronavirus Infections
Viral Vaccines
neutralization
Human Development
Protein C
Names
Immunoglobulin G
Binding Sites
Rabbits
Antibodies
neutralizing antibodies

Keywords

  • Critical neutralizing domain
  • Immunofocusing
  • MERS
  • MERS-CoV
  • Receptor-binding domain
  • Spike protein

ASJC Scopus subject areas

  • Immunology and Microbiology(all)
  • Infectious Diseases
  • Public Health, Environmental and Occupational Health
  • veterinary(all)
  • Molecular Medicine
  • Medicine(all)

Cite this

Searching for an ideal vaccine candidate among different MERS coronavirus receptor-binding fragments-The importance of immunofocusing in subunit vaccine design. / Ma, Cuiqing; Wang, Lili; Tao, Xinrong; Zhang, Naru; Yang, Yang; Tseng, Chien-Te; Li, Fang; Zhou, Yusen; Jiang, Shibo; Du, Lanying.

In: Vaccine, Vol. 32, No. 46, 21.10.2014, p. 6170-6176.

Research output: Contribution to journalArticle

Ma, Cuiqing ; Wang, Lili ; Tao, Xinrong ; Zhang, Naru ; Yang, Yang ; Tseng, Chien-Te ; Li, Fang ; Zhou, Yusen ; Jiang, Shibo ; Du, Lanying. / Searching for an ideal vaccine candidate among different MERS coronavirus receptor-binding fragments-The importance of immunofocusing in subunit vaccine design. In: Vaccine. 2014 ; Vol. 32, No. 46. pp. 6170-6176.
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