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Design, Synthesis and Primary Immunologic Evaluation of M2e-CRM197 Conjugate as a Universal Influenza Vaccine Candidate

[ Vol. 22 , Issue. 14 ]

Author(s):

Lu Xu, Chun Zhang, Jing Zhang, Rong Yu* and Zhiguo Su   Pages 1910 - 1918 ( 9 )

Abstract:


Background: Influenza is a contagious respiratory illness caused by an acute infection of influenza viruses, among which influenza A virus causes seasonal epidemic infections nearly every year. Due to the unpredictability of the evolving influenza A virus and time-consuming vaccine development cycles, novel universal influenza vaccines designed to induce broadly cross-reactive immune responses against frequently mutant influenza A virus strains are urgently required.

Objective: The aim of this study was to synthesize a novel vaccine through the dual-site specific conjugation of the constant epitope of 23 amino acids (M2e) of the influenza A virus with a highly immunogenic carrier protein of Cross-Reacting Material (CRM197) under denaturation and to evaluate its primary immunogenicity in mice.

Methods: The antigen (M2e) and the carrier protein (CRM197) were linked with different types of hetero-functionalized linkers, α-Maleimide-ε-Hydrazide Polyethylene Glycol 2k (MAL-PEG-HZ) and N-β-Maleimidopropionic Acid Hydrazide (BMPH) separately. The immunogenicity of the M2e-CRM197 conjugates with different types of linkers was evaluated in mice, and the M2especific total IgG and IgG-isotypes were determined by ELISA.

Results: Immunogenicity studies revealed that anti-M2e antibody could be induced by the conjugate products, M2e-PEG-CRM197 and M2e-BMPH-CRM197, by approximately 30 and 90-fold higher than that of the M2e group. In addition, the anti-M2e antibody level induced by M2e-PEG-CRM197 conjugate was three times higher than that of M2e-BMPH-CRM197 conjugate, and the former could simultaneously activate both cellular and humoral immune responses.

Conclusion: The M2e-CRM197 conjugated vaccines we synthesized in this study are highly immunogenic compared with M2e alone. Besides, evidence presented here indicated that the hydrophilic, non-immunogenic and biocompatible chain of the cross-linker might be a better choice for the development of a conjugate vaccine.

Keywords:

Influenza, conjugate vaccine, ectodomain of matrix protein 2 (M2e), Cross-Reacting Material (CRM197), polyethylene glycol, anti-M2e antibody.

Affiliation:

Key Laboratory of Drug Targeting and Drug Delivery System, Ministry of Education, West China School of Pharmacy, Sichuan University, Chengdu, Key Laboratory of Drug Targeting and Drug Delivery System, Ministry of Education, West China School of Pharmacy, Sichuan University, Chengdu, State Key Laboratory of Biochemical Engineering, Institute of Process Engineering, Chinese Academy of Sciences, Beijing, Key Laboratory of Drug Targeting and Drug Delivery System, Ministry of Education, West China School of Pharmacy, Sichuan University, Chengdu, State Key Laboratory of Biochemical Engineering, Institute of Process Engineering, Chinese Academy of Sciences, Beijing



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