Recombinant Adenoviruses Displaying Matrix 2 Ectodomain Epitopes on Their Fiber Proteins as Universal Influenza Vaccines

Abstract

Influenza is a zoonotic disease that poses severe threats to public health and the global economy. Reemerging influenza pandemics highlight the demand for universal influenza vaccines. We developed a novel virus platform using extracellular domain IV of the matrix 2 protein (M2e), AdC68-F3M2e, by introducing three conserved M2e epitopes into the HI loop of the chimpanzee adenovirus (AdV) fiber protein. The M2e epitopes were expressed sufficiently on the AdV virion surface without affecting fiber trimerization. Additionally, one recombinant adenovirus, AdC68-F3M2e(H1-H5-H7), induced robust M2e-specific antibody responses in BALB/c mice after two sequential vaccinations and conferred efficient protection against homologous and heterologous influenza virus (IV) challenges. We found that the use of AdV with tandem M2e epitopes in fiber is a potential strategy for influenza prevention.IMPORTANCE Influenza epidemics and pandemics severely threaten public health. Universal influenza vaccines have increasingly attracted interest in recent years. Here, we describe a new strategy that incorporates triple M2e epitopes into the fiber protein of chimpanzee adenovirus 68. We optimized the process of inserting foreign genes into the AdC68 structural protein by one-step isothermal assembly and demonstrated that this 225-bp HI loop insertion could be well tolerated. Furthermore, two doses of adjuvant-free fiber-modified AdC68 could confer sufficient protection against homologous and heterologous influenza virus infections in mice. Our results show that AdC68-F3M2e could be pursued as a novel universal influenza vaccine.

Universal Vaccines and Vaccine Platforms to Protect against Influenza Viruses in Humans and Agriculture

“…M2e is present on the virus' surface in low quantities and, thus, it is poorly immunogenic (Wu et al, 2007 ). However, strategies to improve immunogenicity, such as adjuvants, multimeric forms of M2e, co-immunization with other influenza vaccines, or fusion with carrier proteins (Kim et al, 2013 ; Lee et al, 2015 ; Tang et al, 2017 ) stimulate broad cross-reactive immune responses and provide protection against heterologous, hetorosubtypic challenge in mice (Lee et al, 2015 ; Tao et al, 2017 ). Human clinical trial demonstrated the safety and immunogenicityof different M2e vaccine candidates (reviewed in Turley et al, 2011 ; Kolpe et al, 2017 ).…”

Novel viral vectors in infectious diseases

“…Epitopes from a variety of different pathogens have been tested (e.g. HIV‐1, influenza A, Plasmodium falciparum ). One group, for example, demonstrated that a multivalent HIV‐1 vector based on AdHu5 elicited antibody responses to an externally presented HIV‐1 B‐cell epitope, in addition to cellular response to the virally encoded HIV‐1 gag antigen .…”

Immunoinformatic construction of an adenovirus-based modular vaccine platform and its application in the design of a SARS-CoV-2 vaccine

“…Construction of vaccines based on the display of foreign epitopes in the VRs of the HAdV capsid proteins has been demonstrated to be a strategy that has the potential of eliciting a robust and protective immune response against epitopes of a wide variety of pathogens ( Farrow et al, 2014 ; Tang et al, 2017 ; Wu et al, 2015b ). Different HAdV genotypes have been used as prototypes to display foreign epitopes, and genotype HAdV-5 from species C is the most studied in the context of epitope display and anti-HAdV immune responses ( Vujadinovic and Vellinga, 2018 ).…”