Development and characterization of a novel DC-targeting universal influenza vaccine
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Date
2024-03-07
Authors
Olukitibi, Titus
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Abstract
The highly contagious pandemic potential influenza virus causes around 650,000 annual deaths despite available vaccines. Developing a universal influenza vaccine is crucial for effective disease control. Leveraging Ebola glycoprotein's immunogenicity by targeting dendritic cells (DC) to enhance immune responses is advantageous. Likewise, conserved antigens like influenza HA stalk and M2e hold promise for a universal influenza vaccine but suffer from low immunogenicity, necessitating enhancement.
To improve the immunogenicity of the influenza HA stalk and M2e, the DC-targeting domain of EboGP (EΔM) was fused with the influenza hemagglutinin stalk conserved epitopes (HAcs) from H1, H3, H5 and H7 (HAcs) and ectodomain matrix protein (M2e) derived from human origin to generate E∆M-HM2e. The EΔM was also fused with four copies of M2e (2 from humans, one from swine and one from avian) to generate E∆M-tM2e. Hypothetically, the E∆M would efficiently deliver the influenza HAcs, M2e or both to DCs and induce more robust immune responses against influenza virus strains.
The first observations demonstrated that both E∆M-HM2e and E∆M-tM2e could efficiently target and enter the monocyte-derived DCs/macrophages. Secondly, in the investigation of their in vivo immunogenicity, HIV-1 Virus-like particle (VLP)- and recombinant vesicular stomatitis virus (rVSV)-E∆M-HM2e and E∆M-tM2e elicited robust and broad humoral and cell-mediated immune responses in the serum of the immunized mice with the evidence of antibody-dependent cellular cytotoxicity. Thirdly, the rVSV-E∆M-HM2e and E∆M- immunized mice challenged with mouse-adapted A/PR8/1934 (H1N1) or mouse-adapted A/Hong Kong/1/68 (H3N2) intranasally were fully protected except for rVSV-E∆M-HM2e, which gave 25% protection against a higher dose of H1N1. Fourthly, the UV-inactivated rVSV-E∆M-tM2e immunization yielded comparable immune responses with the live-attenuated rVSV-E∆M-tM2e and protected against the H1N1 lethal challenge. Finally, when the rVSV-E∆M-tM2e is combined with a Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV)-2 spike in a bivalent vaccine, it maintains its ability to provide robust immunogenicity and protection against lethal H1N1 or H3N2 infection even in a single dose.
In conclusion, this thesis strongly supports the development of a novel DC-targeted universal influenza vaccine, showcasing the effectiveness of E∆M-tM2e across diverse platforms and conditions. This vaccine holds potential for broad influenza virus protection and pandemic preparedness.
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Keywords
DC-targeting, Hemaglutinin (HA) stalk, Ebola glycoprotein, Matrix 2 Protein ectodomain (M2e), Universal influenza vaccine, Bivalent vaccine, UV-inactivated vaccine