从H1N1血凝素序列中提取的沙门氏菌递送的COBRA-HA1抗原对甲型流感亚型产生广谱保护作用

Ram Prasad Aganja, Amal Senevirathne, Chandran Sivasankar, John Hwa Lee

工程（英文） ›› 2024, Vol. 32 ›› Issue (1) : 41-56.

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工程（英文） ›› 2024, Vol. 32 ›› Issue (1) : 41-56. DOI: 10.1016/j.eng.2023.08.001
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从H1N1血凝素序列中提取的沙门氏菌递送的COBRA-HA1抗原对甲型流感亚型产生广谱保护作用

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Salmonella-Delivered COBRA-HA1 Antigen Derived from H1N1 Hemagglutinin Sequences Elicits Broad-Spectrum Protection Against Influenza A Subtypes

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Abstract

A universal vaccine is in high demand to address the uncertainties of antigenic drift and the reduced effectiveness of current influenza vaccines. In this study, a strategy called computationally optimized broadly reactive antigen (COBRA) was used to generate a consensus sequence of the hemagglutinin globular head portion (HA1) of influenza virus samples collected from 1918 to 2021 to trace evolutionary changes and incorporate them into the designed constructs. Constructs carrying different HA1 regions were delivered into eukaryotic cells by Salmonella -mediated bactofection using a Semliki Forest virus RNA-dependent RNA polymerase (RdRp)-based eukaryotic expression system, pJHL204. Recombinant protein expression was confirmed by Western blot and immunofluorescence assays. Mice immunized with the designed constructs produced a humoral response, with a significant increase in immunoglobulin G (IgG) levels, and a cell-mediated immune response, including a 1.5-fold increase in CD4 + and CD8 + T cells. Specifically, constructs #1 and #5 increased the production of interferon-γ (IFN-γ) producing CD4 + and CD8+ T cells, skewing the response toward the T helper type 1 cell (Th1) pathway. Additionally, interleukin-4 (IL-4)-producing T cells were upregulated 4-fold. Protective efficacy was demonstrated, with up to 4-fold higher production of neutralizing antibodies and a hemagglutination inhibition titer > 40 against the selected viral strains. The designed constructs conferred a broadly protective immune response, resulting in a notable reduction in viral titer and minimal inflammation in the lungs of mice challenged with the influenza A/PR8/34, A/Brisbane/59/2007, A/California/07/2009, KBPV VR-92, and NCCP 43021 strains. This discovery revolutionizes influenza vaccine design and delivery; Salmonella-mediated COBRA-HA1 is a highly effective in vivo antigen presentation strategy. This approach can effectively combat seasonal H1N1 influenza strains and potential pandemic outbreaks.

Keywords

COBRA / Influenza A / Salmonella / Vaccine / Broad spectral protection

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Ram Prasad Aganja, Amal Senevirathne, Chandran Sivasankar. 从H1N1血凝素序列提取的沙门氏菌传递的COBRA-HA1抗原对甲型流感亚型产生广谱保护作用. Engineering. 2024, 32(1): 41-56 https://doi.org/10.1016/j.eng.2023.08.001

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