新型PLGA胜肽疫苗提供有效對抗A型流感病毒感染之T細胞免疫力

Abstract

流感病毒造成之區域性與全球性大流行至今仍為重要的公衛議題，因此廣效型流感疫苗的發展極具必要性。源自流感病毒蛋白中高度保留區域的抗原性胜肽能夠誘發可對抗多種流感病毒亞型的T細胞免疫反應，而PLGA奈米顆粒因其安全性與致免疫性，可做為理想的疫苗攜帶物質。綜合上述，我們設計了一種由PLGA奈米顆粒同時包裹佐劑CpG與胜肽的新型疫苗，並證明此疫苗相較於沒有包裹之胜肽疫苗能達到更好的專一性T細胞免疫反應，並降低全身性副作用。我們也探討了疫苗接種成效之決定因子，包含佐劑的使用以及周邊初打-局部加打 (peripheral priming – local boosting)策略的必要性。本研究指出，以周邊初打-局部加打的策略接種同時包裹佐劑與胜肽之PLGA奈米疫苗，能建立較多的循環型記憶性T細胞以及適量的肺常駐型記憶性T細胞，而更有效地對抗流感病毒感染。進一步探討該疫苗之作用機制，結果顯示PLGA奈米顆粒能被肺部中的肺泡巨噬細胞與樹突細胞內吞。總結本篇研究，一種新型的PLGA胜肽疫苗能於疫苗接種後被抗原呈現細胞吞噬，使其於作用階段與記憶階段建立有效的專一性T細胞免疫反應，因而能於宿主受到呼吸道病毒感染時達到較佳的保護效果。

Influenza epidemics and pandemics remain a major health problem nowadays, necessitating the development of universal influenza vaccines. Antigenic peptides derived from the conserved regions of viral proteins are candidates for eliciting T cell responses against a broad spectrum of influenza viruses. PLGA nanoparticles have been shown to be an ideal vaccine carrier for their safety and immunogenicity. Here, we demonstrated that a novel P(O+C) vaccine, a peptide-based vaccine co-encapsulated with the adjuvant CpG by the PLGA nanoparticle, achieved enhanced specific T cell immunity and minimal systemic adverse effects as compared with soluble peptide vaccines. Several determining factors regarding the vaccination were also investigated, including the presence of adjuvants, and the necessity of “peripheral priming – local boosting” strategy. We showed that the P(O+C) vaccine with the peripheral priming and local boosting strategy was able to establish a higher number of circulating memory T cells and intermediate amount of lung resident memory T cells, and conferred more potent antiviral activity against influenza virus infection. Looking into the mechanisms of such immunopotency, we revealed that the novel PLGA vaccine is uptaken by alveolar macrophages and dendritic cells in the lung. In conclusion, our novel P(O+C) vaccine can be internalized by antigen-presenting cells to elicit robust antigen-specific T cell immunity in both the effector and the memory phase after the immunization, thereby allowing a superior protection upon respiratory virus infections.