Liệu vắc-xin mRNA có thể tạo ra miễn dịch bảo vệ lâu dài chống lại nhiễm ký sinh trùng?
Cần nhấn mạnh rằng các nghiên cứu về vắc-xin mRNA trên cả thử nghiệm lâm sàng ở người và mô hình động vật đã chứng minh rằng các vắc-xin này có khả năng khởi phát đáp ứng miễn dịch mạnh mẽ, bền vững và sự bảo vệ lâu dài có thể được duy trì nhờ trí nhớ miễn dịch (10, 137).
Một yếu tố then chốt trong phát triển vắc-xin chống ký sinh trùng là đạt được miễn dịch bảo vệ lâu dài thông qua việc tạo ra các tế bào nhớ B và T có thời gian tồn tại lâu dài, có khả năng mang lại hiệu quả vượt trội so với đáp ứng điều hòa thường thấy trong nhiễm tự nhiên (28).Nhiễm giun sán tự nhiên có thể vừa tạo ra đáp ứng bảo vệ, vừa gây đáp ứng điều hòa, mà đáp ứng này lại có khả năng ức chế hiệu quả vắc-xin khác (bystander vaccination) (212). Đáp ứng điều hòa thường đặc trưng bởi sự tiết ra cytokine ức chế (TGF-β, IL-10) từ tế bào T điều hòa (Treg) (213), góp phần làm giảm khả năng kháng tái nhiễm (ví dụ trong sán máng) trên mô hình động vật (214). Ngược lại, một đáp ứng miễn dịch cân bằng giữa các phân nhóm T CD4+ giúp đỡ (Th1, Th2, Th17), với các cytokine chủ chốt như IFN-γ, IL-4 và IL-21, đã được chứng minh có vai trò trong bảo vệ chống tái nhiễm giun sán (215). Vắc-xin mRNA có ưu thế ở chỗ vừa thúc đẩy miễn dịch dịch thể (khởi phát interferon type I, đáp ứng lệch Th1), vừa kích thích miễn dịch tế bào, đặc biệt là hoạt hóa T CD4+ hỗ trợ quá trình biệt hóa tế bào B và hình thành trí nhớ miễn dịch (9, 142, 216). Những đặc điểm này cho thấy mRNA là nền tảng phù hợp để phát triển vắc-xin chống nhiễm giun sán.
Một điểm quan trọng khác là khả năng duy trì miễn dịch bảo vệ của vắc-xin ngay cả khi nồng độ kháng thể giảm xuống hoặc biến mất (do kháng thể chỉ có thời gian bán hủy khoảng 30 ngày). Cơ chế giữ kháng nguyên lâu dài nhờ tế bào tua nang (follicular DCs) tại hạch lympho ngoại vi đã được chứng minh là rất quan trọng để duy trì miễn dịch do vắc-xin mRNA tạo ra (135, 136), cũng như trong các chiến lược miễn dịch–điều trị (I&T) chống sốt rét (61) và sán máng (29).
Tương tự như tranh luận gần đây về hiệu quả của vắc-xin mRNA SARS-CoV-2 so với miễn dịch tự nhiên (217), người ta cho rằng việc tái phơi nhiễm thường xuyên với KSTtại vùng lưu hành sau tiêm chủng có thể giúp duy trì lâu dài miễn dịch do vắc-xin tạo ra. Thêm vào đó, một nghiên cứu gần đây cho thấy đáp ứng miễn dịch của vật chủ đối với vắc-xin chống sán máng có thể được tăng cường nhờ điều trị lặp lại bằng thuốc praziquantel, một loại thuốc hiện vẫn được dùng rộng rãi trong kiểm soát cộng đồng. Bằng cách tiêu diệt giun, phá hủy lớp vỏsán và giải phóng các phân tử KST vào cơ thể, praziquantel cung cấp thêm một nguồn kháng nguyên tự nhiên, giúp kích thích mạnh mẽ đáp ứng miễn dịch (218). Tất cả những đặc điểm này nhấn mạnh rằng vắc-xinmRNA có tiềm năng lớn trong việc tạo ra đáp ứng miễn dịch bảo vệ lâu dài chống lại nhiễm ký sinh trùng.
Phát triển vắc-xin mRNA đa giá chống giun sán: Đã đến lúc tái khởi động
Hiện nay có nhiều bằng chứng thuyết phục rằng việc phát triển các vắc-xin cho phòng chống giun đa giá là cần thiết và hiệu quả nếu mục tiêu kiểm soát hoặc loại trừ nhiễm giun sán ký sinh muốn đạt được (14). Hơn nữa, hướng đi này có thể tiến xa hơn khi các nhà nghiên cứu đề xuất phát triển vắc-xin pan-anthelmintic đơn liều, có thể sử dụng chống lại nhiều loài KST cùng một vật chủ, nhằm khởi phát đáp ứng miễn dịch mạnh và bền vững với tác dụng phụ tối thiểu (14).
Việc phát triển vắc-xin pan-anthelmintic dựa trên nhiều kháng nguyên có tính bảo vệ chéo có thể cung cấp một giải pháp mới thay thế cho vắc-xin toàn kháng nguyên. Cách tiếp cận này càng cấp thiết hơn khi nhiễm đồng thời nhiều loài giun sán là tình trạng phổ biến ở những cộng đồng thiệt thòi tại nhiều quốc gia đang phát triển (219).
Nền tảng mRNA có khả năng nhắm tới nhiều mục tiêu kháng nguyên khác nhau (220) và các hiệu ứng hiệp đồng in vivo khi phối hợp nhiều mRNA có thể làm tăng đáng kể miễn dịch bảo vệ (147). Vì vậy, việc phát triển vắc-xin mRNA đa giá chống giun sán được kỳ vọng sẽ tạo ra bước tiến đột phá trong kiểm soát bệnh ký sinh trùng này, qua đó cải thiện rõ rệt sức khỏe cộng đồng. Điều này càng được củng cố bởi bằng chứng rằng đồng phân phối nhiều mRNA có thể tạo ra hiệu ứng hiệp đồng, giúp tăng cường và mở rộng phạm vi miễn dịch bảo vệ, điển hình là vắc-xin hexaplex MDNP chống Toxoplasma gondii (180).Đáng chú ý, nền tảng mRNA đa giá cũng đã được tối ưu hóa thành công cho nhiều tổ hợp kháng nguyên, mở ra tiềm năng phát triển các vắc-xin đa giá chống lại các biến thể SARS-CoV-2 (148), cũng như virus cúm mùavà cúm trong các vụ dịch (149).
KẾT LUẬN
Nền tảng mRNA là một công nghệ mới đầy tiềm năng, đã làm thay đổi căn bản lĩnh vực phát triển vắc-xin. Vắc-xin mRNA có thể được thiết kế đơn giản, triển khai nhanh chóng, sản xuất dễ dàng, chi phí thấp và quan trọng hơn, chúng có khả năng kích thích miễn dịch dịch thể và miễn dịch tế bào bảo vệ rộng và kéo dài (220). Việc phát triển “thần tốc” và triển khai thành công sau đó các vắc-xin mRNA SARS-CoV-2 hiệu quả cao là kết quả từ sự bùng phát dữ dội chưa từng có của Đại dịch COVID-19. Sự tăng tốc trong phát triển các vắc-xin mRNA, hiện đang ở nhiều giai đoạn thử nghiệm lâm sàng để nhắm đến một loạt các mầm bệnh (168-179), đã khơi dậy sự quan tâm lớn trong việc ứng dụng phương pháp này để phát triển các vắc-xin chống KST hiệu quả và bền vững, bao gồm các vắc-xin chống lại giun sán - tác nhân gây bệnh cho hơn 1/4 dân số toàn cầu, chủ yếu sống trong cảnh nghèo đói cùng cực (237).
Đứng đầu danh sách ưu tiên có thể nói là vắc-xin chống bệnh sán máng, mặc dù những hạn chế trong phát triển và sản xuất vắc-xin mRNA đòi hỏi cần có nhiều nghiên cứu sâu hơn trong tương lai. Đây vẫn là một căn bệnh vừa thúc đẩy nghèo đói, vừa gây kỳ thị xã hội, chủ yếu xảy ra tại các vùng nông thôn nghèo của các quốc gia đang phát triển. Thực tế, hiện chưa có vắc-xin phòng sán máng nào cho người hay động vật, mặc dù tạp chí Science đã xếp vắc-xin chống sán máng vào nhóm 10 loại vắc-xin cấp bách nhất cần thiết để cải thiện sức khỏe cộng đồng toàn cầu (238). Cho đến nay, mặc dù đã xác định và thử nghiệm được nhiều ứng viên vắc-xin chống sán máng, nhưng rất ít trong số đó được đưa vào TNLS, bởi miễn dịch bảo vệ tạo ra vẫn chưa đủ mạnh. Điều cần thiết và cấp bách hiện nay là một nền tảng vắc-xin chống sán máng mang tính cách mạng, hiệu quả, có khả năng thúc đẩy quá trình phát triển và thử nghiệm ứng viên vắc-xin với năng suất cao dựa trên công nghệ tiên tiến.
Bằng cách tận dụng cách tiếp cận vắc-xin mRNA, vốn đã chứng minh thành công rực rỡ trong phát triển các vắc-xin COVID-19 hiệu quả cao, kết hợp với việc sử dụng các mô hình động vật phù hợp để đánh giá hiệu quả bảo vệ của ứng viên vắc-xin và xác định các dấu ấn miễn dịch liên quan đến bảo vệ, mục tiêu này hoàn toàn có thể đạt được. Vắc-xin mRNA chống KST mở ra triển vọng rõ ràng trong việc cải thiện sức khỏe cho con người và động vật ở vùng lưu hành, đồng thời bảo vệ khách du lịch và quân nhân khỏi nguy cơ phơi nhiễm – tất cả đều là những nhóm dân số tiềm năng được hưởng lợi.Ngoài ra, việc tiếp tục tinh chỉnh và tối ưu hóa công nghệ vắc-xin mRNA đa giá chống lại bệnh sán máng và các bệnh KST khác có thể mang lại những cải thiện đáng kể trong khả năng tiếp cận các kỹ thuật vắc-xin tiên tiến, cũng như triển khai các vắc-xin hiệu quả tại các khu vực chịu ảnh hưởng nặng nề nhất bởi KST trên toàn cầu.
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