John Curtin School of Medical Research, The Australian National University, Canberra, Australian Capital Territory, Australia.
Department of Microbiology and Immunology, University of Melbourne, The Peter Doherty Institute for Infection and Immunity, Melbourne, Victoria, Australia.
J Virol. 2019 Oct 15;93(21). doi: 10.1128/JVI.01154-19. Print 2019 Nov 1.
A variety of strains of vaccinia virus (VACV) have been used as recombinant vaccine vectors with the aim of inducing robust CD8 T cell immunity. While much of the pioneering work was done with virulent strains, such as Western Reserve (WR), attenuated strains such as modified vaccinia virus Ankara (MVA) are more realistic vectors for clinical use. To unify this literature, side-by-side comparisons of virus strains are required. Here, we compare the form of antigen that supports optimal CD8 T cell responses for VACV strains WR and MVA using equivalent constructs. We found that for multiple antigens, minimal antigenic constructs (epitope minigenes) that prime CD8 T cells via the direct presentation pathway elicited optimal responses from both vectors, which was surprising because this finding contradicts the prevailing view in the literature for MVA. We then went on to explore the discrepancy between current and published data for MVA, finding evidence that the expression locus and in some cases the presence of the viral thymidine kinase may influence the ability of this strain to prime optimal responses from antigens that require direct presentation. This extends our knowledge of the design parameters for VACV vectored vaccines, especially those based on MVA. Recombinant vaccines based on vaccinia virus and particularly attenuated strains such as MVA are in human clinical trials, but due to the complexity of these large vectors much remains to be understood about the design parameters that alter their immunogenicity. Previous work had found that MVA vectors should be designed to express stable protein in order to induce robust immunity by CD8 (cytotoxic) T cells. Here, we found that the primacy of stable antigen is not generalizable to all designs of MVA and may depend where a foreign antigen is inserted into the MVA genome. This unexpected finding suggests that there is an interaction between genome location and the best form of antigen for optimal T cell priming in MVA and thus possibly other vaccine vectors. It also highlights that our understanding of antigen presentation by even the best studied of vaccine vectors remains incomplete.
多种痘苗病毒（VACV）株已被用作重组疫苗载体，旨在诱导强大的 CD8 T 细胞免疫。虽然大部分开创性工作都是使用强毒株（如西部储备株，WR）完成的，但减毒株，如改良安卡拉痘苗病毒（MVA），更适合用于临床应用。为了统一这一文献，需要对病毒株进行并排比较。在这里，我们使用等效构建体比较了 WR 和 MVA 两种 VACV 株支持最佳 CD8 T 细胞反应的抗原形式。我们发现，对于多种抗原，通过直接呈递途径引发 CD8 T 细胞的最小抗原构建体（表位小基因），可以从两种载体中引发最佳反应，这令人惊讶，因为这一发现与文献中关于 MVA 的主流观点相矛盾。然后，我们继续探讨了 MVA 的当前和已发表数据之间的差异，发现有证据表明，表达基因座，在某些情况下，病毒胸苷激酶的存在，可能会影响该菌株从需要直接呈递的抗原中引发最佳反应的能力。这扩展了我们对 VACV 载体疫苗设计参数的了解，特别是基于 MVA 的疫苗。基于痘苗病毒的重组疫苗，特别是减毒株，如 MVA，正在进行人体临床试验，但由于这些大型载体的复杂性，仍有许多关于改变其免疫原性的设计参数需要了解。以前的工作发现，MVA 载体应该设计为表达稳定的蛋白质，以便通过 CD8（细胞毒性）T 细胞诱导强大的免疫力。在这里，我们发现稳定抗原的首要性并不适用于 MVA 的所有设计，并且可能取决于外源抗原插入 MVA 基因组的位置。这一意外的发现表明，在 MVA 中，基因组位置与最佳抗原形式之间存在相互作用，以实现最佳 T 细胞引发，因此可能对其他疫苗载体也是如此。它还强调了，即使是对研究最充分的疫苗载体，我们对其抗原呈递的理解仍然不完整。
