Perelman School of Medicine at the University of Pennsylvania, Department of Medicine, Division of Infectious Diseases, Philadelphia, PA 19104-6073, United States.
University of Kansas, Macromolecular and Vaccine Stabilization Center, Department of Pharmaceutical Chemistry, 2030 Becker Drive, Lawrence, KS 66047, United States.
Vaccine. 2020 Aug 27;38(38):6007-6018. doi: 10.1016/j.vaccine.2020.07.018. Epub 2020 Jul 30.
Smallpox, a contagious and deadly disease caused by variola virus, was eradicated by a strategy that included vaccination with vaccinia virus, a live-virus vaccine. Because the threat of bioterrorism with smallpox persists and infections with zoonotic poxvirus infections like monkeypox continue, and there may be a time when an alternative vaccine platform is needed, recombinant-subunit vaccine strategies for poxviruses have been pursued. Our prior work focused on understanding the immune responses generated to vaccine-formulations containing the virus protein L1. In this work, we examine vaccine-formulations with additional key protein targets: A33 and B5 (components of the extracellular virus) and another protein on the mature virus (A27) adjuvanted with aluminum hydroxide (AH) with and without CpG- oligonucleotide. Each vaccine was formulated to allow either adsorption or non-adsorption of the protein (and CpG) to AH. Mice given a prime and single boost produced long-lasting antibody responses. A second boost (given ~5-months after the first) further increased antibody titers. Similar to our prior findings with L1 vaccine-formulations, the most protective A33 vaccine-formulations included CpG, resulted in the generation of IgG2a-antibody responses. Unlike the prior findings with L1 (where formulations that adsorbed both the protein and the CpG to AH resulted in 100% survival after challenge and minimal weight loss), the AH-adsorption status of A33 and CpG did not play as important a role, since both AH-adsorbed and non-adsorbed groups lost weight after challenge and had similar survival. Vaccination with B5-formulations gave different results. While CpG-containing formulations were the only ones that generated IgG2a-antibody responses, the vaccine-formulation that adsorbed B5 to AH (without CpG) was as equally effective in protecting mice after challenge. These results indicate that the mechanism of how antibodies against A33 and B5 protect differ. The data also show the complexity of designing optimized vaccine-formulations containing multiple adjuvants and recombinant protein-based antigens.
天花是一种由天花病毒引起的传染性和致命性疾病，通过接种牛痘病毒（一种活病毒疫苗）的策略得以根除。由于天花的生物恐怖主义威胁仍然存在，并且类似于猴痘的人畜共患痘病毒感染仍在继续，并且可能需要替代疫苗平台，因此已经针对痘病毒采用了重组亚单位疫苗策略。我们之前的工作重点是了解针对含有病毒蛋白 L1 的疫苗制剂产生的免疫反应。在这项工作中，我们研究了含有其他关键蛋白靶标（细胞外病毒的 A33 和 B5 成分以及成熟病毒上的另一种蛋白 A27）的疫苗制剂，并用氢氧化铝（AH）和不含 CpG-寡核苷酸对其进行了佐剂处理。每种疫苗的配方都允许蛋白（和 CpG）吸附或不吸附到 AH 上。给予初次免疫和单次加强免疫的小鼠产生了持久的抗体反应。第二次加强免疫（在第一次加强免疫后约 5 个月进行）进一步提高了抗体滴度。与我们之前用 L1 疫苗制剂的研究结果相似，最具保护作用的 A33 疫苗制剂包含 CpG，可产生 IgG2a 抗体反应。与我们之前用 L1 的研究结果不同（其中吸附蛋白和 CpG 的 AH 制剂在挑战后导致 100%的存活率和最小的体重减轻），A33 和 CpG 的 AH 吸附状态并没有起到重要作用，因为吸附和非吸附组在挑战后都减轻了体重，且存活率相似。用 B5 制剂进行疫苗接种会产生不同的结果。虽然含有 CpG 的制剂是唯一产生 IgG2a 抗体反应的制剂，但吸附 B5 到 AH（不含 CpG）的疫苗制剂在挑战后对小鼠的保护作用同样有效。这些结果表明，针对 A33 和 B5 的抗体保护机制不同。数据还表明，设计包含多种佐剂和重组蛋白抗原的优化疫苗制剂的复杂性。
