Callendret Benoit, Vellinga Jort, Wunderlich Kerstin, Rodriguez Ariane, Steigerwald Robin, Dirmeier Ulrike, Cheminay Cedric, Volkmann Ariane, Brasel Trevor, Carrion Ricardo, Giavedoni Luis D, Patterson Jean L, Mire Chad E, Geisbert Thomas W, Hooper Jay W, Weijtens Mo, Hartkoorn-Pasma Jutta, Custers Jerome, Grazia Pau Maria, Schuitemaker Hanneke, Zahn Roland
Janssen Vaccines & Prevention B.V., Leiden, Netherlands.
Bavarian Nordic GmbH, Martinsried, Germany.
PLoS One. 2018 Feb 20;13(2):e0192312. doi: 10.1371/journal.pone.0192312. eCollection 2018.
The search for a universal filovirus vaccine that provides protection against multiple filovirus species has been prompted by sporadic but highly lethal outbreaks of Ebolavirus and Marburgvirus infections. A good prophylactic vaccine should be able to provide protection to all known filovirus species and as an upside potentially protect from newly emerging virus strains. We investigated the immunogenicity and protection elicited by multivalent vaccines expressing glycoproteins (GP) from Ebola virus (EBOV), Sudan virus (SUDV), Taï Forest virus (TAFV) and Marburg virus (MARV). Immune responses against filovirus GP have been associated with protection from disease. The GP antigens were expressed by adenovirus serotypes 26 and 35 (Ad26 and Ad35) and modified Vaccinia virus Ankara (MVA) vectors, all selected for their strong immunogenicity and good safety profile. Using fully lethal NHP intramuscular challenge models, we assessed different vaccination regimens for immunogenicity and protection from filovirus disease. Heterologous multivalent Ad26-Ad35 prime-boost vaccination regimens could give full protection against MARV (range 75%-100% protection) and EBOV (range 50% to 100%) challenge, and partial protection (75%) against SUDV challenge. Heterologous multivalent Ad26-MVA prime-boost immunization gave full protection against EBOV challenge in a small cohort study. The use of such multivalent vaccines did not show overt immune interference in comparison with monovalent vaccines. Multivalent vaccines induced GP-specific antibody responses and cellular IFNγ responses to each GP expressed by the vaccine, and cross-reactivity to TAFV GP was detected in a trivalent vaccine expressing GP from EBOV, SUDV and MARV. In the EBOV challenge studies, higher humoral EBOV GP-specific immune responses (p = 0.0004) were associated with survival from EBOV challenge and less so for cellular immune responses (p = 0.0320). These results demonstrate that it is feasible to generate a multivalent filovirus vaccine that can protect against lethal infection by multiple members of the filovirus family.
埃博拉病毒和马尔堡病毒感染呈散发性但致死率极高，这促使人们寻找一种能抵御多种丝状病毒的通用丝状病毒疫苗。一种优良的预防性疫苗应能为所有已知丝状病毒提供保护，并且有望抵御新出现的病毒株。我们研究了表达来自埃博拉病毒（EBOV）、苏丹病毒（SUDV）、塔伊森林病毒（TAFV）和马尔堡病毒（MARV）糖蛋白（GP）的多价疫苗所引发的免疫原性和保护作用。针对丝状病毒GP的免疫反应与抵御疾病相关。GP抗原由腺病毒血清型26和35（Ad26和Ad35）以及改良安卡拉痘苗病毒（MVA）载体表达，这些载体均因其强大的免疫原性和良好的安全性而被选用。我们使用完全致死性的非人灵长类动物肌肉注射攻毒模型，评估了不同的疫苗接种方案的免疫原性以及对丝状病毒疾病的保护作用。异源多价Ad26 - Ad35初免 - 加强接种方案能为抵御MARV（保护率范围为75% - 100%）和EBOV（保护率范围为50%至100%）攻毒提供完全保护，并为抵御SUDV攻毒提供部分保护（75%）。在一项小型队列研究中，异源多价Ad26 - MVA初免 - 加强免疫为抵御EBOV攻毒提供了完全保护。与单价疫苗相比，使用此类多价疫苗未显示出明显的免疫干扰。多价疫苗诱导了针对疫苗所表达的每种GP的GP特异性抗体反应和细胞IFNγ反应，并且在表达来自EBOV、SUDV和MARV的GP的三价疫苗中检测到了对TAFV GP的交叉反应性。在EBOV攻毒研究中，更高的体液EBOV GP特异性免疫反应（p = 0.0004）与在EBOV攻毒中存活相关，而细胞免疫反应的相关性则较弱（p = 0.0320）。这些结果表明，研发一种能抵御丝状病毒家族多个成员致死性感染的多价丝状病毒疫苗是可行的。
