Salisch Nadine C, Vujadinovic Marija, van der Helm Esmeralda, Spek Dirk, Vorthoren Lars, Serroyen Jan, Kuipers Harmjan, Schuitemaker Hanneke, Zahn Roland, Custers Jerome, Vellinga Jort
Janssen Vaccines & Prevention, Leiden, The Netherlands.
PLoS One. 2017 Mar 31;12(3):e0174728. doi: 10.1371/journal.pone.0174728. eCollection 2017.
Durable protection against complex pathogens is likely to require immunity that comprises both humoral and cellular responses. While heterologous prime-boost regimens based on recombinant, replication-incompetent Adenoviral vectors (AdV) and adjuvanted protein have been able to induce high levels of concomitant humoral and cellular responses, complex manufacturing and handling in the field may limit their success. To combine the benefits of genetic and protein-based vaccination within one vaccine construct and to facilitate their use, we generated Human Adenovirus 35 (HAdV35) vectors genetically encoding a model antigen based on the Plasmodium falciparum (P. falciparum) circumsporozoite (CS) protein and displaying a truncated version of the same antigen (CSshort) via protein IX on the capsid, with or without a flexible glycine-linker and/or a 45Å-spacer. The four tested pIX-antigen display variants were efficiently incorporated and presented on the HAdV35 capsid irrespective of whether a transgene was encoded or not. Transgene-expression and producibility of the display-/expression vectors were not impeded by the pIX-display. In mice, the pIX-modified vectors induced strong humoral antigen-specific immunity that increased with the inclusion of the linker-/spacer molecules, exceeded the responses induced by the genetic, transgene-expressing HAdV35 vector, and surpassed recombinant protein in potency. In addition, the pIX- display/expression vectors elicited high antigen-specific cellular immune responses that matched those of the genetic HAdV35 vector expressing CS. pIX-modified display-/expression HAdV vectors may therefore be a valuable technology for the development of vaccines against complex pathogens, especially in resource-limited settings.
针对复杂病原体的持久保护可能需要同时包含体液免疫和细胞免疫的免疫反应。虽然基于重组、复制缺陷型腺病毒载体（AdV）和佐剂蛋白的异源初免-加强方案能够诱导高水平的同时性体液免疫和细胞免疫反应，但现场复杂的生产和处理可能会限制其成功应用。为了在一种疫苗构建体中结合基因疫苗和蛋白疫苗的优势并便于使用，我们构建了人腺病毒35（HAdV35）载体，该载体通过基因编码基于恶性疟原虫（P. falciparum）环子孢子（CS）蛋白的模型抗原，并通过衣壳上的蛋白IX展示相同抗原的截短版本（CSshort），有或没有柔性甘氨酸连接子和/或45Å间隔序列。无论是否编码转基因，四种测试的pIX-抗原展示变体均能有效整合并呈现在HAdV35衣壳上。pIX展示并未阻碍展示/表达载体的转基因表达和生产能力。在小鼠中，pIX修饰的载体诱导了强烈的体液抗原特异性免疫，随着连接子/间隔分子的加入而增强，超过了基因表达转基因的HAdV35载体诱导的反应，并且在效力上超过了重组蛋白。此外，pIX展示/表达载体引发了与表达CS的基因HAdV35载体相匹配的高抗原特异性细胞免疫反应。因此，pIX修饰的展示/表达HAdV载体可能是开发针对复杂病原体疫苗的一项有价值的技术，特别是在资源有限的环境中。
