Koenig Johannes, Theobald Sebastian J, Stripecke Renata
Laboratory of Regenerative Immune Therapies Applied, Excellence Cluster REBIRTH, Hannover Medical School, Hannover 30625, Germany.
Clinic of Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School, Hannover 30625, Germany.
Vaccines (Basel). 2020 Feb 17;8(1):89. doi: 10.3390/vaccines8010089.
Human cytomegalovirus (HCMV or HHV-5) is a globally spread pathogen with strictly human tropism that establishes a lifelong persistence. After primary infection, high levels of long-term T and B cell responses are elicited, but the virus is not cleared. HCMV persists mainly in hematopoietic reservoirs, whereby occasional viral reactivation and spread are well controlled in immunocompetent hosts. However, when the immune system cannot control viral infections or reactivations, such as with newborns, patients with immune deficiencies, or immune-compromised patients after transplantations, the lytic outbursts can be severely debilitating or lethal. The development of vaccines for immunization of immune-compromised hosts has been challenging. Several vaccine candidates did not reach the potency expected in clinical trials and were not approved. Before anti-HCMV vaccines can be tested pre-clinically in immune-compromised hosts, reliable in vivo models recapitulating HCMV infection might accelerate their clinical translation. Therefore, immune-deficient mouse strains implanted with human cells and tissues and developing a human immune system (HIS) are being explored to test anti-HCMV vaccines. HIS-mice resemble immune-compromised hosts as they are equipped with antiviral human T and B cells, but the immune reactivity is overall low. Several groups have independently shown that HCMV infections and reactivations can be mirrored in HIS mice. However, these models and the analyses employed varied widely. The path forward is to improve human immune reconstitution and standardize the analyses of adaptive responses so that HIS models can be forthrightly used for testing novel generations of anti-HCMV vaccines in the preclinical pipeline.
人巨细胞病毒（HCMV或HHV - 5）是一种全球传播的病原体，具有严格的人嗜性，可建立终身持续性感染。初次感染后，会引发高水平的长期T细胞和B细胞反应，但病毒并未被清除。HCMV主要在造血储存库中持续存在，在免疫功能正常的宿主中，偶尔的病毒再激活和传播能得到很好的控制。然而，当免疫系统无法控制病毒感染或再激活时，如新生儿、免疫缺陷患者或移植后的免疫受损患者，病毒的裂解爆发可能会导致严重衰弱甚至致命。开发针对免疫受损宿主的疫苗一直具有挑战性。几种候选疫苗在临床试验中未达到预期效力，未获批准。在抗HCMV疫苗能够在免疫受损宿主中进行临床前测试之前，能够重现HCMV感染的可靠体内模型可能会加速其临床转化。因此，正在探索植入人类细胞和组织并发育出人类免疫系统（HIS）的免疫缺陷小鼠品系来测试抗HCMV疫苗。HIS小鼠类似于免疫受损宿主，因为它们配备了抗病毒的人类T细胞和B细胞，但总体免疫反应性较低。几个研究小组已独立表明，HCMV感染和再激活情况可在HIS小鼠中得到反映。然而，这些模型和所采用的分析方法差异很大。前进的方向是改善人类免疫重建并规范适应性反应的分析，以便HIS模型能够直接用于在临床前流程中测试新一代抗HCMV疫苗。
