Department of Pediatrics, Virginia Commonwealth University School of Medicine, Richmond.
Clin Infect Dis. 2013 Dec;57 Suppl 4(Suppl 4):S196-9. doi: 10.1093/cid/cit587.
An effective cytomegalovirus (CMV) vaccine could prevent the majority of birth defects caused by congenital CMV infections. Candidate vaccines in clinical evaluation include live attenuated, protein subunit, DNA, and viral-vectored approaches. Subunit approaches have focused on the CMV proteins pp65 and IE1 as important inducers of cytotoxic T cells and glycoprotein B (gB) as an important inducer of neutralizing antibodies. A vaccine comprised of recombinant gB protein with MF59 adjuvant reduced the incidence of primary infection by 50%. Recent revelations regarding CMV entry pathways into different cell types suggest a possible course for improvement. A 5-subunit pentameric complex is uniquely required for endothelial and epithelial cell entry. Sera from naturally infected subjects contain high-potency neutralizing activities specific for this complex, whereas the gB/MF59 vaccine fails to induce comparable neutralizing activities. A vaccine's ability to induce salivary antibodies that neutralize epithelial cell entry may be especially important for preventing oral transmission as the first cells infected are presumably epithelial cells of the oral mucosa. In addition, recent evidence suggests that antibodies can inhibit postentry CMV spread between endothelial and epithelial cells. Such activities may serve to limit viral replication in tissues or impair dissemination to the placenta and fetus. Thus, inclusion of epitopes derived from the pentameric complex may provide enhanced efficacy by inducing potent neutralizing/spread-inhibiting antibodies that target virus replication in a broad spectrum of cell types. Next-generation vaccine candidates in preclinical development incorporate peptides, subunits, or multisubunit complexes representing parts or all of the pentameric complex. Approaches include peptides, recombinant proteins, DNA, replication-defective viral vectors, genetically disabled CMV, and inactivated CMV virions. The diversity of novel strategies under development engenders optimism that a successful candidate will emerge.
一种有效的巨细胞病毒 (CMV) 疫苗可以预防大多数由先天性 CMV 感染引起的出生缺陷。正在临床评估的候选疫苗包括减毒活疫苗、蛋白亚单位疫苗、DNA 疫苗和病毒载体疫苗。亚单位疫苗的重点是 CMV 蛋白 pp65 和 IE1，它们是细胞毒性 T 细胞的重要诱导剂，糖蛋白 B (gB) 是中和抗体的重要诱导剂。用 MF59 佐剂组成的重组 gB 蛋白疫苗将原发性感染的发生率降低了 50%。最近关于 CMV 进入不同细胞类型的途径的揭示表明，可能会有改进的方法。五聚体复合物是进入内皮细胞和上皮细胞所必需的独特结构。天然感染的患者血清中含有针对该复合物的高效中和活性，而 gB/MF59 疫苗不能诱导类似的中和活性。疫苗诱导能够中和上皮细胞进入的唾液抗体的能力可能特别重要，因为首先感染的细胞可能是口腔黏膜的上皮细胞。此外，最近的证据表明，抗体可以抑制进入后的 CMV 在内皮细胞和上皮细胞之间的传播。这些活性可能有助于限制组织中的病毒复制或损害向胎盘和胎儿的传播。因此，包含来自五聚体复合物的表位可能通过诱导针对广泛细胞类型中病毒复制的有效中和/传播抑制抗体来提供增强的功效。正在临床前开发的下一代疫苗候选物包括代表五聚体复合物的部分或全部的肽、亚单位或多亚单位复合物。方法包括肽、重组蛋白、DNA、复制缺陷型病毒载体、基因失活的 CMV 和失活的 CMV 病毒粒子。正在开发的新颖策略的多样性使人乐观地认为，将出现一种成功的候选疫苗。
