Evaluation of new generation Salmonella enterica serovar Typhimurium vaccines with regulated delayed attenuation to induce immune responses against PspA
Evaluation of new generation Salmonella enterica serovar Typhimurium vaccines with regulated delayed attenuation to induce immune responses against PspA
复制标题
新一代肠道沙门氏菌鼠伤寒疫苗的调节延迟减毒诱导抗 PspA 免疫反应的评价
DOI：
10.1073/pnas.0811697106
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发表时间：
2009-01-13
影响因子：
11.1
通讯作者：
Curtiss, Roy, III
中科院分区：
文献类型：
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作者：
Li, Yuhua;Wang, Shifeng;Curtiss, Roy, III
通过重组减毒沙门氏菌疫苗（RASV）提高递送抗原的免疫原性一直是深入研究的主题。考虑到这一目标，我们设计并构建了新一代 RASV，其表现出可调节的延迟衰减。这些疫苗株在免疫时为表型野生型，并在宿主组织定植后减毒。疫苗株在允许表达宿主组织最佳侵袭和定植所需基因的条件下生长。一旦在宿主体内建立，这些毒力基因就会被关闭，从而使疫苗株完全减毒。在本研究中，我们将 2 种新开发的调节性延迟减毒鼠伤寒沙门氏菌血清型 χ9088 和 χ9558 菌株与 Δcya Δcrp Δasd 菌株 χ8133 进行比较，比较它们向小鼠免疫系统表达和呈递肺炎球菌表面蛋白 A (PspA) α 螺旋区域的分泌形式的能力。所有 3 株菌株均在口服免疫小鼠中诱导高水平的 PspA 特异性血清抗体以及沙门氏菌抗原特异性抗体。然而，与其他组相比，表达延迟减毒的两种RASV均引发显着更强的抗PspA免疫反应，包括血清IgG以及IL-4和IFN-γ的T细胞分泌。此外，与接种 χ8133 疫苗的小鼠相比，接种延迟减毒菌株对肺炎链球菌攻击具有更大程度的保护（71-86% vs. 21% 存活率，P ≤ 0.006）。总之，结果表明，受调节的减毒策略可产生用于口服疫苗接种的高免疫原性抗原递送载体。
Increasing the immunogenicity to delivered antigens by recombinant attenuated Salmonella vaccines (RASV) has been the subject of intensive study. With this goal in mind, we have designed and constructed a new generation of RASV that exhibit regulated delayed attenuation. These vaccine strains are phenotypically wild type at the time of immunization and become attenuated after colonization of host tissues. The vaccine strains are grown under conditions that allow expression of genes required for optimal invasion and colonization of host tissues. Once established in the host, these virulence genes are turned off, fully attenuating the vaccine strain. In this study, we compared 2 of our newly developed regulated delayed attenuation Salmonella enterica serovar Typhimurium strains χ9088 and χ9558 with the Δcya Δcrp Δasd strain χ8133, for their abilities to express and present a secreted form of the α-helical region of pneumococcal surface protein A (PspA) to the mouse immune system. All 3 strains induced high levels of serum antibodies specific for PspA as well as to Salmonella antigens in orally immunized mice. However, both RASVs expressing delayed attenuation elicited significantly greater anti-PspA immune responses, including serum IgG and T cell secretion of IL-4 and IFN-γ, than other groups. Also, vaccination with delayed attenuation strains resulted in a greater degree of protection against Streptococcus pneumoniae challenge than in mice vaccinated with χ8133 (71–86% vs. 21% survival, P ≤ 0.006). Together, the results demonstrate that the regulated attenuation strategy results in highly immunogenic antigen delivery vectors for oral vaccination.