Xiong Kun, Chen Zhijin, Zhu Chunyue, Li Jianhua, Hu Xiaomei, Rao Xiancai, Cong Yanguang
Department of Microbiology, Third Military Medical University, Chongqing, 400038, PR China.
Int J Med Microbiol. 2015 Sep;305(6):563-71. doi: 10.1016/j.ijmm.2015.07.004. Epub 2015 Jul 26.
Enteric fever caused by Salmonella enterica serovar Paratyphi A has progressively increased in recent years and became a global health issue. Currently licensed typhoid vaccines do not confer adequate cross-immunoprotection against S. Paratyphi A infection. Therefore, vaccines specifically against enteric fever caused by S. Paratyphi A are urgently needed. In the present study, an attenuated vaccine strain was constructed from S. Paratyphi A CMCC50093 by the deletions of aroC and yncD. The obtained strain SPADD01 showed reduced survival within THP-1 cells and less bacterial burden in spleens and livers of infected mice compared with the wild-type strain. The 50% lethal doses of SPADD01 and the wild-type strain were assessed using a murine infection model. The virulence of SPADD01 is approximately 40,000-fold less than that of the wild-type strain. In addition, SPADD01 showed an excellent immunogenicity in mouse model. Single intranasal inoculation elicited striking humoral and mucosal immune responses in mice and yielded effective protection against lethal challenge of the wild-type strain. A high level of cross-reactive humoral immune response against LPS of Salmonella enterica serovar Typhi was also detected in immunized mice. However, SPADD01 vaccination only conferred a low level of cross-protection against S. Typhi. Our data suggest that SPADD01 is a promising vaccine candidate against S. Paratyphi A infection and deserves further evaluation in clinical trial. To date, no study has demonstrated a good cross-protection between serovars of S. Typhi and S. Paratyphi A, suggesting that the dominant protective antigens of both serovars are likely different and need to be defined in future study.
近年来，由甲型副伤寒沙门氏菌引起的肠热症呈逐渐上升趋势，并成为一个全球性的健康问题。目前已获许可的伤寒疫苗对甲型副伤寒沙门氏菌感染没有提供足够的交叉免疫保护。因此，迫切需要针对甲型副伤寒沙门氏菌引起的肠热症的特异性疫苗。在本研究中，通过缺失aroC和yncD基因，从甲型副伤寒沙门氏菌CMCC50093构建了一株减毒疫苗株。与野生型菌株相比，获得的菌株SPADD01在THP-1细胞内的存活率降低，在感染小鼠的脾脏和肝脏中的细菌载量也较少。使用小鼠感染模型评估了SPADD01和野生型菌株的50%致死剂量。SPADD01的毒力比野生型菌株低约40000倍。此外，SPADD01在小鼠模型中表现出优异的免疫原性。单次鼻内接种在小鼠中引发了显著的体液和黏膜免疫反应，并对野生型菌株的致死性攻击产生了有效的保护作用。在免疫小鼠中还检测到针对伤寒沙门氏菌脂多糖的高水平交叉反应性体液免疫反应。然而，SPADD01疫苗接种仅对伤寒沙门氏菌提供了低水平的交叉保护。我们的数据表明，SPADD01是一种有前景的抗甲型副伤寒沙门氏菌感染的疫苗候选物，值得在临床试验中进一步评估。迄今为止，尚无研究证明伤寒沙门氏菌和甲型副伤寒沙门氏菌血清型之间有良好的交叉保护作用，这表明两种血清型的主要保护性抗原可能不同，需要在未来的研究中加以确定。
