Sears Khandra T, Nasrin Shamima, Baliban Scott M, Council Danielle N, Pasetti Marcela F, Tennant Sharon M
Center for Vaccine Development and Global Health, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
Department of Medicine, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
Vaccines (Basel). 2023 Oct 4;11(10):1562. doi: 10.3390/vaccines11101562.
Nontyphoidal (NTS) is a leading cause of foodborne illness worldwide, including in the United States, where infants show the highest incidence amongst all age groups. serovar Typhimurium is one of the most frequently isolated serovars from NTS infections. We have developed several candidate live-attenuated Typhimurium vaccines to prevent NTS infection. The goal of the current study was to assess three live Typhimurium vaccine strains (CVD 1921, CVD 1921 ∆ and CVD 1926, which have two, three and four gene deletions, respectively) with various levels of reactogenicity and immunogenicity in infant BALB/c mice to predict how they would perform following peroral immunization of infants. We first tested intranasal immunization of 14-day-old mice with three doses delivered at 1-week intervals and evaluated antibody responses and protection against lethal infection with wild-type Typhimurium. The vaccines were administered to 14-day-old mice via the peroral route at 1- or 2-week intervals and to 28-day-old mice at 2-week intervals. The three vaccine strains were immunogenic following intranasal immunization of infant mice with vaccine efficacies of 80% (CVD 1921), 63% (CVD 1921 ∆) and 31% (CVD 1926). In contrast, peroral immunization of 14-day-old mice yielded much poorer protection against lethal infection and only immunization of 28-day-old mice at 2-week intervals showed similar protective capacity as intranasal administration (CVD 1921: 83%, CVD 1921 ∆ 43% and CVD 1926: 58%). CVD 1921 was consistently more protective than both CVD 1921 ∆ and CVD 1926, regardless of the route of vaccination, immunization schedule and age of mice. Anti-LPS serum IgG responses were similar between the three strains and did not correlate with protection. Due to previously observed reactogenicity of CVD 1921, CVD 1921 ∆ and CVD 1926 are our preferred vaccines, but these data show that further improvements would need to be made to achieve suitable protection in young infants when using peroral immunization.
非伤寒型（NTS）是全球食源性疾病的主要病因，在美国亦是如此，美国婴儿在所有年龄组中的发病率最高。鼠伤寒血清型是从NTS感染中最常分离出的血清型之一。我们已研发出几种候选减毒活鼠伤寒疫苗以预防NTS感染。本研究的目的是评估三种活鼠伤寒疫苗株（CVD 1921、CVD 1921 ∆和CVD 1926，分别有两个、三个和四个基因缺失）在幼龄BALB/c小鼠中的反应原性和免疫原性水平各异，以预测它们在婴儿口服免疫后的表现。我们首先对14日龄小鼠进行鼻内免疫，每隔1周接种三剂，并评估抗体反应以及对野生型鼠伤寒致死感染的保护作用。疫苗每隔1周或2周经口服途径给予14日龄小鼠，每隔2周给予28日龄小鼠。这三种疫苗株在对幼龄小鼠进行鼻内免疫后具有免疫原性，疫苗效力分别为80%（CVD 1921）、63%（CVD 1921 ∆）和31%（CVD 1926）。相比之下，对14日龄小鼠进行口服免疫对致死感染的保护作用要差得多，只有每隔2周对28日龄小鼠进行免疫才显示出与鼻内给药相似的保护能力（CVD 1921：83%，CVD 1921 ∆ 43%，CVD 1926：58%）。无论接种途径、免疫程序和小鼠年龄如何，CVD 1921始终比CVD 1921 ∆和CVD 1926更具保护作用。三种菌株的抗LPS血清IgG反应相似，且与保护作用无关。鉴于之前观察到CVD 1921的反应原性，CVD 1921 ∆和CVD 1926是我们首选的疫苗，但这些数据表明，在对幼龄婴儿使用口服免疫时，需要进一步改进以实现适当的保护。
