Toward an effective Staphylococcus vaccine: why have candidates failed and what is the next step?
Toward an effective Staphylococcus vaccine: why have candidates failed and what is the next step?
复制标题
寻找有效的葡萄球菌疫苗：为什么候选疫苗失败了，下一步是什么？
DOI：
10.1080/14760584.2023.2179486
复制
发表时间：
2023
影响因子：
6.2
通讯作者：
Liu,GeorgeY
中科院分区：
文献类型：
--
作者：
Tsai,Chih-Ming;Caldera,Jr;Hajam,IrshadA;Liu,GeorgeY
S. aureus is a leading cause of infection and a major driver of antibiotic resistance. Appropriately, it consistently ranks on the CDC list of ‘THREAT’pathogens that are in dire need of an effective vaccine [1]. S. aureus immunizations have been studied as early as 1902 [2], but the number of vaccine studies peaked over the past three decades in response to the urgent clinical need, and partly spurred by the success of vaccines targeting bacterial pathogens such as S. pneumoniae and H. influenzae. Unexpectedly, there has not been a successful S. aureus vaccine after approximately 30 completed vaccine trials [3, 4]. The reasons behind the failures have been speculated broadly, but there has been no consensus on the cause. This editorial article focuses on a recently published study from our group that demonstrates immune imprinting as a way to reinterpret S. aureus vaccine failures [5]. In this study, we proposed that the reason why staphylococcal vaccines failed in humans and succeeded in mice lies in the early and frequent exposures of humans to S. aureus and the absence of S. aureus exposure in mice [6, 7]. We speculated that prior S. aureus exposure leads to reprogramming of the host immune system that makes S. aureus vaccines ineffective. To test our hypothesis, we recapitulated the failed vaccine trial that targeted the highly conserved, iron-regulated surface determinant protein B (IsdB)[8] and showed that IsdB vaccines were highly effective in mice that have not been exposed to S. aureus, but were ineffective when administered to mice previously infected with S. aureus [5]. Further investigation revealed that IsdB-specific antibodies, although abundantly generated in S. aureus pre-exposed mice, were non-neutralizing and had no effect on the opsonophagocytic killing of S. aureus by neutrophils [5]. Immunizing S. aureus-exposed mice with IsdB led to the generation of antibodies that shared these non-protective features, in sharp contrast to the protective antibodies generated by the same vaccine in naïve mice. Effectively, the preferential recall of non-protective B cell clone was the responsible mechanism and doomed the vaccine to failure. These findings largely follow the ‘original antigenic sin’hypothesis that explains the reduced protective antibody response to influenza strains that have undergone seasonal antigenic drift [9]. Notably, we also found that the recalled non-protective anti-IsdB antibodies further suppressed the efficacy of protective IsdB-specific antibodies by competition. Together, these data provide a mechanistic basis for the significant and unexpected failures of the highly promising IsdB vaccine candidate. The most pressing query going forward is whether the mechanism underlying IsdB vaccine interference could also explain the failure of other S. aureus vaccines? Specifically, are all imprints non-protective or are there protective classes of antigens that could be exploited to develop protective vaccines? Are there antigens that induce no imprints and yet generate protective immunity when administered as vaccines? Predictive modeling of vaccine success based on the character of antibody imprint would prompt rethinking of our current vaccine development platforms. Hence, we propose that the next set of investigations should focus on the effect of humoral imprints on active and passive immunizations that failed vaccine trials, against both cell-wall associated antigens as well as toxins, which could represent classes of nonprotective and protective vaccine antigens, respectively. If the initial assessment of S. aureus vaccines suggests indeed a broader role of immune imprinting in determining S. aureus vaccine outcomes …
