Existing capsular polysaccharide-based vaccines against pneumococcal disease are highly effective against vaccine-included serotypes, but they are unable to combat serotype replacement. We have developed a novel pneumococcal vaccine that confers serotype-independent protection, and could therefore constitute a "universal" vaccine formulation. This preparation is comprised of whole un-encapsulated pneumococci inactivated with gamma irradiation (γ-PN), and we have previously reported induction of cross-reactive immunity after nonadjuvanted intranasal vaccination. To further enhance vaccine immunogenicity and safety, we modified the pneumococcal vaccine strain to induce a stressed state during growth. Specifically, the substrate binding component of the psaBCA operon for manganese import was mutated to create a pneumococcal surface antigen A (psaA) defective vaccine strain. psaA mutation severely attenuated the growth of the vaccine strain in vitro without negatively affecting pneumococcal morphology, thereby enhancing vaccine safety. In addition, antibodies raised against vaccine preparations based on the modified strain [γ-PN(ΔPsaA)] showed more diversified reactivity to wild-type pneumococcal challenge strains compared to those induced by the original formulation. The modified vaccine also induced comparable protective TH 17 responses in the lung, and conferred greater protection against lethal heterologous pneumococcal challenge. Overall, the current study demonstrates successful refinement of a serotype-independent pneumococcal vaccine candidate to enhance safety and immunogenicity.

中文翻译：

---

增强的肺炎球菌表面抗原的安全性和免疫原性突变的全细胞灭活的肺炎球菌疫苗。

现有的针对肺炎球菌疾病的基于荚膜多糖的疫苗对包括疫苗的血清型非常有效，但它们不能对抗血清型替代。我们已经开发了一种新型的肺炎球菌疫苗，可提供不依赖血清型的保护，因此可以构成“通用”疫苗制剂。该制剂由γ射线（γ-PN）灭活的完整未包封的肺炎链球菌组成，我们以前曾报道过非佐剂鼻内疫苗接种后交叉反应免疫的诱导。为了进一步增强疫苗的免疫原性和安全性，我们改良了肺炎球菌疫苗株以在生长过程中诱导应激状态。特别，将用于进口锰的psaBCA操纵子的底物结合成分突变，以产生肺炎球菌表面抗原A（psaA）缺陷疫苗株。psaA突变在不严重影响肺炎球菌形态的情况下，严重减弱了体外疫苗株的生长，从而增强了疫苗的安全性。另外，针对基于改良菌株[γ-PN（ΔPsaA）]的疫苗制剂产生的抗体，与原始制剂诱导的抗体相比，对野生型肺炎球菌攻击菌株表现出更多样化的反应性。改良的疫苗还在肺中诱导了类似的保护性TH 17反应，并针对致命的异源性肺炎球菌攻击提供了更大的保护。总体，