Department of Pharmaceutical Sciences, University of Pittsburgh School of Pharmacy, University of Pittsburgh, Pittsburgh, PA, United States.
Department of Pathology, University of Pittsburgh School of Medicine, University of Pittsburg, Pittsburgh, PA, United States.
Front Immunol. 2022 Oct 4;13:1025341. doi: 10.3389/fimmu.2022.1025341. eCollection 2022.
Respiratory syncytial virus (RSV) remains the most common cause of lower respiratory tract infections in children worldwide. Development of a vaccine has been hindered due the risk of enhanced respiratory disease (ERD) following natural RSV exposure and the young age (<6 months) at which children would require protection. Risk factors linked to the development of ERD include poorly neutralizing antibody, seronegative status (never been exposed to RSV), and a Th2-type immune response. Stabilization of the more antigenic prefusion F protein (PreF) has reinvigorated hope for a protective RSV vaccine that elicits potent neutralizing antibody. While anecdotal evidence suggests that children and adults previously exposed to RSV (seropositive) are not at risk for developing vaccine associated ERD, differences in host immune responses in seropositive and seronegative individuals that may protect against ERD remain unclear. It is also unclear if vaccine formulations that skew towards Th1- versus Th2-type immune responses increase pathology or provide greater protection in seropositive individuals. Therefore, the goal of this work was to compare the host immune response to a stabilized prefusion RSV antigen formulated alone or with Th1 or Th2 skewing adjuvants in seronegative and seropositive BALB/c mice. We have developed a novel BALB/c mouse model whereby mice are first infected with RSV (seropositive) and then vaccinated during pregnancy to recapitulate maternal immunization strategies. Results of these studies show that prior RSV infection mitigates vaccine-mediated skewing by Th1- and Th2-polarizing adjuvants that was observed in seronegative animals. Moreover, vaccination with PreF plus the Th1-skewing adjuvant, Advax, increased RSV F85-93-specific CD8 T cells in both seronegative and seropositive dams. These data demonstrate the importance of utilizing seropositive animals in preclinical vaccine studies to assess both the safety and efficacy of candidate RSV vaccines.
呼吸道合胞病毒（RSV）仍然是全球儿童下呼吸道感染的最常见原因。由于自然 RSV 暴露后发生增强型呼吸道疾病（ERD）的风险以及儿童需要保护的年龄（<6 个月）较小，疫苗的开发受到阻碍。与 ERD 发展相关的危险因素包括中和抗体能力差、血清阴性（从未接触过 RSV）和 Th2 型免疫反应。更具抗原性的预融合 F 蛋白（PreF）的稳定化重新激发了对能够引发有效中和抗体的 RSV 保护性疫苗的希望。虽然有传闻证据表明先前接触过 RSV（血清阳性）的儿童和成人不会有发生疫苗相关 ERD 的风险，但血清阳性和血清阴性个体中针对 ERD 具有保护作用的宿主免疫反应的差异仍不清楚。也不清楚偏向 Th1 型与 Th2 型免疫反应的疫苗配方是否会增加病理学或在血清阳性个体中提供更大的保护。因此，这项工作的目标是比较单独使用或与 Th1 或 Th2 偏向佐剂一起配制的稳定化预融合 RSV 抗原在血清阴性和血清阳性 BALB/c 小鼠中的宿主免疫反应。我们开发了一种新型 BALB/c 小鼠模型，其中小鼠首先感染 RSV（血清阳性），然后在怀孕期间接种疫苗，以重现母体免疫策略。这些研究的结果表明，先前的 RSV 感染减轻了在血清阴性动物中观察到的由 Th1 和 Th2 极化佐剂介导的疫苗介导的偏向。此外，用 PreF 加 Th1 偏向佐剂 Advax 接种疫苗可增加血清阴性和血清阳性母体中 RSV F85-93 特异性 CD8 T 细胞。这些数据表明，在临床前疫苗研究中利用血清阳性动物来评估候选 RSV 疫苗的安全性和疗效非常重要。
