Assessing the pyrogenicity of whole influenza virus particle vaccine in cynomolgus macaques
Assessing the pyrogenicity of whole influenza virus particle vaccine in cynomolgus macaques
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DOI：
10.1016/j.vaccine.2022.12.020
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发表时间：
2022-12-30
期刊：
影响因子：
5.5
通讯作者：
Kida，Hiroshi
中科院分区：
文献类型：
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作者：
Ohno，Marumi;Sagata，Masataka;Kida，Hiroshi
在灭活流感疫苗中，全病毒颗粒疫苗（WPV）在有效诱导体液和细胞免疫方面上级裂解病毒疫苗（SV）。然而，由于WPV具有强大的免疫原性，人们担心它会出现发烧等不良事件。因此，本研究研究了食蟹猴皮下注射良好生产级四价灭活流感疫苗（用于药物或试验用产品）诱导的发热反应。在第一次接种WPV后6-12 h，体温升高1 ℃-2 ℃，但在第二次接种时没有，而SV在两个时间点均不影响体温。鉴于WPV的强致敏能力，WPV诱导的发热可能归因于致敏期间唯一发生的免疫应答。由于WPV诱导的发热可通过吲哚美辛（一种环氧合酶抑制剂）预处理而减弱，因此认为WPV的发热反应取决于环氧合酶合成的野牡丹素的增加。此外，WPV，但不是SV，诱导升高的I型干扰素和单核细胞趋化蛋白1在血浆中，这些因素可能是负责由WPV引起的致热原性，因为它们可以增加脑中的肾上腺素。值得注意的是，通过一半量的WPV获得了足够的抗体应答而不引起发热，表明获得性免疫诱导不需要引发发热应答的过度免疫应答。因此，我们建议应评估抗原剂量减少的WPV的潜在临床用途，特别是在初治人群中。
Among inactivated influenza vaccines, the whole virus particle vaccine (WPV) elicits superior priming responses to split virus vaccine (SV) in efficiently inducing humoral and cellular immunity. However, there is concern for undesired adverse events such as fever for WPV due to its potent immunogenicity. Therefore, this study investigated the febrile response induced by subcutaneous injection with quadrivalent inactivated influenza vaccines of good manufacturing grade for pharmaceutical or investigational products in cynomolgus macaques. Body temperature was increased by 1 °C-2 °C for 6–12 h after WPV administration at the first vaccination but not at the second shot, whereas SV did not affect body temperature at both points. Given the potent priming ability of WPV, WPV-induced fever may be attributed to immune responses that uniquely occur during priming. Since WPV-induced fever was blunted by pretreatment with indomethacin (a cyclooxygenase inhibitor), the febrile response by WPV is considered to depend on the increase in prostaglandins synthesized by cyclooxygenase. In addition, WPV, but not SV, induced the elevation of type I interferons and monocyte chemotactic protein 1 in the plasma; these factors may be responsible for pyrogenicity caused by WPV, as they can increase prostaglandins in the brain. Notably, sufficient antibody responses were acquired by half the amount of WPV without causing fever, suggesting that excessive immune responses to trigger the febrile response is not required for acquired immunity induction. Thus, we propose that WPV with a reduced antigen dose should be evaluated for potential clinical usage, especially in naïve populations.