Lack of antibody affinity maturation due to poor Toll-like receptor stimulation leads to enhanced respiratory syncytial virus disease.
Lack of antibody affinity maturation due to poor Toll-like receptor stimulation leads to enhanced respiratory syncytial virus disease.
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呼吸道合胞病毒（RSV）是婴儿住院的主要原因。1966年，福尔马林灭活的RSV疫苗被用于儿童免疫，并引发了非保护性的致病性抗体。两名免疫婴儿死亡，80%的婴儿在随后的RSV暴露后住院。从那以后，没有疫苗被批准。一种被广泛接受的假设将疫苗失败归因于福尔马林破坏保护性抗原。相反，我们表明缺乏保护不是由于福尔马林引起的改变，而是由于保护性表位的抗体亲和力低。Toll样受体刺激不良后缺乏抗体亲和力成熟。这项研究解释了为什么灭活RSV疫苗未能保护并因此导致严重疾病，阻碍了42年的疫苗开发。此外，这表明灭活RSV疫苗可以通过在其制剂中包含TLR激动剂而变得安全和有效。此外，它确定亲和力成熟为婴儿安全免疫的关键因素。
Respiratory syncytial virus (RSV) is a leading cause of hospitalization in infants. A formalin-inactivated RSV vaccine was used to immunize children in 1966 and elicited non-protective, pathogenic antibody. Two immunized infants died and 80% were hospitalized after subsequent RSV exposure. No vaccine was licensed since. A widely accepted hypothesis attributed vaccine failure to formalin disruption of protective antigens. Instead, we show that lack of protection was not due to alterations caused by formalin, but to low antibody avidity for protective epitopes. Lack of antibody affinity maturation followed poor Toll-like receptor stimulation. This study explains why the inactivated RSV vaccine failed to protect and consequently led to severe disease, hampering vaccine development for forty-two years. Also, it suggests that inactivated RSV vaccines may be rendered safe and effective by inclusion of TLR-agonists in their formulation. In addition, it identifies affinity maturation as a critical factor for the safe immunization of infants.
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