Lack of antibody affinity maturation due to poor Toll-like receptor stimulation leads to enhanced respiratory syncytial virus disease

Abstract

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.

Poly(U) and CpG ameliorate the unbalanced T cell immunity and pneumonia of mice with RSV vaccine-enhanced disease

“…LPS) and TLR4 knockout mice (e.g. C3H/ HeJ mice), the critical role of TLR4 in the pathogenesis of RSV-associated diseases, including RVED, has been confirmed (7,12,14,17,18). Therefore, as a supplement to the above findings, we conducted this research to further study the possible function of TLR7/8 and TLR9 in the onset of RVED.…”

“…While other researchers mainly studied the ineffective humoral immunity of FIRSV recipients (7,23), we highlighted the aberrant cellular immunity. With the help of flow cytometry, we were able to examine the secretions of the representative cytokines in different subtypes of T cells with more sensitivity and accuracy.…”

“…Consequently, we found that mice previously inoculated with FIRSV showed obvious weight loss and extensive pneumonia, as well as T helper 2 cells (Th2)-biased immunity and suppressed CD8 + (5,6). Some researchers demonstrated that the RSVspecific antibodies elicited by inactivated RSV vaccine, including FIRSV and ultraviolet-inactivated RSV vaccine (UVRSV), had relatively low avidity and was considered nonprotective (7,8). It is without a doubt that formalin impaired the immunogenicity of virus antigens to some extent.…”

“…MyD88 is a downstream adaptor of most TLRs, including TLR4 and TLR7/8. Recently MyD88 has been found to be important in the maturation of protective antibodies and viral control against RSV (7,16). Moreover, with the help of TLR agonists (e.g.…”

Неугодная Иммунология

“…Это вызвано тем, что подвергнутые обработке формалином антигенные белки имеют увеличенное количество ак-тивных карбонильных групп, что ведет к нарушению третичной структуры эпитопов [34,90]. 24 В России такая вакцина не зарегистрирована.…”