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

Polack, F.P. et al. Nat. Med. 15, 34-41 (2008)

Speaker: Shih-Ping Chang (張時斌)                               Time: 15:00~16:00, Mar. 4, 2009

Commentator: Dr. Yao Chang (張堯 博士)                   Place: Room 601

Abstract:

Respiratory syncytial virus (RSV) is the leading cause of lower respiratory tract infection in infants and children worldwide. Yet, no licensed RSV vaccine is currently available since formalin-inactivated vaccine against RSV (FIRSV), a vaccine administered to children in 1960s, failed to protect hosts and caused two deaths after infection (2). Non-protective antibodies were found in the children immunized with FIRSV with pulmonary eosinophilia, pneumonia, and airway hyperresponsiveness, known as enhanced respiratory disease (ERD), which increased morbidity after infection (1). Detailed studies towards prevention of vaccine-associated diseases are important for the development of a safe and effective vaccine. Here the author used a mouse model to identify the major problem of FIRSV that turned  into a non-protective vaccine. In disagreement with previous hypothesis proposing that the disruption of RSV antigens by formalin is the major cause of non-protective antibodies, here the author highlighted the importance of affinity maturation of protective antibody. RSV-specific antibody with low avidity was found in FIRSV-immunized mice, which explained the weak neutralizing activity of FIRSV-induced antibody. The author proved that it was poor Toll-like receptor stimulation that led to the incomplete activation of dendritic, T, and B cells and turned out to cause the low avidity of FIRSV-induced antibody. Once Toll-like receptor activation was strengthened, both avidity and neutralizing activity of antibody rose and protected mice from RSV infection without causing ERD. Taken together, the findings here try to unwind the rope that has dampened RSV vaccine development for more than 40 years.

References:

1.         Castilow, E. M., M. R. Olson, and S. M. Varga. 2007. Understanding respiratory syncytial virus (RSV) vaccine-enhanced disease. Immunol Res 39:225-39.

2.         Kim, H. W., J. G. Canchola, C. D. Brandt, G. Pyles, R. M. Chanock, K. Jensen, and R. H. Parrott. 1969. Respiratory syncytial virus disease in infants despite prior administration of antigenic inactivated vaccine. Am J Epidemiol 89:422-34.