Mechanisms of respiratory syncytial virus specific T cell activation

Abstract

Respiratory syncytial virus (RSV) is an important cause of severe lower respiratory tract infections (LRTI) in infants, elderly people and immune compromised individuals. Moreover, RSV causes repeated symptomatic re-infections in healthy individuals, which is presumed to be due to ineffective acquired immunity. A vaccine is currently not available. Vaccine development has been set back dramatically after a disastrous vaccine trial in the 1960s with a formalin-inactivated (FI)-RSV vaccine, which caused disease enhancement upon natural infection. RSV is highly infectious and has a high attack rate very early in life. Thus vaccine development faces major difficulties: 1. intervention is necessary soon after birth, which is challenging due to immaturity of the immune system that is characterized by a Th2 bias, which appears to be unfavorable for RSV, 2. a vaccine needs to be effective in the presence of maternal antibodies, 3. inactivated or subunit vaccines tend to induce immune pathology, 4. the fact that immune protection after natural infection is incomplete. Our study focused on the mechanism of the induction of RSV-specific T cell and antibody responses. We first addressed the role of pre-existing antibodies during the priming phase of the virus specific immune response. We showed that the balance of pre-existing virus-neutralizing versus non-neutralizing antibodies affected the balance of the antiviral CD4+/CD8+ T cell response induced upon viral infection. Neutralizing antibodies decreased the induction of CD8+ T cell responses, while both neutralizing and non-neutralizing antibodies increased CD4+ T cell responses by increasing Fc-receptor mediated antigen presentation via MHC class II molecules. We hypothesize that these antibody mediated effects might be an explanation for the low virus specific CD8+/CD4+ memory T cell ratio’s in frequently re-infected adults that contrasts with a predominantly CD8+ T cell response during primary infection in infants. We also showed that virus specific antibodies can alter the repertoire of CD8+ T cells, which resulted in the mouse model in a memory response against an enhanced epitope repertoire. We further unraveled the mechanism by which the FI-RSV vaccine caused the strong allergic (Th2 biased) response during viral challenge in a mouse model. We excluded that vaccine specific components like the structural alterations caused by formalin treatment, or the alum adjuvant present in the vaccine, or the specific characteristics of viral proteins were responsible for the Th2-biased enhanced disease mechanism. Rather the major reasons for vaccine failure are the lack of induction of a virus specific CD8+ T cell response by the inactivated vaccine and an inefficient Th1 priming, combined with the fact that natural RSV infection does not induce an innate immune response that supports local Th1 maturation. Our findings suggest that future vaccines should induce high titer neutralizing antibodies to prevent virus induced cytopathogenic effects and strong inflammatory responses. Moreover, the vaccine should induce CD8+ T cell responses to prevent allergic features during natural virus exposure. These conditions might be best created by live attenuated vaccines or replication-competent gene-based vectors.