Development of an anti-idiotype based vaccine for respiratory syncytial virus

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PROJECT SUMMARY/ABSTRACT Respiratory Syncytial Virus (RSV) is a common pathogen that causes lower respiratory tract infections leading to significant morbidity and mortality at the extremes of age. Primary RSV infection is responsible for ~60,000 deaths in children under 5. Passive transfer of a monoclonal neutralizing antibody that targets the RSV fusion protein (F) is the only prophylactic treatment for infant RSV infection that has proven to be protective, but its widespread use is limited due to cost limitations. Thus, a vaccine that could elicit protective neutralizing antibodies would have a significant, cost effective, global health benefit. However, the development of an RSV subunit vaccine that is efficacious in infants has remained elusive. This is in part due to the metastable nature of recombinant RSV F, and to the unique challenges facing infant immunization including the presence of pre-existing maternal antibodies that can interfere with infant immune responses, and limited ability of the immature infant immune system to respond to vaccination. A class of antibodies that potently neutralize RSV has recently been identified. These antibodies arise from the chromosomally encoded VH3-21/VL1-40 antibody genes and are unique in that they are structurally pre-configured to bind to and neutralize RSV and do not need to undergo affinity maturation to achieve potent neutralizing activity. A vaccine that can selectively engage B cells capable of producing VH3-21/VL1-40- derived antibodies would hence lead to rapid RSV neutralization following immunization. Here we propose to develop anti-idiotypic monoclonal antibodies (ai-mAbs) that have a high affinity and specificity for B cells expressing re-arranged, unmutated BCRs derived from VH3-21/VL1-40 pairs and use these to develop vaccine immunogens. This unconventional approach is well suited to selectively engage target B cells while at the same time being completely antigenically distinct from RSV F. Importantly since VH3-21/VL1-40 do not require affinity maturation to achieve potent neutralizing activity an ai-mAb-based vaccine could be effective in infants, whose affinity maturation processes are still inefficient. The antigenic disparity between RSV F and ai-mAbs presents additional advantages in the context of infant vaccination, as it should eliminate the ability of maternal antibodies to interfere with the infant humoral response through the masking or disruption of relevant epitopes on RSV F. Moreover, ai-mAbs should eliminate or reduce the risk of vaccine-enhanced disease by not presenting irrelevant RSV F epitopes, which has been attributed to the elicitation of non-neutralizing anti-RSV F antibodies in previous vaccine formulations. Herein we will use complementary approaches to develop and evaluate ai-mAb derived vaccines. If successful, these approaches will provide a crucial proof of concept and clear path for the development of an ai-mAb- derived RSV vaccine for the most vulnerable population.