Rational design of a respiratory syncytial virus vaccine to prevent asthma

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DESCRIPTION (provided by applicant): Respiratory syncytial virus (RSV) severe lower respiratory tract infections (LRTIs) in infants and young children associate with 25-80% greater subsequent rates of recurrent wheezing, airways hyperreactivity (AHR) and asthma compared to same age children not experiencing severe RSV LRTIs. Some of these severe RSV LRTIs may identify those infants genetically predisposed to develop asthma at older age, but epidemiological studies and animal models suggest that severe RSV LRTIs may also specifically contribute to asthma inception. In fact, enough evidence exists today to consider a potential role for protective RSV vaccines in decreasing pediatric asthma rates by preventing severe RSV LRTI. Interestingly, and in line with the overwhelming evidence supporting the Hygiene Hypothesis, upper respiratory tract infections (URTIs) during infancy have been shown to decrease the rates of pediatric asthma and AHR. Moreover, epidemiological data, studies in animal models, and preliminary data from our laboratory support the hypothesis that a rationally designed live attenuated intranasal (IN) RSV vaccine (mimicking an RSV URTI) may contribute to modulate the development of immunity in the host and prevent asthma inception. Data from others and our laboratory show that RSV and its main protective antigen, the fusion (F) protein, can elicit a long-lived natural T regulatory (nTreg) lymphocyte response, presumably through Myd88-dependent activation, negatively modulating asthma inception. In addition, animal and human data from our laboratory demonstrate that RSV can downregulate TLR4 expression in the respiratory tract. TLR4 expression in the respiratory epithelium is critical for the inception f asthma in the classic house dust mite (HDM) model of disease. Therefore, if all these observations - which we propose to study- are confirmed, rationale design of an RSV vaccine considering the aforementioned effects, may change the landscape of pediatric asthma by: I) protecting against the pro-asthmatic effects of RSV LRTI, and 2) "maturing" host immunity. Understanding the protective effects of RSV vaccines and the virus glycoproteins against the inception of asthma, and their mechanisms of risk modulation, can lead to the rationale design of a pediatric vaccine working simultaneously against two critical pediatric diseases. Our Specific Aims are: Aim 1. Determine whether intranasal immunization using RSV surface glycoproteins F and G modulates the inception of asthma. Aim 2. Determine whether RSV F vaccines decrease inception of asthma by expanding nTregs through Tlr2 activation and downregulation of Tlr4 expression in respiratory epithelium. Aim 3. Determine whether IN immunization with cptsRSV248-404 prevents the inception of asthma.