An RSV Prefusion F Vaccine that Overcomes Immunosenescence

Respiratory Syncytial VirusRSVinfection in the elderly causes great human suffering due to hospitalization and deathand is considered a societal burden similar to that of seasonal influenzaVaccines for the prevention of RSV infections are not yet availableand development efforts are made all the more difficult in the elderly due to age associated immunosenescence that impairs their ability to mount protective immune responsesA highly potent vaccine that overcomes immunosenescence is therefore sorely needed! RSV F subunit vaccine immunogens that hold the pre fusion conformationpreFinduce very high neutralizing titers that correlate with potent protectionWe are developing such a preF subunit immunogenDT preFand animal models that will allow us to identify a DT preF formulation that provides the elderly maximal protection from RSVOur preliminary data suggests that our aged mouse model distinguishes between more and less potent vaccinesThis proposal is further strengthened by a set of preclinical data in adult mice and cotton rats demonstrating that our DT preF elicits high neutralizing titersfully protects cotton rats from viral challengeand has impressive stability in vitroIn Phase Iof this fast track proposalwe prove that aged mice effectively distinguish between more and less potent DT preF formulationsenabling their characterization and down selection in immunogenicity and challenge experimentsAim IIn Phase IIwe rank and select the best two formulations for further evaluationbased on anti F Ab and neutralization titers and cellular responses in young and aged mice immunized with eight DT preF dose adjuvant combinationsAim IThen we select our lead dose and adjuvant pair based on viral lung titers following challenge with RSVAim IIWe further support our mouse data in a second animal modelRSV pre immune aged cotton ratswhich better replicates human RSV infectionand that also better mirrors the RSV immune status of the elderlyAim IIIThe key innovation of this proposal is our DT preF that is formulated specifically to maximize protection in the elderlyand that uniquely overcomes immunosenescence! !There is currently no effective vaccine for RSVRSV poses a serious threat to the elderly population whose immune responses are weakened due to age associated decreases in their ability to mount protective responsesWe propose to test adjuvant formulations with our RSV vaccine immunogena recombinant soluble F fusion protein stabilized in its prefusion conformationthat will trigger the production of antibodies in vaccinated individuals that will bind toand neutralize the virus when it enters the bodyWe will select an dose and an adjuvant that enhances the potency of our immunogen in the elderlyand that formulated as a vaccine will protect the elderly from this life threatening infectious disease!