A Respiratory Syncytial Virus (RSV) vaccine is not yet available. Avatar is developing a novel, di-tyrosine crosslinked, conformationally locked preF subunit immunogen (DT-preF) that, formulated with an adjuvant, will form the basis of a preF RSV vaccine. The risk of vaccine-enhanced disease (VED) came into sharp focus with the results of a 1960s formalin- inactivated RSV vaccine that resulted in numerous hospitalizations and the deaths of two children. A maternal- to infant vaccination strategy using a potent immunogen is therefore now considered the safest and most promising strategy for protecting infants. We have developed a maternal-to-infant vaccination mouse model that uses a highly virulent subtype of RSV line 19, and is uniquely able to elicit immune responses and pathology in mice that mirror many of the fundamental, age-dependent characteristics of enhanced RSV disease observed in humans. The model can distinguish between safe and unsafe vaccine immunogen formulations, and using this this model enables us to identify a DT:preF:adjuvant formulation that overcomes the risks of VED. In Phase I of this proposal, we will test four DT-preF:adjuvant formulations and identify the one that elicits the most protective responses that does not cause VED in vaccinated, pregnant dams or non-pregnant female mice, or lead to the development of enhance respiratory disease (ERD) in infant mice born to immunized mothers, following RSV challenge.
In Aim I, we will rank and select the two most potent DT-preF:adjuvant formulations (based on neutralization titers) in immunized, adult female mice;
in Aim II, we will identify a lead DT-preF:adjuvant formulation that most effectively protects postpartum dams, newborn pups and weanlings following maternal vaccination (based on lung viral titers); and in Aim III, we will demonstrate that our DT-preF adjuvant formulation elicits protective responses that do not lead to the development of ERD in dams or infant mice following RSV challenge. In Phase II, we will carry out additional preclinical studies in cotton rats as the next step toward human clinical studies Our lead formulation will be innovative in that it will (i) have sufficient stability for commercial development, (ii) provide infants safe, potent, long-lasting, and cost-effective protection against RSV, and (iii) enable maternal- to-infant vaccination.
There is currently no effective vaccine for RSV; and each year, RSV infects 4-5 million children in the US and is the leading cause of infant hospitalizations (~120,000). Globally, it accounts for 6.7% of deaths in infants, second only to malaria; and in addition it poses a serious threat to the elderly and immuno-compromised. We propose to test adjuvant formulations with our RSV vaccine immunogen ? a recombinant soluble F fusion protein stabilized in its prefusion conformation ? that will trigger the production of antibodies in vaccinated individuals that will bind to, and neutralize the virus when it enters the body. We will select an adjuvant that enhances the potency of our immunogen, and that modulates immune responses to avoid any safety risks. !
