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.
