A Universal Flu Vaccine Based On Conformationally Locked Soluble Headless HA

An Influenza pandemic remains an acute threat to world health; and stockpiling a universally protective
Influenza vaccine provides a strong defense against this potential catastrophe. The hemagglutinin (HA)
protein is the primary target of humoral Ab responses to Influenza; the majority of broadly protective mAbs
(bnAbs) against influenza isolated from humans recognize conserved and conformation-specific epitopes in the
HA Stalk. But, strain-specific, immunodominant epitopes in the Head of HA overwhelm immune responses to
the Stalk. An HA immunogen from which the Head domain has been removed will elicit anti-Stalk antibodies
that protect broadly against seasonal, as well as pandemic, Influenza. Despite significant progress, it has so
far not proved possible to design a stable Headless HA that assumes its fully native conformation and thereby
elicits universally protective Ab responses. None of the most promising, recent designs have progressed to
clinical development.
Avatar has developed a strategy to produce a conformationally intact Headless HA that overcomes these
limitations. This strategy involves first locking the structure of the conserved Stalk with target dityrosine (DT)
crosslinks, so that it can no longer lose its native conformation. Then we remove the variable and
immunodominant Head domain with a site-specific protease, using engineered recognition sites. This DT-
Headless HA immunogen is in its fully native conformation, and responses to this more perfect immunogen will
improve Ab titers and affinities to conserved epitopes, and thus protect broadly against all strains of Influenza.
In Phase I, we successfully designed and characterized our DT-Headless HA (AI118087). In Phase II we will
demonstrate heterologous protection in Balb/c mouse challenge studies, and confirm efficacy of this product in
ferret challenge studies (Aims 1 andamp; 2). We will also transfer our design into a Group II HA and test its
heterologous protection in mouse and ferret lethal challenge studies (Aim 3 andamp; 4). By inducing higher avidity,
higher titer Ab responses to the conserved Stalk, Avatarandapos;s Headless HA immunogen will give rise to broad
protection against homologous and drift variants, as well as Group 1 andamp; 2 heterologous challenge. We will
compare the results obtained with our Group I and II Headless HA immunogens and select a product candidate
for preclinical and clinical development.Influenza pandemic outbreaks remain an acute threat to world health; and stockpiling a broadly protective
influenza vaccine would defend against such a potential catastrophe. We propose to confirm that our highly
innovative Influenza vaccine immunogen protects against all strains of the Influenza virus, including pandemic
strains Influenza, by specifically triggering the production of antibodies in vaccinated individuals that bind to,
and inactivate the virus when it enters the body.