Acronym: PANFLUVAC
EC contribution: €3 334 798
Duration: 48 months
Starting date: 01/01/2007
Instrument: STREP
Key words: Pandemic H5N1 influenza, intranasal
delivery, virosomal vaccine, lipopeptide adjuvants,
dendritic cell targeting, pre-clinical to clinical
evaluation strategy
Influenza epidemics remain a burden for
both human health and national economies,
as witnessed by the recent advance of the
pathogenic avian H5N1 influenza virus. While the
numbers of human deaths in Europe has remained
relatively low, the presence of such cases in Turkey
demonstrates the danger posed by this virus. The
avian H5N1 virus has now been detected in wild
birds in numerous European countries, and the
PANFLUVAC consortium is committed to creating
an efficacious vaccine against this virus, to
provide strong protection in a pandemic situation.
The overall aim of PANFLUVAC is to construct
vaccine delivery systems for intranasal and
parenteral vaccines. New H5N1 vaccines are to be
based on well-established virosome technology
— proven its worth for efficacious interpandemic
vaccines — as well as whole virus vaccines. This
will permit comparison of the intranasal virosomal
vaccine with the whole virus vaccine. The vaccine
potency will be enhanced by novel adjuvants
targeting dendritic cells, offering both antigensparing
potential and immunopotentiation
characteristics. Both ISCOMs and lipopeptide
adjuvants are already proven immunopotentiators,
biosafe for humans. Certain of these have been
employed with experimental influenza vaccines
which allow the new H5N1 vaccines to be
fast-tracked in their development. Accordingly,
PANFLUVAC will generate the first H5N1 vaccine
within the first 18 months of the project.
The PANFLUVAC project is also designed to
facilitate rapid modification of the vaccine in
the face of virus drift. Within the preclinical
evaluation, the new vaccines will be tested for the
degree of heterotypic cross protection they offer.
PANFLUVAC offers a generic vaccine development
system to provide safe and efficacious vaccines
against influenza, fitting in with the European
Commission’s Working Paper on Community
Influenza Pandemic Preparedness and Response
Planning.
The challenge
The avian H5N1 influenza virus is now spreading
among the wild bird population in Europe, and
infection of humans has already reached the borders
of continental Europe. For a truly efficacious vaccine,
one must consider the route of virus entry into the
host (the respiratory tract), and host requirements
for protective immune defences. That is, an ideal
vaccine should induce both local (mucosal) and
systemic (serum) immunity.
Currently, parenterally administered inactivated
influenza vaccine is the best prophylactic control
measure. However, parenteral vaccination does
not ensure induction of local immunity in the
respiratory tract — the route by which the virus
infects humans — and from where it transmits
to other individuals. Inducing mucosal immunity
by vaccination would enhance control of both
disease and transmission. Although mucosal
immunisation has been studied, no acceptable
intranasal vaccine against influenza is yet
available. A major problem for the intranasal
vaccine has been the adjuvant, which is required
for efficient induction of immunity.
WHO recommendations
The WHO assessment of the risk to human
health from the H5N1 avian influenza virus
states: 'The disease in humans has no vaccine
to confer protection and no specific treatment
once illness becomes severe.' The WHO warning
that 'outbreaks in birds pose a significant threat
to human health', and that H5N1 'has the
potential to ignite a global influenza pandemic
in humans', has led to an urgent requirement for
H5N1 pandemic influenza virus vaccines. The
PANFLUVAC vaccines fit this requirement and
allow for a rapid response to the entry of H5N1
into Europe, enforcing the WHO recommendation
that 'trials of experimental influenza pandemic
vaccines for humans be accelerated'.
Antigen-sparing strategies and effects
of immunomodulatory molecules
PANFLUVAC is designed to construct a vaccine delivery and formulation to meet current and
future influenza pandemics. The proposed H5N1
vaccine will be prepared with regard to the
immediate needs, as identified above by the
WHO. In addition, the project will generate the
'mock-up' library of vaccine reagents to meet
the permanent threat from pandemic influenza.
The overall aim is to construct the efficacious
H5N1 vaccine, enhancing the capacity to protect
the people of Europe both now and in the
future, rather than just in the short term. The
rapidly ageing European population, which is
particularly vulnerable to influenza complications
and influenza-related deaths, is a clear reminder
of the need for better interpandemic as well as
pandemic vaccines.
The project allows for ‘robust scale-up of
vaccine production’, being coordinated by the
leading group in virosomal technology – Crucell
(partner 2 CRU). CRU holds the intellectual
property rights for the application of ISCOMs
for influenza vaccines. To this end, the project
employs the latest advances in reverse genetics
(partner 3 - National Biological Standards Board)
— referred to in the Commission Working
Paper (COM(2004)201 final). This allows for
novel vaccines to be provided within a short
time. Vaccine efficacy will be enhanced through
application of novel formulations and adjuvants,
in response to the requirement in the call for
antigen-sparing strategies and the application of
novel immunopotentiating agents. The proposed
adjuvants, both current and under development,
will provide the formulated vaccine with a potent
immunogenicity. Moreover, these selected
adjuvants target the dendritic cells, which are
critically important for the activation of an
efficacious immune response. This allows for the
development of more efficacious vaccination and
better usage of the vaccine available.
By promoting the vaccine to reach the target
organs and cells more efficiently, lower doses of
vaccine are required to maintain immunogenic
concentrations. This increases the likelihood
of manufacturing potential r eaching demand, and reduces the risk of adverse side effects
due to incorrect interaction with organs. It also
responds to the Commission Working Paper
(COM(2004)201 final), on development of a safe
vaccine.
The proposed solution
PANFLUVAC will create an efficacious vaccine
inducing potent local and systemic immune
responses to protect the host and prevent
viral transmission. This is based on virosomal
technology, together with a novel lipopeptide
adjuvant targeting the critical cells of the
immune system – dendritic cells. Consequently,
PANFLUVAC will provide a particularly efficacious
and safe vaccine against influenza virus (H5N1).
In addition, the basis for efficacious intranasal
and parenteral vaccines will be established, for
future demands.