Phase I clinical trial to assess safety and immunogenicity of an MVA-based influenza H5 vaccine in healthy adults

Influenza viruses of the H5N1 subtype are transmitted from birds to humans on a
regular basis since 2003, particularly in South-east Asia and Egypt, resulting
in over 600 clinical infections and and a mortality rate of almost 60%. These
viruses are highly pathogenic and are considered to be a serious threat for
animal and human health. Therefore the development of H5N1 vaccines is
considered a priority by the WHO.

To address the hurdles in pandemic influenza vaccine development new vaccine
platforms are explored and under development. One of the promising platforms is
Modified Vaccinia virus Ankara. This virus is replication deficient in
mammalian cells (with a few exceptions) due to a block in morphogenesis which
means no new infectious virus particles are formed. After immunization the
vector virus can efficiently enter mammalian cells and induces in a single
round of infection with expression of viral and recombinant genes that results
in strong protein/antigen production. MVA has been developed as an alternative
smallpox vaccine and has been administered to over 120,000 individuals and was
shown to be safe and effective in these individuals and also proved to be safe
in immunocompromised subjects.

MVA virus can be used to shuttle a foreign gene, e.g. hemagglutinin gene from
influenza A/H5N1 virus. This way it can function as a viral vector that induces
a neutralizing antibody response against this highly pathogenic avian influenza
virus. Therefore such a vaccine is considered a suitable candidate as pandemic
influenza vaccine.

The preclinical evaluation of an MVA-based H5N1 vaccine candidate in mice and
macaques demonstrated that the vaccine is safe and strongly immunogenic in
these animals. All together this makes MVA a promising pandemic influenza
vaccine platform for the future. Therefore a clinical trial is conducted with
the MVA-H5 vaccine.

Primary objective

Safety assessment of the MVA-H5-sfMR vaccine in humans. Study subjects will
undergo physical examinations performed before and on fixed time points during
the study. Clinical chemistry is performed on the blood samples that are drawn
throughout the study and local and systemic reactions are monitored with a
daily dairy card during the first week after immunization.

Secondary objective

Assessment of the immunogenicity of the MVA-H5-sfMR vaccine in humans. The
immunogenicity will be determined by measuring influenza-specific antibody
titers in the hemagglutination inhibition assay and virus neutralization assay.
Furthermore the induction of HA-specific cytotoxic T cells will be assessed.

-Randomized double blind clinical trial
-Duration: 20 weeks (with 5 site visits: inclusion visit and 0, 4, 8 and 20
weeks after the first immunization)
-Setting: Erasmus MC, Rotterdam, The Netherlands

For further details please refer to the study protocol (document C1 of the CCMO
application)

The study subjects will receive one or two intramuscular immunizations (four
week interval) with the vaccine or the control vaccine in the upper arm.

In a recent study with an MVA-based vaccin (the dose was comparable to the
highest dose in the current study) most subjects experienced mild to moderate
local reactions such as pain at the injection site. This lasted for
approximately two days together with light swelling and redness of the
injection site. The majority of the subjects experienced no or mild to moderate
systemic reactions (headache, fever, myalgia, nausea).

Next to the possible side-effects the burden associated with participation
consists of: investment of time for the study-visits, filling out the dairy
cards, the intramuscular injection(s) in the upper arm (immunizations) and the
blood sampling (inside of the elbow).