The SARS-CoV-2 outbreak has caused millions of deaths globally. It has a particularly
high mortality rate in elderly people and those with chronic disease where mortality
rates can be as high as 20-30%. SARS-COV-2 vaccines remain a key priority to help fight
the current pandemic and prepare for future coronavirus outbreaks. COVID-19 vaccines have
potential to prevent symptomatic infections and may help reduce virus transmission.
Covax-19/Spikogen is the first full length recombinant spike protein vaccine in the world
to receive emergency use authorisation after it was shown in Phase 3 trials to be 60-65%
effective at preventing symptomatic infection with the delta variant. It has been
reported for other Covid-19 vaccines that a longer dose interval between first and second
doses may further increase vaccine immunogenicity and protection. As a 3-week dose
interval was tested in the clinical trials that supported Spikogen's authorisation, it
will be beneficial to test whether a longer dose interval than 3 weeks may have a
favourable effect on vaccine immunogenicity and thereby protection.

SARS-CoV-2 is an enveloped, single positive-stranded RNA virus, with one genome encoding
a non-structural replicase polyprotein and structural proteins including spike (S),
envelope (E), membrane (M) and nucleocapsid (N) proteins. Neutralizing antibodies are
directed against the S protein receptor binding domain (RBD). T cells directed against
the S protein may also play a role in protection and virus clearance.

Spikogen, also known under the Covax-19 tradename in Australia, is based on recombinant
SARS-COV-2 spike protein manufactured in insect cells that is formulated with a
combination adjuvant known as Advax-CpG55.2. Insect cell expression of recombinant
protein is a well-established vaccine manufacturing approach. The purified recombinant
protein is formulated with Advax-CpG55.2 adjuvant to ensure a sufficiently robust immune
response enabling the vaccine to produce protective levels of immunity. Advax-CpG55.2 has
two components, one a natural plant sugar called inulin and the second a short synthetic
polymer made up of oligonucleotides, known as CpG55.2. Advax-CpG adjuvant has been used
in multiple human clinical trials of influenza and Covid-19 vaccines and has been found
to be safe and well tolerated, just causing a mild increase in local injection site
soreness when compared to a saline injection.

Spikogen vaccine is designed to protect against SARS-CoV-2 infection by generation of
antibodies and memory cells against the spike protein. It has been shown to provide
protection against SARS-CoV-2 virus infection in hamster, ferret and monkey models. In
the hamster model it was shown to provide protection against the original Wuhan strain as
well as against the more recent beta and Delta variant strains. In preclinical studies it
was well tolerated and caused no major adverse reactions. Following successful completion
of a Phase 2 trial in 400 adult participants that confirmed its safety and
immunogenicity, a Phase 3 clinical trial was undertaken in Iran involving 16,876
participants randomised 3:1 to receive active vaccine or placebo using two intramuscular
doses administered 3 weeks apart. Spikogen vaccine successfully met its prespecified
primary efficacy endpoint established by the Iranian FDA, namely demonstration of >60%
protection against symptomatic PCR-confirmed infection. On this basis of efficacy shown
in the Phase 3 trial, Spikogen received emergency use authorisation by the Iranian FDA in
October 2021, making it the first such vaccine in the world to receive authorisation.
Since its authorisation more than 1 million doses of Spikogen vaccine have been safely
delivered.

It is now planned to undertake a clinical trial in Australia to determine, based on
measurement of anti-spike antibody levels, the optimal time between the two doses when
the vaccine is used as a primary immunisation regimen in vaccine-naive individuals.

Rationale for schedule of administration The aim is to determine the best dose interval
for a course of 2 doses in vaccine naïve individuals. This trial will administer two
doses of vaccine to vaccine-naïve individuals at variable intervals (3, 4, 5 or 6 weeks)
to assess the effect of timing of the second vaccine dose on anti-spike protein antibody
production.

Rationale for selection of doses In the Phase 3 clinical trial, two 25 ug doses of
vaccine given 3 weeks apart provided 60-65% protection against symptomatic SARS-CoV-2
infection with the delta strain. This trial will test the same dose of the authorised
vaccine as used in the pivotal Phase 3 trial but just with a varying time window between
the two doses.