A study to assess the effect of varying the time interval between doses on the immunogenicity of an adjuvanted recombinant spike protein Covid-19 vaccine (Spikogen/Covax-19)

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.

Inclusion Criteria:

• Provide written informed consent prior to initiation of any study procedures.
• No history of previous Covid-19 vaccinations
• Women of childbearing potential must use an acceptable contraception method from at least 28 days before study vaccination until 14 days after last study vaccination.
• Understand and comply with planned study procedures and be available for all study visits.

Exclusion Criteria:

• Have a history of severe systemic reactions (anaphylaxis, breathing difficulties, severe rash) following previous immunization with licensed or unlicensed vaccines.
• Received an experimental agent within 30 days prior to the study vaccination or expect to receive another experimental agent during the trial-reporting period.
• Intend to receive another Covid-19 vaccine during the time of the study