A Randomised, Controlled, Phase 1 Study to Evaluate the Safety and Immunogenicity of a Candidate Adjuvanted Recombinant Protein SARS-COV-2 Vaccine in Healthy Adult Subjects

Human infections with zoonotic coronaviruses including severe acute respiratory syndrome coronavirus (SARS CoV), Middle East respiratory syndrome-associated coronavirus (MERS CoV) and now 2019 SARS-CoV-2, all pose major human public health threats with high case fatality rates. The outbreak of SARS-CoV-2, which shares high similarity with SARS-CoV in its viral genome, has so far caused more than 4,736,000 cases worldwide (as of May 17, 2020) with 3131,545 deaths, resulting in an estimated overall mortality rate of 4-5%. It has a particularly high mortality rate in elderly people and those with chronic disease. To fight the current outbreak and prepare for future human outbreaks of similar coronaviruses, development of a safe and effective SARS-COV-2 vaccine remains a high priority. The fatality rate in the elderly is very high, being 8% for those over 70 and over 20% for those over 80. Notably, over 16% of the Australian population is aged 65 or older. Currently there is no way to control infection with SARS-COV-2 other than minimise exposure by social isolation.

Development of a vaccine against COVID-19 would deliver major public health and economic benefits for Australia, with potential to prevent numerous deaths, particularly among the Australian elderly, reducing the burden on hospital ICUs, helping to alleviate public concern, and ultimately allowing the Australian economy to return as fast as possible to normal.

SARS-CoV and SARS-CoV-2 are both closely related enveloped, single positive-stranded RNA viruses, with one genome encoding a non-structural replicase polyprotein and structural proteins, including spike (S), envelope (E), membrane (M) and nucleocapsid (N) proteins. SARS virus neutralizing antibodies were shown to be directed against the S protein. S protein can be cleaved into S1 and S2 subunits by proteases and within the S1 subunit there is a receptor-binding domain (RBD), which was shown to bind angiotensin-converting enzyme 2 (ACE2), which mediates SARS virus entry into cells. SARS-CoV-2 spike protein similarly binds ACE2 for cellular entry. Hence a recombinant SARS-CoV-2 spike protein vaccine that induces neutralising antibody against the virus should be effective against SARS-CoV-2 infection just as seen for SARS CoV.

SARS-COV-2 vaccine design is best informed by previous experience with closely related SARS CoV vaccines. Antibodies against the coronavirus spike protein blocks infection. When recombinant SARS spike protein vaccines produced in insect cells were formulated with Advax adjuvant, this enhances neutralizing antibody and T cell responses which translate into rapid lung viral clearance. Based on experience with developing successful and safe SARS and MERS vaccines, Covax-19 vaccine design is based on recombinant insect cell- expressed SARS-COV-2 spike protein formulated with Advax-SM adjuvant. The vaccine is based on recombinant expression of the ecto-domain of spike protein in insect cells. Insect cell expression of recombinant protein is a well characterised platform, allowing standardised procedures to be rapidly transferred to other facilities around the world. In response to the 2009 H1N1 influenza pandemic, roll-out of a pandemic vaccine based on hemagglutinin protein was extremely fast, with the first cGMP batches of vaccine produced within 6 weeks of virus discovery, and the first human trial subject dosed at Flinders just under 3 months after virus discovery . The use of Advax adjuvant doubled the seroconversion and seroprotection rates while maintaining vaccine tolerability and safety. Recombinant proteins manufactured using this method and formulated with Advax adjuvants have been found to be effective and safe in multiple human trials, including of H1N1/2009 and H5N1 (NCT02335164) and H7N9 (NCT03038776) influenza vaccines.

Covax-19 consists of highly purified recombinant SARS-COV-2 spike protein plus Advax-SM adjuvant in a sterile solution for intramuscular injection. COVAX-19™ vaccine is manufactured using a Sf9 platform. Advax-CpG adjuvant has previously been well tolerated and effective in trials of hepatitis B, H5N1 (NCT02335164) and H7N9 (NCT03038776) influenza vaccines and has recently been tested by the NIH in a US multicentre clinical trial with 2 quadrivalent seasonal influenza vaccines (NCT03945825).