Phase 1 trial results published in The Lancet Infectious Diseases found a new subunit vaccine —an MF59-adjuvanted subunit vaccine using recombinant spike glycoprotein stabilized in a prefusion conformation by a novel molecular clamp — targeting the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was safe and effective in producing an antigen-specific response in healthy adults.
The development of new and storage-friendly vaccines would be beneficial for countries that have struggled to inoculate their populations.
The SARS-CoV-2 sclamp antigen vaccine was produced using hamster vary cells and uses the spike glycoprotein ectodomain fused to a molecular clamp. The recombinant protein uses the SARS-CoV-2 strain first detected in Wuhan, China, with several alterations, including replacing the furin cleavage site of spike glycoprotein amino acids and removing the C-terminal domain.
Prior work on the vaccine has shown it adopting a native prefusion conformation that would bind to ACE2 receptor and monoclonal antibodies specific to the virus. Unlike the currently available mRNA viruses, the Sclamp vaccine is refrigerated at 2 to 8°C.
The phase 1 clinical trial took place in Brisbane, Australia, from June 23, 2020, to August 17, 2020. The researchers screened 314 adults ranging from 18 up to 55 years of age for eligibility into the study. Eligibility included people who tested negative for SARS-CoV-2, had no prior exposure to someone with the virus, and showed no evidence of antibodies specific to SARS-CoV-2 that would indicate a previous infection.
About 120 participants met study criteria and were then randomly selected to one of five treatment groups that would include a placebo, two vaccine doses at different quantities (5 μg, 15 μg, or 45 μg) administered intramuscularly, or only one dose of the vaccine at 45 μg with placebo at the second dose. All participants were given their first dose on day 1 and the other dose on day 29 of the study. Of the original 120, 114 or 95% of participants completed the trial up to day 57.
Safety results of vaccine
The vaccine was well-tolerated overall, with a majority of vaccine-induced side-effects to be expected by researchers. The following gained expected adverse effects: 79% of participants in the placebo group, 92% in the 5 μg group, 96% in the 15 μg group, 83% participants in the single vaccine dose 45 μg group, and 88% in the two-dose 45 μg vaccine group.
Unsolicited adverse events were reported in 29% of participants in the placebo group, 54% in the 5 μg group, 29% in the 15 μg group, 33% in the single-dose 45 μg group, and 29% in the two-dose 45 μg vaccine group.
Adverse events that would have been related to the vaccine happened in one participant in the placebo group, 17% in the 5 μg group, 13% in the 15 μg group, 17% participants in the single-dose 45 μg group, and 4% in the two-dose 45 μg vaccine group.
Expected but severe side effects occurred amongst 8% of the placebo group and 3% of participants in any vaccine group. There were no severe side-effects that would warrant discontinuation of the study or death.
The most common expected side effect seven days after vaccination was mild or moderate pain and tenderness around the injection site. This was reported more in participants of any vaccine group compared to the placebo group.
Project co-leader Associate Professor Keith Chappell said 99 per cent of vaccinated participants in the study produced a neutralising immune response. “In 75 per cent of vaccine recipients it was above the average in recovered patients, and in 38 per cent it was more than twice the average for recovered patients," he said. "Adverse events were comparable to those in the saline placebo, with the only exceptions being mild injection site pain and tenderness.”
Vaccine-induced immune response
On day 57, almost 99% of participants in a vaccine group — regardless of dose — displayed neutralizing activity against SARS-CoV-2. Only 25% of participants who received a single vaccine dose but then a placebo produced an immune response. As expected, no one from the placebo group developed immunity.
Regardless of dosage, all groups in the two-dose vaccine groups developed similar antibody responses. The antibody responses of all vaccine groups were more significant than the placebo group at days 15, 29, and 43.
When antibodies were tested against live variants — the Wuhan and Asn501Tyr strains — instead of the pseudovirus spike glycoprotein variants, they showed greater neutralizing activity at day 57 than the placebo group.
The vaccine created robust Th1 responses, and the second vaccine dose boosted antigen-specific IgG responses, including enhanced engagement of Fc gamma receptor ectodomain dimers.
IgA responses increased after the first dose but declined after a second dose — despite a second shot.
The vaccine also produced robust CD4+ T-cell responses targeting SARS-CoV-2 at days 15, 36, 43, and 57 compared to placebo.
Project co-leader Professor Paul Young said the 2020 vaccine candidate was not an option for Australia’s current vaccine rollout. “The team understood the decision in December to shift the focus to other candidates that were showing promise. “Some of these vaccines are now in market and need to remain the immediate priority. “This study has strongly validated the Molecular Clamp technology as a promising rapid response strategy for vaccine development. “The team is continuing to work on alternative clamp constructs that could be used to respond to COVID-19 in the future or other viral diseases.”