First Protein Subunit Vaccine for SARS-CoV-2 Passes Phase 1 Human Trial

A protein subunit vaccine candidate for COVID-19 demonstrated safety and immunogenicity in a phase 1, placebo-controlled, dose escalation trial.

A protein subunit vaccine for SARS-CoV-2 has demonstrated safety and immunogenicity in a first-in-human phase 1 trial that distinguished between 3 doses and 2 adjuvants.The findings, reported in The Lancet, support a vaccine technology for COVID-19 that is distinct from the nucleic acid based strategies now used in the US and the viral vector-based vaccines developed in China and Russia.

Peter Richmond, MBBS, division of pediatrics, University of Western Australia and Wesfarmers Centre of Vaccines and Infectious Diseases, Perth, WA, Australia, and colleagues utilized a proprietary “Trimer-Tag” technology from Clover Biopharmaceuticals, Chengdu, China, to stabilize the native trimeric, “lollypop” structure of the spike (S1) protein of the corona virus, which can be targeted by antibodies before it binds to a host cell (pre-fusion) at the ACE2 receptor and transforms into the “golf tee” shaped S2 protein.

“Interference with this process is the basis of most immunological approaches to prevent SARS-CoV-2 infections, including vaccines,” explains Richmond and colleagues.

In commentary accompanying the report, Anna Blakney, PhD, University of British Columbia and Michael Smith Laboratories, Vancouver, BC, Canada, and Paul McKay, PhD, department of infectious diseases, Imperial College London, London, UK, point out that the Trimer-Tag technology served as an alternative trimer stabilization strategy to the “molecular clamp” derived from HIV proteins. They note that a phase 1 trial on a SARS-CoV-2 vaccine had been stopped in December because the molecular clamp induced antibodies recognized by HIV tests in trial participants after inoculation.

“Trimer-Tag vaccines are unlikely to encounter a similar issue,” Blakney and McKay indicated.

Richmond and colleagues conducted the phase 1 double-blind, placebo-controlled, dose-escalation trial with 2 injections (initial and booster) of 3 different doses of the SCB-2019 candidate vaccine (3μg, 9μg, 30μg) without adjuvant and with 2 different adjuvants (oil-in-water emulsion adjuvant AS03 or Toll-like receptor 9 (TLR9) agonist CpG combined with Alum—CpG/Alum).Healthy volunteers (n=151) in two age groups (median 36.2 and 61.1 years) were enrolled at a specialized clinical trials center in Perth.

The first part of the study was conducted with the younger adults, using a sentinel strategy in which the first two participants in each dose and formulation group were randomly assigned either vaccine or placebo and monitored for 48 hours. The remaining participants in the younger adult groups were then randomized to either one of the vaccine formulations (n=7) or placebo (n=2).

No sentinel strategy was applied to the second part of the study with older adults, who were recruited after the safety data from the younger group were found satisfactory. This older group only received adjuvanted vaccine.

Humoral responses to the vaccine candidate were measured in provoked titers of binding IgG antibodies and ACE2-competitive blocking IgG antibodies, and compared with titers of neutralizing antibodies to wild-type SARS-CoV-2 in convalescent serum.The investigators reported that the higher dose adjuvanted formulations produced targeted antibody responses with good safety profiles.

The ASO3 formulations produced highest geometric mean titers (GMT), peaking at day 36 at levels that were higher than those recorded in convalescent serum samples and persisting at day 50. In addition, there was no significant difference in the immune response to the higher dose, adjuvanted formulations between the younger and older adults.

“Based on these results, 9μg SCB-2019 adjuvanted with AS03 and 30μg SCB-2019 adjuvanted with CpG/Alum are the preferred candidates to be taken into the phase 2/3 trial,” Richmond and colleagues report. “The final selection will be determined by manufacturing considerations.”

Blakney and McKay find a particular strength of the study design in the use of convalescent serum from a donor with standardized Ig and levels, and serum samples from convalescent COVID-19 patients.

“Incorporation of reference standards is absolutely imperative for SARS-CoV-2 vaccine clinical trials moving forward, because of variability in binding and neutralizing antibody assays between different organizations,” they point out.