Since publication in January, 2020, of genomic information about severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), many efforts have been made around the world to develop a vaccine against this virus. Three vaccines with more than 90% efficacy are licensed and beginning roll-out in some countries as of January, 2021, which is a true feat of scientific endeavour and international efforts. However, SARS-CoV-2 continues to be a major threat worldwide and development of new COVID-19 vaccines remains essential.
In The Lancet, Peter Richmond and colleagues report their phase 1, first-in-human, dose-finding and adjuvant justification study testing a stabilised trimeric spike subunit protein vaccine (SCB-2019). This vaccine differs from those already approved as it uses a stabilised protein trimer as the antigen. The researchers used Trimer-Tag, a protein derived from the C-terminus of human type I procollagen which preserves the trimeric conformation of the SARS-CoV-2 spike protein and has not previously been used in clinical trials. Trimer-Tag technology provides an alternative trimer stabilisation strategy to the molecular clamp derived from HIV proteins
A phase 1 clinical trial of a SARS-CoV-2 vaccine (NCT04495933) was halted in December, 2020, because the molecular clamp induced antibodies recognised by HIV tests in trial participants after inoculation. Trimer-Tag vaccines are unlikely to encounter a similar issue.
The current trial tested three doses of protein (3 μg, 9 μg, or 30 μg) alone or with a fixed dose of either AS03, an oil-in-water adjuvant, or the TLR9 agonist CpG combined with Alum (CpG/Alum).
The vaccine requires a two-dose regimen, similar to currently approved vaccines, given at an interval of 21 days. The liquid vaccine formulation is stable for at least 6 months at a temperature of 2–8°C, which is an important added advantage as we attempt to immunise people in challenging environments all over the world. The primary objective of the study was to assess the safety and reactogenicity of the vaccine in healthy adults grouped by age (younger adults aged 18–54 years and older adults aged 55–75 years). 148 of 151 enrolled participants were included in the current analysis, of whom 64 (42%) were men and 87 (58%) women. The vaccine was well tolerated; most local adverse events were mild injection-site pain. Local events were more frequent with SCB-2019 formulations containing AS03 adjuvant (44–69%) than with those containing CpG/Alum adjuvant (6–44%) or no adjuvant (3–13%). Two grade 3 solicited adverse events were reported (pain after 9 μg dose of AS03-adjuvanted SCB-2019 and CpG/Alum-adjuvanted SCB-2019). Tolerability of the vaccine compares favourably with vaccines already approved.
Although immunogenicity data were restricted to humoral responses in the study, Richmond and colleagues noted that SCB-2019 alone (no adjuvant) was poorly immunogenic, but neutralising antibodies were recorded after the first injection with the higher doses (9 μg and 30 μg) of AS03-adjuvanted vaccine, which persisted for the remainder of the interim analysis period, with little meaningful difference between younger and older adults (all participants showed seroconversion). Furthermore, the magnitude of neutralising antibody titre and the ratio to binding antibodies was favourable compared with mRNA-based vaccines with reported efficacy.
A strength of this study is incorporation of the National Institute for Biological Standards and Control 20/130 reference (convalescent serum from a donor with standardised Ig and levels) bolstered by serum samples from convalescent patients who were either hospitalised with COVID-19 or required only outpatient treatment. Incorporation of reference standards is absolutely imperative for SARS-CoV-2 vaccine clinical trials moving forward, because of variability in binding and neutralising antibody assays between different organisations.
The Coalition for Epidemic Preparedness Innovations is also now offering testing of preclinical to phase 2 COVID-19 vaccine trial samples to harmonise assessment and enable comparison of candidates.
One major drawback of the study by Richmond and colleagues is the absence of diversity among the 151 trial participants, of whom 132 (87%) were white,
which does not reflect the demographics of the global population to which this vaccine might one day be administered. Another potential concern is the flexibility and sluggish development of protein vaccines relative to existing authorised nucleic acid modalities (this phase 1 trial is only just complete when mRNA COVID-19 vaccines, for example, are already approved). Difficulties in tweaking and producing new protein vaccines in the landscape of emerging mutations that might escape from or lessen the efficacy of first-generation vaccines could be a severe drawback. However, the future of COVID-19 vaccines lies in promising vaccine candidates, such as this one, that have either equivalence or advantages in efficacy, stability, scalability, or cost.
Source : Lancet