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Safety, tolerability, and immunogenicity of a recombinant adenovirus type-5 vectored COVID-19 vaccine: a dose-escalation, open-label, non-randomised, first-in-human trial

Our take —

The Ad5 vaccine used in this study was well tolerated by participants in the first 28 days post-vaccination, and was able to induce the production of high levels of binding and low levels of neutralizing antibodies against SARS-CoV-2. While this initial trial had many limitations, it also showed promising results and therefore warrants further investigation, including long-term follow-up with the phase I trial participants and a larger scale phase 2 trial.

Phase 2 Results

This vaccine advanced to a Phase 2 Trial. A review and summary of it can be found here.

Study design

Non-Randomized Trial

Study population and setting

This was a Phase I, interventional trial run by CanSino Biologics Inc., taking place at Tongji Hospital in China. The vaccine being tested was an adenovirus type 5 (Ad5) vector engineered to express the Spike (S) gene of SARS-CoV-2. The enrollment period was March 16 to March 27, 2020. 108 healthy participants between 18 to 60 years were recruited and divided into three dose groups. The low-dose group received one dose of 5×1010 viral particles (vp) of recombinant novel coronavirus vaccine (Ad5-nCoV). The middle-dose group received one dose of 1×1011 vp, and the high-dose group received one dose of 1.5×1011 vp. Safety and tolerability of the vaccine were assessed for 28 days post-vaccination. The researchers also examined immunological responses to the vaccine at days 14 and 28 post-vaccination.

Summary of Main Findings

Some minor adverse events occurred within the first seven days post-vaccination, including pain at injection site, fever, fatigue, headache, and muscle pain; no serious adverse events occurred within the first 28 days. Participants with high pre-existing Ad5 immunity, which is the backbone of the vaccine, had a lower rate of fever post-vaccination. However, higher pre-existing Ad5 neutralizing antibodies were also associated with less seroconversion of SARS-CoV-2 neutralizing antibodies post-vaccination, as well as less CD4+ and CD8+ T cell responses against SARS-CoV-2. All three vaccine arms induced high titers of binding antibodies as measured by ELISA. Neutralizing antibody responses specific to SARS-CoV-2 increased in all three arms by day 14 from a baseline of zero, and peaked by day 28 post-vaccination. The high dose vaccine had a significantly stronger binding and neutralizing antibody response, however the magnitude of the neutralizing response appeared to be very low.  The low and middle dose vaccines will continue to a phase II efficacy clinical trial based on their safety profiles.

Study Strengths

This was the first published report of results of a phase I clinical trial for a vaccine against SARS-CoV-2. The S-protein sequence vectored into the Ad5 genome was full length, which may make it more clinically relevant than if it were only the receptor binding domain (RBD), as is being used for some other early stage vaccines. The study also followed multiple metrics to assess immunogenicity of the vaccine, including neutralizing antibodies, specific T-cell responses, and cytokines.

Limitations

This study has not addressed the long-term effects of the Ad5 vaccine, and this is a major concern for health officials when choosing a vaccine against SARS-CoV-2 to use for the public. As a phase I trial, it also had a small cohort size and lacked a randomized control group. Finally, participants only included individuals up to 60 years of age, and since age has been identified as a risk factor for severe SARS-CoV-2 disease, further investigation in older populations is warranted. Lastly, the antibody and T cell responses were not compared to recovered COVID-19 patients, so it is unclear how the vaccine-generated responses compare to those seen in natural infection.

Value added

This study marks the first report of an Ad5 vectored COVID-19 vaccine in a human clinical trial.