Randomized Controlled Trial
Study population and setting
Reported are results from phase 1 and phase 2 clinical trials of a SARS-CoV-2 S protein receptor-binding domain (RBD)-based protein subunit vaccine against COVID-19, ZF2001, manufactured by Anhui Zhifei Longcom Biopharmaceutical. Both trials were randomized, double-blinded, and placebo-controlled. The phase 1 study enrolled 50 healthy adults, aged 18-59 into one of three groups: 25 ug vaccine, 50 ug vaccine, or placebo. All groups were administered 3 doses 30 days apart. The primary endpoint was safety, with the secondary endpoint of immunogenicity. Phase 2 studies enrolled 900 participants and included six groups, with three groups receiving 3 doses of either 25 ug vaccine, 50 ug vaccine, or placebo, and 3 groups receiving 2 doses of either 25 ug vaccine, 50 ug vaccine, or placebo. Primary endpoints were safety and immunogenicity. In both studies, samples were taken at determined intervals to assess immunogenicity. Both trials were conducted in China, with phase 1 in Chongqing and Beijing, and Phase 2 in Xiangtan.
Summary of Main Findings
All vaccine regimens were well tolerated. Local adverse events included pain, swelling, induration, redness, rash and pruritus. Systemic adverse events included fever, cough, dyspnea, diarrhea, anorexia, nausea, vomiting, muscle pain other than the injection site, arthritis, joint pain, headache, fatigue, acute allergic reaction, irritation or inhibition, and mental disorder. No vaccine-related serious adverse events were reported. In the phase 1 study, 61% (25 ug group) and 79% (50 ug group) of participants had seroconverted by day 30 post-first dose and 100% of both groups had seroconverted by day 30 post-second dose. In the phase 2 study, 59-65% seroconverted by day 30 post-first vaccination, 94%-97% at 30 days post-second vaccination, and 97%-99% at 14 days post-third dose. However, for all vaccine groups in both phase 1 and phase 2 studies, neutralizing titers were only similar to or better than convalescent patient serum at time points following the third dose. There was no significant enhancement of neutralizing titers in the 50 ug groups compared to the 25 ug groups. T-cell responses were also observed in all vaccine groups with no significant difference between groups. Maximal responses first observed at 30 days post-second dose.
Demonstration of neutralizing antibodies titers elicited by this vaccine equal to or greater than convalescent plasma is positive. While a correlate of protection has not been determined for SARS-CoV-2, to date, vaccines that have been issued an emergency use authorization (EUA) have demonstrated neutralizing titers similar to or better than convalescent plasma.
While demonstrating that ZF2001 can elicit a T-cell response is positive, it is not clear what type or level of response is needed to confer protection against disease. This study did not include elderly populations and has very limited population diversity. Also, duration of the immune response is not tested past 30 days post-third dose. These limitations will be addressed in the ongoing phase 3 trial. The data indicate that the immune response is greatly boosted with the 3rd vaccination, thus a 25 ug, 3-dose regimen will be used in the phase 3 trial. A 3-dose vaccine regime could prove to be logistically difficult in some areas and compliance may be lower than the current 2-dose regimens for other vaccines already in use under EUA.
This is the first clinical data reported for an RBD-based protein subunit vaccine for COVID-19. The vaccine was well tolerated and immunogenic. The data strongly support continued studies in phase 3 trials.
This review was posted on: 14 January 2021