Immunogenicity and safety of a recombinant fusion protein vaccine (V-01) against coronavirus disease 2019 in healthy adults: a randomized, double-blind, placebo-controlled, phase II trial

Abstract

Background: Innovative coronavirus disease 2019 (COVID-19) vaccines, with elevated global manufacturing capacity, enhanced safety and efficacy, simplified dosing regimens, and distribution that is less cold chain-dependent, are still global imperatives for tackling the ongoing pandemic. A previous phase I trial indicated that the recombinant COVID-19 vaccine (V-01), which contains a fusion protein (IFN-PADRE-RBD-Fc dimer) as its antigen, is safe and well tolerated, capable of inducing rapid and robust immune responses, and warranted further testing in additional clinical trials. Herein, we aimed to assess the immunogenicity and safety of V-01, providing rationales of appropriate dose regimen for further efficacy study.

Methods: A randomized, double-blind, placebo-controlled phase II clinical trial was initiated at the Gaozhou Municipal Centre for Disease Control and Prevention (Guangdong, China) in March 2021. Both younger (n = 440; 18-59 years of age) and older (n = 440; ≥60 years of age) adult participants in this trial were sequentially recruited into two distinct groups: two-dose regimen group in which participants were randomized either to follow a 10 or 25 μg of V-01 or placebo given intramuscularly 21 days apart (allocation ratio, 3:3:1, n = 120, 120, 40 for each regimen, respectively), or one-dose regimen groups in which participants were randomized either to receive a single injection of 50 μg of V-01 or placebo (allocation ratio, 3:1, n = 120, 40, respectively). The primary immunogenicity endpoints were the geometric mean titers of neutralizing antibodies against live severe acute respiratory syndrome coronavirus 2, and specific binding antibodies to the receptor binding domain (RBD). The primary safety endpoint evaluation was the frequencies and percentages of overall adverse events (AEs) within 30 days after full immunization.

Results: V-01 provoked substantial immune responses in the two-dose group, achieving encouragingly high titers of neutralizing antibody and anti-RBD immunoglobulin, which peaked at day 35 (161.9 [95% confidence interval [CI]: 133.3-196.7] and 149.3 [95%CI: 123.9-179.9] in 10 and 25 μg V-01 group of younger adults, respectively; 111.6 [95%CI: 89.6-139.1] and 111.1 [95%CI: 89.2-138.4] in 10 and 25 μg V-01 group of older adults, respectively), and remained high at day 49 after a day-21 second dose; these levels significantly exceed those in convalescent serum from symptomatic COVID-19 patients (53.6, 95%CI: 31.3-91.7). Our preliminary data show that V-01 is safe and well tolerated, with reactogenicity predominantly being absent or mild in severity and only one vaccine-related grade 3 or worse AE being observed within 30 days. The older adult participants demonstrated a more favorable safety profile compared with those in the younger adult group: with AEs percentages of 19.2%, 25.8%, 17.5% in older adults vs. 34.2%, 23.3%, 26.7% in younger adults at the 10, 25 μg V-01 two-dose group, and 50 μg V-01 one-dose group, respectively.

Conclusions: The vaccine candidate V-01 appears to be safe and immunogenic. The preliminary findings support the advancement of the two-dose, 10 μg V-01 regimen to a phase III trial for a large-scale population-based evaluation of safety and efficacy.

Trial registration: http://www.chictr.org.cn/index.aspx (No. ChiCTR2100045107, http://www.chictr.org.cn/showproj.aspx?proj=124702).

Figure 1

Flow diagram of younger (A) and older (B) participants in phase II trial of a recombinant fusion protein vaccine (V-01). ^∗Participant withdrew due to unwilling or unable to complete the subsequent follow-ups; ⁺One participant withdrew due to unwilling or unable to complete the subsequent follow-ups and two due to intolerance of adverse effects.

Figure 2

Solicited local and systemic adverse events stratified by age in phase II trial of a recombinant fusion protein vaccine (V-01). The percentage of participants in each vaccine group with six most frequent adverse events, classified according to the scale issued by the National Medical Products Administration (NMPA) of China, within 7 days after each administration of vaccine displayed as solicited local (A for younger, B for older adults), systemic (C for younger, D for older adults) adverse events, respectively. Mild = grade 1, moderate = grade 2, severe = grade 3 or worse. ^∗ Percentage of participants was 30%.

Figure 3

Humoral immune responses in phase II trials. GMTs (A) and seroconversion rates (B) of neutralizing antibodies at different timepoints after administration of the first vaccine dose in the phase II trial. Pink, yellow, blue represents younger adults, older adults and convalescent patients, respectively. GMTs (C) and seroconversion rates (D) of RBD-binding antibodies at different timepoints after administration of the first vaccine dose in the phase II trial. Error bars represent the 95% CIs of the geomeans. Arrows indicate the days of vaccination. The horizontal dashed lines in panels A and C indicate the limit of detection. CI: Confidence interval; GMTs: Geometric mean titers; RBD: Receptor-binding domain.