Immunogenicity and Safety of a Recombinant Fusion Protein Vaccine (V-01) Against COVID-19 in Adults

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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

Introduction
The COVID-19 pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has underscored the urgent need for vaccines with scalable production, simplified logistics, and enhanced safety profiles. Recombinant protein vaccines, such as V-01, offer advantages in safety, manufacturing feasibility, and thermostability, making them critical for global distribution. V-01 is a novel recombinant fusion protein vaccine comprising an interferon-α (IFN-α) moiety, a pan-HLA-DR-binding epitope (PADRE), the SARS-CoV-2 spike receptor-binding domain (RBD), and a human IgG1 Fc dimer. This design aims to enhance antigen presentation and immune activation. Preclinical studies demonstrated protective efficacy in non-human primates, and a phase I trial established its safety and robust immunogenicity. Building on these findings, this phase II trial evaluated the immunogenicity, safety, and optimal dosing regimen of V-01 in healthy younger (18–59 years) and older (≥60 years) adults.

Study Design and Methodology
This randomized, double-blind, placebo-controlled phase II trial enrolled 880 participants at the Gaozhou Municipal Centre for Disease Control and Prevention (China) from March to May 2021. Participants were stratified into younger (n = 440) and older (n = 440) cohorts, further divided into two dosing groups:

  1. Two-dose regimen: Participants received 10 mg, 25 mg V-01, or placebo (3:3:1 ratio) intramuscularly 21 days apart.
  2. One-dose regimen: Participants received a single 50 mg V-01 or placebo (3:1 ratio).

Primary immunogenicity endpoints included geometric mean titers (GMTs) of neutralizing antibodies against live SARS-CoV-2 and RBD-specific IgG antibodies. Safety assessments focused on adverse events (AEs) within 30 days post-vaccination. Blood samples were collected at multiple timepoints (days 0, 7, 14, 21, 28, 35, and 49) to evaluate antibody kinetics. Neutralizing antibody titers were measured using live-virus microneutralization assays, while RBD-binding antibodies were quantified via ELISA. A panel of convalescent sera from 38 COVID-19 patients (GMT: 53.6) served as a benchmark.

Safety Outcomes
V-01 exhibited a favorable safety profile across all groups. Most AEs were mild (Grade 1) or moderate (Grade 2), with no vaccine-related life-threatening events (Grade 4). Older adults reported fewer AEs than younger participants:

  • Two-dose groups: AE rates in younger vs. older adults were 34.2% vs. 19.2% (10 mg), 23.3% vs. 25.8% (25 mg), and 25.0% vs. 22.5% (placebo).
  • One-dose groups: AE rates were 26.7% vs. 17.5% (50 mg) and 47.5% vs. 25.0% (placebo).

The most common solicited local reaction was injection-site pain (≤30% in younger, ≤15% in older adults). Systemic AEs included fatigue (≤7.5%), headache (≤5%), and fever (≤6.7%). Only one vaccine-related Grade 3 AE (fever) occurred in the 25 mg older adult group. No significant differences in unsolicited AEs were observed between vaccine and placebo recipients.

Immunogenicity Results
Neutralizing Antibody Responses
Both two-dose regimens induced robust neutralizing antibody responses, exceeding convalescent serum levels (GMT: 53.6):

  • Younger adults:
    • 10 mg: GMTs peaked at 161.9 (95% CI: 133.3–196.7) on day 35, declining to 117.0 (95% CI: 97.0–141.2) by day 49.
    • 25 mg: GMTs reached 149.3 (95% CI: 123.9–179.9) on day 35, stabilizing at 121.7 (95% CI: 102.9–143.8) by day 49.
  • Older adults:
    • 10 mg: GMTs peaked at 111.6 (95% CI: 89.6–139.1) on day 35, remaining elevated at 99.2 (95% CI: 82.2–119.8) by day 49.
    • 25 mg: GMTs were 111.1 (95% CI: 89.2–138.4) on day 35, rising slightly to 118.1 (95% CI: 96.3–144.8) by day 49.

Seroconversion rates (≥4-fold rise from baseline) in two-dose groups were ≥95% in younger and ≥78.6% in older adults by day 28, reaching ≥96.6% in both age groups by day 49.

RBD-Binding Antibody Responses
Anti-RBD IgG GMTs mirrored neutralizing antibody trends:

  • Younger adults:
    • 10 mg: GMTs surged from 1283.5 (day 28) to 3861.6 (day 35), declining to 2732.2 by day 49.
    • 25 mg: GMTs rose from 1791.9 (day 28) to 3843.5 (day 35), stabilizing at 2910.1 by day 49.
  • Older adults:
    • 10 mg: GMTs increased from 737.6 (day 28) to 3239.2 (day 35), remaining at 2655.8 by day 49.
    • 25 mg: GMTs climbed from 1257.0 (day 28) to 3128.1 (day 35), reaching 2675.4 by day 49.

One-Dose Regimen
The single 50 mg dose elicited inferior immunogenicity:

  • Neutralizing antibodies: GMTs plateaued at 24.9 (younger) and 21.4 (older) by day 28, significantly lower than two-dose regimens.
  • RBD-binding antibodies: GMTs reached 734.9 (younger) and 654.2 (older) by day 28, far below two-dose peaks.

Comparison With Convalescent Sera
Two-dose V-01 regimens generated neutralizing antibody titers 2.0–3.0 times higher than convalescent sera (GMT: 53.6), suggesting robust immune protection.

Discussion
This phase II trial confirms V-01’s favorable immunogenicity and safety, supporting advancement to phase III evaluation. Key findings include:

  1. Superiority of Two-Dose Regimens: Both 10 mg and 25 mg two-dose schedules elicited neutralizing and RBD-binding antibody levels exceeding convalescent sera, with no significant difference between doses. The 10 mg regimen is recommended for phase III due to comparable efficacy and marginally better safety in older adults.
  2. Age-Related Immune Responses: Antibody GMTs were 1.3–1.5-fold lower in older vs. younger adults, consistent with immunosenescence. However, seroconversion rates remained high (≥96.6%), indicating robust efficacy across age groups.
  3. Safety Profile: Reactogenicity was predominantly mild, with older adults reporting fewer AEs. The absence of severe vaccine-related AEs underscores V-01’s suitability for large-scale use.
  4. One-Dose Limitations: The 50 mg single dose induced suboptimal immunity, emphasizing the necessity of a prime-boost strategy.

Limitations

  1. Convalescent Serum Variability: The convalescent panel included mostly mild-to-moderate cases, potentially underestimating comparative efficacy against severe disease.
  2. Demographic Homogeneity: Participants were predominantly Han Chinese; international trials are needed to assess ethnic diversity.
  3. Cellular Immunity and Durability: T-cell responses and long-term antibody persistence were not evaluated but will be critical for understanding protection against variants.

Conclusion
V-01 demonstrates a compelling balance of safety and immunogenicity, particularly in older populations. The two-dose 10 mg regimen, eliciting antibody levels 2–3 times higher than natural infection, is poised for phase III evaluation. Future studies should address durability, variant cross-reactivity, and real-world effectiveness to solidify V-01’s role in global COVID-19 control.

doi:10.1097/CM9.0000000000001702

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