A novel orf virus vector-based COVID-19 booster vaccine shows cross-neutralizing activity in the absence of anti-vector neutralizing immunity

Abstract

Next-generation COVID-19 vaccines are being developed to expand the breadth of coverage against existing and future variants and to extend the duration of protection. Prime-2-CoV_Beta is an orf virus (ORFV) based multi-antigen COVID-19 vaccine that co-expresses Spike (S) and Nucleocapsid (N) antigens. The safety and immunogenicity of Prime-2-CoV_Beta is investigated in a phase 1 first-in-human (FIH) dose-finding trial (ORFEUS study, ClinicalTrials.gov: NCT05367843). Participants of two age groups (18-55 and 65-85 years) who previously completed at least two doses of mRNA vaccines were enrolled and sequentially assigned to different dose groups to receive one intramuscular dose of 3 × 10⁵, 3 × 10⁶, 1.5 × 10⁷, or 3 × 10⁷ plaque-forming units (PFU) of Prime-2-CoV_Beta on day 1 and a second dose on day 29. Here, we report safety and immunogenicity data collected up to 6 months after the first study vaccination. Prime-2-CoV_Beta is safe and well tolerated and elicits immune responses at higher dose levels in participants aged 18-55. A single dose of 3 × 10⁷ PFU boosted binding and cross-neutralizing antibody responses that are maintained through 6 months after the first booster vaccination. Polyfunctional S-specific CD4+ and CD8+ T cell responses are observed after vaccination. No pre-existing or vaccine-induced neutralizing anti-vector antibodies are detected. Our findings highlight the potential of the ORFV vector as a safe platform for future vaccine design, which provides the ability to deliver multiple antigens and allows for repeat immunization.

Keywords: COVID-19; ORF virus-vector; SARS-CoV-2 variants; booster vaccine; first-in-human trial; immunogenicity; safety.

Figure 1.

Participant disposition and analysis sets analyzed.

Figure 2.

Solicited adverse reactions within 7 days after each study vaccination. (a) The percentages of participants reporting any solicited local AEs of the indicated severity up to 7 days after the first (left) or second (right) vaccination. (b) The percentages of participants reporting any solicited AEs of the indicated severity up to 7 days after the first (left) or second (right) vaccination. The highest severity grade is shown in case there were multiple reports of a given reaction per participant. Number of participants included in the solicited safety population are shown on the right of each diagram.

Figure 2.

Continued.

Figure 3.

SARS-CoV-2 neutralizing antibody responses at key time points.

Figure 4.

SARS-CoV-2 IgG-binding antibody responses at key time points.

Figure 5.

Fold-increase of neutralizing antibodies in participants with low versus high baseline titers.

Figure 6.

Change in IgG antibody avidity and neutralizing response in participants with high versus low antibody avidity at baseline.

Figure 7.

Prime-2-CoV_Beta induced T cell responses to S1/S2 peptide pools.