The same trend was observed for SARS-CoV-2-specific IgG responses (Figure S4). == Physique 5. pre-existing or vaccine-induced neutralizing anti-vector antibodies are detected. Our findings spotlight 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:SARS-CoV-2 variants, COVID-19, booster vaccine, ORF virus-vector, first-in-human trial, immunogenicity, security == Introduction == The emergence of COVID-19 has highlighted the need to develop new vaccine platforms to efficiently tackle any future pandemic. While existing SARS-CoV-2 vaccines have profoundly altered the course of the pandemic, the emergence of new variants with the capacity to evade S-specific immune responses continues to pose a challenge for current S-targeting vaccine strategies. In addition, repeat booster-doses of variant-adapted vaccines are needed to address the waning of antibodies and the continued genetic development of SARS-CoV-2.1The development of next-generation COVID-19 vaccines to induce long-lasting cross-protective immune responses against newly emerging SARS-CoV-2 variants is, therefore, subject of intensive research. To address this challenge, a novel vaccine platform based on the attenuated ORFV strain D1701-VrV, a member of the genus Parapoxvirus, was used to develop a multi-antigen COVID-19 vaccine (Material S1). The ORFV vector platform was specifically designed to support multi-antigenic vaccine concepts. Key benefits of this novel virus vector system are the very restricted host range of wild-type ORFV (sheep and goats), the short-term vector-specific immunity without formation of neutralizing PNU-176798 antibodies, enabling repeat immunizations, and its ability to induce potent immunogenicity against foreign antigens.24Prime-2-CoV_Beta is a D1701-VrV-derived multi-antigen SARS-CoV-2 vaccine candidate, expressing full-length S (including the receptor-binding domain name (RBD) of the Beta variant) and N of the Wuhan Hu-1 strain. The widely conserved N-protein has been proposed as a target for the development of broadly protective next-generation vaccines PNU-176798 and has been used in combination with S-protein in clinical vaccine candidates.57Prime-2-CoV_Beta and variant-specific derivatives of Primary-2-CoV have shown robust immunogenicity in various species and guarded hamsters and non-human primates against SARS-CoV-2 challenge.8,9 The novel ORFV platform has not previously been tested in humans. Here, we statement the results of the FIH clinical trial to assess the security and immunogenicity of the first clinical vaccine candidate Prime-2-CoV_Beta as a COVID-19 booster in healthy adults previously vaccinated with mRNA vaccines. Our results support the favorable security and tolerability profile of the novel viral vector platform and demonstrate that heterologous booster immunization with Prime-2-CoV_Beta induces cross-neutralizing antibody responses in participants aged 1855, which is impacted by pre-existing immunity. Results furthermore revealed the absence of pre-existing or vaccination-induced neutralizing anti-vector immunity, enabling the possibility of repeat immunization, if needed. Overall, these FIH clinical data spotlight the potential of the ORFV vector platform for broader applications for future emerging and re-emerging pathogens. == Materials and methods == == Study design and participants == The ORFEUS study was a phase 1 multi-center, open label, dose-finding trial conducted at two sites in Germany and five in US. The study enrolled healthy adults aged 1855 and 6585 who experienced completed at least two doses of an FLNC mRNA-based COVID-19 vaccine (Corminaty/Pfizer-BioNTech or Spikevax/Moderna, main series with or without booster doses henceforth referred to as pre-vaccinated) at least 3 months prior to study access. Enrollment of vaccine-nave adults was prematurely discontinued due to feasibility (Physique 1). Participants with a history of prior nucleic acid amplification test (NAAT)-confirmed SARS-CoV-2 infection in the previous 2 months and those with an NAAT-positive pharyngeal swab were excluded. This statement presents the security and immunogenicity data collected over a period PNU-176798 of 6 months following the administration of Prime-2-CoV_Beta. The study met all ethics and regulatory requirements as decided in a review by the US Central Institutional Review Table (Advarra Inc, Columbia, MD, USA), local Institutional Biosafety.