# Broadening SARS-CoV-2 Immunity by Combining ORFV and Protein-Based Vaccines

## TL;DR

This study shows that combining ORFV-based and protein vaccines improves broad immunity against SARS-CoV-2 variants.

## Contribution

The novel contribution is demonstrating that ORFV-S priming followed by protein boosting enhances cross-variant antibody and T-cell responses.

## Key findings

- ORFV-S alone induced potent and broad spike-specific IgG responses.
- Heterologous ORFV-S plus VidPrevtyn Beta boosting enhanced antibody breadth and magnitude.
- ORFV-S regimens elicited strong CD4+ and CD8+ T-cell responses.

## Abstract

Background: Emerging immune-evasive viral variants threaten the efficacy of current vaccines, underscoring the need for strategies that elicit broad and durable protection. Heterologous prime–boost regimens combining distinct vaccine platforms can enhance humoral and cellular immunity through complementary mechanisms. Methods: Using an intramuscular immunization scheme aligned with clinical vaccination practice, CD-1 mice received homologous or heterologous prime–boost regimens combining a replication-deficient Orf virus (Parapoxvirus orf, ORFV)-based spike vaccine (ORFV-S) with the licensed adjuvanted recombinant protein vaccine VidPrevtyn Beta. Spike-specific humoral and cellular immune responses were assessed. Results: ORFV-S alone induced potent and broad spike-specific IgG responses and achieved the strongest ACE2-binding inhibition across variants of concern. ORFV-S priming followed by VidPrevtyn Beta boosting markedly enhanced the magnitude and cross-variant breadth of antibody responses compared with homologous protein vaccination. Both homologous ORFV-S and heterologous regimens incorporating ORFV-S elicited strong CD4+ and CD8+ T-cell responses, whereas VidPrevtyn Beta alone induced only modest T-cell activity, demonstrating that ORFV-S effectively complements protein-based vaccines. Conclusions: The ORFV-S vector represents a potent vaccine platform capable of inducing broad humoral and cellular immunity. Its use in heterologous prime–boost combinations enhances both antibody magnitude and breadth beyond homologous protein vaccination, supporting its application in vaccination strategies against evolving viral pathogens.