Background

Contagious ecthyma, caused by orf virus (ORFV), is a highly contagious disease in sheep and goats, characterized by proliferative lesions around the lips and oral cavity. In young animals, the pain can lead to poor feeding, growth retardation, and even death. It is also a zoonotic disease that can be transmitted to humans who come into contact with infected animals. Recurrence is possible after recovery, making it difficult to eliminate the virus within a herd.

Current control strategies rely primarily on commercial live vaccines. While live vaccines induce relatively strong immunity, they involve the use of live virus, which carries the risk of lesions at the injection site, transmission to unvaccinated animals, and environmental contamination. Furthermore, there are limitations in distinguishing between vaccine strains and field strains.

Messenger RNA (mRNA) vaccines, on the other hand, do not involve the use of infectious viruses and allow for the rapid design of vaccine candidates by simply changing the antigen sequence. While their use has expanded in human medicine, research on vaccines for livestock animals is still in its early stages.

Key Findings

The researchers selected F1L, a major immunodominant surface protein of ORFV, as the antigen. mRNA encoding the F1L gene was synthesized via in vitro transcription and encapsulated in lipid nanoparticles (LNPs) to create 'F1L-mRNA-LNP'. F1L is known to induce neutralizing antibodies on the viral surface and was therefore chosen as a target to induce protective immunity without using infectious viruses.

Seventy BALB/c mice were divided into five groups of 14 mice each and administered 5, 10, or 15 micrograms of F1L-mRNA-LNP, a commercial live vaccine, or phosphate-buffered saline (PBS). The primary immunization was administered by intramuscular injection, followed by a booster injection 14 days later. Immune responses were evaluated 14 days after the booster. The animal study design and reporting followed the ARRIVE 2.0 guidelines.

Both the mRNA vaccine groups at all three doses and the live vaccine group showed higher F1L-specific antibody responses compared to the PBS control group. This indicates that the mRNA delivered by the LNP was translated into antigen protein in vivo and recognized by the adaptive immune system, similar to the live vaccine. Importantly, the non-replicating, single-antigen platform demonstrated immunogenicity comparable to that of the commercial live vaccine. However, this comparison is based on immune markers measured after vaccination and does not necessarily equate to 'efficacy' in the same sense as a challenge study that confirms whether it prevents ORFV infection or reduces lesions.

Significance and Outlook

This study demonstrates the potential to extend the mature mRNA-LNP technology used in human vaccines to infectious diseases in small ruminants. The production process does not require large-scale cultivation of ORFV, and the risk of release of live vaccine strains is reduced. If the sequence of the prevalent strain changes, it is relatively easy to replace the mRNA sequence or develop a multivalent vaccine by including other antigens, such as B2L.

However, a clear limitation is that the experimental animals were mice, not the natural hosts of the disease, goats or sheep. It remains to be verified whether the antibodies neutralize the virus, whether cellular immunity and the duration of immunity are sufficient, and whether they inhibit clinical lesions and viral shedding in a challenge study with field strains. For livestock vaccines, immunogenicity is only one factor; cold chain logistics, the cost per dose, and ease of large-scale administration are also crucial for adoption. Further studies, including trials in natural hosts and cost-effective manufacturing, are needed to make it a viable alternative to live vaccines.