A Nucleic Acid-Based Orthopoxvirus Vaccine Targeting the Vaccinia Virus L1, A27, B5, and A33 Proteins Protects Rabbits against Lethal Rabbitpox Virus Aerosol Challenge

• Published in: Journal of virology 2022-02, Vol.96 (3), p.e0150421-e0150421
• Main Authors: Mucker, Eric M, Golden, Joseph W, Hammerbeck, Christopher D, Kishimori, Jennifer M, Royals, Michael, Joselyn, Mathew D, Ballantyne, John, Nalca, Aysegul, Hooper, Jay W
• Format: Article
• Language: English
• Subjects: Animals; B-Lymphocytes - immunology; B-Lymphocytes - metabolism; Dose-Response Relationship, Immunologic; Electroporation; Female; Immunization - methods; Immunogenicity, Vaccine; Lymphocyte Activation - immunology; Nucleic Acid-Based Vaccines - administration & dosage; Nucleic Acid-Based Vaccines - immunology; Oligodeoxyribonucleotides - administration & dosage; Oligodeoxyribonucleotides - immunology; Orthopoxvirus - immunology; Poxviridae Infections - prevention & control; Rabbits; Vaccines and Antiviral Agents; Vaccines, DNA - immunology; Vaccinia - prevention & control; Vaccinia virus - genetics; Vaccinia virus - immunology; Viral Proteins - immunology; Viral Vaccines - administration & dosage; Viral Vaccines - immunology; Virology
• ISSN: 0022-538X; 1098-5514
• DOI: 10.1128/JVI.01504-21

In the age of COVID, nucleic acid vaccines have garnered much attention, at least in part, because of the simplicity of construction, production, and flexibility to adjust and adapt to an evolving outbreak. Orthopoxviruses remain a threat on multiple fronts, especially as emerging zoonoses. In response, we developed a DNA vaccine, termed 4pox, that protected nonhuman primates against monkeypox virus (MPXV)-induced severe disease. Here, we examined the protective efficacy of the 4pox DNA vaccine delivered by intramuscular (i.m.) electroporation (EP) in rabbits challenged with aerosolized rabbitpox virus (RPXV), a model that recapitulates the respiratory route of exposure and low dose associated with natural smallpox exposure in humans. We found that 4pox-vaccinated rabbits developed immunogen-specific antibodies, including neutralizing antibodies, and did not develop any clinical disease, indicating protection against aerosolized RPXV. In contrast, unvaccinated animals developed significant signs of disease, including lesions, and were euthanized. These findings demonstrate that an unformulated, nonadjuvanted DNA vaccine delivered i.m. can protect against an aerosol exposure. The eradication of smallpox and subsequent cessation of vaccination have left a majority of the population susceptible to variola virus or other emerging poxviruses. This is exemplified by human monkeypox, as evidenced by the increase in reported endemic and imported cases over the past decades. Therefore, a malleable vaccine technology that can be mass produced and does not require complex conditions for distribution and storage is sought. Herein, we show that a DNA vaccine, in the absence of a specialized formulation or adjuvant, can protect against a lethal aerosol insult of rabbitpox virus.