Abstract
Orthopoxviruses remain a threat as biological weapons and zoonoses. The licensed live-virus vaccine is associated with serious health risks, making its general usage unacceptable. Attenuated vaccines are being developed as alternatives, the most advanced of which is modified-vaccinia virus Ankara (MVA). We previously developed a gene-based vaccine, termed 4pox, which targets four orthopoxvirus antigens, A33, B5, A27 and L1. This vaccine protects mice and non-human primates from lethal orthopoxvirus disease. Here, we investigated the capacity of the molecular adjuvants GM-CSF and Escherichia coli heat-labile enterotoxin (LT) to enhance the efficacy of the 4pox gene-based vaccine. Both adjuvants significantly increased protective antibody responses in mice. We directly compared the 4pox plus LT vaccine against MVA in a monkeypox virus (MPXV) nonhuman primate (NHP) challenge model. NHPs were vaccinated twice with MVA by intramuscular injection or the 4pox/LT vaccine delivered using a disposable gene gun device. As a positive control, one NHP was vaccinated with ACAM2000. NHPs vaccinated with each vaccine developed anti-orthopoxvirus antibody responses, including those against the 4pox antigens. After MPXV intravenous challenge, all control NHPs developed severe disease, while the ACAM2000 vaccinated animal was well protected. All NHPs vaccinated with MVA were protected from lethality, but three of five developed severe disease and all animals shed virus. All five NHPs vaccinated with 4pox/LT survived and only one developed severe disease. None of the 4pox/LT-vaccinated animals shed virus. Our findings show, for the first time, that a subunit orthopoxvirus vaccine delivered by the same schedule can provide a degree of protection at least as high as that of MVA.
Highlights
Occurring smallpox was eradicated in the late 20th century through a coordinated worldwide vaccination campaign [1]
To determine if it was possible to enhance the immune response to the 4pox DNA vaccine using DNA encoded immunostimulatory (DEI) molecules, we examined the extent to which granulocyte-macrophage colony-stimulating factor (GM-CSF) or E. coli heat-labile enterotoxin (LT) could enhance the immune response against the 4pox vaccine targets
We report the first study where a smallpox DNA vaccine delivered as a single boost has been tested in the nonhuman primate (NHP) monkeypox virus (MPXV) intravenous challenge model
Summary
Occurring smallpox was eradicated in the late 20th century through a coordinated worldwide vaccination campaign [1]. Other orthopoxviruses are a threat to public health in the form of emerging zoonoses [2] These include human monkeypox virus (MPXV), cowpox virus (CPXV), and a variety of vaccinia virus (VACV)-like viruses circulating throughout the world [3,4,5,6]. These viruses, though not as virulent as VARV, still cause significant morbidity and occasional mortality in places such as central Africa, Eurasia and South America. Whereas protecting groups of the population against emerging zoonoses is relatively unappreciated, the desire to defend against a potential biological weapons attack has led to a renewed effort to develop and stockpile orthopoxvirus vaccines and therapeutics [8]
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