Christopher Trindade, Jay W. Hooper, Aysegul Nalca, Peter Silvera, Genoveffa Franchini, Jean-Michel Heraud, Vaniambadi S. Kalyanaraman, Victor I. Ayala, Irene Kalisz, David Venzon, Barney S. Graham, Wen-Po Tsai, Anna Hryniewicz, Monica Vaccari, Mike Bray, Yvette Edghill-Smith, Meredith Hassett, Jody Manischewitz, Hana Golding, Lisa R. King, Janie Parrino, National Cancer Institute [Bethesda] (NCI-NIH), National Institutes of Health [Bethesda] (NIH), Advanced Bioscience Laboratories (ABL), National Institute of Allergy and Infectious Diseases [Bethesda] (NIAID-NIH), U.S. Food and Drug Administration (FDA), University of Bialystok, U.S. Army Medical Research Institute of Infectious Diseases, Southern Research Institute [Birmingham, USA], This work was supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research, the National Institute of Allergy and Infectious Diseases Intramural Biodefense Research Award program, and and National Institutes of Health Contract N01-AI-15451.
The smallpox vaccine Dryvax, a live vaccinia virus (VACV), protects against smallpox and monkeypox, but is contraindicated in immunocompromised individuals. Because Abs to VACV mediate protection, a live virus vaccine could be substituted by a safe subunit protein-based vaccine able to induce a protective Ab response. We immunized rhesus macaques with plasmid DNA encoding the monkeypox orthologs of the VACV L1R, A27L, A33R, and B5R proteins by the intradermal and i.m. routes, either alone or in combination with the equivalent recombinant proteins produced in Escherichia coli. Animals that received only DNA failed to produce high titer Abs, developed innumerable skin lesions after challenge, and died in a manner similar to placebo controls. By contrast, the animals vaccinated with proteins developed moderate to severe disease (20–155 skin lesions) but survived. Importantly, those immunized with DNA and boosted with proteins had mild disease with 15 or fewer lesions that resolved within days. DNA/protein immunization elicited Th responses and binding Ab titers to all four proteins that correlated negatively with the total lesion number. The sera of the immunized macaques recognized a limited number of linear B cell epitopes that are highly conserved among orthopoxviruses. Their identification may guide future efforts to develop simpler, safer, and more effective vaccines for monkeypox and smallpox.