Immune Recognition of Foreign DNA: Review A Cure for Bioterrorism? (1999)

Section of Retroviral ImmunologyCenter for Biologics Evaluation and Research MHC, thereby stimulating a strong immune responseFood and Drug Administration (Wolff et al., 1990; Manthorpe et al., 1993; Ulmer et al.,Bethesda, Maryland 20892 1993, 1997). Animal studies demonstrate that DNA vac-cines can successfully prevent infection by commonpathogens (such as flu, hepatitis, HIV, and malaria)The threat posed by bioterrorism has been recognized (Ulmer et al., 1993; Sedegah et al., 1994; Wang et al.,by the military, articulated by the President, and de- 1995; Boyer et al., 1997; Davis and Brazolot Millan, 1997).scribed in articles published in leading newspapers and SeveralphaseIclinicaltrialshaveexaminedthesafetyscholarlyjournals(Henderson,1999).We’velearnedthat ofDNAplasmidsinhumans.Findingsindicatethattheseforeign governments developed biological agents (in- agents can be administered at high doses to normalcluding anthrax, smallpox, and plague) for use as weap- recipients without serious side effects (Calarota et al.,ons of mass destruction, and that the technology to 1998;Wangetal.,1998).Suchstudiesalsoprovideinfor-create these agents was transferred to nations with in- mation on the immunogenicity of DNA vaccines in hu-terests inimical to those of the United States (Altas, mans (Calarota et al., 1998; Wang et al., 1998). Without1998; Henderson, 1999; Seelos, 1999). The low cost and exception,thedoseofvaccinerequiredtoelicitadetect-relative ease with which biowarfare agents can be able immune responses in humans was considerablyprepared led to their acquisition by radical/dissident higherthanthatexpectedonthebasisofanimalstudies.groups. For example, the Japanese Aum Shinrikyo cult Moreover, the magnitude of the human antibody (Ab)prepared and reportedly exposed Japanese civilians to andcytotoxicTlymphoctye(CTL)responsewasconsid-anthrax and botulinum toxin. Researchers endeavoring erably lower than that observed in mice (Calarota et al.,to counter such threats are developing novel and effec- 1998; Wang et al., 1998).tive antimicrobial drugs, pathogen-specific vaccines, The difference in immunogenicity of DNA vaccines inand immunostimulatory agents capable of boosting the mice versus humans has not been explained. It is possi-host’s resistance to infectious agents. An important ble that the plasmid vectors used to construct DNAcomponent of these efforts involves the use of foreign vaccines contain motifs that are immunosuppressive inDNA to improve innate and adaptive immunity to bio- humans (Krieg et al., 1998b). Alternatively, physiologicwarfare pathogens. differences in muscle mass, uptake, or processing ofTheimmunesystemevolvedtwogeneralmechanisms plasmid DNA by antigen-presenting cells, or plasmidfor combating infectious diseases. The initial or “innate” half-lifeinvivomayexplaindifferencesinvaccineimmu-immuneresponseistriggeredwithinminutesofinfection nogenicity between species. Multiple strategies to im-and serves to limit the pathogen’s spread in vivo. Host prove the activity of DNA vaccines in primates are beingrecognition of conserved determinants expressed by a pursued, including plans to “humanize” the antigen-diverse range of infectious microorganisms but absent encoding gene, coadminister plasmids encoding cytokinefrom the host (such as LPS) stimulate elements of the and/or costimulatory molecules, improve promoter re-innate immune system to produce immunomodulatory gionfunction,deletesuppressivesequences,and/orim-cytokines and polyreactive IgM antibodies (reviewed in provecellularuptakeoftheplasmid(Henggeetal.,1995;Marrack and Kappler, 1994; Medzhitov and Janeway, Xiang and Ertl, 1995; Hartikka et al., 1996; Iwasaki et al.,1997; Okada et al., 1997; Cohen et al., 1998; Kim et al.,1997, 1998). Subsequently, an “adaptive” or antigen-1998; Krieg et al., 1998b; Weiss et al., 1998).specificimmuneresponseisgeneratedagainstdetermi-The use of DNA plasmids offers several importantnants expressed uniquely by the pathogen. Efforts areadvantagesoverconventionalvaccinestrategiesforde-underway touse DNA-basedtechnology, includingDNAveloping antibiowarfare agents. DNA vaccines can bevaccines and immunostimulatory synthetic oligodeoxy-prepared from minute amounts of DNA isolated from anucleotides (ODN), to induce both innate and adaptivepathogen, eliminating the need to culture or attenuateimmune responses against biothreat agents.large stocks of deadly bacteria or viruses. For this pur-pose, the genes that encode immunogenic proteins can