Genetic Vaccination: One-Shot Shopping for Immediate and Sustained Protection
Authors: Elmieke PJ Boot, Paul WHI Parren
Journal: Molecular Therapy (2007)

Therapeutic monoclonal antibodies (mAbs) have proven their value for the treatment of cancer, inflammation, and infectious disease. The rapidly expanding market of therapeutic mAbs currently includes 21 products approved for human use. At present, only one of these antibodies is indicated for the treatment of an infectious disease (Synagis, for respiratory syncytial virus). Thus far, polyclonal antibodies (pAbs) have been more widely successful in treating infectious diseases and are being marketed for the treatment of various viral infections, including respiratory syncytial virus, rabies, hepatitis B virus, varicella zoster virus, vaccinia virus, and cytomegalovirus. Many additional mAbs and pAbs targeting viral, fungal, and bacterial pathogens are under development and will become available in coming years.1Matthews RC Burnie JP Human recombinant antibody to HSP90: a natural partner in combination therapy.Curr Mol Med. 2005; 5: 403-411Crossref PubMed Scopus (34) Google Scholar,2Wiberg FC Rasmussen SK Frandsen TP Rasmussen LK Tengbjerg K Coljee VW et al.Production of target-specific recombinant human polyclonal antibodies in mammalian cells.Biotechnol Bioeng. 2006; 94: 396-405Crossref PubMed Scopus (68) Google Scholar Typical for the treatment of infectious diseases is that both acute and prolonged protection are needed, because infectious agents often persist in the environment and the risk of repeated infection exists. Prolonged protection is furthermore essential when countering a bioterrorism attack, because the pathogen might be deliberately re-introduced. Multiple sequential mAb or pAb administrations are therefore warranted. In this issue of Molecular Therapy, De et al. provide evidence that it may be feasible to induce both rapid and sustained protection against a pathogen with a “one-shot” mAb gene therapy approach3De BP Hackett NR Crystal RG Boyer JL Rapid/persistent anti-anthrax passive immunity mediated by co-administration of Ad/AAV vectors encoding an anti-anthrax antibody.Mol Ther. 2008; 16: 203-209Abstract Full Text Full Text PDF PubMed Scopus (38) Google Scholar (Figure 1). The potential value of in vivo production of mAbs via gene transfer for the treatment of infectious diseases has been well recognized. An important issue hindering development of mAb gene therapy in the area of infectious diseases, however, is the lag time before sufficient mAb plasma levels are achieved.4Bakker JM Bleeker WK Parren PW Therapeutic antibody gene transfer: an active approach to passive immunity.Mol Ther. 2004; 10: 411-416Abstract Full Text Full Text PDF PubMed Scopus (28) Google Scholar Most studies show that it takes about 1 to 2 weeks for mAb levels to build up to therapeutically effective plasma concentrations, even with virus-based expression systems capable of achieving high production levels in vivo.5Fang J Qian J-J Yi S Harding TC Tu GH VanRoey M et al.Stable antibody expression at therapeutic levels using the 2A peptide.Nat Biotechnol. 2005; 23: 584-590Crossref PubMed Scopus (310) Google Scholar,6Lamikanra A Myers KA Ferris N Mitrophanous KA Carroll MW In vivoevaluation of an EIAV vector for the systemic genetic delivery of therapeutic antibodies.Gene Ther. 2005; 12: 988-998Crossref PubMed Scopus (13) Google Scholar,7Jiang M Shi W Zhang Q Wang X Guo M Cui Z et al.Gene therapy using adenovirus-mediated full-length anti-HER-2 antibody for HER-2 overexpression cancers.Clin Cancer Res. 2006; 12: 6179-6185Crossref PubMed Scopus (47) Google Scholar De et al.3De BP Hackett NR Crystal RG Boyer JL Rapid/persistent anti-anthrax passive immunity mediated by co-administration of Ad/AAV vectors encoding an anti-anthrax antibody.Mol Ther. 2008; 16: 203-209Abstract Full Text Full Text PDF PubMed Scopus (38) Google Scholar present an elegant solution to this problem. Previously this group demonstrated in a mouse model of anthrax infection that, following administration of an adenovirus vector expressing a (single-chain) antibody against anthrax toxin, complete protection was acquired within 2 days.8Kasuya K Boyer JL Tan Y Alipui DO Hackett NR Crystal RG Passive immunotherapy for anthrax toxin mediated by an adenovirus expressing an anti-protective antigen single-chain antibody.Mol Ther. 2005; 11: 237-244Abstract Full Text Full Text PDF PubMed Scopus (28) Google Scholar As described in the current article, they induced mAb production in vivo using a combination of an adenovirus type 5 (injected intravenously) and an adeno-associated virus (AAV) expression vector (injected intrapleurally). The adenovirus vector provides rapid but transient mAb production, whereas mAb production induced by the AAV vector is slower but sustained. Interestingly, their combined administration to C57BL/6 mice conferred in vivo protection against a lethal challenge with anthrax toxins that was effective from day 1 and lasted for 6 months. The speed with which the administration of this vector combination provides protection has advantages over conventional methods of vaccination, which usually generate neutralizing antibody responses but often require repeated injections and require at least several weeks to achieve protective antibody levels.9Demicheli V Rivetti D Deeks JJ Jefferson T Pratt M The effectiveness and safety of vaccines against human anthrax: a systematic review.Vaccine. 1998; 16: 880-884Crossref PubMed Scopus (37) Google Scholar,10Gorse GJ Keitel W Keyserling H Taylor DN Lock M Alves K et al.Immunogenicity and tolerance of ascending doses of a recombinant protective antigen (rPA102) anthrax vaccine: a randomized, double-blinded, controlled, multicenter trial.Vaccine. 2006; 24: 5950-5959Crossref PubMed Scopus (98) Google Scholar Moreover, in the event of an urgent threat with an infectious (bioterrorist) agent such as Bacillus anthracis, this approach may be valuable, because challenged and at-risk individuals can obtain immediate protection and prolonged prophylaxis against the pathogen. Combining mAb gene therapy with antigenic (protein or DNA) vaccination could lengthen prophylaxis even further, by stimulating an endogenous pAb response while ensuring rapid passive immunity via immediate in vivo mAb production. Protein-based pAb therapy in combination with antigenic vaccination is already current practice for individuals exposed to rabies virus. The approach of De et al. might be further reinforced by adding additional mAb genes, thereby developing a genetic antibody cocktail. Nowakowski et al., for example, have shown significant synergy between noncompeting mAbs for protection against botulinum toxin.11Nowakowski A Wang C Powers DB Amersdorfer P Smith TJ Montgomery VA et al.Potent neutralization of botulinum neurotoxin by recombinant oligoclonal antibody.Proc Natl Acad Sci USA. 2002; 99: 11346-11350Crossref PubMed Scopus (291) Google Scholar Cocktails of antibodies, furthermore, are less sensitive to genotypic or phenotypic variations in pathogens and are less likely to allow the pathogen's escape from protection.12Parren PW Burton DR The antiviral activity of antibodies in vitro and in vivo.Adv Immunol. 2001; 77: 195-262Crossref PubMed Scopus (214) Google Scholar The strength of a genetic antibody cocktail is that it may combine some of the advantages inherent to pAb and mAb approaches. These include the increased protective potency due to synergism of pAb and the in-depth knowledge on mechanism of action, pharmacokinetics, and pharmocodynamics usually available for mAbs. Also, genetic antibody cocktail administration might circumvent some of the complexities of manufacturing and regulatory approval of mAb mixtures. The compelling synergies observed for mAbs against some viruses and bacterial toxins as well as the recent advancement of recombinant antibody mixtures into phase I clinical trials2Wiberg FC Rasmussen SK Frandsen TP Rasmussen LK Tengbjerg K Coljee VW et al.Production of target-specific recombinant human polyclonal antibodies in mammalian cells.Biotechnol Bioeng. 2006; 94: 396-405Crossref PubMed Scopus (68) Google Scholar,13de Kruif J Bakker AB Marissen WE Kramer RA Throsby M Rupprecht CE et al.A human monoclonal antibody cocktail as a novel component of rabies postexposure prophylaxis.Annu Rev Med. 2007; 58: 359-368Crossref PubMed Scopus (68) Google Scholar strongly encourage the future development of recombinant pAb cocktails. One issue deserving further attention is the use of adenovirus and AAV vectors in humans. Recent studies that indicate an increased chance for developing hepatocellular carcinomas,14Russell DW AAV vectors, insertional mutagenesis, and cancer.Mol Ther. 2007; 15: 1740-1743Abstract Full Text Full Text PDF PubMed Scopus (40) Google Scholar and other previously identified risks, such as germ-line integration, have caused reluctance to use such vectors in human patients. Also, many individuals have preexisting anti-capsid immunity, which strongly decreases the in vivo transfection in humans using these vector systems, even with local application.15Boissier MC Lemeiter D Clavel C Valvason C Laroche L Begue T et al.Synoviocyte infection with adeno-associated virus (AAV) is neutralized by human synovial fluid from arthritis patients and depends on AAV serotype.Hum Gene Ther. 2007; 18: 525-535Crossref PubMed Scopus (31) Google Scholar Although nonviral vector systems may represent an attractive alternative in this respect, these approaches have so far not produced antibody expression levels to the extent observed with viral vectors. More practical issues are the development of large-scale production and stockpiling methods to ensure sufficient vector availability during a disease outbreak, as well as convenient routes for human delivery. Further research is therefore needed to allow successful translation of this technology to the clinic and the field. Notwithstanding, the current study by De et al. provides proof of concept for an interesting and promising one-shot method for generating immediate and sustained antibody protection in the face of an imminent pathogenic threat. The authors thank Wim Bleeker (Genmab), Iacob Mathiesen (Inovio A/S) for helpful advice, and Joost Bakker (Genmab) for graphics.