Genetic Vaccines for Anthrax Based on Recombinant Adeno-associated Virus Vectors

Overview

Journal Mol Ther

Publisher Cell Press

Specialties Molecular Biology
Pharmacology

Date 2008 Nov 13

PMID 19002162

Citations 8

Authors

Te-Hui Liu

Jon Oscherwitz

Bruce Schnepp

Jana Jacobs

Fen Yu

Kemp B Cease

Philip R Johnson

Affiliations

Soon will be listed here.

Abstract

Bacillus anthracis represents a formidable bioterrorism and biowarfare threat for which new vaccines are needed with improved safety and efficacy over current options. Toward this end, we created recombinant adeno-associated virus type 1 (rAAV1) vectors containing synthetic genes derived from the protective antigen (PA) or lethal factor (LF) of anthrax lethal toxin (LeTx) and tested them for immunogenicity and induction of toxin-neutralizing antibodies in rabbits. Codon-optimized segments encoding activated PA (PA63), or LF, were synthesized and cloned into optimized rAAV1 vectors containing a human cytomegalovirus (hCMV) promoter and synthetic optimized leader. Serum from rabbits immunized intramuscularly with rAAV1/PA (monovalent), rAAV1/LF (monovalent), rAAV1/PA + rAAV1/LF (bivalent), or rAAV1/enhanced green fluorescent protein (control) exhibited substantial PA- and LF-specific antibody responses at 4 weeks by both western blot (> 1:10,000 dilution) and enzyme-linked immunosorbent assay (ELISA) (mean end-point titer: 32,000-260,000), and contained anthrax LeTx-neutralizing activity in vitro, with peak titers approximating those of a rabbit hyperimmune antisera raised against soluble PA and LF. Compared to the monovalent groups (rAAV1/PA or rAAV1/LF), the bivalent group (rAAV1/PA + rAAV1/LF) exhibited marginally higher ELISA and neutralization activity with dual specificity for both PA and LF. The finding of robust neutralizing antibody responses after a single injection of these rAAV1-based vectors supports their further development as candidate anthrax vaccines.

Citing Articles

Evaluation of immune response to recombinant LFD1-PA4 chimeric protein.

Mirhaj H, Honari H, Zamani E Iran J Vet Res. 2019; 20(2):112-119.

PMID: 31531033 PMC: 6716276.

Epitope-focused peptide immunogens in human use adjuvants protect rabbits from experimental inhalation anthrax.

Oscherwitz J, Feldman D, Yu F, Cease K Vaccine. 2014; 33(3):430-6.

PMID: 25454087 PMC: 4391504. DOI: 10.1016/j.vaccine.2014.11.042.

Recombinant vaccine displaying the loop-neutralizing determinant from protective antigen completely protects rabbits from experimental inhalation anthrax.

Oscherwitz J, Yu F, Jacobs J, Cease K Clin Vaccine Immunol. 2013; 20(3):341-9.

PMID: 23283638 PMC: 3592347. DOI: 10.1128/CVI.00612-12.

Recombinant adeno-associated virus-mediated gene transfer for the potential therapy of adenosine deaminase-deficient severe combined immune deficiency.

Silver J, Elder M, Conlon T, Cruz P, Wright A, Srivastava A Hum Gene Ther. 2010; 22(8):935-49.

PMID: 21142972 PMC: 6468955. DOI: 10.1089/hum.2010.121.

A chimeric protein that functions as both an anthrax dual-target antitoxin and a trivalent vaccine.

Wu G, Hong Y, Guo A, Feng C, Cao S, Zhang C Antimicrob Agents Chemother. 2010; 54(11):4750-7.

PMID: 20713663 PMC: 2976106. DOI: 10.1128/AAC.00640-10.

References

Logan G, Wang L, Zheng M, Cunningham S, Coppel R, Alexander I . AAV vectors encoding malarial antigens stimulate antigen-specific immunity but do not protect from parasite infection. Vaccine. 2006; 25(6):1014-22. DOI: 10.1016/j.vaccine.2006.09.072. View

Xu Q, Zeng M . Detoxified lethal toxin as a potential mucosal vaccine against anthrax. Clin Vaccine Immunol. 2008; 15(4):612-6. PMC: 2292655. DOI: 10.1128/CVI.00402-07. View

Grimm D, Kay M . From virus evolution to vector revolution: use of naturally occurring serotypes of adeno-associated virus (AAV) as novel vectors for human gene therapy. Curr Gene Ther. 2003; 3(4):281-304. DOI: 10.2174/1566523034578285. View

. Biological products; bacterial vaccines and toxoids; implementation of efficacy review. Final rule and final order. Fed Regist. 2004; 69(2):255-67. View

Clark K, Voulgaropoulou F, Fraley D, Johnson P . Cell lines for the production of recombinant adeno-associated virus. Hum Gene Ther. 1995; 6(10):1329-41. DOI: 10.1089/hum.1995.6.10-1329. View

Fellows P, Linscott M, Ivins B, Pitt M, Rossi C, Gibbs P . Efficacy of a human anthrax vaccine in guinea pigs, rabbits, and rhesus macaques against challenge by Bacillus anthracis isolates of diverse geographical origin. Vaccine. 2001; 19(23-24):3241-7. DOI: 10.1016/s0264-410x(01)00021-4. View

Ivins B, Pitt M, Fellows P, Farchaus J, Benner G, Waag D . Comparative efficacy of experimental anthrax vaccine candidates against inhalation anthrax in rhesus macaques. Vaccine. 1998; 16(11-12):1141-8. DOI: 10.1016/s0264-410x(98)80112-6. View

Hermanson G, Whitlow V, Parker S, Tonsky K, Rusalov D, Ferrari M . A cationic lipid-formulated plasmid DNA vaccine confers sustained antibody-mediated protection against aerosolized anthrax spores. Proc Natl Acad Sci U S A. 2004; 101(37):13601-6. PMC: 518760. DOI: 10.1073/pnas.0405557101. View

Manning W, Paliard X, Zhou S, Pat Bland M, Lee A, Hong K . Genetic immunization with adeno-associated virus vectors expressing herpes simplex virus type 2 glycoproteins B and D. J Virol. 1997; 71(10):7960-2. PMC: 192154. DOI: 10.1128/JVI.71.10.7960-7962.1997. View

10.

Pitt , Little , Ivins , Fellows , Boles , Barth . In vitro correlate of immunity in an animal model of inhalational anthrax. J Appl Microbiol. 1999; 87(2):304. DOI: 10.1046/j.1365-2672.1999.00897.x. View

11.

Johnson P, Schnepp B, Connell M, Rohne D, Robinson S, Krivulka G . Novel adeno-associated virus vector vaccine restricts replication of simian immunodeficiency virus in macaques. J Virol. 2004; 79(2):955-65. PMC: 538580. DOI: 10.1128/JVI.79.2.955-965.2005. View

12.

Gu M, Leppla S, Klinman D . Protection against anthrax toxin by vaccination with a DNA plasmid encoding anthrax protective antigen. Vaccine. 1999; 17(4):340-4. DOI: 10.1016/s0264-410x(98)00210-2. View

13.

Tenenbaum L, Lehtonen E, Monahan P . Evaluation of risks related to the use of adeno-associated virus-based vectors. Curr Gene Ther. 2003; 3(6):545-65. DOI: 10.2174/1566523034578131. View

14.

Puziss M, Wright G . Studies on immunity in anthrax. X. Gel-adsorbed protective antigen for immunization of man. J Bacteriol. 1963; 85:230-6. PMC: 278112. DOI: 10.1128/jb.85.1.230-236.1963. View

15.

Galloway D, Liner A, Legutki J, Mateczun A, Barnewall R, Estep J . Genetic immunization against anthrax. Vaccine. 2004; 22(13-14):1604-8. DOI: 10.1016/j.vaccine.2003.09.043. View

16.

dos Santos Coura R, Nardi N . The state of the art of adeno-associated virus-based vectors in gene therapy. Virol J. 2007; 4:99. PMC: 2104528. DOI: 10.1186/1743-422X-4-99. View

17.

Ferrari F, Samulski T, Shenk T, Samulski R . Second-strand synthesis is a rate-limiting step for efficient transduction by recombinant adeno-associated virus vectors. J Virol. 1996; 70(5):3227-34. PMC: 190186. DOI: 10.1128/JVI.70.5.3227-3234.1996. View

18.

Gallez-Hawkins G, Li X, Franck A, Thao L, Lacey S, Diamond D . DNA and low titer, helper-free, recombinant AAV prime-boost vaccination for cytomegalovirus induces an immune response to CMV-pp65 and CMV-IE1 in transgenic HLA A*0201 mice. Vaccine. 2004; 23(6):819-26. DOI: 10.1016/j.vaccine.2004.06.048. View

19.

Price B, Liner A, Park S, Leppla S, Mateczun A, Galloway D . Protection against anthrax lethal toxin challenge by genetic immunization with a plasmid encoding the lethal factor protein. Infect Immun. 2001; 69(7):4509-15. PMC: 98526. DOI: 10.1128/IAI.69.7.4509-4515.2001. View

20.

Collier R, Young J . Anthrax toxin. Annu Rev Cell Dev Biol. 2003; 19:45-70. DOI: 10.1146/annurev.cellbio.19.111301.140655. View