Eric K Dumas1, Lori Garman1, Hannah Cuthbertson2, Sue Charlton2, Bassam Hallis2, Renata J M Engler3, Shyamal Choudhari4, William D Picking4, Judith A James5, A Darise Farris6. 1. Arthritis and Clinical Immunology Program, Oklahoma Medical Research Foundation (OMRF), 825 NE 13th St., Oklahoma City, OK 73104, USA; Department of Microbiology and Immunology, University of Oklahoma Health Sciences Center (OUHSC), 940 Stanton L. Young Blvd, Oklahoma City, OK 73104, USA. 2. Public Health England, National Infection Service, Porton Down, Salisbury, Wiltshire SP4 0JG, United Kingdom. 3. Walter Reed National Military Medical Center, 8901 Wisconsin Ave, Bethesda, MD 20814, USA. 4. Department of Pharmaceutical Chemistry, University of Kansas, 320B Multidisciplinary Research Building, 2030 Becker Dr., Lawrence, KS 66047, USA. 5. Arthritis and Clinical Immunology Program, Oklahoma Medical Research Foundation (OMRF), 825 NE 13th St., Oklahoma City, OK 73104, USA; Department of Microbiology and Immunology, University of Oklahoma Health Sciences Center (OUHSC), 940 Stanton L. Young Blvd, Oklahoma City, OK 73104, USA; Departments of Medicine and Pathology, OUHSC, 1000 Stanton L. Young Blvd, Oklahoma City, OK 73104, USA. 6. Arthritis and Clinical Immunology Program, Oklahoma Medical Research Foundation (OMRF), 825 NE 13th St., Oklahoma City, OK 73104, USA; Department of Microbiology and Immunology, University of Oklahoma Health Sciences Center (OUHSC), 940 Stanton L. Young Blvd, Oklahoma City, OK 73104, USA. Electronic address: darise-farris@omrf.org.
Abstract
A major difference between two currently licensed anthrax vaccines is presence (United Kingdom Anthrax Vaccine Precipitated, AVP) or absence (United States Anthrax Vaccine Adsorbed, AVA) of quantifiable amounts of the Lethal Toxin (LT) component Lethal Factor (LF). The primary immunogen in both vaccine formulations is Protective Antigen (PA), and LT-neutralizing antibodies directed to PA are an accepted correlate of vaccine efficacy; however, vaccination studies in animal models have demonstrated that LF antibodies can be protective. In this report we compared humoral immune responses in cohorts of AVP (n=39) and AVA recipients (n=78) matched 1:2 for number of vaccinations and time post-vaccination, and evaluated whether the LF response contributes to LT neutralization in human recipients of AVP. PA response rates (≥95%) and PA IgG concentrations were similar in both groups; however, AVP recipients exhibited higher LT neutralization ED50 values (AVP: 1464.0±214.7, AVA: 544.9±83.2, p<0.0001) and had higher rates of LF IgG positivity (95%) compared to matched AVA vaccinees (1%). Multiple regression analysis revealed that LF IgG makes an independent and additive contribution to the LT neutralization response in the AVP group. Affinity purified LF antibodies from two independent AVP recipients neutralized LT and bound to LF Domain 1, confirming contribution of LF antibodies to LT neutralization. This study documents the benefit of including an LF component to PA-based anthrax vaccines.
A major difference between two currently licensed anthrax vaccines is presence (United Kingdom pan class="Species">Anthrax Vaccine Precipitated, AVP) or absence (United States Anthrax Vaccine Adsorbed, AVA) of quantifiable amounts of the Lethal Toxin (LT) component Lethal Factor (LF). The primary immunogen in both vaccine formulations is Protective Antigen (PA), and LT-neutralizing antibodies directed to PA are an accepted correlate of vaccine efficacy; however, vaccination studies in animal models have demonstrated that LF antibodies can be protective. In this report we compared humoral immune responses in cohorts of AVP (n=39) and AVA recipients (n=78) matched 1:2 for number of vaccinations and time post-vaccination, and evaluated whether the LF response contributes to LT neutralization in human recipients of AVP. PA response rates (≥95%) and PA IgG concentrations were similar in both groups; however, AVP recipients exhibited higher LT neutralization ED50 values (AVP: 1464.0±214.7, AVA: 544.9±83.2, p<0.0001) and had higher rates of LF IgG positivity (95%) compared to matched AVA vaccinees (1%). Multiple regression analysis revealed that LF IgG makes an independent and additive contribution to the LT neutralization response in the AVP group. Affinity purified LF antibodies from two independent AVP recipients neutralized LT and bound to LF Domain 1, confirming contribution of LF antibodies to LT neutralization. This study documents the benefit of including an LF component to PA-based anthrax vaccines.
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