Lethal factor antibodies contribute to lethal toxin neutralization in recipients of anthrax vaccine precipitated

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.

Anthrax Vaccine Precipitated Induces Edema Toxin-Neutralizing, Edema Factor-Specific Antibodies in Human Recipients

“…The actual concentration of EF in AVP is unclear but is lower than that of LF (26). In contrast to the present results, we recently showed that LF antibodies in AVP vaccinees contribute to LT neutralization (29). As LF is present in AVP at a concentration of approximately 1.9 g/ml (26), we suggest that this should be the minimum amount of EF or its derivative that should accompany recombinant PA in any future studies investigating the capacity of EF to enhance recombinant PA vaccines.…”

“…The marginal effect of gender on ET neutralization in response to AVP reflected interaction with PA IgG concentration, where changes in PA antibody concentration resulted in detectably larger changes in ET neutralization in females than males. In contrast to our recent report noting a selective association between LF titers and LT neutralization in female recipients of AVP (29), no interaction between gender and EF IgG response in the outcome of ET neutralization in AVP recipients was detected. In contrast, gender significantly impacted the AVA response, with ET neutralization being higher in males than females.…”

“…In contrast, gender significantly impacted the AVA response, with ET neutralization being higher in males than females. This is consistent with prior observations showing higher LT neutralization (29) and higher PA IgG responses (56) in male AVA recipients using samples from a real-world military cohort. A large, well-controlled clinical trial evaluating different routes and schedules of AVA vaccination showed no gender effects on PA IgG concentration after subcutaneous administration and higher PA IgG concentrations in females at early but not late time points after intramuscular vaccination (57).…”

“…While both vaccines elicit PA-specific antibody responses that mediate protection, we recently observed that the presence of LF in the AVP formulation elicits LF-specific antibodies that additively contribute to LT neutralization (29). However, the potential contribution of EF antibodies to ET neutralization in AVP recipients remains unclear.…”

Confronting the threat of bioterrorism: realities, challenges, and defensive strategies

“…Since naturally occurring inhalation anthrax is extremely rare, there have been safety and immunogenicity profiles of the anthrax vaccine in humans, 97 but the efficacy has only been tested in animal models, and not in clinical trials. [98][99][100] The current anthrax vaccine is made from culture filtrates of a toxigenic, avirulent, nonencapsulated mutant of the Bacillus anthracis Vollum strain, and is administered in five intramuscular doses, followed by annual boosters. The protective, antigen specific memory B cells persist for many years after vaccination and are associated with humoral immunity.…”