Safety and Immunogenicity of the Second Generation Anthrax Vaccine Candidate
By Luciana L. Borio, M.D. and John G. Bartlett, M.D., June 16, 2006
Vaxgen, Inc. (Brisbane, CA) reported in a study  currently in press and to be published in the next issue of Vaccine the results of a phase 1 clinical trial designed to assess the safety and immunogenicity of their recombinant anthrax vaccine candidate, rPA102. In the double-blinded trial, 100 adult healthy volunteers were randomized to receive 5, 25, 50, or 75 ug of rPA102 at 0, 4, and 6 weeks or AVA (BiothraxTM, Bioport Corporation, Lansing, Michigan) at 0 and 4 weeks. AVA is the currently licensed anthrax vaccine in the U.S.
Antibodies to protein antigen (PA) are thought to be the most significant determinant of protection from disease after immunization with anthrax vaccine. The PA in AVA is derived from the supernatant of a modified B. anthracis cell culture; thus, the concentrations of PA in AVA vary from lot to lot. AVA contains 600 ug of aluminum hydroxide adjuvant (Al) per dose. In contrast, rPA102 is a purified protein derived from the culture supernatant of a modified Bacillus anthracis strain that contains a recombinant plasmid encoding PA. The vaccine candidate was adsorbed Al adjuvant with a final concentration of only 82.5 ug per dose. In November 2004, DHHS awarded a contract to VaxGen for 75 million doses of rPA for the Strategic National Stockpile at a price of $877.5 million .
Safety: Local reactogenicity, mostly pain and tenderness, lasting less than 3 days, was more common with AVA than with rPA102 after the first and second vaccinations (94.7% vs. 44.4% and 84.2% versus 35.4%). Systemic reactogenicity, mostly headache, lasting approximately 1 day, was more common in the rPA102 group, but only after the first vaccination (33.3% versus 5.3%).
Immunogenicity: Anti-PA antibodies were measured by lethal toxin neutralization activity (TNA) and anti-PA IgG ELISA. Although responses were measured over the course of 32 weeks, the AVA group received only 2 vaccinations. Thus, the table below summarizes the results of the peak response after the second dose of either group (i.e. the most applicable comparison between the two groups).
Geometric mean titers (GMT) for lethal toxin neutralization activity (TNA), 2 weeks after second vaccination
Geometric mean concentrations (GMC) by anti-PA
At the 75 ug dose, the resulting GMT for TNA between rPA and AVA was not statistically significant. The differences between the two vaccines when measured by way of anti-PA IgG ELISA were markedly significant. The authors suggest that a possible explanation for these differences is the fact that additional proteins, possibly including degraded PA, may have a greater effect on the results of anti-PA measured via ELISA than via TNA. “TNA is an in vitro assessment of the ability of the induced antibody to directly neutralize B. anthracis exotoxins, while ELISA measures antibody binding to PA, potentially including binding to non-functional epitopes as well as neutralizing epitopes.” Thus, TNA is a better measurement of functional antibodies present.
In pre-clinical studies, rPA102 protected rabbits and non-human primates from an inhalational challenge with B. anthracis. This clinical trial shows that the rPA102 vaccine candidate was well tolerated. Immunogenicity at higher rPA102 doses was not statistically inferior to that of AVA when measured by TNA despite a much larger amount of Al adjuvant in the AVA. Overall, these results are encouraging. Vaxgen is proceeding with optimizing their vaccine candidate’s formulation and scheduling. Recently, Vaxgen has encountered manufacturing problems that may delay its delivery to the U.S. government. Although Vaxgen’s candidate vaccine does not appear to be a significant step forward with regard to protecting citizens rapidly in the event of an attack, since it requires multiple doses and needs to be administered intramuscularly, it is reassuring to have more than one producer of anthrax vaccine in the U.S.
Gorse GJ, et al. Immunogenicity and tolerance of ascending doses of a recombinant protective antigen (rPA102) anthrax vaccine: A randomized, double-blinded, controlled, multicenter trial. Vaccine, In Press.
HHS Buys New Anthrax Vaccine for Stockpile. Available at http://www.cidrap.umn.edu/news-perspective/2004/11/hhs-buy-5-million-doses-licensed-anthrax-vaccine-stockpile. Accessed June 13, 2006.