Human Immune Response to a Plague Vaccine Comprising Recombinant F1 and V Antigens

Abstract

The human immune response to a new recombinant plague vaccine, comprising recombinant F1 (rF1) and rV antigens, has been assessed during a phase 1 safety and immunogenicity trial in healthy volunteers. All the subjects produced specific immunoglobulin G (IgG) in serum after the priming dose, which peaked in value after the booster dose (day 21), with the exception of one individual in the lowest dose level group, who responded to rF1 only. Three subjects, found to have an anti-rV titer at screening, were excluded from the overall analysis. Human antibody functionality has been assessed by quantification of antibody competing for binding to rV in vitro and also by the transfer of protective immunity in human serum into the naïve mouse. Human and macaque IgG competed for binding to rV in vitro with a mouse monoclonal antibody, previously shown to protect mice against challenge with plague, suggesting that this protective B-cell epitope on rV is conserved between these three species. Total IgG to rV in individuals and the titer of IgG competing for binding to rV correlated significantly at days 21 (r ‫؍‬ 0.72; P < 0.001) and 28 (r ‫؍‬ 0.82; P < 0.001). Passive transfer of protective immunity into mice also correlated significantly with total IgG titer to rF1 plus rV at days 21 (r 2 ‫؍‬ 98.6%; P < 0.001) and 28 (r 2 ‫؍‬ 76.8%; P < 0.03). However, no significant vaccination-related change in activation of peripheral blood mononuclear cells was detected at any time. Potential serological immune correlates of protection have been investigated, but no trends specific to vaccination could be detected in cellular markers.

Sequential Proteolytic Processing of the Capsular Caf1 Antigen of Yersinia pestis for Major Histocompatibility Complex Class II-restricted Presentation to T Lymphocytes

“…Immunization against Caf1 alone (12)(13)(14)(15)(16)(17) or in combination with the Ysc-Yop LcrV plasmid-encoded V antigen protects mice against bubonic (18 -21) and pneumonic (22)(23)(24) forms of plague and has been used in human trials (25). Recombinant Caf1 (rCaf1) 2 forms polymers in a similar manner to the native Caf1 encapsulating Y. pestis, and monomerization by denaturation dramatically reduces the protective efficacy, without a detectable effect on the anti-Caf1 antibody response induced (26).…”

Treatment of plague: promising alternatives to antibiotics

“…Immunodominant epitopes have been found for the F1 (Sabhnani & Rao, 2000;Sabhnani et al, 2003;Zav'yalov et al, 1995) and V (Hill et al, 1997) antigens. Passive administration of antibodies against target antigens protects macrophages from Y. pestis-induced cell death, promotes phagocytosis (Cowan et Une & Brubaker, 1984;Williamson et al, 2005). Importantly, therapy based on a single antibody against a single antigen or epitope will be ineffective in the case of infection with a virulent strain lacking the antigen or expressing a different serological variant of the antigen (Anisimov et al, 2004;Friedlander et al, 1995;Roggenkamp et al, 1997).…”

“…A number of subunit-based vaccines are currently under development and/or at different stages of preclinical/clinical trials. These offer the advantage of employing a defined antigen that possesses the ability to elicit high-level protection, and they are also less reactogenic than the currently used whole-cell vaccines (Anisimov et al, 2004;Williamson, 2001;Williamson et al, 2005). The main limitation of the prevention of plague by vaccination is that protection is delayed for at least 1 week after immunization, and this time may be crucial with respect to the lethal outcome of the disease (Butler, 1983;Dennis et al, 1999;Domaradskii, 1993Domaradskii, , 1998Inglesby et al, 2000;Lien-Teh et al, 1936;Naumov & Samoilova, 1992;Nikolaev, 1972;Perry & Fetherston, 1997;Pollitzer, 1954;Rudnev, 1940).…”

Plague in Guinea Pigs and Its Prevention by Subunit Vaccines

“…22,23 Furthermore, the ability of LcrV-or F1-mediated immune responses in humans to generate protective immunity against pneumonic plague has not yet been demonstrated. 21 The current incidence of plague is low, estimated to be approximately 4000 cases worldwide, and efficacy testing of plague vaccines may not be feasible with vaccine trials in human populations. 6 Animal models of plague infection have been adopted as a surrogate for human plague and vaccine efficacy testing to fulfill the "Animal Rule," a government regulation enabling the Food and Drug Administration to license biodefense vaccines for diseases with low incidence (Code of Federal Regulations, Title 21, Volume 5, Part 314 -Approval of New Drugs when Human Efficacy Studies Are Not Ethical or Feasible).…”