Syphilis vaccine: up-regulation of immunogenicity by cyclophosphamide, Ribi adjuvant, and indomethacin confers significant protection against challenge infection in rabbits.

Many unsuccessful attempts have been made to develop effective vaccines against experimental syphilitic infection. The focus of this report was to evaluate newer approaches to up-regulate immune responses following immunization with Treponema pallidum. Rabbits were injected once on day 0 with heat-inactivated treponemes suspended in the Ribi adjuvant system containing monophosphoryl lipid A (MPL) and trehalose dimycolate; animals were challenged dermally on day 29 with viable organisms. Various up-regulating agents were then tested using this general immunization protocol. When rabbits were pretreated on day -2 with cyclophosphamide (CYC), no protection was apparent. CYC pretreatment exhibited some protection when combined with a daily course of indomethacin on days 29 to 36. When rabbits were injected on day 0, then given a boost of MPL alone on day +2 plus indomethacin on days 29 to 36, minor protection was again apparent. Excellent protection was achieved when the vaccine protocol involved a combination of CYC pretreatment on day -2, an MPL boost on day +2, and indomethacin on days 29 to 36. Ninety-two percent of the subsequent lesions were atypical as indicated by their flat appearance, small size, lack of ulceration, and rapid healing. Importantly, this vaccine regimen also decreased dissemination of T. pallidum to distant tissues. These results suggest a new perspective in understanding immune responses in syphilis. We propose that vaccination, like infection, generates immune down-regulation that counter-balances immune stimulation. THus, effective vaccines will depend on removal and/or neutralization of treponemal components that down-regulate immune reactivity.