Antibodies Contribute to Effective Vaccination against Respiratory Infection by Type A Francisella tularensis Strains

Abstract

Pneumonic tularemia is a life-threatening disease caused by inhalation of the highly infectious intracellular bacterium Francisella tularensis. The most serious form of the disease associated with the type A strains can be prevented in experimental animals through vaccination with the attenuated live vaccine strain (LVS). The protection is largely cell mediated, but the contribution of antibodies remains controversial. We addressed this issue in a series of passive immunization studies in Fischer 344 (F344) rats. Subcutaneous LVS vaccination induced a robust serum antibody response dominated by IgM, IgG2a, and IgG2b antibodies. Prophylactic administration of LVS immune serum or purified immune IgG reduced the severity and duration of disease in naïve rats challenged intratracheally with a lethal dose of the virulent type A strain SCHU S4. The level of resistance increased with the volume of immune serum given, but the maximum survivable SCHU S4 challenge dose was at least 100-fold lower than that shown for LVS-vaccinated rats. Protection correlated with reduced systemic bacterial growth, less severe histopathology in the liver and spleen during the early phase of infection, and bacterial clearance by a T cell-dependent mechanism. Our results suggest that treatment with immune serum limited the sequelae associated with infection, thereby enabling a sterilizing T cell response to develop and resolve the infection. Thus, antibodies induced by LVS vaccination may contribute to the defense of F344 rats against respiratory infection by type A strains of F. tularensis.

Increased Susceptibility of IgA-Deficient Mice to Pulmonary Francisella tularensis Live Vaccine Strain Infection

“…Furthermore, our data implicate a minimal role for IgG and IgM, in protection against pulmonary tularemia. These findings contrast with previous studies in which passive transfer of purified IgG antibodies, specific for F. tularensis LVS, was found to be protective against both systemic (23) and mucosal (14) challenges. Overproduction of protective IgG antibody, as observed in our model, should in theory compensate for the absence of IgA.…”

“…Cell-mediated immunity is generally considered to be essential for immunity against intracellular pathogens, and humoral immunity is thought to have more of an ancillary role. However, significant evidence in the literature indicates an important role of antibodies against F. tularensis LVS infection (13)(14)(15)(16)(17). Moreover, studies from our laboratory have recently reported a synergistic effect of humoral and cellular immune responses in providing sterilizing immunity against respiratory LVS infection (13).…”

“…In those studies, the beneficiary effect of F. tularensis LVS-specific IgG antibodies was lost after depletion of T cells from the recipient mice (14,23). This observation is consistent with our previous findings that serum antibody treatment failed to protect SCID mice from F. tularensis LVS infection (13).…”

Monophosphoryl Lipid A Enhances Efficacy of a Francisella tularensis LVS-Catanionic Nanoparticle Subunit Vaccine against F. tularensis Schu S4 Challenge by Augmenting both Humoral and Cellular Immunity

“…tularensis replicates intracellularly, and thus the role of humoral immunity against this pathogen has been controversial; however, significant contributions of the humoral response in F. tularensis infection are supported by a growing body of literature (46)(47)(48)(49)(50)(51)(52). The fact that passive administration of LVS-VϩMPL immune sera fully protected mice against challenge with F. tularensis LVS (data not shown) and extended the mean time to death significantly in mice challenged with F. tularensis Schu S4 by the s.c. route, but not by the i.n.…”

Putting the Jigsaw Together - A Brief Insight Into the Tularemia

“…These results nevertheless clearly demonstrated that immune sera contain protective antibodies and their protective effect correlated well with precipitating antibody content [232]. More recently, studies on the passive transfer of immunity against tularemia in prophylactic mode utilizing both (hyper)immune sera as well as monoclonal antibodies have shown that specific antibodies limited manifestation of the disease, thereby facilitating a sterilizing T cell response to resolve the infection [233][234][235][236][237][238]. Moreover, antibodies can also be used in therapeutic mode, especially when given early after infection [193,239].…”