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ABSTRACTFrancisella tularensis, a Gram-negative bacterium, is the causative agent of tularemia. No licensed vaccine is currently available for protection against tularemia, although an attenuated strain, dubbed the live vaccine strain (LVS), is given to at-risk laboratory personnel as an investigational new drug (IND). In an effort to develop a vaccine that offers better protection, recombinant attenuated derivatives of a virulent type A strain, SCHU S4, were evaluated in New Zealand White (NZW) rabbits. Rabbits vaccinated via scarification with the three attenuated derivatives (SCHU S4 ?guaBA, ?aroD, and ?fipBstrains) or with LVS developed a mild fever, but no weight loss was detected. Twenty-one days after vaccination, all vaccinated rabbits were seropositive for IgG to F. tularensislipopolysaccharide (LPS). Thirty days after vaccination, all rabbits were challenged with aerosolized SCHU S4 at doses ranging from 50 to 500 50% lethal doses (LD50). All rabbits developed fevers and weight loss after challenge, but the severity was greater for mock-vaccinated rabbits. The ?guaBAand ?aroDSCHU S4 derivatives provided partial protection against death (27 to 36%) and a prolonged time to death compared to results for the mock-vaccinated group. In contrast, LVS and the ?fipBstrain both prolonged the time to death, but there were no survivors from the challenge. This is the first demonstration of vaccine efficacy against aerosol challenge with virulent type A F. tularensisin a species other than a rodent since the original work with LVS in the 1960s. The ?guaBAand ?aroDSCHU S4 derivatives warrant further evaluation and consideration as potential vaccines for tularemia and for identification of immunological correlates of protection.

Each year, more than 5 million individuals are newly infected with HIV-1 [1]. To address this, the development of an HIV/AIDS vaccine has remained one of the highest priorities in biomedical research for the last 25 years. During this time, we have witnessed some success with the development of antiretroviral therapies capable of lowering the viral loads and decreasing the severity of disease. While treatment has extended the time course of infection, it has not resulted in a cure and/or prevention of HIV-1 infection. On the other hand, a large number of vaccine candidates have been tested with less than stellar success. Over the last two decades, researchers have focused almost exclusively on vaccines that exploit either cellular or humoral immunity as a goal for AIDS vaccine development. After more than two decades of limited success with vaccines, most researchers now believe that the goal of an AIDS vaccine should be to elicit as robust and broadly active cellular and humoral immunity as possible, thereby maximizing the potential for protection from variant HIV-1 strains by different routes of exposure. Researchers are returning focus back to the importance of antibody-mediated neutralization as a prime determinant in the protection against HIV-1 infection. One of the challenges for the development of an HIV/AIDS vaccine remains the great diversity of sequences present in viral isolates, particularly those in Env. HIV-1 isolates are divided into three different groups based on sequence diversity: Group M, N and O [2]. Isolates of group M (main) comprise the majority of worldwide infections and these viruses are further subdivided into nine different clades A-D, F-H, J, and K. These subtypes are separated by approximately 25-35% amino acid divergence in the surface glycoprotein Env. In addition, there are also circulating recombinant forms (CRFs) which are mosaics of two or more different viral isolates found in at least three epidemiologically independent individuals [2]. Therefore, the elicitation of an antibody response with broad neutralizing activity against primary isolates of multiple HIV-1 subtypes continues to be a desired characteristic of candidate HIV-1 vaccines. Standardized criteria for measuring the immune responses are critical and are being established. The use of new methodologies and testing requirements will provide a stronger environment for the development of broadly protective HIV-1 vaccines. In order to develop a successful AIDS vaccine depends on strategies to overcome the ability of the virus to evade humoral immunity at both the mucosal and systemic sites. This issue of Current HIV Research focuses on several aspects of our present scientific understanding of HIV neutralization. The structure and epitopes of the envelope glycoprotein are reviewed in association with design vaccine immunogens. Hu and Statamatos [3] provide an overview on Env modifications and their limitations vs. successes in vaccine design, while and Lin and Nara [4] discuss the design of core, functional Env modifications using immune dampening and immune refocusing strategies designed to counter immunodominant, decoy responses generated by the virus. Zwick and Burton provide an elegant review of the stoichiometry, kinetic, and thermodynamic parameters involved in neutralization [12]. Pinter describes the roles of Env variable regions important in HIV-1 neutralization that should be considered in vaccine development [5] and Burke and Barnett [13] provide a comparative overview of the described neutralizing epitopes in Env. The HIV-1 envelope is able to assume a variety of structures during binding to various cell receptors during the fusion and entry process, thereby exposing new epitopes to the immune system. DeVico describes the accessibility, antigenicity and immunogenicity of CD4-induced epitopes as possible vaccine immuongens [7]. Two reviews tackle the important issues regarding the diversity of the HIV-1 envelope. McKnight and Aasa-Chapman [6] describe the advantages of clade-specific versus clade-generic vaccines while Gao et al. [8] provide an overview of the use of centralized Env sequences to develop immunogens to elicit broadly reactive antibodies that neutralize isolates from all clades. Two reviews address the critical issue of HIV-1 transmissions across mucosal barriers....