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The mechanisms underlying epitope selection and the potential impact of immunodominance hierarchies on peptide-based vaccines are not well understood. Recently, we have shown that two immunodominant MHC class I-restricted epitopes, NP366–374/Db (nucleoprotein (NP)) and PA224–233/Db (acidic polymerase (PA)), which drive the CD8+ T cell response to influenza virus infection in C57BL/6 mice, are differentially expressed on infected cells. Whereas NP appears to be strongly expressed on all infected cells, PA appears to be strongly expressed on dendritic cells but only weakly expressed on nondendritic cells. Thus, the immune response to influenza virus may involve T cells specific for epitopes, such as PA, that are poorly expressed at the site of infection. To examine the consequences of differential Ag presentation on peptide vaccination, we compared the kinetics of the T cell response and influenza virus clearance in mice vaccinated with the NP or PA peptide. Vaccination with either the NP or PA peptide resulted in accelerated and enhanced Ag-specific T cell responses at the site of infection following influenza virus challenge. These T cells were fully functional in terms of their ability to produce IFN-γ and TNF-α and to mediate cytolytic activity. Despite this enhancement of the Ag-specific T cell response, PA vaccination had a detrimental effect on the clearance of influenza virus compared with unvaccinated or NP-vaccinated mice. These data suggest that differential Ag presentation impacts the efficacy of T cell responses to specific epitopes and that this needs to be considered for the development of peptide-based vaccination strategies.

Kinetic studies and short pulses of injected 5-bromo-2-deoxyuridine have been used to analyze the development and renewal of peripheral CD8+ memory T cells in the lungs during primary and secondary respiratory virus infections. We show that developing peripheral CD8+ memory T cells proliferate during acute viral infection with kinetics that are indistinguishable from those of lymphoid CD8+ memory T cells. Secondary exposure to the same virus induces a new round of T cell proliferation and extensive renewal of the peripheral and lymphoid CD8+ memory T cell pools in both B cell-deficient mice and mice with immune Abs. In mice with virus-specific Abs, CD8+ T cell proliferation takes place with minimal inflammation or effector cell recruitment to the lungs. The delayed arrival of CD8+ memory T cells to the lungs of these animals suggests that developing memory cells do not require the same inflammatory signals as effector cells to reach the lung airways. These studies provide important new insight into mechanisms that control the maintenance and renewal of peripheral memory T cell populations during natural infections.

The release of Bacillus anthracis spores can cause significant morbidity and mortality and an effective vaccine as well as directed immunotherapeutics are needed. The currently licensed vaccine requires six primary vaccinations, annual boosters, and has been associated with serious adverse events. Thus there is increasing interest in developing an improved vaccination strategy which can generate lasting protective immunity with reduced vaccinations. This study seeks to identify the major humoral targets of B. anthracis that provide protection. To this end, plasma was obtained from two hundred vaccinated individuals and thirty unvaccinated controls. Ninety-five percent of all vaccinated individuals had anti-protective antigen antibodies and these antibodies correlated with in vitro protection against lethal toxin. Utilizing overlapping decapeptides, we identified common antigenic regions within those individuals with high toxin neutralizing activity. Epitope-specific antibodies directed against three of these regions were isolated and were able to mediate protection in vitro and in a mouse model of in vivo lethal toxin challenge. Identification of common, protective, peptide-specific humoral immune responses provide key information for further immunotherapeutic and vaccine development. NIAID: 5U19AI062629

The goal of this study is to understand intrinsic and extrinsic defects in influenza vaccination responses in systemic lupus erythematosus (SLE) patients. SLE is a prototypic autoimmune disease characterized by high titers of autoantibodies. We enrolled 72 patients to evaluate anti-influenza antibody responses, autoantibody titers and disease activity after vaccination. In addition, detailed clinical and demographic information was collected. Individuals received the current influenza vaccine and sera were collected at baseline, 2, 6, and 12 weeks post vaccination. Based upon post-vaccination antibody responses, relative antibody affinities and hemaglutination inhibition levels, patients were grouped into "high" and "low" responders. Surprisingly, the high responder group was enriched in older subjects and African Americans. Patients with high anti-influenza antibodies had an increased frequency of discoid rash and anti-nRNP autoantibodies, while patients with low antibody responses had an increase in hematological criteria and anti-aPL autoantibodies. Interestingly, several patients had increased autoantibody titers following vaccination, but there were no significant associated increases in disease flare. In summary, specific demographic, clinical, and autoantibody features were associated with poor antibody responses to influenza vaccination in SLE patients. NIH: NO1-AI-50026

The currently licensed anthrax vaccine (AVA) has been designed to elicit primarily an anti-protective antigen response. However, animal studies have clearly demonstrated that antibodies to the lethal factor component of the toxin can provide protection against challenge. This study was designed to identify AVA vaccinated individuals that generate anti-LF responses and to determine if these anti-LF antibodies can mediate protection. Plasma was obtained from one thousand vaccinated individuals and thirty unvaccinated controls. Only 69 individuals (6.9%) had significant levels of anti-LF antibodies. The presence of these antibodies did not correlate with in vitro protection against lethal toxin. To determine if antibodies against specific regions of LF could mediate protection, we used overlapping decapeptides to identify six common antigenic regions within those individuals with high levels of anti-LF antibodies and high toxin neutralizing activity. Epitope-specific antibodies directed against three of these common antigenic regions were isolated and select antibodies were able to protect in both in vitro tissue culture and in vivo mouse toxin challenge models. Findings from these studies have important implications for vaccine design and immunotherapeutic development. NIAID: 5U19AI062629