We chose to study mAb

We chose to study mAb41 because it is a potent neutralizing antibody that arises from an antigenic region that can induce both neutralizing and non-neutralizing antibodies, providing a basis for investigating whether mAb41 mimotopes could induce immune responses with mAb41-like properties, including neutralization. MAb41-based mimotopes by themselves may have limitations as HCV vaccines, due to the genotype-specificity of mAb41 neutralization. Although peptides are generally not considered ideal vaccine antigens, due to their ability to adopt many conformations, we propose that such antigens have potential utility as priming antigens to induce initial immune responses with desired attributes, setting the stage for boosting with wild type proteins or viral particles. mRNA display-selected peptides, carrying information specific to neutralizing Fostriecin sodium salt cost and the ability to direct epitope-targeted immune responses, would potentially be more useful as priming antigens than would wild type peptides. The magnitude of the immune response observed after immunization of mice with mAb41-selected peptides, is similar to that of some effective human vaccines, even with a single epitope. While antibody titers needed to protect against HCV infections are not known, neutralizing titers of 1:10 (or lower) are generally considered correlates of efficacy for rubella and measles vaccines (Hilleman et al., 1967). The magnitude of the neutralizing titers induced after selected peptide immunization could potentially be further improved using other antigen presentation techniques (e.g., by addition of scaffold proteins or presentation of antigens on the surface of virus-like particles) or adjuvants, or by using a mixture of mRNA-display-selected mimotopes to present multiple epitopes to the immune system.
Declaration of Interests
Author Contributions
Funding This study was funded with intramural FDA funds. As FDA employees, the authors wrote the manuscript and decided to submit it for publication. The authors were not paid to write the article by a pharmaceutical company.
Acknowledgments
Introduction Tuberculosis (TB) claims 1.6million lives every year. Efforts to control the global epidemic are further undermined by an ever-increasing subset of Mycobacterium tuberculosis (M.tb) strains that is resistant to existing anti-TB drugs. In affected immune-competent individuals with no active disease, the bacilli remain protected at the primary sites of infection in granulomas that provide immunologic and physical barrier to ensure bacterial survival, and may promote the development of persistent bacteria or persisters, reduced drug penetration, and diminished antimicrobial killing until loss of immune protection reactivates disease. A leading hypothesis is that persisters develop as an adaptation to host immune pressure within granulomatous lesions. Under this hypothesis, persisters represent phenotypic variants which, due to immunologic stress, enter a slow-sporadic, or non-growing state which makes them tolerant to antimicrobial killing (McCune et al., 1957). This hypothesis suggests that a strategy to accelerate cure is to prevent entry into the poorly growing persister phenotypic state and to reactivate quiescent lesions by transient immune modulation. This transient reactivation and subsequent antimicrobial killing, or “wake ‘em and whack ’em” strategy, has been recently advocated as one of the novel approaches to combat the spread of tuberculosis by the global Stop TB Partnership (Robertson et al., 2012), which, in collaboration with the World Health Organization, recently set the goal of eliminating tuberculosis world-wide by 2050. The mechanisms by which M.tb persisters modulate host responses to ensure survival remain unclear. It is believed that a balance between pro-inflammatory cytokines such as IL-12, IFN-γ, and TNF-α, and anti-inflammatory cytokines such as IL-10 plays a role (Cilfone et al., 2013; Marino et al., 2015). An effective reactivation strategy would therefore aim at tipping this balance by either suppressing pro-inflammatory responses, or promoting anti-inflammatory responses, or both. In fact, an increased incidence of tuberculosis has been noted among patients on TNF-α inhibitors (Salgado and Gomez-Reino, 2011), and several laboratory and human clinical studies have demonstrated the efficacy of adding TNF-α inhibitors (TNF-Is) to antibacterial chemotherapy for TB (Wallis et al., 2004; Skerry et al., 2012); TNF neutralization also induces reactivation in nonhuman primates with latent tuberculosis infection (Lin et al., 2010). However in this model, TNF neutralization also alters chemokine receptor expression, and impaired cellular recruitment, resulting in a disparate degree of extra-pulmonary disease. More importantly, at least in a third of animals, reactivation was not achieved following anti-TNF treatment, indicating that TNF may not be a critical factor in maintaining persisters (Lin et al., 2010).