Lactoferrin enhanced efficacy of the BCG vaccine to generate host protective responses against challenge with virulent Mycobacterium tuberculosis

Abstract

Tuberculosis (TB), caused by Mycobacterium tuberculosis (MTB), is a disease with world wide consequences, affecting nearly a third of the world's population. The established vaccine for TB, an attenuated strain of Mycobacterium bovis Calmette Guerin (BCG), has existed since 1921. Lactoferrin, an iron binding protein found in mucosal secretions and granules of neutrophils was hypothesized to be an ideal adjuvant to enhance the efficacy of the BCG vaccine, specifically because of previous reports of lactoferrin enhancement of IL-12 production from macrophages infected with BCG. Different vaccination protocols were investigated for generation of host protective responses against MTB infection using lactoferrin admixed to the BCG vaccine. Resulting effects demonstrate that BCG/lactoferrin increased host protection against MTB infection by decreasing organ bacterial load and reducing lung histopathology; significant reduction in tissue CFUs and pathology were observed post challenge compared to those seen with BCG alone. Addition of lactoferrin to the vaccine led to reduced pathological damage upon subsequent infection with virulent MTB, with positive results demonstrated when admixed in oil-based vehicle (incomplete Freund's adjuvant; IFA) or when given with BCG in saline. The observed post-challenge results paralleled increasing production of IFN-γ and IL-6, but only limited changes to proinflammatory mediators TNF-α or IL-1β from BCG stimulated splenocytes. Overall, these studies indicate that lactoferrin is a useful and effective adjuvant to improve efficacy of the BCG vaccine, with potential to reduce related tissue damage and pulmonary histopathology.

Influence of bovine lactoferrin on expression of presentation molecules on BCG-infected bone marrow derived macrophages

“…Production of IL-12, which can indirectly influence IFN-g production [26,27,72], was not affected, suggesting that the increase in T-cell IFN-γ production was the result of direct cell to cell contact instead of promotion by the cytokine environment. Overall, the increase in T-cell IFN-γ production suggests that lactoferrin cultured BCG-infected BMMs can generate signals via surface molecules and cytokine expression which would aid in the development of in vivo T H 1 immunity observed in previous studies [22,23].…”

“…Previous studies demonstrated that addition of lactoferrin to the BCG vaccine increased host protection against subsequent virulent MTB challenge as observed by a decrease in organ bacterial load and a reduction in pulmonary disease pathology. This improvement in host response to disease correlated to an increase in development of a protective mycobacterial antigen-specific T-cell response, specially a T H 1 response hallmarked by production of IFN-γ [22,23]. Thus, lactoferrin has the ability to modulate innate immune function during vaccination in a way that augments generation of long-lasting protective immunity.…”

“…Mice immunized with BCG in the presence of bovine lactoferrin demonstrated increased host protection post-challenge with virulent MTB, as observed by decreasing organ bacterial load and pulmonary disease granulomatous pathology. The BCG/ lactoferrin immunized mice displayed increased presence of lymphocytes in granulomas and elevated production of IFN-γ from splenocytes reactive to BCG antigens [22,23]. Overall responses indicated that mice immunized with BCG admixed with bovine lactoferrin developed an enhanced mycobacterial antigen-specific T-cell response, suggesting that facilitation of efficacy of the BCG vaccine is through promotion of development of T-cell helper type 1 (T H 1) immunity.…”

Selection of Adjuvants for Enhanced Vaccine Potency

“…Indeed, it was shown that co-administration of lactoferrin with a BCG vaccine increased host protection against Mycobacterium tuberculosis (MTB) infection in terms of organ bacterial load, lung histopathology, and significant reduction in tissue CFUs compared with BCG alone in mice [370]. In addition, it was shown that the sialylated form of lactoferrin was more effective in increasing the immune response in terms of IFN-, IL-6 and IL-12 production in mice and in protecting the animals against infection in challenge studies [371].…”

Potential use of bovine lactoferrin as adjuvant for the modulation of the specific immune response in rainbow trout (Oncorhynchus mykiss W.)

“…Zimecki and Kruzel (2000) demonstrated remarkable stimulatory properties of bLF on the T cellular immune response of mice, enhancing the delayed type hypersensitivity (DHT) reaction following subcutaneous treatment with an antigen-adjuvant formulation. According to Hwang et al (2007), bLF used as adjuvant improves antiMycobacterium tuberculosis vaccine efficacy in mice by reducing organ bacterial load and lung histopathology. Moreover, specific T cell helper type1 response is improved by the use of bLF as adjuvant, increasing INF-c protein production against antigens (Hwang et al 2007).…”