Vaccine-induced anti-tuberculosis protective immunity in mice correlates with the magnitude and quality of multifunctional CD4 T cells

Laboratory of Mycobacterial Diseases and Cellular Immunology, Center for Biologics Evaluation and Research, United States Food and Drug Administration, Bethesda, MD 20892, United States.
Vaccine (Impact Factor: 3.49). 02/2011; 29(16):2902-9. DOI: 10.1016/j.vaccine.2011.02.010
Source: PubMed

ABSTRACT The development of improved vaccines against Mycobacterium tuberculosis has been hindered by a limited understanding of the immune correlates of anti-tuberculosis protective immunity. In this study, we examined the relationship between long-term anti-tuberculosis protection and the mycobacterial-specific CD4 multifunctional T (MFT) cell responses induced by five different TB vaccines (live-attenuated, subunit, viral vectored, plasmid DNA, and combination vaccines) in a mouse model of pulmonary tuberculosis. In a 14-month experiment, we showed that TB vaccine-induced CD4 T cell responses were heterogenous. Antigen-specific monofunctional CD4 T cells expressing single cytokines and MFT CD4 T cells expressing multiple cytokines (IFN-γ and TNF-α, IFN-γ and IFN-γ, TNF-α, and IL-2, and all three cytokines) were identified after the immunizations. Interestingly, compared to the monofunctional cells, significantly higher median fluorescent intensities (MFIs) for IFN-γ and TNF-α were detected for triple-positive MFT CD4 T cells induced by the most protective vaccines while modest differences in relative MFI values were seen for the less protective preparations. Most importantly during the 14-month study, the levels of vaccine-induced pulmonary and splenic protective immunity correlated with the frequency and the integrated MFI (iMFI, frequency×MFI) values of triple-positive CD4 T cells that were induced by the same vaccines. These data support efforts to use MFT cell analyses as a measure of TB vaccine immunogenicity in human immunization studies.

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    • "However, in most of these studies, the frequency of specific cytokine (IFN-γ) secreting T cells was typically used as the parameter to measure the specific T cell responses. But this might not be the best indicator of protective T cell responses, because several lines of evidence have already suggested that the mean fluorescent intensity (MFI) also was an important coparameter [12] [13] [14]. In order to further improve the immunogenicity of epitope-based DNA vaccine, in this study, we constructed epitope-based DNA vaccines by using a combined immunogenicity-enhancing design. "
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    ABSTRACT: Previous studies suggested that both the frequency and the mean fluorescence intensity (MFI) of cytokine secreting T cells could be of great value for immunogenicity evaluation of a vaccine. In this study, by constructing epitope-based DNA vaccines encoding a previously identified CD8(+) T cell epitope, we investigated the influence of multiplying epitope copies on both the frequency and the MFI of specific IFN-γ secreting CD8(+) T cells. We found that frequencies of specific CD8(+) T cell could be improved by multiplying epitope copies, while the MFI of IFN-γ secreted by epitope-specific CD8(+) T cells decreased synchronously. And further analysis showed that the decrease of MFI was not caused by the functional avidity variation of CD8(+) T cell receptor.
    Clinical and Developmental Immunology 11/2012; 2012:478052. DOI:10.1155/2012/478052 · 2.93 Impact Factor
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    • "-1, 4, 10 TH2 ND IFN-␥, TNF-␣, IL-2 Polyfunctional T cells Inconsistent data [79] [112] [168] [169] "
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    ABSTRACT: Vaccines have been a major innovation in the history of mankind and still have the potential to address the challenges posed by chronic intracellular infections including tuberculosis, HIV and malaria which are leading causes of high morbidity and mortality across the world. Markers of an appropriate humoral response currently remain the best validated correlates of protective immunity after vaccination. Despite advancements in the field of immunology over the past few decades currently there are, however, no sufficiently validated immune correlates of vaccine induced protection against chronic infections in neither human nor veterinary medicine. Technological and conceptual advancements within cell-mediated immunology have led to a number of new immunological read-outs with the potential to emerge as correlates of vaccine induced protection. For T(H)1 type responses, antigen-specific production of interferon-gamma (IFN-γ) has been promoted as a quantitative marker of protective cell-mediated immune responses over the past couple of decades. More recently, however, evidence from several infections has pointed towards the quality of the immune response, measured through increased levels of antigen-specific polyfunctional T cells capable of producing a triad of relevant cytokines, as a better correlate of sustained protective immunity against this type of infections. Also the possibilities to measure antigen-specific cytotoxic T cells (CTL) during infection or in response to vaccination, through recombinant major histocompatibility complex (MHC) class I tetramers loaded with relevant peptides, has opened a new vista to include CTL responses in the evaluation of protective immune responses. Here, we review different immune markers and new candidates for correlates of a protective vaccine induced immune response against chronic infections and how successful they have been in defining the protective immunity in human and veterinary medicine.
    Vaccine 05/2012; 30(33):4907-20. DOI:10.1016/j.vaccine.2012.05.049 · 3.49 Impact Factor
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    • "It should be noted that IFN-␥ expression alone is not always indicative of protection against E. ruminantium infection in vivo (Vachiéry et al., 2006). Recent studies on protective immunity against Mycobacterium tuberculosis have shown a better correlation between protection and the number of multifunctional T (MFT) cells which were detected in immune pulmonary and spleen cell preparations (Derrick et al., 2011). MFT cells are single cells that produce high concentrations of the cytokines IFN-␥; TNF-␣ and IL-2. "
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    ABSTRACT: Ehrlichia ruminantium is an obligate intracellular bacterial pathogen which causes heartwater, a serious tick-borne disease of ruminants throughout sub-Saharan Africa. The development of promising recombinant vaccines has been reported previously, but none has been as effective as immunisation with live organisms. In this study we have used reverse vaccinology to identify proteins that elicit an in vitro cellular immune response similar to that induced by intact E. ruminantium. The experimental strategy involved four successive steps: (i) in silico selection of the most likely vaccine candidate genes from the annotated genome; (ii) cloning and expression of the selected genes; (iii) in vitro screening of the expressed proteins for their ability to induce interferon-gamma (IFN-γ) production in E. ruminantium-immune lymphocytes; and (iv) further examination of the cytokine response profiles of those lymphocytes which tested positive for IFN-γ induction. Based on their overall cytokine induction profiles the recombinant proteins were divided into four distinct groups. Eleven recombinant proteins induced a cytokine profile that was similar to the recall immune response induced by immune peripheral blood mononuclear cells (PBMC) stimulated with intact E. ruminantium. This response comprised the upregulation of cytokines associated with adaptive cellular immune responses as well as innate immunity. A successful vaccine may therefore need to contain a combination of recombinant proteins which induce both immune pathways to ensure protection against heartwater.
    Veterinary Immunology and Immunopathology 01/2012; 145(1-2):340-9. DOI:10.1016/j.vetimm.2011.12.003 · 1.75 Impact Factor
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