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  • Andersen, Peter  (35)
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  • 1
    Language: English
    In: PLoS ONE, 2012, Vol.7(6), p.e39909
    Description: The current vaccine against tuberculosis (TB), BCG, has failed to control TB worldwide and the protective efficacy is moreover limited to 10–15 years. A vaccine that could efficiently boost a BCG-induced immune response and thus prolong protective immunity would therefore have a significant impact on the global TB-burden. ; In the present study we show that the fusion protein HyVac4 (H4), consisting of the mycobacterial antigens Ag85B and TB10.4, given in the adjuvant IC31® or DDA/MPL effectively boosted and prolonged immunity induced by BCG, leading to improved protection against infection with virulent (M.tb). Increased protection correlated with an increased percentage of TB10.4 specific IFNγ/TNFα/IL-2 or TNFα/IL-2 producing CD4 T cells at the site of infection. Moreover, this vaccine strategy did not compromise the use of ESAT-6 as an accurate correlate of disease development/vaccine efficacy. Indeed both CD4 and CD8 ESAT-6 specific T cells showed significant correlation with bacterial levels. ; H4-IC31® can efficiently boost BCG-primed immunity leading to an increased protective anti-M.tb immune response dominated by IFNγ/TNFα/IL-2 or TNFα/IL2 producing CD4 T cells. H4 in the CD4 T cell inducing adjuvant IC31® is presently in clinical trials.
    Keywords: Research Article ; Biology ; Medicine ; Immunology ; Microbiology
    E-ISSN: 1932-6203
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  • 2
    Language: English
    In: PLoS ONE, 2009, Vol.4(4), p.e5139
    Description: Although CD4 T cells are crucial for defense against M.tb, it is still not clear whether the optimal response against M.tb in fact involves both CD4 and CD8 T cells. To test this, we used a new vaccine strategy that generated a strong balanced T cell response consisting of both CD4 and CD8 T cells. ; To compare CD4 and CD8 responses against Ag85B-TB10.4 (H4), H4 was delivered as a subunit vaccine in cationic liposomes (CAF01), expressed in Ad5 (Ad-H4) or as a heterologous prime boost vaccination. H4/CAF01 induced primarily CD4 T cells and Ad-H4 gave predominantly a CD8 T cell response. In contrast, the heterologous prime boost combination resulted in augmentation of both the CD4 and CD8 response. The majority (〉40%) of the CD4 T cells induced by the heterologous prime boost protocol were polyfunctional, and expressed IFN-γ, IL-2, and TNF-α, whereas most of the CD8 T cells expressed IFN-γ and TNF-α and possessed strong cytotoxic potential. The heterologous prime boost protocol also gave an increase in protective efficacy against challenge compared to H4/CAF01 and Ad-H4. Both the H4 specific CD4 and CD8 T cells were recruited to the site of infection, at the onset of infection. However, compared to CD8 T cells, CD4 T cells showed more extensive recruitment and were the main T cell subset proliferating at the site of infection. ; Heterologous prime boost based on H4, produced an additive effect on the priming of CD4 and CD8 cells and in terms of the protective capacity of the vaccine, and therefore represent an interesting new vaccine strategy against . However, CD4 and CD8 T cells respond very differently to live challenge, in a manner which supports the consensus that CD4 T cells do play the major role during the early stages of an infection.
    Keywords: Research Article ; Immunology ; Infectious Diseases ; Immunology -- Immune Response ; Immunology -- Immunity To Infections ; Infectious Diseases -- Bacterial Infections
    E-ISSN: 1932-6203
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  • 3
    Language: English
    In: PLoS ONE, 2009, Vol.4(6), p.e5930
    Description: Previously we have shown that Ag85B-TB10.4 is a highly efficient vaccine against tuberculosis when delivered in a Th1 inducing adjuvant based on cationic liposomes. Another Th1 inducing adjuvant, which has shown a very promising profile in both preclinical and clinical trials, is IC31®. In this study, we examined the potential of Ag85B-TB10.4 delivered in the adjuvant IC31® for the ability to induce protection against infection with Mycobacterium tuberculosis . In addition, we examined if the antigen dose could influence the phenotype of the induced T cells. ; We found that vaccination with the combination of Ag85B-TB10.4 and IC31® resulted in high numbers of polyfunctional CD4 T cells co-expressing IL-2, IFN-γ and TNF-α. This correlated with protection against subsequent challenge with in the mouse TB model. Importantly, our results also showed that both the vaccine induced T cell response, and the protective efficacy, was highly dependent on the antigen dose. Thus, whereas antigen doses of 5 and 15 µg did not induce significant protection against , reducing the dose to 0.5 µg selectively increased the number of polyfunctional T cells and induced a strong protection against infection with . The influence of antigen dose was also observed in the guinea pig model of aerosol infection with In this model a 2.5 fold increase in the antigen dose reduced the protection against infection with to the level observed in non-vaccinated animals. ; Small changes in the antigen dose can greatly influence the induction of specific T cell subpopulations and the dose is therefore a crucial factor when testing new vaccines. However, the adjuvant IC31® can, with the optimal dose of Ag85B-TB10.4, induce strong protection against . This vaccine has now entered clinical trials.
    Keywords: Research Article ; Immunology ; Infectious Diseases ; Immunology -- Immune Response ; Infectious Diseases -- Bacterial Infections
    E-ISSN: 1932-6203
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  • 4
    In: PLoS ONE, 2013, Vol.8(8)
    Description: Here we report for the first time on the immunogenicity and protective efficacy of a vaccine strategy involving the adjuvanted fusion protein “H28” (consisting of Ag85B-TB10.4-Rv2660c) and Modified Vaccinia Virus Ankara expressing H28. We show that a heterologous prime-boost regimen involving priming with H28 in a Th1 adjuvant followed by boosting with H28 expressed by MVA (H28/MVA28) induced the highest percentage of IFN-γ expressing T cells, the highest production of IFN-γ per single cell and the highest induction of CD8 T cells compared to either of the vaccines given alone. In contrast, in mice vaccinated with adjuvanted recombinant H28 alone (H28/H28) we observed the highest production of IL-2 per single cell and the highest frequency of antigen specific TNF-α/IL-2 expressing CD4 T cells pre and post infection. Interestingly, TNF-α/IL-2 expressing central memory-like CD4 T cells showed a significant positive correlation with protection at week 6 post infection, whereas the opposite was observed for post infection CD4 T cells producing only IFN-γ. Moreover, as a BCG booster vaccine in a clinically relevant non-human primate TB model, the H28/H28 vaccine strategy induced a slightly more prominent reduction of clinical disease and pathology for up to one year post infection compared to H28/MVA28. Taken together, our data showed that the adjuvanted subunit and MVA strategies led to different T cell subset combinations pre and post infection and that TNF-α/IL-2 double producing but not IFN-γ single producing CD4 T cell subsets correlated with protection in the mouse TB model. Moreover, our data demonstrated that the H28 vaccine antigen was able to induce strong protection in both a mouse and a non-human primate TB model.
    Keywords: Research Article ; Biology
    E-ISSN: 1932-6203
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  • 5
    Language: English
    In: 2014, Vol.9(6), p.e100879
    Description: The development of new low cost inactivated polio virus based vaccines (IPV) is a high priority, and will be required to eradicate polio. In addition, such a vaccine constitutes the only realistic polio vaccine in the post-eradication era. One way to reduce the cost of a vaccine is to increase immunogenicity by use of adjuvants. The CAF01 adjuvant has previously been shown to be a safe and potent adjuvant with several antigens, and here we show that in mice IPV formulated with CAF01 induced increased systemic protective immunity measured by binding and neutralization antibody titers in serum. CAF01 also influenced the kinetics of both the cellular and humoral response against IPV to produce a faster, as well as a stronger, response, dominated by IgG2a, IgG2b, and IgG2c isotypes as well as IPV specific T cells secreting IFN-γ/IL-2. Finally, as intestinal immunity is also a priority of polio vaccines, we present a vaccine strategy based on simultaneous priming at an intradermal and an intramuscular site that generate intestinal immune responses against polio virus. Taken together, the IPV-CAF01 formulation constitutes a new promising vaccine against polio with the ability to generate strong humoral and cellular immunity against the polio virus.
    Keywords: Research Article ; Biology And Life Sciences
    E-ISSN: 1932-6203
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  • 6
    Language: English
    In: PLoS ONE, 01 January 2017, Vol.12(4), p.e0175707
    Description: Streptococcus pyogenes (group A streptococcus, GAS) is responsible for a wide array of infections. Respiratory transmission via droplets is the most common mode of transmission but it may also infect the host via other routes such as lesions in the skin. To advance the development of a future vaccine against GAS, it is therefore important to investigate how protective immunity is related to the route of vaccine administration. To explore this, we examined whether a parenterally administered anti-GAS vaccine could protect against an intranasal GAS infection or if this would require locally primed immunity. We foundd that a parenteral CAF01 adjuvanted GAS vaccine offered no protection against intranasal infection despite inducing strong systemic Th1/Th17/IgG immunity that efficiently protected against an intraperitoneal GAS infection. However, the same vaccine administered via the intranasal route was able to induce protection against repeated intranasal GAS infections in a murine challenge model. The lack of intranasal protection induced by the parenteral vaccine correlated with a reduced mucosal recall response at the site of infection. Taken together, our results demonstrate that locally primed immunity is important for the defense against intranasal infection with Streptococcus pyogenes.
    Keywords: Sciences (General)
    E-ISSN: 1932-6203
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  • 7
    Language: English
    In: PLoS ONE, June 23, 2014, Vol.9(6)
    Description: The development of new low cost inactivated polio virus based vaccines (IPV) is a high priority, and will be required to eradicate polio. In addition, such a vaccine constitutes the only realistic polio vaccine in the post-eradication era. One way to reduce the cost of a vaccine is to increase immunogenicity by use of adjuvants. The CAF01 adjuvant has previously been shown to be a safe and potent adjuvant with several antigens, and here we show that in mice IPV formulated with CAF01 induced increased systemic protective immunity measured by binding and neutralization antibody titers in serum. CAF01 also influenced the kinetics of both the cellular and humoral response against IPV to produce a faster, as well as a stronger, response, dominated by IgG2a, IgG2b, and IgG2c isotypes as well as IPV specific T cells secreting IFN-[gamma]/IL-2. Finally, as intestinal immunity is also a priority of polio vaccines, we present a vaccine strategy based on simultaneous priming at an intradermal and an intramuscular site that generate intestinal immune responses against polio virus. Taken together, the IPV-CAF01 formulation constitutes a new promising vaccine against polio with the ability to generate strong humoral and cellular immunity against the polio virus.
    Keywords: Vaccines ; Poliomyelitis
    ISSN: 1932-6203
    Source: Cengage Learning, Inc.
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  • 8
    Language: English
    In: PLoS ONE, 2009, Vol.4(6), p.e5928
    Description: Recently we and others have identified CD8 and CD4 T cell epitopes within the highly expressed M. tuberculosis protein TB10.4. This has enabled, for the first time, a comparative study of the dynamics and function of CD4 and CD8 T cells specific for epitopes within the same protein in various stages of TB infection. ; We focused on T cells directed to two epitopes in TB10.4; the MHC class I restricted epitope TB10.4 (CD8/10.4 T cells) and the MHC class II restricted epitope TB10.4 (CD4/10.4 T cells). CD4/10.4 and CD8/10.4 T cells displayed marked differences in terms of expansion and contraction in a mouse TB model. CD4/10.4 T cells dominated in the early phase of infection whereas CD8/10.4 T cells were expanded after week 16 and reached 5–8 fold higher numbers in the late phase of infection. In the early phase of infection both CD4/10.4 and CD8/10.4 T cells were characterized by 20–25% polyfunctional cells (IL-2, IFN-γ, TNF-α), but whereas the majority of CD4/10.4 T cells were maintained as polyfunctional T cells throughout infection, CD8/10.4 T cells differentiated almost exclusively into effector cells (IFN-γ, TNF-α). Both CD4/10.4 and CD8/10.4 T cells exhibited cytotoxicity in vivo in the early phase of infection, but whereas CD4/10.4 cell mediated cytotoxicity waned during the infection, CD8/10.4 T cells exhibited increasing cytotoxic potential throughout the infection. ; Our results show that CD4 and CD8 T cells directed to epitopes in the same antigen differ both in their kinetics and functional characteristics throughout an infection with . In addition, the observed strong expansion of CD8 T cells in the late stages of infection could have implications for the development of post exposure vaccines against latent TB.
    Keywords: Research Article ; Immunology ; Infectious Diseases ; Immunology -- Immune Response ; Immunology -- Immunity To Infections
    E-ISSN: 1932-6203
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  • 9
    Language: English
    In: Veterinary Microbiology, 2006, Vol.112(2), pp.163-169
    Description: The development of a new and improved vaccine against tuberculosis has in the last 10 years been accelerated tremendously from the completed genome and the progress in molecular biology. This has resulted in the identification of a large number of antigens with potential in tuberculosis vaccines. The next phase of this work has now started—putting the most relevant molecules back together as fusion molecules and cocktails. This requires carefully monitoring of aspects as immunodominance, recognition in different populations as well as the influence of different adjuvants and delivery systems. The most advanced of these vaccines such as the fusion between ESAT6 and Ag85B have been evaluated in a range of animal models including non-human primates and are now entering into clinical trials. For these vaccines to be successfully implemented in future vaccination programmes it is necessary to understand the immunological background for the failure of BCG and optimize the vaccines for their ability to boost the immuneresponse primed by BCG.
    Keywords: Tuberculosis ; Bacterial ; Vaccination ; Biology ; Veterinary Medicine
    ISSN: 0378-1135
    E-ISSN: 1873-2542
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  • 10
    Language: English
    In: Tuberculosis, 2006, Vol.86(3), pp.163-168
    Description: An estimated 2 billion people are latently infected with , the majority of which are already BCG vaccinated and repeatedly sensitized to mycobacterial strains from the environment. To be successful in the high endemic regions, any future TB vaccine strategy will have to be tailored in accordance with the resulting complexity of the TB infection and anti-mycobacterial immune response. In this review we will discuss some of the most advanced attempts to address this challenge.
    Keywords: Tuberculosis ; Bacterial ; Vaccination ; Bcg ; Latency ; Medicine
    ISSN: 1472-9792
    E-ISSN: 1873-281X
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