Béhazine Combadière

Polytech Paris-UPMC, Lutetia Parisorum, Île-de-France, France

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Publications (73)407.65 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Transcutaneous immunization (TCI) requires targeting of a maximum number of skin antigen-presenting cells as non-invasive as possible on small skin areas. In two clinical trials, we introduced cyanoacrylate skin surface stripping (CSSS) as a safe method for TCI. Here, using ex vivo human skin, we demonstrate that one CSSS procedure removed only 30% of stratum corneum, but significantly increased the penetration of 200nm polystyrene particles deep into vellus and intermediate hair follicles from where they could not been retrieved by conventional tape stripping. Two subsequent CSSS had no striking additional effect. CSSS increased particle penetration in superficial stratum corneum and induced Langerhans cell activation. Formulation in amphiphilic ointment or massage did not substantially influence the interfollicular penetration profiles. Hair follicle targeting by CSSS could become a highly effective tool for TCI when combined with carrier-based delivery and is gaining new attention as our understanding on the hair follicle immune system increases.This article is protected by copyright. All rights reserved.
    Experimental Dermatology 11/2014; · 3.58 Impact Factor
  • AIDS research and human retroviruses. 10/2014; 30 Suppl 1:A124.
  • AIDS research and human retroviruses. 10/2014; 30 Suppl 1:A126-7.
  • Clement Levin, Helene Perrin, Behazine Combadiere
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    ABSTRACT: Skin vaccination aims at targeting epidermal and dermal antigen-presenting cells (APCs), indeed many subsets of different origin endowed with various functions populate the skin. The idea that the skin could represent a particularly potent site to induce adaptive and protective immune response emerged after the success of vaccinia virus vaccination by skin scarification. Recent advances have shown that multiple subsets of APCs coexist in the skin and participate in immunity to infectious diseases. Induction of an adaptive immune response depends on the initial recognition and capture of antigens by skin APCs and their transport to lymphoid organs. Innovative strategies of vaccination have thus been developed to target skin APCs for tailored immunity, hence this review will discuss recent insights into skin APC subsets characterization and how they can shape adaptive immune responses.
    Human Vaccines and Therapeutics 08/2014; 11(1). · 3.64 Impact Factor
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    ABSTRACT: As the primary protective barrier of the body, the skin plays a crucial role of immune-surveillance through a highly diverse skin immune system. Epidermal and dermal skin layers are particularly rich in antigen presenting cells (APCs): Langerhans cells (LCs) and several subsets of dermal dendritic cells (DCs) endowed with specific roles in capturing antigens, initiating and driving the appropriate adaptive immune response against antigen intrusion (1).This article is protected by copyright. All rights reserved.
    Experimental Dermatology 08/2014; · 3.58 Impact Factor
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    ABSTRACT: The magnitude, quality, and maintenance of immunological memory after infection or vaccination must be considered for future design of effective influenza vaccines. In 2009, the influenza pandemic produced disease that ranged from mild to severe, even fatal, illness in infected healthy adults and led to vaccination of a portion of the population with the adjuvanted, inactivated influenza A(H1N1)pdm09 vaccine. Here, we have proposed a multiparameter quantitative and qualitative approach to comparing adaptive immune memory to influenza 1 year after mild or severe infection or vaccination. One year after antigen encounter, severely ill subjects maintained high levels of humoral and polyfunctional effector/memory CD4+ T cells responses, while mildly ill and vaccinated subjects retained strong cellular immunity, as indicated by high levels of mucosal homing and degranulation markers on IFN-γ+ antigen-specific T cells. A principal component analysis distinguished 3 distinct clusters of individuals. The first group comprised vaccinated and mildly ill subjects, while clusters 2 and 3 included mainly infected individuals. Each cluster had immune memory profiles that differed in magnitude and quality. These data provide evidence that there are substantial similarities between the antiinfluenza response that mildly ill and vaccinated individuals develop and that this immune memory signature is different from that seen in severely ill individuals.
    The Journal of clinical investigation. 06/2014;
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    ABSTRACT: It is accepted that an effective prophylactic HIV-1 vaccine is likely to have the greatest impact on viral transmission rates. As previous reports have implicated DNA-prime, protein-boost regimes to be efficient activators of humoral responses, we sought to optimise this regime to further augment vaccine immunogenicity. Here we evaluated single verses concurrent intradermal (ID) and intramuscular (IM) vaccination as a DNA-priming strategy for their abilities to elicit humoral and cellular responses against a model HIV-1 vaccine antigen, CN54gp140. To further augment vaccine-elicited T and B cell responses, we enhanced cellular transfection with electroporation and then boosted the DNA-primed responses with Subcutaneous (SC), Intranasal (IN), Intramuscular (IM) or Transcutaneous (TC) homologous protein. In mice, the concurrent priming regime resulted in significantly elevated IFN-γ T cell and high avidity antigen-specific IgG B cell responses, a hallmark of B cell maturation. Protein-boosting of the concurrent DNA strategy further enhanced IgG concentrations but had little impact on T cell reactivity. Interestingly protein-boosting by the subcutaneous route increased antibody avidity to a greater extent than either IM, IN or TC administration, suggesting this route may be preferential for driving B cell maturation. Using an alternative and larger animal model, the rabbit, we found the concurrent DNA-priming strategy followed by SC protein-boosting to again be capable of eliciting high avidity humoral responses and able to also neutralize HIV-1 pseudoviruses from diverse clades (A, B and C). Taken together we show that concurrent multiple-route DNA vaccinations induce strong cellular immunity in addition to potent and high avidity humoral immune responses. The route of vaccination has profound effects on prevailing immune responses. Due to the insufficient immunogenicity and protection of current DNA delivery strategies, we evaluated concurrent DNA delivery via simultaneous administration of plasmid DNA by the IM and ID route. The rationale behind this paper was to provide clear evidence to the utility of concurrent vaccinations for an up and coming human clinical trial. Furthermore this work will guide future preclinical studies by evaluating the use of model antigens and plasmids for prime-boost strategies. This paper will not only be of interest to virologists and vaccinologists working in the HIV field but also for researchers working in other viral vaccine settings and critically to the wider field of vaccine delivery.
    Journal of Virology 04/2014; · 5.08 Impact Factor
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    ABSTRACT: Rationale: The biology of fatal pandemic influenza infection remains undefined. Methods: This multicenter study included 34 unvaccinated patients with very severe or fatal confirmed influenza A(H1N1) infections. It analyzed plasma A(H1N1) 2009 RT-PCR, hemagglutinin 222G viral mutation, and humoral and cellular immune responses to the virus, assessed in hemagglutination inhibition (HI), microneutralization, ELISA, lymphoproliferative, ELISpot IFN-, and cytokine/chemokine assays. Measurements and Main Results: The patients' median age was 34 years. Influenza A(H1N1) 2009 viremia was detected in 4/34 cases, and a 222G hemagglutinin mutation in 7/17 cases, all of them with SOFA≥8. HI antibodies were detectable in 19/26 survivors and undetectable in all 6 fatal fulminant cases. ELISA and microneutralization titers were concordant. B-cell immunophenotyping and plasma levels of immunoglobulin classes did not differ between patients who survived and died. After immune complex dissociation, influenza ELISA serology became strongly positive in the bronchoalveolar lavage of the 2 fatal cases tested. H1N1-specific T-cell responses in lymphoproliferative and IFN- assays were weak in survivors' peripheral blood, and lymphoproliferative assays were negative in the 3 fatal cases tested. Plasma levels of IL-6 and IL-10 were high in fatal cases and correlated with severity. Finally, a negative HI serology 4 days after the onset of influenza symptoms predicted death from fulminant influenza (p=0.04). Conclusions: Early negative A(H1N1) 2009 HI serology can predict death from influenza. This negative serology in fatal cases in young adults reflects the trapping of anti-H1N1 antibodies in immune complexes in the lungs, associated with poor specific helper T-cell response.
    American Journal of Respiratory and Critical Care Medicine 03/2014; · 11.04 Impact Factor
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    ABSTRACT: Activating different adaptive immune component is required to confer long-time protection against influenza viruses. By investigating the co-mobilization of immune compartments following A/H1N1 2009 pandemic vaccine (A(H1N1)pdm09 influenza vaccine–Panenza®, Sanofi Pasteur), we show that multiple vaccination with 2000-2003 seasonal influenza vaccines leads to a broader immune repertoire than the one theoretically expected by vaccine strains. Moreover, in case of contact with strains previously encountered, the A(H1N1)pdm09-specific immune response is extended to non-humoral immune components (i.e. CD8+ and/or CD4+ T-cells response).
    European geriatric medicine 01/2014; · 0.63 Impact Factor
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    ABSTRACT: Transcutaneous immunization is a promising vaccination strategy for the treatment of infectious diseases and cancer. In this study, we investigate the combination of cyanoacrylate skin surface stripping (CSSS) and particle-based antigen delivery to target the HIV-1 p24 protein to skin antigen presenting cells (APC). The CSSS treatment pre-activates skin APC and opens hair follicles, where protein-loaded particles accumulate and allow for sustained delivery of the loaded antigen to perifollicular APC. We found that poly-lactic acid and (PLA) polystyrene (PS) particles targeted the adsorbed HIV-1 p24 protein to the hair follicles. Small amounts of PS and PLA particles were found to translocate to the epidermis and be internalized by skin cells, whereas most of the particles aggregated in the hair follicle canal, where they released the loaded antigen. The p24 protein diffused to the epidermis and dermis and was detected in skin cells, especially in Langerhans cells and dermal dendritic cells. Furthermore, the combination of CSSS and particle-based delivery resulted in activation and maturation of Langerhans cells (HLA-DR, CD80, CD83). We conclude that particle-based antigen delivery across partially disrupted skin barrier is a feasible and effective approach to needle-free transcutaneous vaccination.
    Journal of Controlled Release 12/2013; · 7.63 Impact Factor
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    ABSTRACT: Most vaccines, including those against influenza, were developed by focusing solely on humoral response for protection. However, vaccination activates different adaptive compartments that might play a role in protection. We took advantage of the pandemic 2009 A(H1N1) influenza vaccination to conduct a longitudinal integrative multiparametric analysis of seven immune parameters in vaccinated subjects. A global analysis underlined the predominance of induction of humoral and CD4 T cell responses, whereas pandemic 2009 A(H1N1)-specific CD8 responses did not improve after vaccination. A principal component analysis and hierarchical clustering of individuals showed a differential upregulation of influenza vaccine-specific immunity including hemagglutination inhibition titers, IgA(+) and IgG(+) Ab-secreting cells, effector CD4 or CD8 T cell frequencies at day 21 among individuals, suggesting a fine-tuning of the immune parameters after vaccination. This is related to individual factors including the magnitude and quality of influenza-specific immune responses before vaccination. We propose a graphical delineation of immune determinants that would be essential for a better understanding of vaccine-induced immunity in vaccination strategies.
    The Journal of Immunology 06/2013; · 5.52 Impact Factor
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    ABSTRACT: Expression of the CC chemokine receptor 1 (CCR1) by tumor cells has been associated with protumoral activity; however, its role in nontumoral cells during tumor development remains elusive. Here, we investigated the role of CCR1 deletion on stromal and hematopoietic cells in a liver metastasis tumor model. Metastasis development was strongly impaired in CCR1-deficient mice compared to control mice and was associated with reduced liver monocyte infiltration. To decipher the role of myeloid cells, sublethally irradiated mice were reconstituted with CCR1-deficient bone marrow (BM) and showed better survival rates than the control reconstituted mice. These results point toward the involvement of CCR1 myeloid cell infiltration in the promotion of tumor burden. In addition, survival rates were extended in CCR1-deficient mice receiving either control or CCR1-deficient BM, indicating that host CCR1 expression on nonhematopoietic cells also supports tumor growth. Finally, we found defective tumor-induced neoangiogenesis (in vitro and in vivo) in CCR1-deficient mice. Overall, our results indicate that CCR1 expression by both hematopoietic and nonhematopoietic cells favors tumor aggressiveness. We propose CCR1 as a potential therapeutical target for liver metastasis therapy.
    Neoplasia (New York, N.Y.) 06/2013; 15(6):641-8. · 5.48 Impact Factor
  • Archives de Pédiatrie 04/2013; 20(4):449–458. · 0.36 Impact Factor
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    ABSTRACT: The bone marrow (BM) has been identified as a possible organ for T cell priming, yet the fundamental mechanisms of a polyclonal immune response in the BM remain unknown. We found that after intradermal injection of modified vaccinia Ankara virus, unexpected sources of newly primed polyclonal virus-specific CD8(+), but not CD4(+), T cells were localized in the BM and the draining lymph nodes (dLNs) prior to blood circulation. We identified neutrophils as the virus-carrier cells from the dermis to the BM. In both neutrophil-depleted and Ccr1(-/-) mice, virus-specific BM CD8(+) responses were lost. Myeloid antigen-presenting cells were required for BM CD8(+) T cell priming. A systems biology analysis of dLN and BM virus-specific CD8(+) T cells revealed distinct transcriptional and multifunctional profiles for cells primed in each organ. We provide direct evidence for how antigen is transported to the BM, providing a source of virus-specific memory CD8(+) T cells.
    Immunity 11/2012; · 19.80 Impact Factor
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    ABSTRACT: While the immunological correlates of hepatitis C virus (HCV)-specific immunity are not well understood, it is now admitted that an effective vaccine against HCV will need to induce both cellular and humoral immune responses and address viral heterogeneity to prevent immune escape. We developed a vaccine platform specifically aimed at inducing such responses against HCV antigens displayed by recombinant retrovirus-based virus-like particles (VLPs) made of Gag of murine leukemia virus. Both ex vivo produced VLPs and plasmid DNA encoding VLPs can be used as vaccines. Here, we report that immunizations with plasmid DNA forming VLPs pseudotyped with HCV E1 and E2 envelope glycoproteins (HCV-specific plasmo-retroVLPs) induce strong T-cell-mediated immune responses that can be optimized by using proper DNA delivery methods and/or genetic adjuvants. Additionally, multigenotype or multi-specific T-cell responses were observed after immunization with plasmids that encode VLPs pseudotyped with E1E2 derived from numerous viral genotypes and/or displaying NS3 antigen in capsid proteins. While homologous prime-boost immunizations with HCV-specific plasmo-retroVLPs or ex vivo produced VLPs induce a low level of specific antibody responses, optimal combination of plasmo-retroVLPs and VLPs was identified for inducing HCV-specific T-cell and B-cell responses as well as neutralizing antibodies. Altogether, these results have important meanings for the development of anti-HCV preventive vaccines and exemplify the flexibility and potential of our retrovirus-based platform in inducing broad cellular and humoral immune responses.
    Vaccine 05/2012; · 3.77 Impact Factor
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    ABSTRACT: The protective host immune response to viral infections requires both effective innate and adaptive immune responses. Cross-talk between the two responses is coordinated by the chemokine network and professional APCs such as dendritic cells (DCs). In mice, subpopulations of myeloid DCs in peripheral tissues such as lungs and in blood express CX3CR1 depending on the inflammation state. We thus examined the host response of mice deficient in the chemokine receptor CX3CR1 to an intranasal vaccinia virus infection. CX3CR1-deficient mice displayed significantly more severe morbidity and mortality compared with control wild-type mice within 10 d following vaccinia virus infection. CX3CR1(-/-) mice had increased viral loads and a reduced T cell response compared with wild-type mice. Finally, an adoptive transfer of CX3CR1(+/+) DCs completely protected CX3CR1(-/-) mice to a previously lethal infection. This study therefore opens up the possibility of novel antiviral therapeutics targeting lung DC recruitment.
    The Journal of Immunology 01/2012; 188(3):952-6. · 5.52 Impact Factor
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    ABSTRACT: The potential of the skin immune system for the generation of both powerful humoral and cellular immune responses is now well established. However, the mechanisms responsible for the efficacy of skin antigen-presenting cells (APCs) during intradermal (ID) vaccination still remain to be elucidated. We have previously demonstrated in clinical trials that preferential targeting of Langerhans cells (LCs) by transcutaneous immunization shapes the immune response toward vaccine-specific CD8 T cells. Others have shown that ID inoculation of a vaccine, which targets dermal APCs, mobilizes both the cellular and humoral arms of immunity. Here, we investigated the participation of epidermal LCs in response to ID immunization. When human or mouse skin was injected ID with a particle-based vaccine, we observed significant modifications in the morphology of epidermal LCs and their mobilization to the dermis. We further established that this LC recruitment after ID administration was essential for the induction of antigen-specific CD8 T cells, but was, however, dispensable for the generation of specific CD4 T cells and neutralizing antibodies. Thus, epidermal and dermal APCs shape the outcome of the immune responses to ID vaccination. Their combined potential provides new avenues for the development of vaccination strategies against infectious diseases.
    Journal of Investigative Dermatology 12/2011; 132(3 Pt 1):615-25. · 6.19 Impact Factor
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    ABSTRACT: The annual meeting of the Infectious Disease Society of America (IDSA) ; which brought together nearly 5000 participants from over 80 countries in Vancouver, Canada, October 21 to 24, 2010 ; provided a review of the influenza (H1N1) 2009 pandemic, evaluated vaccination programmes and presented new vaccines under development. With 12,500 deaths in the United States in 2009-2010, the influenza (H1N1) 2009 pandemic was actually less deadly than the seasonal flu. But it essentially hit the young, and the toll calculated in years of life lost is high. The monovalent vaccines, whether live attenuated or inactivated with or without adjuvants, were well tolerated in toddlers, children, adults and pregnant women. In order to protect infants against pertussis, family members are urged to get their booster shots. The introduction of the 13-valent Pneumococcal conjugated vaccine in the beginning of 2010 may solve - but for how long ? - the problem of serotype replacement, responsible for the re-increasing incidence of invasive Pneumococcal infections observed in countries that had introduced the 7-valent vaccine. The efficacy of a rotavirus vaccine has been confirmed, with a reduction in hospitalization in the United States and a reduction in gastroenteritis-related deaths in Mexico. In the United States, vaccination of pre-adolescents against human papillomavirus (HPV) has not resulted in any specific undesirable effects. Routine vaccination against chicken pox, recommended since 1995, has not had an impact on the evolution of the incidence of shingles. Vaccination against shingles, recommended in the United States for subjects 60 years and over, shows an effectiveness of 55 %, according to a cohort study (Kaiser Permanente, Southern California). Although some propose the development of personalized vaccines according to individual genetic characteristics, the priority remains with increasing vaccine coverage, not only in infants but also in adults and the elderly. Vaccine calendars that cover a whole lifetime should be promoted, since the vaccination of adults and seniors is a determining factor of good health at all ages.
    Archives de Pédiatrie 11/2011; 18(11):1234-46. · 0.36 Impact Factor
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    Behazine Combadiere, Christelle Liard
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    ABSTRACT: Most vaccines are administered by intramuscular (i.m.) or subcutaneous (s.c.) routes, however, intradermal (i.d.) and transcutaneous (t.c.) techniques are regaining popularity. We will discuss in this review several factors that strongly justify the use of the cutaneous tissues and development of alternative methods for vaccination. That includes (1) our improved knowledge of skin physiology and better understanding of the barrier role of the horny layer, (2) the rationalization for targeting the different cutaneous layers, i.e. the epidermis, dermis, or hypodermis, (3) our advances in knowledge of the skin immune system, especially the plasticity of antigen-presenting cells (APCs) (i.e Langerhans cells (LC), dermal dendritic cells (DDC) and dermal macrophages) in the induction of immune responses, (4) the reduction of antigenic dose for some modes of cutaneous administration, (5) the increased need in needlefree vaccination strategies for developing countries to cope with blood contamination issues. Progress in skin immunization methods and better understanding of skin immunity allow proposing innovative and efficient vaccination strategies against infectious diseases.
    Human vaccines 08/2011; 7(8):811-27. · 3.14 Impact Factor
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    ABSTRACT: Detection of human Ag-specific T cells is limited by sensitivity and blood requirements. As dendritic cells (DCs) can potently stimulate T cells, we hypothesized that their induction in PBMCs in situ could link Ag processing and presentation to Ag-specific T-cell activation. To this end, unfractionated PBMCs (fresh or frozen) or whole blood were incubated for 48 hours with protein or peptide Ag together with different DC-activating agents to rapidly and sequentially induce, pulse, and mature DCs. DC activation was therefore lined up with Ag recognition by neighboring T cells, thus telescoping the sequential steps of T-cell activation. Efficient processing of protein Ags made prior knowledge of epitopes and HLA restrictions dispensable. While reducing stimulation time, manipulation and blood requirements, in situ DC induction specifically amplified Ag-specific T-cell responses (cytokine secretion, proliferation, CD137/CD154 up-regulation, and binding of peptide-HLA multimers). IL-1β, although released by DCs, was also secreted in an Ag-specific fashion, thus providing an indirect biomarker of T-cell responses. These accelerated cocultured DC (acDC) assays offered a sensitive means with which to evaluate T-cell responses to viral and melanoma Ag vaccination, and may therefore find application for immune monitoring in viral, tumor, autoimmune, and transplantation settings.
    Blood 06/2011; 118(8):2128-37. · 9.78 Impact Factor

Publication Stats

2k Citations
407.65 Total Impact Points


  • 2014
    • Polytech Paris-UPMC
      Lutetia Parisorum, Île-de-France, France
  • 2005–2014
    • Pierre and Marie Curie University - Paris 6
      • Unité immunité et infection
      Lutetia Parisorum, Île-de-France, France
  • 2002–2013
    • French Institute of Health and Medical Research
      Lutetia Parisorum, Île-de-France, France
  • 2012
    • French National Centre for Scientific Research
      Lutetia Parisorum, Île-de-France, France
  • 2002–2012
    • Unité Inserm U1077
      Caen, Lower Normandy, France
  • 2006–2008
    • Charité Universitätsmedizin Berlin
      • Department of Dermatology, Venerology and Allergology
      Berlin, Land Berlin, Germany
  • 2007
    • University of Milan
      • Department of Pharmacological Sciences
      Milano, Lombardy, Italy
  • 1998
    • National Institutes of Health
      Maryland, United States
    • National Institute of Allergy and Infectious Diseases
      • Laboratory of Immunoregulation
      Maryland, United States