Original Encounter with Antigen Determines Antigen-Presenting Cell Imprinting of the Quality of the Immune Response in Mice

BACKGROUND:Obtaining a certain multi-functionality of cellular immunity for the control of infectious diseases is a burning question in immunology and in vaccine design. Early events, including antigen shuttling to secondary lymphoid organs and recruitment of innate immune cells for adaptive immune response, determine host responsiveness to antigens. However, the sequence of these events and their impact on the quality of the immune response remain to be elucidated. Here, we chose to study Modified Vaccinia virus Ankara (MVA) which is now replacing live Smallpox vaccines and is proposed as an attenuated vector for vaccination strategies against infectious diseases. METHODOLOGY/PRINCIPAL FINDINGS:We analyzed in vivo mechanisms triggered following intradermal (i.d.) and intramuscular (i.m.) Modified Vaccinia virus Ankara (MVA) administration. We demonstrated significant differences in the antigen shuttling to lymphoid organs by macrophages (MPhis), myeloid dendritic cells (DCs), and neutrophils (PMNs). MVA i.d. administration resulted in better antigen distribution and more sustained antigen-presenting cells (APCs) recruitment into draining lymph nodes than with i.m. administration. These APCs, which comprise both DCs and MPhis, were differentially involved in T cell priming and shaped remarkably the quality of cytokine-producing virus-specific T cells according to the entry route of MVA. CONCLUSIONS/SIGNIFICANCE:This study improves our understanding of the mechanisms of antigen delivery and their consequences on the quality of immune responses and provides new insights for vaccine development

Demographic and Clinical Factors Associated with Response to Smallpox Vaccine in Preimmunized Volunteers

CONTEXT: In March 2003, the French Ministry of Health implemented a program on preparedness and response to a biological attack using smallpox as weapon. This program included the establishment of a preoutbreak national team that could be revaccinated against smallpox. OBJECTIVE: To identify demographic and clinical factors associated with vaccination success defined as the presence of a pustule at the inoculation site at day 8 (days 7-9), with an undiluted vaccinia virus derived from a Lister strain among preimmunized volunteers. VOLUNTEERS AND METHODS: From March 2003 to November 2006, we have studied prospectively 226 eligible volunteers. Demographic data were recorded for each volunteer (age, sex, number of previously smallpox vaccinations and date of the last vaccination). Smallpox vaccine adverse reactions were diagnosed on the basis of clinical examination performed at days 0, 7, 14, 21 and 28 after revaccination. RESULTS: A total of 226 volunteers (sex ratio H/F = 2.7) were revaccinated. Median age was 45 years (range: 27-63 yrs). All volunteers completed follow-up. Median number of vaccinations before revaccination was 2 (range: 1-8). The median delay between time of the study and the last vaccination was 29 years (range; 18-60 yrs). Sixty-one volunteers (27%) experienced one (n = 40) or more (n = 21) minor side effects during the 2-14 days after revaccination. Successful vaccination was noted in 216/226 volunteers (95.6%) at day 8 and the median of the pustule diameter was 5 mm (range: 1-20 mm). Size of the pustule at day 8 was correlated with age (p = 0.03) and with the presence of axillary adenopathy after revaccination (p = 0.007). Sex, number of prior vaccinations, delay between the last vaccination and revaccination, and local or systemic side effects with the exception of axillary adenopathy, were not correlated with the size of the pustule at day 8. CONCLUSIONS: Previously vaccinated volunteers can be successfully revaccinated with the Lister strain

Les chimiokines : un réseau sophistiqué de guidage cellulaire

L’efficacité du système immunitaire dépend de la mobilité des différents types cellulaires qui le composent et ne cessent de circuler entre le sang, les tissus périphériques et les organes lymphoïdes. Au cours de leur développement ou de leur activation, les capacités migratoires de ces cellules évoluent afin de leur permettre de quitter les organes où elles ont été produites, comme le thymus ou la moelle osseuse, de se positionner dans des sites stratégiques ou encore d’interagir avec d’autres partenaires cellulaires pour éliminer les agents pathogènes. Cette circulation permanente est très organisée et met en jeu de nombreuses protéines, notamment des molécules d’adhérence, des protéases et des facteurs chimiotactiques. Parmi ces derniers, les chimiokines, ou cytokines chimio-attractantes, forment une famille que l’on commence à bien connaître. Nous résumons ici leurs propriétés récemment découvertes, en insistant sur leurs implications physiopathologiques. Nous décrivons ensuite leurs éventuelles utilisations thérapeutiques

Immunité adaptative contre le virus SARS-CoV-2

International audienceLe rôle protecteur de la réponse immunitaire adaptative de l’hôte au cours de l’infection par le SARS-CoV-2 est devenu une question critique en l’absence d’un traitement spécifique, d‘un vaccin préventif ou d’une immunothérapie. Au cours de l’infection par le SARS-CoV-2, la réponse immunitaire contribuerait à la défense de l’hôte dans la majorité des cas, mais serait responsable de sa pathogénèse chez certains malades. Notamment, au cours des formes sévères, un déséquilibre entre les réponses immunitaires innée et adaptative pourrait être fatal. Au cours de la COVID-19, de nombreuses questions se posent sur la génération de l’immunité spécifique contre les diverses protéines du virus, la cinétique, la fonction des anticorps, ainsi que la qualité des réponses des lymphocytes effecteurs CD4+ et CD8+ pour la protection de l’hôte. L’étude bio-informatique des épitopes T et B des coronavirus a soulevé la question de l’immunité croisée entre le SARS-COV-2 et d’autres coronavirus sources d’infection bénigne ou responsables de pneumopathies graves telles que le MERS-CoV et le SARS-CoV. Dans cette revue, nous faisons le point sur les réponses immunitaires adaptatives au cours de la COVID-19 et leurs rôles potentiels dans la protection des personnes infectées

Prédire la réponse à la vaccination contre la grippe

La vaccination est l’un des progrès majeurs de la médecine moderne. Mais afin d’améliorer l’efficacité des vaccins existants et d’en élaborer de nouveaux, nous devons mieux connaître les mécanismes d’action à l’origine de l’immunité protectrice et les stratégies vaccinales permettant d’induire une défense durable. La voie cutanée est une stratégie de vaccination importante, en raison de la richesse qu’elle présente en cellules de l’immunité innée qui ont un rôle clé dans la qualité, l’intensité et la persistance des réponses adaptatives qu’elles induisent. L’intégration des données biologiques obtenues au cours d’un essai clinique de vaccination antigrippale nous donne un aperçu de l’impact de la voie d’immunisation et de la signature innée sur la qualité des réponses immunitaires

New challenges in modern vaccinology

International audienceVaccination has been a major advance for health care, allowing eradication or reduction of incidence and mortality of various infectious diseases. However, there are major pathogens, such as Human Immunodeficiency Virus (HIV) or the causative agent of malaria, for which classical vaccination approaches have failed, therefore requiring new vaccination strategies. The development of new vaccine strategies relies on the ability to identify the challenges posed by these pathogens. Understanding the pathogenesis and correlates of protection for these diseases, our ability to accurately direct immune responses and to vaccinate specific populations are such examples of these roadblocks. In this respect, the use of a robust, cost-effective and predictive animal model that recapitulates features of both human infection and vaccination is currently a much-needed tool. We discuss here the major limitations faced by modern vaccinology and notably, the development of humanized mice for assessing the immune system, along with their potential as vaccine models

Critical Role for Skin-Derived Migratory DCs and Langerhans Cells in TFH and GC Responses after Intradermal Immunization

International audienceIntradermal delivery of antigen represents a potent route of immunization that involves multiple blood- and skin-derived dendritic cell subpopulations endowed with specialized functions and dynamics in their ability to prime naïve CD4+ T cells in the draining lymph nodes. However, their individual contributions to the generation of CD4+ T follicular helper (TFH) cells and germinal centers (GCs) remain to be understood. We found that intradermal immunization of mice with a particle-based vaccine induced robust TFH and germinal center B-cell responses in skin draining lymph nodes, which were completely abrogated when skin cell emigration was prevented. However, in this later condition, both lymph node-resident and blood-derived inflammatory cells access the antigen in the draining lymph nodes but are not able to induce TFH cell differentiation. Rather, only skin-derived dendritic cells up-regulated key genes related to TFH cell development in the draining lymph nodes. Depletion of Langerhans cells partially abrogated TFH and germinal center B-cell responses. Thus, after intradermal immunization, only skin-derived migratory dendritic cells, including Langerhans cells, permit the generation of TFH cells and germinal centers. Identifying the relative contributions of tissue and lymphoid organ dendritic cell subsets in generating humoral immune responses is of great importance for the development of tailored vaccines