Intradermal injection of an anti‐Langerin‐HIVGag fusion vaccine targets epidermal Langerhans cells in nonhuman primates and can be tracked in vivo

Abstract

The development of new immunization strategies requires a better understanding of early molecular and cellular events occurring at the site of injection. The skin is particularly rich in immune cells and represents an attractive site for vaccine administration. Here, we specifically targeted vaccine antigens to epidermal Langerhans cells (LCs) using a fusion protein composed of HIV antigens and a monoclonal antibody targeting Langerin. We developed a fluorescence imaging approach to visualize, in vivo, the vaccine-targeted cells. Studies were performed in nonhuman primates (NHPs) because of their relevance as a model to assess human vaccines. We directly demonstrated that in NHPs, intradermally injected anti-Langerin-HIVGag specifically targets epidermal LCs and induces rapid changes in the LC network, including LC activation and migration out of the epidermis. Vaccine targeting of LCs significantly improved anti-HIV immune response without requirement of an adjuvant. Although the co-injection of the TLR-7/8 synthetic ligand, R-848 (resiquimod), with the vaccine, did not enhance significantly the antibody response, it stimulated recruitment of HLA-DR+ inflammatory cells to the site of immunization. This study allowed us to characterize the dynamics of early local events following the injection of a vaccine-targeted epidermal LCs and R-848. Keywords:Fluorescence imaging r Langerhans cell r Nonhuman primate r Skin r Vaccination Additional supporting information may be found in the online version of this article at the publisher's web-site Correspondence: Dr. Catherine Chapon e-mail: catherine.chapon@cea.fr IntroductionFluorescence imaging is a powerful and minimally invasive technology for real-time visualization in vivo of the dynamics of the behavior of immune cells in their natural microenvironment [1][2][3][4][5][6].C 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu 690Nina Salabert et al. Eur. J. Immunol. 2016. 46: 689-700 It also facilitates the characterization of the fate of vaccine antigens in the organism allowing unprecedented progress in the understanding of vaccine-induced immune response mechanisms [7,8]. Up to now, most in vivo studies have used transgenic mouse models expressing fluorescent molecules under specific promoters. However, relevance of mouse models to the study of human vaccines is questionable. Major differences between the two species have been reported, when comparing mature immune system [9][10][11][12][13][14]. Mice models turned out to be little predictive of vaccine immunogenicity and efficacy in humans, even when highly advanced transgenic and humanized animals were used [15]. Currently, due to their close genetic relatedness with humans, and immune compartment similarities in particular, nonhuman primates (NHP) are considered to be the most appropriate model species for predicting vaccine immunogenicity and efficacy in humans [16,17]. The development of new strategies for immunization [17,18] requires a better understanding of molecular and cellular change...

Fibered Confocal Fluorescence Microscopy for the Noninvasive Imaging of Langerhans Cells in Macaques

“…In this study, LC density observed by in vivo imaging remained unchanged over time, suggesting that in vivo antibody injection, in this experimental setup, did not interfere with LC migration. This is consistent with previous reports showing that the intradermal injection of monoclonal antibodies targeting LCs, in the absence of costimulation signals such as the Toll-Like Receptor Ligand agonist, does not induce LC activation [ 41 , 42 ].…”

The anti-influenza M2e antibody response is promoted by XCR1 targeting in pig skin

“…In addition, the lack of requirement for adjuvants appeared to depend on helper peptides available in the Ig backbone of the antibody used for targeting, such as motives in the IgG2a backbone in the case of C57BL6 mice 49 . Similarly in non-human primates, an increase of antibody response independently of adjuvant has been observed in the case of antigen targeting to CLEC9A 49 , DCIR 52 , and langerin 53 . No further increase could be obtained with TLR7/8 ligand 53 nor double stranded poly(I:C) 52 , suggesting that a maximal antibody response had been reached or that a key factor was limiting.…”

“…Similarly in non-human primates, an increase of antibody response independently of adjuvant has been observed in the case of antigen targeting to CLEC9A 49 , DCIR 52 , and langerin 53 . No further increase could be obtained with TLR7/8 ligand 53 nor double stranded poly(I:C) 52 , suggesting that a maximal antibody response had been reached or that a key factor was limiting. In these cases, the Ig backbone used for targeting may also have played a role and may be involved in the heterogeneity of the responses across individuals.…”

Targeting MOG to skin macrophages prevents EAE in macaques through TGFβ-induced peripheral tolerance

“…Different from anti-DC-ASGPR-MOG, the intradermal injection of rhMOG was captured by skin CD1a+CD40+ DC, with pro-inflammatory properties (Salabert et al , 2016). Thus, animals receiving injections of both rhMOG and anti-DC-ASGPR-MOG, likely experienced concomitant priming of MOG-specific effector and regulatory lymphocytes with notorious restraint of otherwise strongly pathogenic autoreactive T cells.…”