Vaccine molecules targeting Xcr1 on cross‐presenting DCs induce protective CD8<sup>+</sup> T‐cell responses against influenza virus

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The development of vaccines inducing efficient CD8+ T cell responses is the focus of intense research. Dendritic cells (DCs) expressing the XCR1 chemokine receptor, also known as CD103+ or CD8α+ DCs, excel in the presentation of extracellular Ags to CD8+ T cells. Because of its high numbers of DCs, including XCR1+ DCs, the skin dermis is an attractive site for vaccine administration. By creating laser-generated micropores through the epidermis, we targeted a model protein Ag fused to XCL1, the ligand of XCR1, to dermal XCR1+ DCs and induced Ag-specific CD8+ and CD4+ T cell responses. Efficient immunization required the emigration of XCR1+ dermal DCs to draining lymph nodes and occurred irrespective of TLR signaling. Moreover, a single intradermal immunization protected mice against melanoma tumor growth in prophylactic and therapeutic settings, in the absence of exogenous adjuvant. The mild inflammatory milieu created in the dermis by skin laser microporation itself most likely favored the development of potent T cell responses in the absence of exogenous adjuvants. The existence of functionally equivalent XCR1+ dermal DCs in humans should permit the translation of laser-assisted intradermal delivery of a tumor-specific vaccine targeting XCR1+ DCs to human cancer immunotherapy. Moreover, considering that the use of adjuvants in vaccines is often associated with safety issues, the possibility of inducing protective responses against melanoma tumor growth independently of the administration of exogenous adjuvants should facilitate the development of safer vaccines.

Section: Generation Of Vaccibodiesmentioning

confidence: 99%

Section: Xcl1-mentioning

confidence: 99%

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Laser-Assisted Intradermal Delivery of Adjuvant-Free Vaccines Targeting XCR1+ Dendritic Cells Induces Potent Antitumoral Responses

Terhorst‐Molawi

Fossum

Barańska

et al. 2015

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“…Initially, these experiments were performed with Ag that had been chemically conjugated to APCspecific Abs (5)(6)(7)(8)(9)(10). Later, genetic fusion of an APC-specific targeting unit and Ag has been a preferred method (11)(12)(13)(14)(15)(16)(17). Several different versions of APC-specific targeting units have been reported, including Ig-based formats (11,13), single-chain variable fragment (scFv) formats (14,15), and chemokines (12,16,17).…”

mentioning

confidence: 99%

Antigen Targeting to Human HLA Class II Molecules Increases Efficacy of DNA Vaccination

Grødeland

Fredriksen²,

Løset

et al. 2016

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It has been difficult to translate promising results from DNA vaccination in mice to larger animals and humans. Previously, DNA vaccines encoding proteins that target Ag to MHC class II (MHC-II) molecules on APCs have been shown to induce rapid, enhanced, and long-lasting Ag-specific Ab titers in mice. In this study, we describe two novel DNA vaccines that as proteins target HLA class II (HLA-II) molecules. These vaccine proteins cross-react with MHC-II molecules in several species of larger mammals. When tested in ferrets and pigs, a single DNA delivery with low doses of the HLA-II–targeted vaccines resulted in rapid and increased Ab responses. Importantly, painless intradermal jet delivery of DNA was as effective as delivery by needle injection followed by electroporation. As an indication that the vaccines could also be useful for human application, HLA-II–targeted vaccine proteins were found to increase human CD4+ T cell responses by a factor of ×103 in vitro. Thus, targeting of Ag to MHC-II molecules may represent an attractive strategy for increasing efficacy of DNA vaccines in larger animals and humans.

“…This approach combines the attractiveness of DNA immunization with the well-known principle of APC targeting of Ag to increase Ag immunogenicity (22)(23)(24). Interestingly, targeting of Ag to different APC surface molecules may skew immune responses toward different arms of immunity (19,25,26). Thus, the technology may allow matching of vaccine-induced immune responses to the type of immunity needed for protection against a particular pathogen.…”

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confidence: 99%

Simultaneous Targeting of Multiple Hemagglutinins to APCs for Induction of Broad Immunity against Influenza

Anderson

Baranowska-Hustad

Braathen

et al. 2018

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There is a need for vaccines that can confer broad immunity against highly diverse pathogens, such as influenza. The efficacy of conventional influenza vaccines is dependent on accurate matching of vaccines to circulating strains, but slow and limited production capacities increase the probability of vaccine mismatches. In contrast, DNA vaccination allows for rapid production of vaccines encoding novel influenza Ags. The efficacy of DNA vaccination is greatly improved if the DNA-encoded vaccine proteins target APCs. In this study, we have used hemagglutinin (HA) genes from each of six group 1 influenza viruses (H5, H6, H8, H9, H11, and H13), and inserted these into a DNA vaccine format that induces delivery of the HA protein Ags to MHC class II molecules on APCs. Each of the targeted DNA vaccines induced high titers of strain-specific anti-HA Abs. Importantly, when the six HA vaccines were mixed and injected simultaneously, the strain-specific Ab titers were maintained. In addition, the vaccine mixture induced Abs that cross-reacted with strains not included in the vaccine mixture (H1) and could protect mice against a heterosubtypic challenge with the H1 viruses A/Puerto Rico/8/1934 (H1N1) and A/California/07/2009 (H1N1). The data suggest that vaccination with a mixture of HAs could be useful for induction of strain-specific immunity against strains represented in the mixture and, in addition, confer some degree of cross-protection against unrelated influenza strains.