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The Porcine Reproductive and Respiratory Syndrome Virus (PRRSV) induces reproductive disorders in sows and respiratory illnesses in growing pigs and is considered as one of the main pathogenic agents responsible for economic losses in the porcine industry worldwide. Modified live PRRSV vaccines (MLVs) are very effective vaccine types against homologous strains but they present only partial protection against heterologous viral variants. With the goal to induce broad and cross-protective immunity, we generated DNA vaccines encoding B and T antigens derived from a European subtype 1 strain that include T-cell epitope sequences known to be conserved across strains. These antigens were expressed either in a native form or in the form of vaccibodies targeted to the endocytic receptor XCR1 and CD11c expressed by different types of antigen-presenting cells (APCs). When delivered in skin with cationic nanoparticles and surface electroporation, multiple DNA vaccinations as a stand-alone regimen induced substantial antibody and T-cell responses, which were not promoted by targeting antigens to APCs. Interestingly, a DNA-MLV prime–boost strategy strongly enhanced the antibody response and broadened the T-cell responses over the one induced by MLV or DNA-only. The anti-nucleoprotein antibody response induced by the DNA-MLV prime–boost was clearly promoted by targeting the antigen to CD11c and XCR1, indicating a benefit of APC-targeting on the B-cell response. In conclusion, a DNA-MLV prime–boost strategy, by enhancing the potency and breadth of MLV vaccines, stands as a promising vaccine strategy to improve the control of PRRSV in infected herds.

Current influenza vaccines are effective but imperfect, failing to cover against emerging strains of virus and requiring seasonal administration to protect against new strains. A key step to improving influenza vaccines is to improve our understanding of vaccine induced protection. Whilst it is clear that antibodies play a protective role, vaccine induced CD8+ T cells can improve protection. To further explore the role of CD8+ T cells we used a DNA vaccine that encodes antigen dimerised to an immune cell targeting module. Immunising CB6F1 mice with the DNA vaccine in a heterologous prime boost regime with the seasonal protein vaccine improved the resolution of influenza disease compared to protein alone. This improved disease resolution was dependent on CD8+ T cells. However, DNA vaccine regimes that induced CD8+ T cells alone were not protective and did not boost the protection provided by protein. The MHC targeting module used was an anti-I-Ed single chain antibody specific to the BALB/c strain of mice. To test the role of MHC targeting we compared the response between BALB/c, C57BL/6 mice and an F1 cross of the two strains (CB6F1). BALB/c mice were protected, C57BL/6 were not and the F1 had an intermediate phenotype; showing that the targeting of antigen is important in the response. Based on these findings, and in agreement with other studies using different vaccines, we conclude that in addition to antibody, inducing a protective CD8 response is important in future influenza vaccines

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BACKGROUND: Recent advances in the field of cancer immunotherapy have identified CD8+ T cell responses against tumor-specific neoantigens as a key driver of tumor regression and prolonged survival. VB10.NEO is a highly potent DNA plasmid vaccine with intrinsic adjuvant effect designed for efficient delivery of personalized tumor-specific neoantigens. VB10.NEO plasmid is translated in vivo and the secreted protein will covalently bind to endocytic receptors on APC by a targeting unit expressing CCL3 (MIP-1α) allowing efficient uptake and presentation of the neoantigens. In addition, CCL3 will attract immune cells by chemotaxis and induce maturation of APC locally. The objective of this study is to demonstrate the potential of VB10.NEO to induce tumor-specific T cell responses and control tumor growth. METHODS: VB10.NEO was delivered i.m to study CD8+ and CD4+ neoantigen-specific T cell responses in four different pre-clinical mouse models. Immunogenicity was compared with delivery of neoantigen as traditional peptide-adjuvant immunization. The tumor protective effect of VB10.NEO in the presence or absence of anti-PD-1 therapy was investigated in the CT26 colon carcinoma model. RESULTS: Vaccibody DNA Vaccine Platform VB10.NEO is flexible and can hold up to at least 40 neoepitopes. VB10.NEO vaccination induced strong neoantigen-specific T cell responses. Homologous boost vaccinations further augmented the response. T cell responses against predicted CD8+ T cell epitopes previously reported as non-immunogenic or activating only weak T cell responses using a conventional peptide-adjuvant or RNA immunization showed strong CD8+ T cell responses when delivered in the Vaccibody format, demonstrating a unique and strong priming of CD8+ T cells using VB10.NEO. The response was also accompanied by CD4+ T cell responses. In a therapeutic tumor setting VB10.NEO vaccinated mice (monotherapy) induced tumor protective responses. The effect was augmented when combining VB10.NEO with anti-PD-1 where complete regression of large established tumors was observed. All tumour-free mice rechallenged with a lethal tumor dose were protected indicating induction of long-lasting memory responses. Furthermore, the critical role of CD8+ T cells for the observed tumour protection was confirmed when depleting CD8+ T cells. CONCLUSION: VB10.NEO immunotherapy induce strong CD8+ T cell responses critical for anti-tumor effect which demonstrate the unique characteristic of the Vaccibody platform to potentiate activation of CD8+ T cells. VB10.NEO in combination with anti-PD-1 further synergize the potent immune responses resulting in durable complete tumor regression in pre-clinical models supporting the scientific rational for the current ongoing clinical trial investigating VB10.NEO in combination with CPI in patients with advanced solid tumors. Citation Format: Elisabeth Stubsrud, Stine Granum, Helene Zell-Flagstad, Audun Bersaas, Lise Madelene Skullerud, Monika Sekelja, Karoline Schjetne, Agnete Fredriksen. Vaccibody DNA vaccine platform VB10.NEO induces strong neo-antigen specific CD8+ T cell responses critical to cure established tumors in pre-clinical models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 5003.

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