Induction of CD8+ T-cell responses against subunit antigens by the novel cationic liposomal CAF09 adjuvant

Korsholm, Karen Smith; Hansen, Jens Munk; Karlsen, Kasper K.; Filskov, Jonathan; Mikkelsen, Marianne; Lindenstrøm, Thomas; Schmidt, S.; Andersen, Peter; Christensen, Dennis

doi:10.1016/j.vaccine.2014.05.050

Cited by 99 publications

(123 citation statements)

References 37 publications

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“…The vaccine Ag was given in the novel crosspriming adjuvant CAF09 (DDA/MMG-1/pI:C) (19), and the adjuvant dose was kept identical for all groups. We hypothesized that with the CAF09 adjuvant, which selectively and efficiently delivers Ag to and activates DCs, we would be able to induce a CTL response using low vaccine Ag doses and, hence, overcome the threshold issues observed with low-dose vaccinations using conventional adjuvants and viral vectors.…”

Section: Resultsmentioning

confidence: 99%

“…One such adjuvant, cationic adjuvant formulation (CAF)09, efficiently induces Th and CTL responses (19). Combining novel potent adjuvants with low-dose immunizations has not been done previously; in this study, we investigated this promising strategy for the induction of high-avidity T cells and improved vaccine efficacy.…”

Section: N Ovel Vaccine Candidates Have Traditionally Been Evaluatedmentioning

confidence: 99%

“…Ags were mixed in a total volume of 100 ml of 10 mM Tris-HCl (pH 7.4) and mixed 1:1 with 100 ml of the liposomal CAF09 (19), consisting of dimethyldioctadecylammonium bromide (DDA; NCK, Copenhagen, Denmark), synthetic monomycolyl glycerol (MMG; NCK) analog MMG-1, and the TLR-3 agonist polyinosinic-polycytidylic acid (pI:C; SigmaAldrich, Copenhagen, Denmark) and formulated by the film method, as previously described (22). Thus, a total of 200 ml of vaccine was given per mouse dose that contained 250 mg of DDA, 50 mg of MMG-1, and 50 mg of pI:C. Vaccines were vortexed for 30 s and left for .10 min before injection.…”

Section: Vaccines Ags and Immunizationsmentioning

confidence: 99%

See 2 more Smart Citations

Low Antigen Dose in Adjuvant-Based Vaccination Selectively Induces CD4 T Cells with Enhanced Functional Avidity and Protective Efficacy

Billeskov

Wang

Solaymani-Mohammadi

et al. 2017

The Journal of Immunology

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T cells with high functional avidity can sense and respond to low levels of cognate Ag, a characteristic that is associated with more potent responses against tumors and many infections, including HIV. Although an important determinant of T cell efficacy, it has proven difficult to selectively induce T cells of high functional avidity through vaccination. Attempts to induce high-avidity T cells by low-dose in vivo vaccination failed because this strategy simply gave no response. Instead, selective induction of high-avidity T cells has required in vitro culturing of specific T cells with low Ag concentrations. In this study, we combined low vaccine Ag doses with a novel potent cationic liposomal adjuvant, cationic adjuvant formulation 09, consisting of dimethyldioctadecylammonium liposomes incorporating two immunomodulators (monomycolyl glycerol analog and polyinosinic-polycytidylic acid) that efficiently induces CD4 Th cells, as well as cross-primes CD8 CTL responses. We show that vaccination with low Ag dose selectively primes CD4 T cells of higher functional avidity, whereas CD8 T cell functional avidity was unrelated to vaccine dose in mice. Importantly, CD4 T cells of higher functional avidity induced by low-dose vaccinations showed higher cytokine release per cell and lower inhibitory receptor expression (PD-1, CTLA-4, and the apoptosis-inducing Fas death receptor) compared with their lower-avidity CD4 counterparts. Notably, increased functional CD4 T cell avidity improved antiviral efficacy of CD8 T cells. These data suggest that potent adjuvants, such as cationic adjuvant formulation 09, render low-dose vaccination a feasible and promising approach for generating high-avidity T cells through vaccination.

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Section: Resultsmentioning

confidence: 99%

Section: N Ovel Vaccine Candidates Have Traditionally Been Evaluatedmentioning

confidence: 99%

Section: Vaccines Ags and Immunizationsmentioning

confidence: 99%

See 1 more Smart Citation

Low Antigen Dose in Adjuvant-Based Vaccination Selectively Induces CD4 T Cells with Enhanced Functional Avidity and Protective Efficacy

Billeskov

Wang

Solaymani-Mohammadi

et al. 2017

The Journal of Immunology

Self Cite

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“…Recently, we reported that CAF09 enhanced and skewed CD8 ϩ and CD4 ϩ T cells toward a T EM response that was able to control tumors in a therapeutic human papillomavirus 16 (HPV-16) E7-expressing model (40). In concordance with these findings, another group reported that a vigorous vaccine-induced T EM response dominated by double-positive IFN-␥ ϩ TNF-␣ ϩ CD8 ϩ T cells controlled tumors more efficiently than a central memory T cell (T CM ) phenotypic response (82).…”

Section: Discussionmentioning

confidence: 99%

“…This process, which directs antigens from the endosomal to the cytosolic compartment, can be enhanced in a type I IFN-dependent manner by stimulation with the Toll-like receptor 3 (TLR-3) ligand polyinosinic-poly(C) [poly(I·C)] (35-37). The CAF01 adjuvant, with a good safety record and proven to induce potent T helper type 1 (T H 1)/interleukin 17 (IL-17)-inducing responses in humans (38,39), has recently been refined to enhance both CD4 ϩ and CD8 ϩ T cell responses in the cationic liposomal formulation CAF09, consisting of dimethyldioctadecylammonium bromide (DDA), monomycolyl glycerol (MMG), and poly(I·C) (40).…”

Section: Importancementioning

confidence: 99%

Broadening CD4⁺and CD8⁺T Cell Responses against Hepatitis C Virus by Vaccination with NS3 Overlapping Peptide Panels in Cross-Priming Liposomes

Filskov

Mikkelsen

Hansen

et al. 2017

J Virol

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Despite the introduction of effective drugs to treat patients with chronic hepatitis C virus (HCV) infection, a vaccine would be the only means to substantially reduce the worldwide disease burden. An incomplete understanding of how HCV interacts with its human host and evades immune surveillance has hampered vaccine development. It is generally accepted that in infected individuals, a narrow repertoire of exhausted T cells is a hallmark of persistent infection, whereas broad, vigorous CD4 ϩ and CD8 ϩ T cell responses are associated with control of acute hepatitis C. We employed a vaccine approach based on a mixture of peptides (pepmix) spanning the entire sequence of HCV nonstructural protein 3 (NS3) in cross-priming cationic liposomes (CAF09) to facilitate a versatile presentation of all possible T cell epitopes, regardless of the HLA background of the vaccine recipient. Here, we demonstrate that vaccination of mice with NS3 pepmix broadens the repertoire of epitopespecific T cells compared to the corresponding recombinant protein (rNS3). Moreover, vaccination with rNS3 induced only CD4 ϩ T cells, whereas the NS3 pepmix induced a far more vigorous CD4 ϩ T cell response and was as potent a CD8 ϩ T cell inducer as an adenovirus-vectored vaccine expressing NS3. Importantly, the cellular responses are dominated by multifunctional T cells, such as gamma interferonpositive (IFN-␥ ϩ ) tumor necrosis factor alpha-positive (TNF-␣ ϩ ) coproducers, and displayed cytotoxic capacity in mice. In conclusion, we present a novel vaccine approach against HCV, inducing a broadened T cell response targeting both immunodominant and potential subdominant epitopes, which may be key elements to counter T cell exhaustion and prevent chronicity.IMPORTANCE With at least 700,000 annual deaths, development of a vaccine against hepatitis C virus (HCV) has high priority, but the tremendous ability of the virus to dodge the human immune system poses great challenges. Furthermore, many chronic infections, including HCV infection, have a remarkable ability to drive initially strong CD4 ϩ and CD8 ϩ T cell responses against dominant epitopes toward an exhausted, dysfunctional state. Thus, new and innovative vaccine approaches to control HCV should be evaluated. Here, we report on a novel peptide-based nanoparticle vaccine strategy (NS3 pepmix) aimed at generating T cell immunity against potential subdominant T cell epitopes that are not efficiently targeted by vaccination with full-length recombinant protein (rNS3) or infection with HCV. As proof of concept, we found that NS3 pepmix excels in broadening the repertoire of epitope-

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At the bench: Engineering the next generation of cancer vaccines

Shae

Baljon

Wehbe

et al. 2019

Journal of Leukocyte Biology

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Cancer vaccines hold promise as an immunotherapeutic modality based on their potential to generate tumor antigen-specific T cell responses and long-lived antitumor responses capable of combating metastatic disease and recurrence. However, cancer vaccines have historically failed to deliver significant therapeutic benefit in the clinic, which we maintain is due in part to drug delivery challenges that have limited vaccine immunogenicity and efficacy. In this review, we examine some of the known and putative failure mechanisms of common first-generation clinical cancer vaccines, and describe how the rational design of materials engineered for vaccine delivery and immunomodulation can address these shortcomings. First, we outline vaccine design principles for augmenting cellular immunity to tumor antigens and describe how well-engineered materials can improve vaccine efficacy, highlighting recent innovations in vaccine delivery technology that are primed for integration into neoantigen vaccine development pipelines. We also discuss the importance of sequencing, timing, and kinetics in mounting effective immune responses to cancer vaccines, and highlight examples of materials that potentiate antitumor immunity through spatiotemporal control of immunomodulation. Furthermore, we describe several engineering strategies for improving outcomes of in situ cancer vaccines, which leverage local, intratumoral delivery to stimulate systemic immunity. Finally, we highlight recent innovations leveraging nanotechnology for increasing the immunogenicity of the tumor microenvironment (TME), which is critical to enhancing tumor infiltration and function of T cells elicited in response to cancer vaccines. These immunoengineering strategies and tools complement ongoing advances in cancer vaccines as they reemerge as an important component of the immunotherapeutic armamentarium.

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Induction of CD8+ T-cell responses against subunit antigens by the novel cationic liposomal CAF09 adjuvant

Cited by 99 publications

References 37 publications

Low Antigen Dose in Adjuvant-Based Vaccination Selectively Induces CD4 T Cells with Enhanced Functional Avidity and Protective Efficacy

Low Antigen Dose in Adjuvant-Based Vaccination Selectively Induces CD4 T Cells with Enhanced Functional Avidity and Protective Efficacy

Broadening CD4⁺and CD8⁺T Cell Responses against Hepatitis C Virus by Vaccination with NS3 Overlapping Peptide Panels in Cross-Priming Liposomes

At the bench: Engineering the next generation of cancer vaccines

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Induction of CD8+ T-cell responses against subunit antigens by the novel cationic liposomal CAF09 adjuvant

Cited by 99 publications

References 37 publications

Low Antigen Dose in Adjuvant-Based Vaccination Selectively Induces CD4 T Cells with Enhanced Functional Avidity and Protective Efficacy

Low Antigen Dose in Adjuvant-Based Vaccination Selectively Induces CD4 T Cells with Enhanced Functional Avidity and Protective Efficacy

Broadening CD4+and CD8+T Cell Responses against Hepatitis C Virus by Vaccination with NS3 Overlapping Peptide Panels in Cross-Priming Liposomes

At the bench: Engineering the next generation of cancer vaccines

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Broadening CD4⁺and CD8⁺T Cell Responses against Hepatitis C Virus by Vaccination with NS3 Overlapping Peptide Panels in Cross-Priming Liposomes