Liposomes as Carriers of Peptide Antigens: Induction of Antibodies and Cytotoxic T Lymphocytes to Conjugated and Unconjugated Peptides

A variety of DNA vaccine prime and recombinant viral boost immunization strategies have been developed to enhance immune responses in humans, but inherent limitations to these strategies exist. There is still an overwhelming need to develop safe and effective approaches that raise broad humoral and T cell-mediated immune responses systemically and on mucosal surfaces. We have developed a novel mucosal immunization regimen that precludes the use of viral vectors yet induces potent T cell responses. Using hepatitis B surface Ag (HBsAg), we observed that vaccination of BALB/c mice with an i.m. HBsAg-DNA vaccine prime followed by an intranasal boost with HBsAg protein encapsulated in biologically inert liposomes enhanced humoral and T cell immune responses, particularly on mucosal surfaces. Intranasal live virus challenge with a recombinant vaccinia virus expressing HBsAg revealed a correlation between T cell immune responses and protection of immunized mice. A shortened immunization protocol was developed that was successful in both adult and neonatal mice. These results support the conclusion that this new approach is capable of generating a Th-type-1-biased, broad spectrum immune response, specifically at mucosal surfaces. The success of this design may provide a safe and effective vaccination alternative for human use.

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“…Both of these components are safe, easily manufactured, and have demonstrated capability in the development of vaccines (37)(38)(39).…”

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confidence: 99%

A DNA Vaccine Prime Followed by a Liposome-Encapsulated Protein Boost Confers Enhanced Mucosal Immune Responses and Protection

Yang¹,

Whalen²,

Tirabassi

et al. 2008

The Journal of Immunology

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“…Liposomes have long been used to carry drugs, proteins, peptides or, more recently, DNA (Alving et al, 1995;Lasic, 1998;Gregoriadis, 1999), and to protect them from degradation. Liposome based vaccine preparations specific for infectious agents have been successfully tested (Gluck, 1995).…”

Section: Discussionmentioning

confidence: 99%

“…Liposomes constructed according to different formulations have long been used as drug carriers (Langer, 1998;Lasic, 1998) or vaccine components (Alving et al, 1995;Gluck, 1995;Gregoriadis, 1999;Gregoriadis et al, 1999). Interestingly, liposomes containing lipopeptides derived from MUC1 human TAA and monophosphoryl lipid A as adjuvant were shown to be able to induce specific immune responses in vitro (Agrawal et al, 1998).…”

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confidence: 99%

Encapsulation into sterically stabilised liposomes enhances the immunogenicity of melanoma-associated Melan-A/MART-1 epitopes

et al. 2004

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Tumour-associated antigens (TAA)-specific vaccination requires highly immunogenic reagents capable of inducing cytotoxic T cells (CTL). Soluble peptides are currently used in clinical applications despite an acknowledged poor immunogenicity. Encapsulation into liposomes has been suggested to improve the immunogenicity of discrete antigen formulations. We comparatively evaluated the capacity of HLA-A2.1 restricted Melan-A/MART-1 epitopes in soluble form (S) or following inclusion into sterically stabilised liposomes (SSL) to be recognised by specific CTL, to stimulate their proliferation and to induce them in healthy donors' peripheral blood mononuclear cells (PBMC), as well as in melanoma-derived tumour-infiltrating lymphocytes (TIL). HLA-A2.1 þ , Melan-A/ MART-1-NA-8 melanoma cells served as targets of specific CTL in 51Cr release assays upon pulsing by untreated or human plasmatreated soluble or SSL-encapsulated Melan-A/MART-1 27 -35 (M27 -35) or 26 -35 (M26 -35) epitopes. These reagents were also used to stimulate CTL proliferation, measured as 3H-thymidine incorporation, in the presence of immature dendritic cells (iDC), as antigen-presenting cells (APC). Induction of specific CTL upon stimulation with soluble or SSL-encapsulated peptides was attempted in healthy donors' PBMC or melanoma-derived TIL, and monitored by 51Cr release assays and tetramer staining. Na-8 cells pulsing with SSL M27 -35 resulted in a five-fold more effective killing by specific CTL as compared with equal amounts of S M27 -35. Encapsulation into SSL also provided a partial (50%) protection of M27 -35 from plasma hydrolysis. No specific advantages regarding M26 -35 were detectable in these assays. However, at low epitope concentrations (p100 ng ml À1 ), SSL M26 -35 was significantly more effective in inducing CTL proliferation than S M26 -35, in the presence of iDC, as APC. Preincubation with iDC for 6 h virtually abolished the capacity of S M26 -35 to stimulate specific CTL proliferation, but only partially affected that of SSL M26 -35. Most importantly, SSL M26 -35 was able to enhance the induction of specific CTL in healthy donors PBMC and in melanoma-derived TIL as compared to S M26 -35. Taken together, our data indicate that encapsulation of TAA epitopes into SSL results in effective immunogenic formulations suitable for clinical use in active specific tumour immunotherapy.

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“…The use of liposomes as potential carriers for vaccines has been extensively explored (Alving et al, 1995). Among their many advantages, these vesicles are characterised by a marked absence of toxicity and a low intrinsic immunogenicity.…”

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Induction of effective and antigen-specific antitumour immunity by a liposomal ErbB2/HER2 peptide-based vaccination construct

et al. 2005

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Efficient delivery of tumour-associated antigens to appropriate cellular compartments of antigen-presenting cells is of prime importance for the induction of potent, cell-mediated antitumour immune responses. We have designed novel multivalent liposomal constructs that co-deliver the p63 -71 cytotoxic T Lymphocyte epitope derived from human ErbB2 (HER2), and HA307 -319, a T-helper (Th) epitope derived from influenza haemagglutinin. Both peptides were conjugated to the surface of liposomes via a Pam 3 CSS anchor, a synthetic lipopeptide with potent adjuvant activity. In a murine model system, vaccination with these constructs completely protected BALB/c mice from subsequent s.c. challenge with ErbB2-expressing, but not ErbB2-negative, murine renal carcinoma (Renca) cells, indicating the induction of potent, antigen-specific immune responses. I.v. re-challenge of tumour-free animals 2 months after the first tumour cell inoculation did not result in the formation of lung tumour nodules, suggesting that longlasting, systemic immunity had been induced. While still protecting the majority of vaccinated mice, a liposomal construct lacking the Th epitope was less effective than the diepitope construct, also correlating with a lower number of CD8 þ IFN-g þ T-cells identified upon ex vivo peptide restimulation of splenocytes from vaccinated animals. Importantly, in a therapeutic setting treatment with the liposomal vaccines resulted in cures in the majority of tumour-bearing mice and delayed tumour growth in the remaining ones. Our results demonstrate that liposomal constructs which combine Tc and Th peptide antigens and lipopeptide adjuvants can induce efficient, antigen-specific antitumour immunity, and represent promising synthetic delivery systems for the design of specific antitumour vaccines.

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Liposomes as Carriers of Peptide Antigens: Induction of Antibodies and Cytotoxic T Lymphocytes to Conjugated and Unconjugated Peptides

Cited by 135 publications

References 73 publications

A DNA Vaccine Prime Followed by a Liposome-Encapsulated Protein Boost Confers Enhanced Mucosal Immune Responses and Protection

A DNA Vaccine Prime Followed by a Liposome-Encapsulated Protein Boost Confers Enhanced Mucosal Immune Responses and Protection

Encapsulation into sterically stabilised liposomes enhances the immunogenicity of melanoma-associated Melan-A/MART-1 epitopes

Induction of effective and antigen-specific antitumour immunity by a liposomal ErbB2/HER2 peptide-based vaccination construct

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