A vaccine conjugate of ‘ISCAR’ immunocarrier and peptide epitopes of the E7 cervical cancer‐associated protein of human papillomavirus type 16 elicits specific Th1‐ and Th2‐type responses in immunized mice in the absence of oil‐based adjuvants

• Published in: Clinical and experimental immunology Vol. 101; no. 2; pp. 265 - 271
• Main Authors: TINDLE, R. W., CROFT, S., HERD, K., MALCOLM, K., GECZY, A. F., STEWART, T., FERNANDO, G. J. P.
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01.08.1995; Blackwell
• Subjects: Adjuvants, Immunologic - pharmacology; AIDS/HIV; Amino Acid Sequence; Animals; Antibodies, Viral - biosynthesis; Antibodies, Viral - blood; Antigens, Neoplasm - immunology; Bacterial Outer Membrane Proteins - immunology; Biological and medical sciences; CTL; Epitopes - immunology; Escherichia coli; Escherichia coli Proteins; Female; Host-tumor relations. Immunology. Biological markers; HPV16 E7; Human papillomavirus 16; Immunization; Interleukin-2 - biosynthesis; Interleukin-4 - biosynthesis; ISCAR; Lymphocyte Activation - drug effects; Lymphocyte Activation - immunology; Medical sciences; Mice; Mice, Inbred C57BL; Molecular Sequence Data; Neoplasms, Experimental - prevention & control; Oncogene Proteins, Viral - immunology; Papillomaviridae; Papillomavirus E7 Proteins; Papillomavirus Vaccines; peptide vaccine; T-Lymphocytes, Cytotoxic - immunology; T-Lymphocytes, Cytotoxic - metabolism; Th1 Cells - drug effects; Th1 Cells - immunology; Th1 Cells - metabolism; Th1/Th2; Th2 Cells - drug effects; Th2 Cells - immunology; Th2 Cells - metabolism; Tumors; Vaccines, Conjugate - pharmacology; Viral Vaccines - pharmacology; Immunoprotection; Membrane protein; Immune response; Escherichia coli; Rodentia; Helper cell; Cytotoxicity; Cellular immunity; Vaccine; Papovaviridae; Papillomavirus; Virus; Human papillomavirus 16; Vertebrata; Mammalia; Immunogenicity; Mouse; T-Lymphocyte; Bacteria; Tumor; Conjugated compound; Enterobacteriaceae
• ISSN: 0009-9104; 1365-2249
• DOI: 10.1111/j.1365-2249.1995.tb08349.x

SUMMARY TraT protein, known as ISCAR (= Immunostimulatory Carrier), is one of a family of integral membrane proteins (Imps) of Escherichia coli representing powerful carrier molecules which when injected into experimental animals generate substantial antibody and T proliferative responses to molecules conjugated to it. We extend these findings to show that ISCAR functions to stimulate Th1‐ and Th2‐type responses, including specific cytotoxic T cells and tumour protection. We report here that by conjugating to ISCAR a 19mer peptide containing linear B epitopes, a T helper (Th) epitope, and a H‐2b‐restricted T cytotoxic (CTL) epitope of E7 protein of human papillomavirus type 16 (HPV16), and immunizing C57B1/6 (H‐2b) mice, we elicited (i) specific IgG2a and IgG1 antibodies; (ii) IL‐2 and IL‐4 production by specifically recalled lymph node cells in vitro; (iii) cytotoxic T lymphocytes which specifically killed both E7 peptide‐pulsed, and whole E7 gene‐transfected tumour target cells; and (iv) in vivo protection against an E7 gene‐transfected tumour cell inoculum. These findings have implications for the design of vaccines to stimulate immune responses to endogenously processed target antigens (e.g. tumour‐associated antigens) without the unwanted side effects of oil‐based adjuvants. In addition they support the case for a E7‐targeted therapeutic vaccine for HPV‐associated human cervical cancer.