Vaccines: all things considered.
Explore the source record for details and available documents.
Adjuvants, Immunologic↗
Biomedical subjects
Daniel H Zimmerman
Publications and source records attributed to Daniel H Zimmerman.
The L.E.A.P.S. approach to vaccine development.
The Ligand Epitope Antigen Presentation System (L.E.A.P.S.) approach to vaccine development utilizes immune peptides to promote the immunogenicity and influence the type of immune response generated towards epitopes in peptides which may be too small to elicit an immune response. The covalent attachment of these immune peptides to the antigenic peptide promotes the interaction of the epitope with T cells (T cell binding ligand (TCBL)) or antigen presenting cells (immune cell binding ligand (ICBL)) and ultimately promotes binding with the T cell receptor on CD4 or CD8 T cells. The, J, ICBL/TCBL peptide derived from the beta-2-microglobulin chain of MHC I molecules promotes Th1 type responses to the antigenic peptide while the, G, ICBL/TCBL peptide derived from the beta chain of MHC II molecules promotes Th2 types of responses. The efficacy of this approach has been demonstrated by characterization of the immune responses to L.E.A.P.S. vaccines and by elicitation of protection from infectious challenge with herpes simplex virus and other pathogens. The protection studies show that the L.E.A.P.S. approach allows customization of the immune response appropriate for inducing protection from disease. The theory, background, examples and studies of the mechanism of action of the L.E.A.P.S. vaccines will be discussed.
Animals↗
Ligand epitope antigen presentation system vaccines against herpes simplex virus.
The Ligand Epitope Antigen Presentation System (L.E.A.P.S.) approach to vaccine development allowed construction of immunogens from defined T cell epitopes from herpes simplex virus (HSV) proteins that conferred protection against lethal challenge by the virus. This technology utilizes specific peptides which bind to CD4, CD8 or other proteins on the surface of T cells (T cell binding ligand (TCBL)), macrophage and dendritic cells (immune cell binding ligand (ICBL)) to promote the immunogenicity of an epitope, activate T cell and other protective responses, and direct the immune response to either a Th1 or a Th2 type of response. The J TCBL/ICBL is a peptide from beta-2-microglobulin which binds to the CD8 protein and promotes Th1 responses and the G TCBL/ICBL is a peptide from the beta chain of MHC II molecules that binds to the CD4 protein and promotes Th2 responses. Epitopes from the ICP27 (H1, H2), glycoprotein B (gB) and glycoprotein D (gD) proteins of HSV-1 were attached to either the J TCBL/ICBL or the G TCBL/ICBL. The JH1, JH2, JgB and JgD vaccines elicited DTH responses without antibody but conferred protection upon lethal challenge. Th1 related antibody was produced after challenge of the JgB and JgD immunized mice. Immunization with the GH1, GgB or GgD vaccines did not yield protection. The GgB and GgD produced Th2 related antibodies upon virus challenge. Initiation of the immune response by the JgD vaccine was dependent on functional CD4, CD8 expressing cells and interferon gamma and delivery of protection was dependent upon CD4 and interferon gamma. The L.E.A.P.S. HSV vaccines appear to elicit the appropriate immune responses for protection and further work is being performed to develop the JgD vaccine for human use.
Animals↗
CEL-1000--a peptide with adjuvant activity for Th1 immune responses.
CEL-1000 (derG, DGQEEKAGVVSTGLIGGG) is a small immunomodulatory peptide which delivers demonstrated protective activity in two infectious disease challenge models (HSV and malaria) and an allogenic tumor vaccine model. CEL-1000 and other activators (defensin-beta, CpG ODN, and imiquimod) of the innate immune system promote IFN-gamma-associated protective responses. CEL-1000 is an improved form of peptide G (a peptide from human MHC II beta chain second domain, aa 135-149) known to enhance immune responses of other immunogenic peptides. Since defensin-beta, CpG ODN, and imiquimod have been shown to possess adjuvant activity, we investigated the adjuvant effect of peptide G and CEL-1000 as conjugates with HIV and malaria peptides. Antibody titers and isotypes were evaluated on serum taken from select days following immunization. Results for CEL-1000 and G peptide conjugates were compared with results for KLH conjugates of the same HIV peptide from the p17 molecule (87-116) referred to as HGP-30. Studies demonstrated that comparable titers were seen on day 28, 42, 63, and 77 with either G or KLH-HGP-30 peptide conjugates. In another study, CEL-1000 conjugates (CEL-1000-HGP-30) demonstrated a 4-10-fold higher titer antibody response than seen with several other peptide conjugates of the same HGP-30 peptide. Improved adjuvant activity of CEL-1000 in peptide conjugates was also demonstrated by a shift in the antibody isotypes toward a Th1 response (IgG2a). The IgG2a/IgG1, ratio for G-HGP-30 HIV or KLH-HGP-30 HIV conjugates were lower than for the CEL-1000-HGP-30 HIV conjugate. A similar favoring of the IgG2a/IgG1 ratio was seen for a malaria peptide conjugate (CEL-1000-SF/GF) compared to the un-conjugated peptide (SF-GF). CEL-1000 also showed adjuvant activity in an allogenic tumor vaccine model. As expected for an adjuvant, CEL-1000 or G does not induce detectable self-directed or cross reactive antibodies. CEL-1000 is currently being investigated for use as an adjuvant with conventional vaccines. It is expected that IgG2a antibodies would be preferably generated by CEL-1000 adjuvancy and could enhance in vivo clearance of antigens or pathogens.
Adjuvants, Immunologic↗
A small peptide (CEL-1000) derived from the beta-chain of the human major histocompatibility complex class II molecule induces complete protection against malaria in an antigen-independent manner.
CEL-1000 (DGQEEKAGVVSTGLIGGG) is a novel potential preventative and therapeutic agent. We report that CEL-1000 confers a high degree of protection against Plasmodium sporozoite challenge in a murine model of malaria, as shown by the total absence of blood stage infection following challenge with 100 sporozoites (100% protection) and by a substantial reduction (400-fold) of liver stage parasite RNA following challenge with 50,000 sporozoites. CEL-1000 protection was demonstrated in A/J (H-2(a)) and C3H/HeJ (H-2(k)) mice but not in BALB/c (H-2(d)) or CAF1 (A/J x BALB/c F(1) hybrid) mice. In CEL-1000-treated and protected mice, high levels of gamma interferon (IFN-gamma) in serum and elevated frequencies of hepatic and splenic CD4+ IFN-gamma-positive T cells were detected 24 h after administration of an additional dose of CEL-1000. Treatment of A/J mice that received CEL-1000 with antibodies against IFN-gamma just prior to challenge abolished the protection, and a similar treatment with antibodies against CD4+ T cells partially reduced the level of protection, while treatment with control antibodies or antibodies specific for interleukin-12 (IL-12), CD8+ T cells, or NK cells had no effect. Our data establish that the protection induced by CEL-1000 is dependent on IFN-gamma and is partially dependent on CD4+ T cells but is independent of CD8+ T cells, NK cells, and IL-12 at the effector phase and does not induce a detectable antibody response.
Amino Acid Sequence↗
A modification of the epidermal scarification model of herpes simplex virus infection to achieve a reproducible and uniform progression of disease.
A slight modification in the method used to remove the top keratinized layer of skin in the epidermal scarification model of HSV infection results in an easier, less painful, more uniform and reproducible means of infection. The back of mice was depilated and the top skin layer was removed either by scratching with the side of a 26 gauge needle, or by abrading with sand paper or a hand held motorized pedicure/manicure instrument. The virus was then applied on the scarified or abraded skin and the mice were observed for lesion development from day 3 to 10 post-infection. A uniform pattern of lesion development in terms of onset of lesions by day 3, progression to zosteriform by day 5 occurred for mice whose skin was abraded whereas variability in the time course, progression of symptoms and greater trauma occurred for mice whose skin was scratched with needle.
Animals↗