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Biomedical subjects

M A Liu

Publications and source records attributed to M A Liu.

At least 19 recordsLinked to original sources
PubMed1997

DNA vaccines.

Immunization with plasmid DNA encoding antigenic proteins elicits both antibody and cell-mediated immune responses. This method of producing the protein antigens of interest directly in host cells can provide appropriate tertiary structure for the induction of conformationally specific antibodies, and also facilitates the induction of cellular immune responses. DNA immunization has provided effective protective immunity in various animal models. The immune responses induced by DNA vaccines may in some instances be preferable to those produced by immunization using conventional methods. DNA vaccination appears to be applicable to a variety of pathogens and is a useful method of raising immune responses. Thus this approach to vaccination has the potential to be a successful method of rapidly screening for antigens capable of inducing protective immunity, and of inducing protective immunity against pathogens of clinical importance.

Animals↗
PubMed1997

Characterization of humoral immune responses induced by an influenza hemagglutinin DNA vaccine.

We have examined in detail the characteristics of the humoral immune response and protective efficacy induced by an influenza hemagglutinin (HA) DNA vaccine. In mice injected intramuscularly with HA DNA, the magnitude of the immune responses generated, as measured by ELISA and hemagglutination inhibiting (HI) antibodies, was directly related to the amount of DNA injected and the number of doses administered. The level of anti-HA antibodies in DNA-vaccinated mice was higher than that in convalescent immune mice and was maintained for at least 1.5 years. The immunoglobulin isotype profile of the antibodies was predominantly IgG2a, similar to that induced by live virus infection but in contrast to the relative abundance of IgG1 antibodies observed after inoculation with formalin-inactivated whole virus. The presence of pre-challenge HI antibodies was found to be a good correlate of protection, in that every animal with a detectable HI titer was protected from a lethal challenge. Complete protection from a lethal dose of influenza virus (A/PR/34), as judged by 100% survival and no weight loss, was conferred by as little as 1 microgram of DNA (given twice). Furthermore, mice injected with 10 to 100 micrograms doses, when subsequently challenged with virus, showed no increase in HI titer and no production of antibodies directed against the challenge virus, suggesting a substantial inhibition of virus replication after challenge.

Animals↗
PubMed1997

Protective cellular immunity: cytotoxic T-lymphocyte responses against dominant and recessive epitopes of influenza virus nucleoprotein induced by DNA immunization.

DNA immunization offers a novel means to induce cellular immunity in a population with a heterogeneous genetic background. An immunorecessive cytotoxic T-lymphocyte (CTL) epitope in influenza virus nucleoprotein (NP), residues 218 to 226, was identified when mice were immunized with a plasmid DNA encoding a full-length mutant NP in which the anchor residues for the immunodominant NP147-155 epitope were altered. Mice immunized with wild-type or mutant NP DNA were protected from lethal cross-strain virus challenge, and the protection could be adoptively transferred by immune splenocytes, indicating the role of cell-mediated immunity in the protection. DNA immunization is capable of eliciting protective cellular immunity against both immunodominant and immunorecessive CTL epitopes in the hierarchy seen with virus infection.

Animals↗
PubMed1996

Immunization with DNA vaccines encoding glycoprotein D or glycoprotein B, alone or in combination, induces protective immunity in animal models of herpes simplex virus-2 disease.

DNA vaccines expressing herpes simplex virus type 2 (HSV-2) full-length glycoprotein D (gD), or a truncated form of HSV-2 glycoprotein B (gB) were evaluated for protective efficacy in two experimental models of HSV-2 infection. Intramuscular (i.m.) injection of mice showed that each construction induced neutralizing serum antibodies and protected the mice from lethal HSV-2 infection. Dose-titration studies showed that low doses (< or = 1 microgram) of either DNA construction induced protective immunity, and that a single immunization with the gD construction was effective. The two DNAs were then tested in a low-dosage combination in guinea pigs. Immune sera from DNA-injected animals had antibodies to both gD and gB, and virus neutralizing activity. When challenged by vaginal infection with HSV-2, the DNA-immunized animals were significantly protected from primary genital disease.

Animals↗
PubMed1996

DNA vaccines.

Preclinical DNA vaccine development has continued apace during the past year, with the investigation of several new infectious and non-infectious disease targets as well as advances in our understanding of some of the basic immunologic mechanisms, such as effector cells, responsible for conferring protection. The coming year promises to be at least as exciting, as initial human clinical studies have begun.

Animals↗
PubMed1996

Toward the development of DNA vaccines.

DNA vaccination has proved to be a generally applicable technology in various preclinical animal models of infectious and noninfectious disease and several DNA vaccines have now entered phase I human clinical trials. It is too early to predict the effectiveness of DNA vaccines in humans and whether improved formulations of DNA vaccines will be required but several lines of investigation have suggested ways in which DNA vaccines may be improved, such as increases in expression, facilitation of DNA targeting or uptake, and enhancement of immune responses.

Animals↗
PubMed1996

Humoral and cellular immunities elicited by HIV-1 vaccination.

Recently it has been shown that immunization with plasmid DNA encoding genes for viral or bacterial antigens can elicit both humoral and cellular immune responses in rodents and nonhuman primates. In this study, mice and nonhuman primates were vaccinated by intramuscular injection with plasmids that express either a secreted form of HIV-1 gp120 or rev proteins. Mice receiving the tPA-gp120 DNA developed antigen-specific antibody responses against recombinant gp120 protein and the V2 peptide neutralization epitope as determined by ELISA. Vaccinated mice also exhibited gp120-specific T cell responses, such as in vitro proliferation of splenocytes and MHC Class I-restricted cytotoxic T lymphocyte (CTL) activities, following antigen restimulation. In addition, supernatants from these lymphocyte cultures showed high levels of gamma-interferon production compared with IL-4, suggesting that primarily type 1-like helper T (Th1) lymphocyte responses were induced by both vaccines. Th1-like responses were also obtained for mice vaccinated with rev DNA. Immune responses induced by gp120 or rev vaccines were dose-dependent, boostable, and long-lived (> or = 6 months). Nonhuman primates vaccinated with tPA-gp120 DNA also showed antigen-specific T lymphocyte proliferative and humoral responses, including moderate levels of neutralizing sera against homologous HIV. These results suggest that plasmid DNA may provide a powerful means for eliciting humoral and cellular immune responses against HIV.

AIDS Vaccines↗
PubMed1996

Immunogenicity and protective efficacy of a tuberculosis DNA vaccine.

Tuberculosis is the most widespread and lethal infectious disease affecting humans. Immunization of mice with plasmid DNA constructs encoding one of the secreted components of Mycobacterium tuberculosis, antigen 85 (Ag85), induced substantial humoral and cell-mediated immune responses and conferred significant protection against challenge with live M. tuberculosis and M. bovis bacille Calmette-Guérin (BCG). These results indicate that immunization with DNA encoding a mycobacterial antigen provides an efficient and simple method for generating protective immunity and that this technique may be useful for defining the protective antigens of M. tuberculosis, leading to the development of a more effective vaccine.

Animals↗
PubMed1996

Generation of MHC class I-restricted cytotoxic T lymphocytes by expression of a viral protein in muscle cells: antigen presentation by non-muscle cells.

Expression of reporter genes in muscle cells has been achieved by intramuscular (i.m.) injection of plasmid DNA expression vectors. We previously demonstrated that this technique is an effective means of immunization to elicit both antibodies capable of conferring homologous protection and cell-mediated immunity leading to cross-strain protection against influenza virus challenge in mice. These results suggested that expression of viral proteins by muscle cells can result in the generation of cellular immune responses, including cytotoxic T lymphocytes (CTL). However, because DNA has the potential to be internalized and expressed by other cell types, we sought to determine whether or not induction of CTL required synthesis of antigen in non-muscle cells and if not whether transfer of antigen to antigen-presenting cells from muscle cells may be involved. In the present study we demonstrate that transplantation of nucleoprotein (NP)-transfected myoblasts into syngeneic mice led to the generation of NP-specific antibodies and CTL and cross-strain protective immunity against a lethal challenge with influenza virus. Furthermore transplantation of NP-expressing myoblasts (H-2k) intraperitoneally into F1 hybrid mice (H-2d x H-2k) elicited NPCTL restricted by the MHC haplotype of both parental strains. These results indicate that NP expression by muscle cells after transplantation was sufficient to generate protective cell-mediated immunity and that induction of the CTL response was mediated at least in part, by transfer of antigen from the transplanted muscle cells to a host cell.

Animals↗
PubMed1996

Protection against papillomavirus with a polynucleotide vaccine.

Genital infections with human papillomavirus (HPV) are increasingly recognized as a significant source of human disease; HPV is now implicated in up to 90% of cervical carcinomas. Neutralizing antibodies against papillomaviruses recognize conformational epitopes formed when viral capsid proteins assemble into virions or virus-like particles. Immunization with plasmid DNA encoding the major viral capsid protein L1 was studied as a means of inducing neutralizing antibodies and protection against virus challenge. In a cottontail rabbit papillomavirus (CRPV) model, immunization with plasmid DNA encoding L1 elicited conformationally specific neutralizing antibodies and provided immunity against papilloma formation upon challenge with CRPV. Immunization with DNA encoding the capsid protein may provide a means of protecting humans against HPV and would simplify the production of multivalent vaccines by combining plasmids that encode the viral capsid proteins of different strains. This may be of importance given the multiplicity of HPV types capable of causing disease.

Animals↗
PubMed1995

Cytotoxic T lymphocyte and helper T cell responses following HIV polynucleotide vaccination.

Expression vectors encoding either HIV-1 gp160/rev, gp120, or rev alone were used for direct vaccination of mice and nonhuman primates. Each vaccine elicited long-lived (> 7 months) helper T cell responses in mice and monkeys as measured by in vitro proliferation of splenocytes following recombinant antigen treatment. Cytokine assays of the cell supernatants showed that approximately 100-fold more gamma-interferon than IL-4 was secreted during culture indicating that these vaccines elicited TH1-like responses. CD8+ CTL activities were also observed both in mice and rhesus. The gp120 and gp160/rev vaccines elicited antigen-specific antibodies, although these responses were more variable and lower magnitude for gp160/rev, and gp120 DNA-vaccinated African green monkeys had moderate levels of neutralizing antibodies. No antibodies were found against rev (an intracellular protein) with either rev vaccine. Similar antibody titers were obtained for gp120 by either intramuscular or intradermal injection although T cell responses were generally lower by intradermal route. These results indicate that DNA vaccines may provide a powerful means to elicit cellular and humoral immune responses against HIV.

AIDS Vaccines↗
PubMed1995

Preclinical efficacy of a prototype DNA vaccine: enhanced protection against antigenic drift in influenza virus.

Vaccination with plasmid DNA expression vectors encoding foreign proteins elicits antibodies and cell-mediated immunity and protects against disease in animal models. We report a comparison of DNA vaccines, using contemporary human strains of virus, and clinically licensed (inactivated virus or subvirion) vaccines in preclinical animal models, to better predict their efficacy in humans. Influenza DNA vaccines elicited antibodies in both non-human primates and ferrets and protected ferrets against challenge with an antigenically distinct epidemic human influenza virus more effectively than the contemporary clinically licensed vaccine. These studies demonstrate that DNA vaccines may be more effective, particularly against different strains of virus, than inactivated virus or subvirion vaccines.

Animals↗