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An ideal vaccine delivery system would elicit persistent protection following a single administration, preferably by a noninvasive route, and be safe even in the face of immunosuppression, either inherited or acquired, of the recipient. We have exploited the unique life cycle of the autonomous parvoviruses to develop a nonproliferating vaccine platform that appears to both induce priming and continually boost a protective immune response following a single inoculation. A crippled parvovirus vector was constructed, based on a chimera between minute virus of mice (MVM) and LuIII, which expresses Borrelia burgdorferi outer surface protein A (OspA) instead of its coat protein. The vector was packaged into an MVM lymphotropic capsid and inoculated into naive C3H/HeNcr mice. Vaccination with a single vector dose, either intravenously or intranasally, elicited high-titer anti-OspA-specific antibody that provided protection from live spirochete challenge and was sustained over the lifetime of the animal. Both humoral and cell-mediated Th[sub 1] immunity was induced, as shown by anti-OspA immunoglobulin G2a antibody and preferential gamma interferon production by OspA-specific CD4[sup +] T cells. [ABSTRACT FROM AUTHOR]

Abstract: In the 1960s, infant immunization with a formalin-inactivated respiratory syncytial virus (FI-RSV) vaccine candidate caused enhanced respiratory disease (ERD) following natural RSV infection. Because of this tragedy, intensive effort has been made to understand the root causes of how the FI-RSV vaccine induced a pathogenic response to subsequent RSV infection in vaccinees. A well-established cotton rat model of FI-RSV vaccine-enhanced disease has been used by numerous researchers to study the mechanisms of ERD. Here, we have dissected the model and found it to have significant limitations for understanding FI-RSV ERD. This view is shaped by our finding that a major driver of lung pathology is cell-culture contaminants, although FI-RSV immunization and RSV challenge serve as co-factors to exacerbate disease. Specifically, non-viral products from the vaccine and challenge preparations that are devoid of RSV give rise to alveolitis, which is considered a hallmark of FI-RSV ERD in the cotton rat model. Although FI-RSV immunization and RSV challenge promote more severe alveolitis, they also drive stronger cellular immune responses to non-viral antigens. The severity of alveolitis is associated with T cells specific for non-viral antigens more than with T cells specific for RSV. These results highlight the limitations of the cotton rat ERD model and the need for an improved animal model to evaluate the safety of RSV vaccine candidates. [Copyright &y& Elsevier]

Obtaining suitable seed viruses for influenza vaccines poses a challenge for public health authorities and manufacturers. We used reverse genetics to generate vaccine seed-compatible viruses from the 2009 pandemic swine-origin influenza virus. Comparison of viruses recovered with variations in residues 186 and 194 (based on the H3 numbering system) of the viral hemagglutinin showed that these viruses differed with respect to their ability to grow in eggs and cultured cells. Thus, we have demonstrated that molecular cloning of members of a quasispecies can help in selection of seed viruses for vaccine manufacture. [ABSTRACT FROM AUTHOR]

Abstract: Influenza is a globally important respiratory pathogen that causes a high degree of morbidity and mortality annually. Although current vaccines are effective against virus infection, new strategies need to be developed to satisfy the global demand for an influenza vaccine. To address this point, we have engineered and produced the full-length hemagglutinin (HA) protein from the A/Wyoming/03/03 (H3N2) strain of influenza in plants. The antigenicity of this plant-produced HA was confirmed by ELISA and single-radial immunodiffusion (SRID) assays. Immunization of mice with plant-produced HA resulted in HA-specific humoral (IgG1, IgG2a and IgG2b) and cellular (IFNγ and IL-5) immune responses. In addition, significant serum hemagglutination inhibition (HI) and virus neutralizing (VN) antibody titers were obtained with an antigen dose as low as 5μg. These results demonstrate that plant-produced HA protein is antigenic and can induce immune responses in mice that correlate with protection. [Copyright &y& Elsevier]

Background Influenza A viruses are of major concern for public health, causing worldwide epidemics associated with high morbidity and mortality. Vaccines are critical for protection against influenza, but given the recent emergence of new strains with pandemic potential, and some limitations of the current production systems, there is a need for new approaches for vaccine development. Objective To demonstrate the immunogenicity and protective efficacy of plant-produced influenza antigens. Method We engineered, using influenza A/Wyoming/3/03 (H3N2) as a model virus, the stem and globular domains of hemagglutinin (HA) produced in plants as fusions to a carrier protein and used purified antigens with and without adjuvant for ferret immunization. Results These plant-produced antigens were highly immunogenic and conferred complete protection against infection in the ferret challenge model. The addition of plant-produced neuraminidase was shown to enhance the immune response in ferrets. Conclusions Plants can be used as a production vehicle for vaccine development against influenza. Domains of HA can generate protective immune responses in ferrets. [ABSTRACT FROM AUTHOR]

Abstract: The current approved vaccine against anthrax is based on protective antigen (PA) of Bacillus anthracis, requires six injections over an 18-month period and has a known history of side effects. Therefore, there is significant effort towards developing an improved vaccine against B. anthracis. Here we separately engineered and expressed domain 4 of PA (PAD4) and domain 1 of lethal factor (LFD1) as fusions to lichenase (LicKM), a thermostable enzyme from Clostridium thermocellum, and transiently expressed these fusions in Nicotiana benthamiana. Plant-produced antigens were combined and immunogenicity was evaluated in mice. All animals that received the experimental vaccine developed high antibody titers that were predominantly IgG1 and were able to neutralize the effects of LeTx in vitro. [Copyright &y& Elsevier]

Abstract: Production of vaccine antigens in plants has received considerable attention over the last decade. However, despite many antigens being expressed in plant systems, and promising efficacy data with rodent models, few vaccine candidates have advanced into studies in non-human primates or human clinical trials. Here, we report on the transient expression of the F1 and LcrV antigens of Yersinia pestis in Nicotiana benthamiana. The antigens were expressed as fusions to the thermostable enzyme of Clostridium thermocellum. When administered to Cynomolgus Macaques the purified plant-produced antigens induced serum IgG and IgA responses specific to F1 and LcrV, and conferred complete protection against lethal challenge with Y. pestis. This study clearly demonstrates the efficacy of a plant-produced plague vaccine candidate in a primate model. [Copyright &y& Elsevier]

The SOCS family of genes are negative regulators of cytokine signalling with SOCS-1 displaying tumor suppressor activity. SOCS-1, CIS and SOCS-3 have been implicated in the regulation of red blood cell production. In this study, a detailed examination was conducted on the expression patterns of these three SOCS family members in normal erythroid progenitors and a panel of erythroleukemic cell lines. Unexpectedly, differences in SOCS gene expression were observed during maturation of normal red cell progenitors, viz changes to CIS were inversely related to the alterations of SOCS-1 and SOCS-3. Similarly, these SOCS genes were differentially expressed in transformed erythoid cells - erythroleukemic cells immortalized at an immature stage of differentiation expressed SOCS-1 and SOCS-3 mRNA constitutively, whereas in more mature cell lines SOCS-1 and CIS were induced only after exposure to erythropoietin (Epo). Significantly, when ectopic expression of the tyrosine kinase Lyn was used to promote differentiation of immature cell lines, constitutive expression of SOCS-1 and SOCS-3 was completely suppressed. Modulation of intracellular signalling via mutated Epo receptors in mature erythroleukemic lines also highlighted different responses by the three SOCS family members. Close scrutiny of SOCS-1 revealed that, despite large increases in mRNA levels, the activity of the promoter did not alter after erythropoietin stimulation; in addition, erythroid cells from SOCS-1-/- mice displayed increased sensitivity to Epo. These observations indicate complex, stage-specific regulation of SOCS genes during normal erythroid maturation and in erythroleukemic cells.Oncogene (2003) 22, 3221-3230. doi:10.1038/sj.onc.1206381 [ABSTRACT FROM AUTHOR]

A letter to the editor is presented concerning the lack of protection of the formalin-inactivated respiratory synctial virus vaccine candidate (FI-RSV).