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Immunomatrix: A Novel Vaccine Delivery Paradigm - Katarzyna Sawicka - TEDxSBU

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Schnieder, Meg February 9, Business Ethics For Dummies. Similarly to i. These summarized data clearly demonstrate the immune-stimulating properties of BLPs and the ability to convert conventional influenza vaccines into effective mucosal vaccines. Importantly, the immune responses elicited by FluGEM-A provide solid protection against both homologous and heterologous influenza infections, and this protection seems to be superior to the protection observed after i.

Another type of BLP-based influenza vaccine is prepared by physical coupling non-covalent binding of purified influenza antigen e. The main aim of this approach is to also use the BLP as a carrier that present the antigens in a biologically active manner to the immune system. To this end, trimeric HA influenza proteins with a Protan tag were produced in mammalian cell expression systems. The HA-Protan fusion protein is able to form trimers because of the presence of a synthetic multimerization domain that replaces the native HA transmembrane and cytoplasmic domains.

FluGEM-B with trimeric HA is biologically active as demonstrated by its ability to agglutinate red blood cells to a high extent Figure 4 A , in contrast to its monomeric counterpart bound to BLPs, which does not display any hemagglutination properties Figure 4 B. Figure 4. This suggests that trimeric HA bound to BLPs is properly folded and in biologically active conformation.

An important safety aspect is that the process of FluGEM-B preparation allows for simple purification of the recombinant HA protein from the host cells and does not require material originating from inactivated viruses, which is required for the preparation of FluGEM-A. This would be particularly beneficial for preparation of multivalent vaccines, e. Finally, it has been shown that physical coupling of soluble recombinant antigens to an adjuvant enhances vaccine immunogenicity, by allowing the antigen to be delivered to the same cell activated by the adjuvant 29 , In both studies, only vaccination with FluGEM-B formulations induced seroconversion in all the animals, while vaccination with antigen HA or M2e alone induced low serum IgG titers in only a few mice.

Moreover, physical coupling of BLP with the antigens contributed to further, approximately fourfold, increase in IgG titers. Additionally, i. Figure 5.

Immune responses induced upon i. Groups of 10 mice were vaccinated i. Animals received in total three doses day 0, 10, and 20 and were sacrificed 2 weeks after the final immunization day Animals received in total three doses day 0, 21, and 42 and were sacrificed 3 weeks after the final immunization day Animals were sacrificed 6 days post-challenge and virus titers were evaluated as a protection parameter.

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In lungs of all infected mice vaccinated i. Binding of antigen to BLPs presents the further refinement of BLP-based vaccines, as it allows for easier preparation of highly purified proteins with well-preserved biological activity. This concept might also be beneficial for the preparation of multivalent vaccines, as it allows for simple incorporation of different viral antigens in the same vaccine formulation.

Finally, it corroborates the assumption that subunit antigens require physical interaction with the adjuvant for optimal vaccine immunogenicity, as illustrated by the examples of HA- and M2e-based vaccines. Respiratory syncytial virus represents a very important target for development of successful vaccine candidates, as it is the single most important cause of viral bronchiolitis in infants and young children and it is the world-wide leading cause of infant hospitalization Furthermore, elderly and immune-compromised individuals are also at high risk of developing severe RSV disease 32 , Currently, there is no vaccine available and the only commercially available prophylactic treatment is based on the neutralizing antibody Palivizumab 34 , Although there is a clear unmet medical need, the development of a safe RSV vaccine has been hampered for decades by the fiasco of the first RSV vaccine developed, Formalin-inactivated RSV FI-RSV which induced exacerbation of disease symptoms in a high percentage of vaccinated children and increased the rate of hospitalizations among vaccinees, including some fatalities The choice of antigen was based on the finding that RSV F protein is highly conserved throughout different virus isolates 37 and the only available neutralizing antibody Palivizumab is directed against this antigen.

The immunogenicity of SynGEM has been tested in a mouse and cotton rat model. Interestingly, results of both mouse and cotton rat immunization studies with SynGEM were well in line with immunogenicity results obtained from immunizations of mice with FluGEM More specifically, i. Additionally, unlike i. One of the most important criteria for a successful RSV vaccine is safety in the context of absence of induction of enhanced disease symptoms. It has been suggested that increased production of IL4 is responsible for exacerbation of disease symptoms, as manifested by severe eosinophilia, lack of neutralizing antibodies and lack of efficient cellular responses e.

Therefore, vaccination-induced IL4 levels are used as a predictor of the potential immunopathology.

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An illustrative example of severely Th2 skewed immune responses induced by vaccination is immunization with alum-adjuvanted FI-RSV FluGEM vaccination. Additionally, as expected based on the cytokine profile, histopathological analyses in cotton rats indicated that i. The induced responses were shown to be protective against RSV infection, without inducing enhanced disease symptoms. Successful activation of specific adaptive immune responses relies on optimal activation of innate immune responses, which controls and determines the development of specific adaptive response 42 , Dendritic cells DCs play a crucial role in this process, by being the direct link between the innate and adaptive responses Activation of DCs typically results in cytokine and chemokine production, which further on determine the nature of cellular and humoral responses The capacity of BLPs to stimulate the innate immunity was well demonstrated in the study of Ramirez et al.

Adjuvantes:Un componente esencial de las vacunas de Neisseria

These results are summarized in Table 2. Upon acquisition of a mature phenotype, DCs become capable of antigen cross- presentation, which activates the cellular arm of the adaptive immune response. In line with this dogma is the observation that DCs stimulated with BLPs display reduced capacity for antigen uptake, which indicates that these cells became effective antigen-presenters Table 2.

BLP-induced maturation and activation of mouse and human DCs. In addition to the induction of a mature phenotype, BLPs stimulated these DCs to produce proinflammatory, Th1-promoting and regulatory cytokines.

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In the study of Ramirez et al. The latter organs are considered to be reservoirs of vaccine-induced plasma cells that support production and maintenance of circulating antibodies. Together, these findings imply that the immunostimulating properties of BLPs rely mainly on the capacity to activate innate immune responses, or more specifically DCs, which are the crucial link between innate and specific adaptive responses.

As demonstrated, the basis for successful induction of robust adaptive immune responses by BLP-based vaccines is activation of innate immune pathways. This is mainly mediated by non-specific recognition of invading pathogens, pathogen-derived components, or microbial-derived components in general. More specifically, the innate immune response is activated by recognition of common microbial associated molecular patterns MAMPs by a family of innate immune receptors, such as family of Toll-like receptors TLRs 47 — Activated innate immune cells are capable of shaping the adaptive B- and T-cell-mediated responses, depending on the information extracted from the activation signal Toll-like receptors are expressed on the surface or in the endosomal compartment of innate immune cells, DCs in particular, and their engagement typically induces cytokine and chemokine production, activation of DCs and subsequent priming of adaptive immune response 50 — Due to their innate immune-stimulating properties, TLR ligands have been explored as promising new-generation adjuvants.

An advantage of this new generation of vaccine adjuvants is that their mode of action is well-understood and characterized. Moreover, it has been shown that injection of healthy human subjects with CpG induces systemic innate immune activation manifested by expression of Th1-polarizing cytokines and IFN-inducible chemokines Bacterium-like particles belong to this group of new-generation immunostimulators, as its mode of action is well-defined and is based on activation of innate receptor — TLR2, which is a membrane surface receptor, specific for numerous bacterial, fungal, and viral components.