Browsing by Subject "Vaccines"

Now showing 1 - 3 of 3

Open Access
Encapsulation of two different TLR ligands into liposomes confer protective immunity and prevent tumor development
(Elsevier B.V., 2017) Bayyurt, B.; Tincer, G.; Almacioglu, K.; Alpdundar, E.; Gursel, M.; Gursel, I.
Nucleic acid-based Toll-like receptor (TLR) ligands are promising adjuvants and immunotherapeutic agents. Combination of TLR ligands potentiates immune response by providing synergistic immune activity via triggering different signaling pathways and may impact antigen dependent T-cell immune memory. However, their short circulation time due to nuclease attack hampers their clinical performance. Liposomes offer inclusion of protein and nucleic acid-based drugs with high encapsulation efficiency and drug loading. Furthermore, they protect cargo from enzymatic cleavage while providing stability, and enhancing biological activity. Herein, we aimed to develop a liposomal carrier system co-encapsulating TLR3 (polyinosinic-polycytidylic acid; poly(I:C)) and TLR9 (oligodeoxynucleotides (ODN) expressing unmethylated CpG motifs; CpG ODN) ligands as immunoadjuvants together with protein antigen. To demonstrate that this depot system not only induce synergistic innate immune activation but also boost antigen-dependent immune response, we analyzed the potency of dual ligand encapsulated liposomes in long-term cancer protection assay. Data revealed that CpG ODN and poly(I:C) co-encapsulation significantly enhanced cytokine production from spleen cells. Activation and maturation of dendritic cells as well as bactericidal potency of macrophages along with internalization capacity of ligands were elevated upon incubation with liposomes co-encapsulating CpG ODN and poly(I:C). Immunization with co-encapsulated liposomes induced OVA-specific Th1-biased immunity which persisted for eight months post-booster injection. Subsequent challenge with OVA-expressing tumor cell line, E.G7, demonstrated that mice immunized with liposomes co-encapsulating dual ligands had significantly slower tumor progression. Tumor clearance was dependent on OVA-specific cytotoxic memory T-cells. These results suggest that liposomes co-encapsulating TLR3 and TLR9 ligands and a specific cancer antigen could be developed as a preventive cancer vaccine. ï¿½ 2017 Elsevier B.V.
Open Access
Investigation of Pre-clinical and Phase II clinical studies of VLP-58-1023- AL-K3-PII vaccine for Alpha variant
(2022-08) Saraydar, Berfu
In the late December of 2019, SARS-CoV-2, a new coronavirus, was discovered in Wuhan, China and described as the causative agent of Coronavirus Disease 2019 (COVID-19). The disease has spread rapidly across the world due to its high transmissibility and has been declared a pandemic by the World Health Organization (WHO). The development of an effective vaccine has become the most significant issue to constrain the pandemic. Several COVID-19 vaccines have been authorized for human use and others are in clinical trials. Although SARS-CoV-2 encodes four structural proteins, which are Spike (S), Nucleocapsid (N), Membrane (M) and Envelope (E), most of the current vaccines used only Spike as antigen in order to generate antibodies for preventing the virus entry and replication. However, concerns have raised about Spike-based vaccines with the emerging of variants as they can moderately escape from neutralizing antibodies. For these purposes, we developed Virus-like particle (VLP) vaccine which displays hexaproline prefusion-stabilized spike (S-6p), N, M, E proteins, and adjuvanted with Alum and K3-CpG ODN. Rather than using wild type, we preferred to use the sequence of Alpha variant because of its high mortality risk and selection advantages. At the beginning of the study, we designed three different vaccine formulations and based on the results of humoral immune response in mice we determined the optimal formulation and dosage for human use. Our pre-clinical studies revealed that the best vaccine combination was high dose antigen and low dose adjuvants. Next, we wondered whether a 3rd dose has an impact on long-lasting immunity or enhancing immunogenicity in mice so that its applicability to humans could be determined. It was found that 3rd dose injection increased the antibody levels much higher than 2nd dose administration and prevented humoral immunity from decreasing after a certain amount of time. Further, both humoral and cellular immunity were studied with serum and PBMC samples from 117 volunteers who participated in the Phase II clinical trial. All IgG ELISA experiments indicated that VLP-58-1023-AL-K3-PII vaccine induced great amount of humoral immune responses against S,N proteins and WT, Alpha, Delta RBDs. In terms of T cell responses, it is known that Alum-induced robust Th2 response can be redirected to the Th1 axis with the use of CpG ODN. So, we investigated whether Th1 or Th2 type of cell response was dominant after vaccination. All cytokine levels specific to SARS-CoV-2 peptides demonstrated that the vaccine elicited Th1-biased responses. Taken together, this study revealed that VLP-58-1023-AL-K3-PII vaccine for Alpha variant successfully elicited both humoral and cellular immune responses, its effectiveness against other variants was indicated and the efficiency of vaccine could be increased with the administration of 3rd dose, in terms of ensuring long-lasting immunity.
Open Access
Targeting adenosine receptors to improve vaccine efficacy
(2016-12) Savaş, Ali Can
Vaccination is the major protection method against many diseases caused by pathogens through creating acquired immunity. Vaccines can be classified in two major groups, which are subunit vaccines and attenuated vaccines. Attenuated vaccines can create effective immunity however; they also can induce many different side effects such as fever and allergic reactions. On the contrary, with subunit vaccines side effects are decreased but the efficacy of the vaccines is also decreased and there is a need for repetitive vaccinations to provide long lasting immunity. That is why, there is a need for developing more efficient vaccines and particularly vaccine adjuvants. Adenosine receptors, as part of purinergic signaling, have a regulatory role in immune system. Adenosine and 4 different adenosine receptors have an immunosuppressive role in major immune cells to create acquired immunity such as DCs, macrophages and lymphocytes. That is why, we hypothesize that, the efficacy of vaccines can be decreased by endogenous adenosine and the usage of antagonists in adjuvant formulations can increase this efficacy by inhibiting the suppressive effects caused by endogenous adenosine. To be able to test this hypothesis, we first determine the specific adenosine receptor and antagonists taking a role in this immunosuppressive effect. For this purpose, we use primary dendritic cells and macrophages. We see that A2A and A2B receptors create most effective immunosuppression and SCH 58261 (A2A antagonist) and PSB 603 (A2B antagonist) are the main antagonists taking a role in the inhibition of this suppression. We then evaluated these two molecules in a vaccine formulation comprising MPL-A and AddaVax. As a result, these antagonists do not significantly change the general initial immune responses significantly however they create more antigen specific response. On the other hand, after antigen re-stimulation, mice taking these antagonists shows more antigen specific response and they also create higher antibody titers. With this study, adenosine receptor antagonists used in adjuvant formulations for the first time and it was shown that, with more study, they can be important in increasing vaccine efficacy created by immunostimulatory adjuvants.