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HIV-1 adenoviral vector vaccines expressing multi-trimeric BAFF and 4-1BBL enhance T cell mediated anti-viral immunity.

ABSTRACT: Adenoviral vectored vaccines have shown considerable promise but could be improved by molecular adjuvants. Ligands in the TNF superfamily (TNFSF) are potential adjuvants for adenoviral vector (Ad5) vaccines based on their central role in adaptive immunity. Many TNFSF ligands require aggregation beyond the trimeric state (multi-trimerization) for optimal biological function. Here we describe Ad5 vaccines for HIV-1 Gag antigen (Ad5-Gag) adjuvanted with the TNFSF ligands 4-1BBL, BAFF, GITRL and CD27L constructed as soluble multi-trimeric proteins via fusion to Surfactant Protein D (SP-D) as a multimerization scaffold. Mice were vaccinated with Ad5-Gag combined with Ad5 expressing one of the SP-D-TNFSF constructs or single-chain IL-12p70 as adjuvant. To evaluate vaccine-induced protection, mice were challenged with vaccinia virus expressing Gag (vaccinia-Gag) which is known to target the female genital tract, a major route of sexually acquired HIV-1 infection. In this system, SP-D-4-1BBL or SP-D-BAFF led to significantly reduced vaccinia-Gag replication when compared to Ad5-Gag alone. In contrast, IL-12p70, SP-D-CD27L and SP-D-GITRL were not protective. Histological examination following vaccinia-Gag challenge showed a dramatic lymphocytic infiltration into the uterus and ovaries of SP-D-4-1BBL and SP-D-BAFF-treated animals. By day 5 post challenge, proinflammatory cytokines in the tissue were reduced, consistent with the enhanced control over viral replication. Splenocytes had no specific immune markers that correlated with protection induced by SP-D-4-1BBL and SP-D-BAFF versus other groups. IL-12p70, despite lack of anti-viral efficacy, increased the total numbers of splenic dextramer positive CD8+ T cells, effector memory T cells, and effector Gag-specific CD8+ T cells, suggesting that these markers are poor predictors of anti-viral immunity in this model. In conclusion, soluble multi-trimeric 4-1BBL and BAFF adjuvants led to strong protection from vaccinia-Gag challenge, but the protection was independent of standard immune markers. Soluble multi-trimeric SP-D-4-1BBL and SP-D-BAFF provide a novel technology to enhance adenoviral vector vaccines against HIV-1.

SUBMITTER: Kanagavelu S

PROVIDER: S-EPMC3938597 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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HIV-1 adenoviral vector vaccines expressing multi-trimeric BAFF and 4-1BBL enhance T cell mediated anti-viral immunity.

Kanagavelu Saravana S Termini James M JM Gupta Sachin S Raffa Francesca N FN Fuller Katherine A KA Rivas Yaelis Y Philip Sakhi S Kornbluth Richard S RS Stone Geoffrey W GW

PloS one 20140228 2

Adenoviral vectored vaccines have shown considerable promise but could be improved by molecular adjuvants. Ligands in the TNF superfamily (TNFSF) are potential adjuvants for adenoviral vector (Ad5) vaccines based on their central role in adaptive immunity. Many TNFSF ligands require aggregation beyond the trimeric state (multi-trimerization) for optimal biological function. Here we describe Ad5 vaccines for HIV-1 Gag antigen (Ad5-Gag) adjuvanted with the TNFSF ligands 4-1BBL, BAFF, GITRL and CD2 ...[more]

PMID: 24587225

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Project description:Emergence of the novel coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) outbreak identified in late 2019 in Wuhan, China, was declared a pandemic in March 2020. High fatality rate in afflicted patients prompted scientists and physicians to develop various vaccines against the virus. While administration of millions of doses of the adenoviral vector vaccines (e.g., Oxford-AstraZeneca (ChAdOx1 nCoV-19) and Janssen/Johnson & Johnson (Ad26.COV2. S)) has helped control the disease, numerous cases of cerebral venous sinus thrombosis (CVST) with thrombocytopenia have been reported in vaccinated individuals. In this article, we aim to review the cases reported thus far and further discuss the association between the vaccine administration and subsequent cerebral thromboembolic events. Our study was performed and reported based on the guidelines outlined in the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). PubMed, Google Scholar and Norris Medical Library databases were searched using the following terms: coronavirus disease 2019 (COVID-19) vaccines (“AstraZeneca” or “AZD1222 COVID vaccine” or “ChAdOx1 nCoV-19 COVID-19 vaccine” or “Janssen” or “Johnson & Johnson COVID vaccine” or “Ad26.COV2 COVID vaccine”), coagulopathy (“cerebral venous sinus thrombosis (CVST)” and “vaccine-induced immune thrombotic thrombocytopenia (VITT)” or “cerebral venous thrombosis (CVT)”) and thrombocytopenia. All the relevant studies within the English literature up to August 1, 2021, were included. Fourteen most recent articles reporting on 66 patients with CVST and VITT after adenoviral vector vaccination were reviewed by two independent authors. Age of the patients ranged from 18 to 60 years. The majority of cases were women (43 females versus 14 males). Platelet count was between 5 and 127 × 109/L. Above-normal D-dimer was found in 86% of the patients. A total of 68% of the patients had positive platelet factor 4 IgG assay in the absence of prior exposure to heparin. Among CVST cases following COVID vaccination, 44% succumbed to death. Early diagnosis and treatment of CVST plays a fundamental role in decreasing morbidity and mortality. Health care professional should be familiar with this rare complication post vaccination against COVID-19. Given the rarity of CVST after the COVID-19 vaccine, the benefit of vaccination outweighs the potential harm.

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HIV-1 adenoviral vector vaccines expressing multi-trimeric BAFF and 4-1BBL enhance T cell mediated anti-viral immunity.

Publications

HIV-1 adenoviral vector vaccines expressing multi-trimeric BAFF and 4-1BBL enhance T cell mediated anti-viral immunity.

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