mRNA as a Therapeutics: Understanding mRNA Vaccines

2021 ◽  
Author(s):  
Ferdi Oguz ◽  
Harika Atmaca
Keyword(s):  
Ex Vivo ◽  
Protective Efficacy ◽  
Direct Injection ◽  
Specific Antigen ◽  
Antigen Expression ◽  
Humoral And Cellular Immunity ◽  
Related Disease ◽  
Protective Antigens ◽  
And Control

Vaccination is one of the important approaches in the prevention and control of diseases. Although the capacity to present antigens other than the disease-specific antigen in the traditional vaccine composition provides a potential benefit by increasing its protective efficacy, many components that are not needed for the related disease are also transferred. These components can reduce vaccine activity by lowering immunity against protective antigens. The reasons such as the low effectiveness of traditional vaccines and the high cost of production and time-consuming reasons show that it is necessary to develop a new vaccine method for our world, which is struggling with epidemics almost every year. Among nucleic acids, mRNA has many advantages, such as genomic integration, induction of anti-DNA autoantibodies, and immune tolerance induced by long-term antigen expression. mRNA vaccines have become a therapeutic target for reasons such as efficacy, safety, fast and non-expensive production. The fact that mRNA triggers both humoral and cellular immunity and goes only to the cytoplasm, not to the nucleus, makes it highly efficient. The mRNA must cross the lipid bilayer barrier and entry to the cytoplasm where it is translated into protein. There are two main ways of mRNA vaccine delivery for this: ex vivo loading of mRNA into dendritic cells and direct injection of mRNA with or without a carrier. Studies continue to understand which delivery system is therapeutically more efficient. Preclinical and clinical trials showed that mRNA vaccines trigger a long-lasting and safe immune response.

scholarly journals Targeting Haemagglutinin Antigen of Avian Influenza Virus to Chicken Immune Cell Receptors Dec205 and CD11c Induces Differential Immune-Potentiating Responses

Vaccines ◽  
2021 ◽  
Vol 9 (7) ◽  
pp. 784
Author(s):  
Angita Shrestha ◽  
Jean-Remy Sadeyen ◽  
Deimante Lukosaityte ◽  
Pengxiang Chang ◽  
Marielle Van Hulten ◽  
...  
Keyword(s):  
Influenza A ◽  
Immune Cell ◽  
Ex Vivo ◽  
Protective Efficacy ◽  
Haemagglutination Inhibition ◽  
Primary Vaccination ◽  
Antigen Delivery ◽  
Single Chain ◽  
Protective Antigens ◽  
Single Chain Fragment Variable

Improving the immunogenicity and protective efficacy of vaccines is critical to reducing disease impacts. One strategy used to enhance the immunogenicity of vaccines is the selective delivery of protective antigens to the antigen presenting cells (APCs). In this study, we have developed a targeted antigen delivery vaccine (TADV) system by recombinantly fusing the ectodomain of hemagglutinin (HA) antigen of H9N2 influenza A virus to single chain fragment variable (scFv) antibodies specific for the receptors expressed on chicken APCs; Dec205 and CD11c. Vaccination of chickens with TADV containing recombinant H9HA Foldon-Dec205 scFv or H9HA Foldon-CD11c scFv proteins elicited faster (as early as day 6 post primary vaccination) and higher anti-H9HA IgM and IgY, haemagglutination inhibition, and virus neutralisation antibodies compared to the untargeted H9HA protein. Comparatively, CD11c scFv conjugated H9HA protein showed higher immunogenic potency compared to Dec205 scFv conjugated H9HA protein. The higher immune potentiating ability of CD11c scFv was also reflected in ex-vivo chicken splenocyte stimulation assay, whereby H9HA Foldon-CD11c scFv induced higher levels of cytokines (IFNγ, IL6, IL1β, and IL4) compared to H9HA Foldon-Dec205 scFv. Overall, the results conclude that TADV could be a better alternative to the currently available inactivated virus vaccines.

scholarly journals Correction of Fanconi Anemia Group C Hematopoietic Stem Cells Following Intrafemoral Gene Transfer

Anemia ◽  
2010 ◽  
Vol 2010 ◽  
pp. 1-13 ◽  
Author(s):  
Ouassila Habi ◽  
Johanne Girard ◽  
Valérie Bourdages ◽  
Marie-Chantal Delisle ◽  
Madeleine Carreau
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Gene Transfer ◽  
Hematopoietic Stem Cells ◽  
Fanconi Anemia ◽  
Ex Vivo ◽  
Direct Injection ◽  
Negative Effects ◽  
Hematopoietic Stem

The main cause of morbidity and mortality in Fanconi anemia patients is the development of bone marrow (BM) failure; thus correction of hematopoietic stem cells (HSCs) through gene transfer approaches would benefit FA patients. However, gene therapy trials for FA patients using ex vivo transduction protocols have failed to provide long-term correction. In addition, ex vivo cultures have been found to be hazardous for FA cells. To circumvent negative effects of ex vivo culture in FA stem cells, we tested the corrective ability of direct injection of recombinant lentiviral particles encoding FancC-EGFP into femurs ofFancC−/−mice. Using this approach, we show thatFancC−/−HSCs were efficiently corrected. Intrafemoral gene transfer of theFancCgene prevented the mitomycin C-induced BM failure. Moreover, we show that intrafemoral gene delivery into aplastic marrow restored the bone marrow cellularity and corrected the remaining HSCs. These results provide evidence that targeting FA-deficient HSCs directly in their environment enables efficient and long-term correction of BM defects in FA.

scholarly journals Immunogenicity and Efficacy Evaluation of Subunit Astrovirus Vaccines

Vaccines ◽  
2019 ◽  
Vol 7 (3) ◽  
pp. 79 ◽  
Author(s):  
Mehdi R.M. Bidokhti ◽  
Karin Ullman ◽  
Anne Sofie Hammer ◽  
Trine Hammer Jensen ◽  
Mariann Chriél ◽  
...  
Keyword(s):  
Amino Acids ◽  
Ex Vivo ◽  
Protective Efficacy ◽  
Clinical Signs ◽  
Efficacy Evaluation ◽  
Virus Shedding ◽  
Booster Immunization ◽  
Cytokine Induction ◽  
Th2 Cytokine ◽  
And Control

A full understanding of the immune response to astrovirus (AstV) infection is required to treat and control AstV-induced gastroenteritis. Relative contributions of each arm of the immune system in restricting AstV infection remain unknown. In this study, two novel subunit AstV vaccines derived from capsid protein (CP) of mink AstV (MAstV) such as CPΔN (spanning amino acids 161–775) and CPΔC (spanning amino acids 1–621) were evaluated. Their immunogenicity and cytokine production in mice, as well as protective efficacy in mink litters via maternal immunization, were studied. Truncated CPs induced higher levels of serum anti-CP antibodies than CP, with the highest level for CPΔN. No seronegativity was detected after booster immunization with either AstV CP truncates in both mice and mink. All mink moms stayed seropositive during the entire 104-day study. Furthermore, lymphoproliferation responses and Th1/Th2 cytokine induction of mice splenocytes ex vivo re-stimulated by truncated CPs were significantly higher than those by CP, with the highest level for CPΔN. Immunization of mink moms with truncated CPs could suppress virus shedding and clinical signs in their litters during a 51-day study after challenge with a heterogeneous MAstV strain. Collectively, AstV truncated CPs exhibit better parameters for protection than full-length CP.

Differential Effects of HOXB4 Overexpression on Short and Long-Term Repopulating Cells in Nonhuman Primates.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 33-33
Author(s):  
Xiao-Bing Zhang ◽  
Brian C. Beard ◽  
Katherine Beebe ◽  
R. Keith Humphries ◽  
Hans-Peter Kiem
Keyword(s):  
Ex Vivo ◽  
Pronounced Effect ◽  
Transduction Efficiency ◽  
Pcr Analysis ◽  
Post Transplantation ◽  
Hematopoietic Stem ◽  
Cd34 Cells ◽  
Ex Vivo Culture ◽  
And Control

Abstract The inability to expand hematopoietic stem cells (HSCs) has been a significant limitation for clinical transplantation and gene therapy applications. Here we examined in a clinically relevant nonhuman primate model the ability of HOXB4 to expand HSCs and thus potentially overcome this limitation. Using a competitive repopulation assay we directly compared engraftment of HOXB4-transduced and control-transduced CD34+ cells. In 3 animals, cells were infused after a 3-day transduction and in 2 animals after an additional 6 to 9 days ex vivo expansion. Follow-up for these animals is up to 15-months. In the 3 animals that received HOXB4GFP-transduced cells without additional ex vivo culture, gene transfer efficiencies in CD34+ cells were similar between HOXB4GFP and YFP transduced cells: 45% (range 36–55%) vs. 38% (range 36– 40%). We observed a dramatic increase in HOXB4GFP marked cells from 20–30% to 52–62% during the early engraftment period, resulting in an up to 10-fold difference in granulocyte marking between HOXB4GFP and YFP marked cells at 5 weeks post-transplantation. Although gene-marking levels declined over time, HOXB4 marking was still about 2 to 3-fold higher than marking in control cells even at 15 months post-transplantation. A more pronounced effect was observed in the 2 animals that received HOXB4-overexpressing cells after an additional 6 to 9 days of ex vivo culture. Again, no difference in transduction efficiency was observed between YFP (range 34–49%) and HOXB4GFP (range 39–43%) marked cells before transplantation. However, HOXB4 marking was higher than YFP marking 1 week after transplantation, with up to a 34-fold difference in granulocyte marking at 2 weeks post-transplantation. Although the difference was decreased thereafter, a 4 to 10-fold difference was maintained in granulocyte marking after 3 months post-transplantation, suggesting a potential effect on the expansion of long-term repopulating cells. Subset analysis by flow cytometry and Taqman PCR showed HOXB4GFP and YFP marking in all subsets. Marking in CD13+ granulocytes and CD14+ monocytes was higher with HOXB4GFP-transduced cells and marking in CD3+ T cells was higher with YFP-transduced cells, suggesting that HOXB4 overexpression may have a more pronounced effect on engraftment and differentiation of myeloid than T-lymphoid precursors. LAM-PCR analysis demonstrated multiple clones of HOXB4GFP+ cells and control YFP+ cells. Our results demonstrate that HOXB4 overexpression in CD34+ cells has a very dramatic effect on expansion and engraftment of short-term repopulating cells with a less pronounced effect on long-term repopulating cells. These data should have important implications for the expansion and transplantation of HSCs, in particular for cord blood transplantations.

Suppressed, but Not Forgotten

2011 ◽  
Vol 70 (1) ◽  
pp. 5-11 ◽  
Author(s):  
Beat Meier ◽  
Anja König ◽  
Samuel Parak ◽  
Katharina Henke
Keyword(s):  
Memory Trace ◽  
Thought Suppression ◽  
Test Phase ◽  
Indirect Test ◽  
Final Test ◽  
Test Experiment ◽  
And Control ◽  
Cue Words ◽  
The Impact

This study investigates the impact of thought suppression over a 1-week interval. In two experiments with 80 university students each, we used the think/no-think paradigm in which participants initially learn a list of word pairs (cue-target associations). Then they were presented with some of the cue words again and should either respond with the target word or avoid thinking about it. In the final test phase, their memory for the initially learned cue-target pairs was tested. In Experiment 1, type of memory test was manipulated (i.e., direct vs. indirect). In Experiment 2, type of no-think instructions was manipulated (i.e., suppress vs. substitute). Overall, our results showed poorer memory for no-think and control items compared to think items across all experiments and conditions. Critically, however, more no-think than control items were remembered after the 1-week interval in the direct, but not in the indirect test (Experiment 1) and with thought suppression, but not thought substitution instructions (Experiment 2). We suggest that during thought suppression a brief reactivation of the learned association may lead to reconsolidation of the memory trace and hence to better retrieval of suppressed than control items in the long term.

Differential Outcomes for Long Term ex vivo Lung Perfusion in a Porcine Model - With or without Red Cells?

2015 ◽  
Vol 63 (S 01) ◽  
Author(s):  
W. Sommer ◽  
M. Avsar ◽  
J. Salman ◽  
C. Kühn ◽  
I. Tudorache ◽  
...  
Keyword(s):  
Porcine Model ◽  
Ex Vivo ◽  
Lung Perfusion ◽  
Red Cells ◽  
Ex Vivo Lung Perfusion ◽  
Differential Outcomes

The Estimation of prostate specific antigen (PSA) concentrations in patients with prostatitis by fully automated ELISA technique.

2020 ◽  
Vol 3 (11) ◽  
pp. 1100-1104
Author(s):  
Hussein Naeem Aldhaheri ◽  
Ihsan Edan AlSaimary ◽  
Murtadha Mohammed ALMusafer
Keyword(s):  
Personal Information ◽  
Receptor Gene ◽  
Specific Antigen ◽  
Gene Clusters ◽  
Control Group ◽  
P Value ◽  
Group Data ◽  
Elisa Technique ◽  
And Control

      The Aim of this study was to determine Immunogenetic expression of  Toll-like receptor gene clusters related to prostatitis, to give acknowledge about Role of TLR in prostatitis immunity in men from Basrah and Maysan provinces. A case–control study included 135 confirmed prostatitis patients And 50 persons as a control group. Data about age, marital status, working, infertility, family history and personal information like (Infection, Allergy, Steroid therapy, Residency, Smoking, Alcohol Drinking, Blood group, Body max index (BMI) and the clinical finding for all patients of Prostatitis were collected. This study shows the effect of PSA level in patients with prostatitis and control group, with P-value <0.0001 therefore the study shows a positive significant between elevated PSA levels and Prostatitis.

Strengthening of occupational health promotion by the German Prevention Health Care Act

2019 ◽  
pp. 188-190
Author(s):  
Diana Hart
Keyword(s):  
Public Health ◽  
Health Care ◽  
Health Promotion ◽  
Primary Prevention ◽  
Occupational Health ◽  
Life Expectancy ◽  
Prevention And Control ◽  
Occupational Health Promotion ◽  
And Control

All countries are faced with the problem of the prevention and control of non-communicable diseases (NCD): implement prevention strategies eff ectively, keep up the momentum with long term benefi ts at the individual and the population level, at the same time tackling hea lth inequalities. Th e aff ordability of therapy and care including innovative therapies is going to be one of the key public health priorities in the years to come. Germany has taken in the prevention and control of NCDs. Germany’s health system has a long history of guaranteeing access to high-quality treatment through universal health care coverage. Th r ough their membership people are entitled to prevention and care services maintaining and restoring their health as well as long term follow-up. Like in many other countries general life expectancy has been increasing steadily in Germany. Currently, the average life expectancy is 83 and 79 years in women and men, respectively. Th e other side of the coin is that population aging is strongly associated with a growing burden of disease from NCDs. Already over 70 percent of all deaths in Germany are caused by four disease entities: cardiovascular disease, cancer, chronic respiratory disease and diabetes. Th ese diseases all share four common risk factors: smoking, alcohol abuse, lack of physical activity and overweight. At the same time, more and more people become long term survivors of disease due to improved therapy and care. Th e German Government and public health decision makers are aware of the need for action and have responded by initiating and implementing a wide spectrum of activities. One instrument by strengthening primary prevention is the Prevention Health Care Act. Its overarching aim is to prevent NCDs before they can manifest themselves by strengthening primary prevention and health promotion in diff erent sett ings. One of the main emphasis of the Prevention Health Care Act is the occupational health promotion at the workplace.

Strategies to Protect Hematopoietic Stem Cells from Culture-Induced Stress Conditions

2020 ◽  
Vol 15 ◽  
Author(s):  
Fatima Aerts-Kaya
Keyword(s):  
Stem Cells ◽  
Hematopoietic Stem Cells ◽  
Ex Vivo ◽  
Stress Conditions ◽  
Stress Factors ◽  
Hematopoietic Stem ◽  
Induced Stress

: In contrast to their almost unlimited potential for expansion in vivo and despite years of dedicated research and optimization of expansion protocols, the expansion of Hematopoietic Stem Cells (HSCs) in vitro remains remarkably limited. Increased understanding of the mechanisms that are involved in maintenance, expansion and differentiation of HSCs will enable the development of better protocols for expansion of HSCs. This will allow procurement of HSCs with long-term engraftment potential and a better understanding of the effects of the external influences in and on the hematopoietic niche that may affect HSC function. During collection and culture of HSCs, the cells are exposed to suboptimal conditions that may induce different levels of stress and ultimately affect their self-renewal, differentiation and long-term engraftment potential. Some of these stress factors include normoxia, oxidative stress, extra-physiologic oxygen shock/stress (EPHOSS), endoplasmic reticulum (ER) stress, replicative stress, and stress related to DNA damage. Coping with these stress factors may help reduce the negative effects of cell culture on HSC potential, provide a better understanding of the true impact of certain treatments in the absence of confounding stress factors. This may facilitate the development of better ex vivo expansion protocols of HSCs with long-term engraftment potential without induction of stem cell exhaustion by cellular senescence or loss of cell viability. This review summarizes some of available strategies that may be used to protect HSCs from culture-induced stress conditions.

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