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Taming the Enemy
Published in Norman Begg, The Remarkable Story of Vaccines, 2023
The second type of genetic vaccine is based on mRNA, the messenger of DNA. When injected, mRNA vaccines directly instruct the body to make antigen. Unlike DNA, RNA is unstable and gets broken down by your body soon after being injected. To prevent this from happening too quickly, it needs to be protected with something (often a lipid, which is a type of fat) before being injected. Even with this protective coat, the RNA only lasts a few hours, so it’s a race against time to make the antigen. Some types of mRNA vaccines use a trick of modifying the RNA so that it is able to multiply inside the cell, known as self-amplifying messenger RNA or SAM for short. Like DNA vaccines, mRNA vaccines produce a broad range of immune responses but are even easier to manufacture. Two of the earliest approved COVID-19 vaccines, from Pfizer/BioNTech and Moderna, are mRNA-based.
Non-Viral Delivery of Genome-Editing Nucleases for Gene Therapy
Published in Yashwant Pathak, Gene Delivery, 2022
Numerous other polymers, such as poly[(2-dimethylamino) ethyl methacrylate] (pDMAEMA), poly(β-amino ester)s, and various carbohydrate-based polymers and dendrimers, are currently under preclinical trials account for DNA delivery. A polymeric vector consists of non-ionic poloxamer CRL1005, and the cationic surfactant benzalkonium chloride has been pushed to clinical development. This formulation is being under investigation in a Phase II/III clinical trial for a genetic vaccine to prevent CMV infection in patients with allogeneic hematopoietic cell transplant [1, 85, 86] [Table 12.2]
Immunization
Published in Julius P. Kreier, Infection, Resistance, and Immunity, 2022
Michael F. Para, Susan L. Koletar, Carter L. Diggs
This recent approach to vaccine development has received considerable attention because of its potential for revolutionizing the entire field. A gene coding for a relevant antigen is inserted in a plasmid containing a viral promoter which enables expression in a mammalian system. Purified plasmid is injected into the individual to be immunized and produces the gene product in situ. This endogenously released antigen then induces an immune response. This system could potentially greatly accelerate vaccine development since the often rate-limiting step of production process development could be greatly shortened; recombinant protein expression technology is circumvented reducing production process development to construction of the plasmid. Purification process development is minimized since the purification process is the same for all plasmids regardless of the antigen gene inserted. If a genetic vaccine was developed to the point of registration and large-scale manufacture, it is likely that it could be produced at less expense than its recombinant protein counterpart. For these reasons, the approach is under active investigation. Protection from experimental infection of immunized hosts has been demonstrated in laboratory animal systems (for example, rodent malaria), and initial clinical trials of investigational HIV, influenza, and malaria vaccine in human volunteers have already taken place. Obstacles to development of the approach include a lack of knowledge of how to optimize the immune response to genetic vaccines and how to modulate the type of immune response obtained. Route of administration (intramuscular or intradermal) appears to be an important determinant of whether the response is predominantly humoral or cellular, but no useful general rules have emerged in this regard. A persistent concern is that the foreign DNA could become integrated into host DNA resulting in insertional activation of oncogenes and subsequent development of neoplastic disease. Another type of problem would arise if foreign antigen were to be incorporated in the membrane of the infected cell; cell-mediated immunity directed against the host cell could result in cell death. These concerns will continue to be evaluated. Only time will tell whether or not the potential of genetic immunization will be realized; but this and other emerging technologies insure that the next several years will be an exciting period in vaccine development.
Strategies for inducing effective neutralizing antibody responses against HIV-1
Published in Expert Review of Vaccines, 2019
Iván del Moral-Sánchez, Kwinten Sliepen
Since the dawn of genetic vaccine development, this approach has shown notable success in the protection of small animals and macaques against diverse pathogens, resulting in the licensure of several DNA vaccines to prevent veterinary infections such as West Nile virus in horses and infectious hematopoietic necrosis factor disease in salmon [230,231]. However, DNA immunogens usually induce suboptimal humoral responses in humans [230]. Thus, DNA vaccines have been mainly explored in DNA prime-protein boost studies, in which DNA kick-starts both humoral and cellular responses that are then boosted by protein-based immunogens to induce higher titre Ab responses [149,232–236]. Other immunization experiments have used DNA and protein co-immunization mixtures to increase the durability of humoral responses [237–239]. Jalah et al. used a SIVmac239 DNA construct and a sequence-matched protein immunogen to compare DNA only (D), DNA prime-protein boost (D-P) and DNA-protein co-immunization (D&P) regimens in rhesus macaques. The DNA only scheme induced no detectable antibody responses after two vaccinations. Both D-P and D&P strategies elicited robust Env-specific antibody responses. However, while the D-P titres showed a decay of 2.4 logs over 6 months, D&P induced Ab titres that showed no decay over a period of 8 months [237]. DNA has also been successfully combined in prime-boost regimens with modified vaccinia Ankara (MVA) for HIV-1 vaccination experiments [240,241].
Current research into novel therapeutic vaccines against cervical cancer
Published in Expert Review of Anticancer Therapy, 2018
Marcelo Nazário Cordeiro, Rita de Cássia Pereira De Lima, Francesca Paolini, Alanne Rayssa da Silva Melo, Ana Paula Ferreira Campos, Aldo Venuti, Antonio Carlos De Freitas
Vaccines are developed as preventive measures. Primarily, vaccines are immunity inductors by either humoral or cellular ways. Their role is to prepare the immune system to attack pathogens before establishing a productive infection or another health menace. The protective effect, therefore, depends on the adequate production of highly specific neutralizing antibodies or activation of specialized cells to immediate recognition and attack to infected cells. However, defense against immune-evasive viruses, such as high-risk human papillomaviruses (HPV), or against epidermal/mucosal tumors, as observed in HPV-related genital warts, relies on both a strong cytolytic response of CD8+ lymphocytes [2] as well as a specific and long-term CD4+ helper lymphocytes response [3]. Despite the fact that anti-HPV prophylactic vaccines can provide a significant impact on cervical cancer incidence [4], control measures against high-disseminated HPVs still require therapeutic alternatives. Therapeutic vaccines, such as DNA and RNA-based vaccines through genetic manipulation and synthetic long peptides, allowed to design immunostimulatory strategies against virus-infected and/or tumor cells antigens. Gene therapy appears to be one of the most promising tools to induce strong effective immune responses and, therefore, this review will be focused on DNA vaccine immunotherapy. Briefly, this approach consists of in vivo transfection of antigen-expressing recombinant plasmids or viral vectors into key recognition cells, namely local dendritic cells (major therapy target), or even muscle cells (cross-priming), allowing activation pathways of cytolytic and helper T cells responses. Consequently, choosing the appropriate antigen to be encoded into a DNA vaccine is the most important determinant of a successful approach. Other key features of a genetic vaccine are the level of antigen expression in the target cell, its post-translational processing, and its effective binding to lymphocyte cell family receptors. Furthermore, the immune response is modulated against tumor cells or even oncogenic virus host cells at a level of specificity and efficacy still rarely achieved.