DNA and mRNA Vaccines for Chronic Viral Infections and Cancer: Rationale, Mechanisms, and Progress.

Interest in the capabilities of nucleic acid vaccines, (DNA and mRNA vaccines) for both prophylactic and therapeutic uses have greatly increased following the successful deployment of two mRNA and, on a more limited scale, one DNA vaccine for COVID-19. In addition to targeting other pathogens for prophylactic vaccines, efforts are also being made towards using them for therapies for chronic infections and cancer. An examination of past and current successes for such therapies using other technologies with an emphasis on the immunological mechanisms will be provided followed by an assessment of the relevant characteristics of DNA and mRNA vaccines to predict their utility for therapies for chronic viral infections and cancer. Efforts and progress for these targets will be described.

WHO informal consultation on regulatory considerations for evaluation of the quality, safety and efficacy of RNA-based prophylactic vaccines for infectious diseases, 20-22 April 2021.

This paper presents the key outcomes of the above WHO informal consultation with global stakeholders including regulatory authorities, vaccine developers and manufacturers, academia and other international health organizations and institutions involved in the development, evaluation and use of messenger RNA (mRNA) vaccines. The aim of the consultation was to further clarify the main principles to be presented in an upcoming WHO guidance document on the regulatory considerations in evaluating the quality, safety and efficacy of mRNA prophylactic vaccines for infectious diseases. This WHO guidance document is intended to facilitate global mRNA vaccine development and regulatory convergence in the assessment of such vaccines. The urgent need to develop such a document as a new WHO written standard is outlined in this report along with the key scientific and regulatory challenges. A number of key conclusions are provided at the end of this report along with an update on the steps taken following this meeting.

The Key Role of Nucleic Acid Vaccines for One Health.

The ongoing SARS-CoV-2 pandemic has highlighted both the importance of One Health, i.e., the interactions and transmission of pathogens between animals and humans, and the potential power of gene-based vaccines, specifically nucleic acid vaccines. This review will highlight key aspects of the development of plasmid DNA Nucleic Acid (NA) vaccines, which have been licensed for several veterinary uses, and tested for a number of human diseases, and will explain how an understanding of their immunological and real-world attributes are important for their efficacy, and how they helped pave the way for mRNA vaccines. The review highlights how combining efforts for vaccine development for both animals and humans is crucial for advancing new technologies and for combatting emerging diseases.

Development of mRNA Vaccines: Scientific and Regulatory Issues.

The global research and development of mRNA vaccines have been prodigious over the past decade, and the work in this field has been stimulated by the urgent need for rapid development of vaccines in response to an emergent disease such as the current COVID-19 pandemic. Nevertheless, there remain gaps in our understanding of the mechanism of action of mRNA vaccines, as well as their long-term performance in areas such as safety and efficacy. This paper reviews the technologies and processes used for developing mRNA prophylactic vaccines, the current status of vaccine development, and discusses the immune responses induced by mRNA vaccines. It also discusses important issues with regard to the evaluation of mRNA vaccines from regulatory perspectives. Setting global norms and standards for biologicals including vaccines to assure their quality, safety and efficacy has been a WHO mandate and a core function for more than 70 years. New initiatives are ongoing at WHO to arrive at a broad consensus to formulate international guidance on the manufacture and quality control, as well as nonclinical and clinical evaluation of mRNA vaccines, which is deemed necessary to facilitate international convergence of manufacturing and regulatory practices and provide support to National Regulatory Authorities in WHO member states.

A timely update of global COVID-19 vaccine development.

This commentary provides an overview and links to presentations of a recent virtual congress series organized by the International Society for Vaccines (ISV) focused on COVID-19 vaccines. The series provided the academic community and vaccine developers as well as the wider general public with balanced information of the global response and resources for COVID-19 vaccines under development featuring: 1) NGOs and the regulatory perspective, 2) the status of vaccine development efforts, and 3) panel discussions to present and discuss challenges. ISV is a non-profit scientific organization whose members work on all areas relevant to vaccines. ISV plans to host additional virtual symposia including regional meetings and incorporating other topics along with COVID-19 vaccines.

A Comparison of Plasmid DNA and mRNA as Vaccine Technologies.

This review provides a comparison of the theoretical issues and experimental findings for plasmid DNA and mRNA vaccine technologies. While both have been under development since the 1990s, in recent years, significant excitement has turned to mRNA despite the licensure of several veterinary DNA vaccines. Both have required efforts to increase their potency either via manipulating the plasmid DNA and the mRNA directly or through the addition of adjuvants or immunomodulators as well as delivery systems and formulations. The greater inherent inflammatory nature of the mRNA vaccines is discussed for both its potential immunological utility for vaccines and for the potential toxicity. The status of the clinical trials of mRNA vaccines is described along with a comparison to DNA vaccines, specifically the immunogenicity of both licensed veterinary DNA vaccines and select DNA vaccine candidates in human clinical trials.

An interview with Margaret A Liu: the future of gene-based vaccines and immunotherapies, and other musings.

Interview by Jenaid Rees, commissioning editor. Margaret A Liu is best known for her pioneering work in the area of DNA vaccines. A world renowned scientist, Liu was named one of 'The 50 Most Important Women Scientists' by Discover magazine in 2002. Liu obtained her M.D. from Harvard Medical School, and has held positions at numerous institutions including Harvard Medical School, Massachusetts Institute of Technology, University of Pennsylvania, UCSF, and the Karolinska Institutet in Stockholm. In her career she has served as Senior Advisor in Vaccinology at the Bill & Melinda Gates Foundation and Executive Vice-Chair of the International Vaccine Institute in Seoul, Korea and worked for companies including Merck, Transgène and Chiron Corporation. Her research achievements have led to her receipt of honorary lectureships, and she has held many board positions throughout her career. Liu currently consults in the fields of vaccines and immunotherapy for companies, universities, and non-governmental and governmental scientific organizations, and is a Foreign Adjunct Professor at the Karolinska Institutet in Stockholm, and an Adjunct Professor at the University of California, San Francisco.

Cancer vaccines.

While vaccines are primarily thought of in terms of their use for prevention of infectious diseases, they can potentially be used to prevent or treat cancer. This manuscript explores the rationale for vaccines and immunotherapies for cancer from both the scientific and the global needs perspectives. Pathogens that are aetiologic agents of certain cancers provide perhaps the most obvious successful examples of the prophylactic utility of vaccines (such as the hepatitis B vaccine) to prevent not just the infectious disease (hepatitis), but the potential subsequent cancer (hepatocellular carcinoma). The use of monoclonal antibodies illustrates the effectiveness of the immune system for cancer therapy. In addition, the increased understanding of the role and mechanisms of the immune system in the processes of immune surveillance, as well as of its failure during immunosuppression, have yielded better insights into how to design cancer vaccines and immunotherapies. Examples of targets for cancer vaccines will be discussed, as will the challenges and few successes in this arena.

DNA vaccines: an historical perspective and view to the future.

This review provides a detailed look at the attributes and immunologic mechanisms of plasmid DNA vaccines and their utility as laboratory tools as well as potential human vaccines. The immunogenicity and efficacy of DNA vaccines in a variety of preclinical models is used to illustrate how they differ from traditional vaccines in novel ways due to the in situ antigen production and the ease with which they are constructed. The ability to make new DNA vaccines without needing to handle a virulent pathogen or to adapt the pathogen for manufacturing purposes demonstrates the potential value of this vaccine technology for use against emerging and epidemic pathogens. Similarly, personalized anti-tumor DNA vaccines can also readily be made from a biopsy. Because DNA vaccines bias the T-helper (Th) cell response to a Th1 phenotype, DNA vaccines are also under development for vaccines against allergy and autoimmune diseases. The licensure of four animal health products, including two prophylactic vaccines against infectious diseases, one immunotherapy for cancer, and one gene therapy delivery of a hormone for a food animal, provides evidence of the efficacy of DNA vaccines in multiple species including horses and pigs. The size of these target animals provides evidence that the somewhat disappointing immunogenicity of DNA vaccines in a number of human clinical trials is not due simply to the larger mass of humans compared with most laboratory animals. The insights gained from the mechanisms of protection in the animal vaccines, the advances in the delivery and expression technologies for increasing the potency of DNA vaccines, and encouragingly potent human immune responses in certain clinical trials, provide insights for future efforts to develop DNA vaccines into a broadly useful vaccine and immunotherapy platform with applications for human and animal health.

Immunologic basis of vaccine vectors.

Efforts to make vaccines against infectious diseases as well as immunotherapies for cancer, autoimmune diseases and allergy have utilized a variety of heterologous expression systems, including viral and bacterial vectors, as well as DNA and RNA constructs. This review explores the immunologic rationale and provides an update of insights obtained from preclinical and clinical studies of such vaccines.

Gene-based vaccines: Recent developments.

Gene-based vaccines are under development for a broad variety of applications, ranging from vaccines to immunotherapies for infectious diseases, cancer, autoimmune diseases and allergy. In addition, following the licensing of DNA vaccines for use in fish and horses, and DNA immunotherapy for the treatment of cancer in dogs, several veterinary uses of vaccines have been demonstrated for species ranging from fish and shrimp to cattle and horses. A variety of publications describing preclinical and clinical studies of the technologies used to increase the potency of gene-based vaccines, and research further elucidating the immune mechanisms involved have recently become available. This review discusses the progress and observations described in the recent literature, including a survey of the diseases and approaches that are being targeted with gene-based vaccines.

Vaccine delivery methods using viral vectors.

Viral vectors have different capabilities as gene delivery vehicles for vaccines and immunotherapeutics. This review discusses selected viral vector systems and plasmid DNA and provides an overview of their specific characteristics, strengths, and limitations. The features, modes of viral entry and replication, expression of heterologous proteins, issues related to both preexisting and heterologous immunity, and vaccine strategies are discussed for the different vectors. Comparisons of the features and capabilities of the vectors are provided.

DNA vaccines: recent developments and future possibilities.

The field of DNA vaccines continues to advance and several new strategies to augment the immunogenicity of DNA vaccines are under evaluation. The majority of these studies are in the early preclinical stage, but some DNA vaccines have moved into clinical trials. In this review, we describe some of the more recent efforts aimed at increasing the immunogenicity of DNA vaccines, including the use of genetic adjuvants and plasmid-based expression of viral replicons. In addition, we discuss the possibility of using DNA vaccines to address emerging infectious agents where they may provide an advantage over other vaccine strategies and we review some areas where DNA vaccines have been used to target self-antigens.

Gene-based vaccines: recent technical and clinical advances.

DNA vaccines have been widely used in efforts to develop vaccines against various pathogens as well as for cancer, autoimmune diseases and allergy. DNA vaccines offer broad efficacy (particularly for their ability to generate both cellular and humoral immunity), ease of construction and manufacture and the potential for world-wide usage even in low-resource settings. However, despite their successful application in many preclinical disease models, their potency in human clinical trials has been insufficient to provide protective immunity. Nevertheless, two DNA vaccines were recently licensed for use in animals (horse and fish), underscoring the potential of this technology. Here, we describe recent advances in increasing the potency of these vaccines, in understanding their immunological mechanisms, and in their applications and efficacy in clinical trials so far.

DNA vaccines: recent technological and clinical advances.

DNA vaccines generate both T cell and B cell (or antibody) mediated immunities. Methods such as prime-boost regimens and the use of adjuvants in combination with the DNA vaccine have enhanced the therapeutic effectiveness of DNA vaccines in the treatment of cancer, infectious diseases, autoimmune diseases, asthma, and other conditions.

DNA vaccines for HIV/AIDS.

PURPOSE OF REVIEW: The year 2005 saw the licensure of two DNA vaccines for veterinary use (horses and salmon), thus demonstrating that limitations of potency and delivery have been overcome for certain real-life applications. The purpose of this review is to evaluate the advances specific for application of DNA vaccines to HIV vaccines for humans. RECENT FINDINGS: The potency of DNA vaccines has been greatly increased by new formulations and delivery methods. The use of various adjuvants and immune modulators has likewise been shown to increase or specifically focus immune responses. Heterologous prime/boost strategies utilizing DNA as the priming agent followed by viral vectors or protein have been shown to be useful for increased antibody as well as cellular responses. Results from early-phase clinical trials are being utilized to direct the development of gene-based vaccines. SUMMARY: Recent advances in increasing the potency of DNA vaccines via novel adjuvants, formulations, and delivery systems, along with prime/boost strategies and nonhuman primate studies, are reviewed in terms of their potential for developing an HIV/AIDS vaccine for clinical usage.

Human clinical trials of plasmid DNA vaccines.

This article gives an overview of DNA vaccines with specific emphasis on the development of DNA vaccines for clinical trials and an overview of those trials. It describes the preclinical research that demonstrated the efficacy of DNA vaccines as well as an explication of the immunologic mechanisms of action. These include the induction of cognate immune responses, such as the generation of cytolytic T lymphocytes (CTL) as well as the effect of the plasmid DNA upon the innate immune system. Specific issues related to the development of DNA as a product candidate are then discussed, including the manufacture of plasmid, the qualification of the plasmid DNA product, and the safety testing necessary for initiating clinical trials. Various human clinical trials for infectious diseases and cancer have been initiated or completed, and an overview of these trials is given. Finally, because the early clinical trials have shown less than optimal immunogenicity, methods to increase the potency of the vaccines are described.

DNA vaccines: progress and challenges.

In the years following the publication of the initial in vivo demonstration of the ability of plasmid DNA to generate protective immune responses, DNA vaccines have entered into a variety of human clinical trials for vaccines against various infectious diseases and for therapies against cancer, and are in development for therapies against autoimmune diseases and allergy. They also have become a widely used laboratory tool for a variety of applications ranging from proteomics to understanding Ag presentation and cross-priming. Despite their rapid and widespread development and the commonplace usage of the term "DNA vaccines," however, the disappointing potency of the DNA vaccines in humans underscores the challenges encountered in the efforts to translate efficacy in preclinical models into clinical realities. This review will provide a brief background of DNA vaccines including the insights gained about the varied immunological mechanisms that play a role in their ability to generate immune responses.