Editorial overview: Vaccines 2020.

Current Opinion in Immunology 2020, 65:xx–yy

0952-7915/© 2020 Published by Elsevier Ltd.

Vaccination represents one of the greatest inventions of humankind and has saved billions of lives. Although in much of the world the beneficial effects of vaccination are taken for granted, the COVID-19 pandemic has underscored our dependency on vaccines. The past decade has witnessed major strides in the application of novel technologies to virtually every aspect of vaccine design, ranging from novel antigen discovery to unravelling the mechanisms of action adjuvants, to the development of novel platforms and delivery systems for targeting antigens and adjuvants. The advent of high-throughput ‘omics’ technologies, combined with the computational and statistical methods necessary to analyze such data, have revolutionized biology, enabling a global view of the complex molecular processes and interactions that occur within a biological system. Systems-based approaches have begun to be used in the evaluation of immune responses to vaccination, with the goal of identifying predictive biomarkers capable of rapidly evaluating vaccine efficacy, transforming our understanding of the immune mechanisms responsible for protective responses to vaccination and contributing to a new generation of rationally designed vaccines. These exciting new advances are discussed in the reviews contained in this volume.

An essential element of a vaccine is the antigen. A significant advance during the past decade is innovative structure-based design of candidate vaccine antigens against pathogens such as RSV, influenza and HIV. Ward and Wilson [1] discuss how atomic-level structures of glycoproteins that comprise the surface antigens of human enveloped viruses, such as RSV, influenza, and HIV, are guiding the design of novel immunogens with the capacity to neutralizing antibodies. Many of these immunogens are being tested in human clinical trials and will likely need to go through iterative design and testing to optimize their capacity to achieve enhanced breadth and potency. Their review highlights some of the recent advances in this emerging area.

Another essential element of a vaccine is the adjuvant. Adjuvants boost the immune response to an antigen. Yet, despite their importance adjuvant development has been described as one of the slowest processes in the history of medicine, with alum being the only adjuvant licensed for human use for 70 years since its introduction in the 1920s. However the past two decades have witnessed a flurry of activity in understanding the science of adjuvants, and in the inclusion of a further 5 adjuvants in licensed vaccines. This has been catalyzed to a great extent by advances in our understanding of the innate immune system, and in the discovery of toll like receptors (TLRs). Reed et al. [2] discuss the use of TLR agonists such as mono-phosphoryl lipid A, MPL in licensed vaccine products, and in formulations than enhance and complement the MPL activity. They further discuss the challenges that remain in adjuvant development, particularly for those capable of inducing T cell responses. They also discuss how the RNA based adjuvants, that trigger nucleic acid sensing receptors could potentially offer novel adjuvants to stimulate CD8 T cell responses.

Although antigens and adjuvants comprise the essential elements of a vaccine, formulating them appropriately to enhance the magnitude and durability of immune responses is a major challenge. The past decade has witnessed an exciting convergence between the fields of bioengineering and vaccinology, and Irvine and Read [3] discuss how advances in bioengineering are paving the way for innovative nanoparticle-based vaccines that formulate antigens in a particulate format, mimicking the physical form of viruses. They review recent studies that are defining the critical variables governing how nanoparticle-based vaccines stimulate immune responses, and the factors governing the fate of nanoparticle immunogens in lymph nodes.

There are many different platform technologies for developing vaccines such as live attenuated viral vectors (smallpox, measles, yellow fever), or inactivated vaccines (seasonal influenza), carbohydrate vaccines (meningococcal and pneumococcal vaccines), recombinant vaccines (hepatitis B vaccine) and DNA vaccines. A recent technology that has gained worldwide attention as a result of the COVID-19 pandemic is the so-called messenger RNA technology. Messenger RNA (mRNA) vaccines represent a relatively new vaccine class showing great promise for the future. Norbert et al. [4] review advances in this exciting new area. They discuss critical recent innovations in the field, such as the development of safe and efficient materials for in vivo mRNA delivery and advanced protocols for the production of high quality mRNA.

Another promising vaccine platform is DNA-based vaccines. Gary and Weiner [5] discuss recent studies of synthetic DNA vaccines for the prevention or treatment of infectious diseases and highlight innovations in adaptive electroporation for delivery. They describe how improvements in DNA delivery such as jet delivery, gene gun delivery, and advanced electroporation (EP) techniques, have been pivotal in improving the immunogenicity of DNA vaccines in both preventative as well as therapeutic studies. Furthermore, advancements in the design of the DNA inserts and improved insert designs, as well as increased concentrations of DNA, and skin delivery, appear to complement newer delivery strategies. They also discuss that these advances also provide a framework for the in vivo production of synthetic DNA biologics.

Another platform technology is the conjugate vaccine platform. Glycoconjugate vaccines are among most successful vaccines developed during the past 30 years, and include vaccines against Haemophilus influenzae type b infection, conjugate vaccines against Neisseria meningitidis and Streptococcus pneumoniae protein). Berti and Micoli [6] discuss recent advances in conjugate vaccines, including coupling of chemically synthesized oligosaccharides to proteins, or engineering Escherichia coli to directly produce bioconjugates or by delivery of the native carbohydrate antigen in engineered membrane vesicles (i.e. Generalized Modules for Membrane Antigens, GMMA). Their review, gives the reader insights into the history of conjugate vaccines, and factors that might affect their immunogenicity and their potential for future applications.

Once a vaccine has been designed, the next step is to see if it works. Testing of candidate vaccines is first performed in animal models such as mice and nonhuman primates, and the most promising candidates are advances to human clinical trials. A major bottleneck in the vaccine development pipeline is that of the many hundreds of potential vaccine candidates that look promising in mice, only a small fraction may induce safe and effective immunity in humans.

Exciting new advances in the field of systems vaccinology over the past decade has begun to address this challenge. Systems vaccinology leverages the explosion in throughput technologies to define the mechanisms of protective immunity and to identify molecular signatures of vaccine efficacy. Wimmers and Pulendran [7] review these emerging directions in systems vaccinology, with a particular focus on the epigenome, and its impact on modulating vaccination induced memory in the innate and adaptive immune systems.

During the first year of life children receive many vaccines against infectious diseases. However, most of these vaccines are not tailor made for the immune system of young children. There is currently a paucity in our understanding of how newborn immune systems differ from adult counterparts is incomplete. Brodin [8] reviews exciting new advances in the application of high throughput technologies to probing the immune systems in the infant and neonatal populations. He discusses the implications of this for studying vaccine responses in young children and developing better vaccines, tailored to this important population of susceptible individuals in the future.

Although antibodies represent a major mechanism by which vaccination stimulates protective immunity, the induction of antigen-specific T cells provides a complimentary and synergistic arm of host defense. Indeed T cells are known to be a critical part of most pathogen responses, yet there is very limited knowledge about what would constitute an effective protective T cell response against a given pathogen. Davis discusses [9] the role of T cells in vaccination and emphasizes the critical need to identify key T cell response metrics in early vaccine trials. Given the explosion of new technologies that are available, he describes exciting new advances that permit a detailed analysis of the dynamics of the T cell response to vaccination at an unprecedented degree of detail. He further considers what should be measured, with the caveat that some of these will be more important than others.

Finally, vaccination has contributed tremendously to improvements in life expectancy over the past two centuries. However vaccination has not worked in isolation, and improved hygiene and the use of antibiotics have also been pivotal in profound improvements in global health. In the backdrop of this triumph in public health, the specter of emerging infections such as SARS-CoV-2 and the emergence of antimicrobial resistance, pose major threats to humanity. The article by Troisi et al. [10] discusses the three main pillars (vaccination, improved hygiene and antibiotics) that have contributed to improved life expectancy, and the role of vaccines in fighting antimicrobial resistance and global pandemics.

Taken together, these reviews highlight exciting new frontiers in vaccinology that represent a promising future for the development of a new generation of rationally designed vaccines against infectious diseases.