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To design the vaccines of the future we need to fully exploit microbial genomes and understand the basic mechanisms of the immune system.

SARS-CoV-2 can escape natural immune responses, but can the virus evade monoclonal antibodies and vaccine-mediated immunity?

The technological revolution in vaccination — from the empirical approach pioneered by Jenner and Pasteur to the recent developments in structural and reverse vaccinology, combined with synthetic biology — promises great hope for the development of safer and more effective vaccines against all infectious diseases. Vaccination, which is the most effective medical intervention that has ever been introduced, originated from the observation that individuals who survived a plague or smallpox would not get the disease twice. To mimic the protective effects of natural infection, Jenner — and later Pasteur — inoculated individuals with attenuated or killed disease-causing agents. This empirical approach inspired a century of vaccine development and the effective prophylaxis of many infectious diseases. From the 1980s, several waves of new technologies have enabled the development of novel vaccines that would not have been possible using the empirical approach. The technological revolution in the field of vaccination is now continuing, and it is delivering novel and safer vaccines. In this Timeline article, we provide our views on the transition from empiricism to rational vaccine design.

In the last century, vaccination has been the most effective medical intervention to reduce death and morbidity caused by infectious diseases. It is believed that vaccines save at least 2–3 million lives per year worldwide. Smallpox has been eradicated and polio has almost disappeared worldwide through global vaccine campaigns. Most of the viral and bacterial infections that traditionally affected children have been drastically reduced thanks to national immunization programs in developed countries. However, many diseases are not yet preventable by vaccination, and vaccines have not been fully exploited for target populations such as elderly and pregnant women. This review focuses on the state of the art of recent clinical trials of vaccines for major unmet medical needs such as HIV, malaria, TB, and cancer. In addition, we describe the innovative technologies currently used in vaccine research and development including adjuvants, vectors, nucleic acid vaccines, and structure‐based antigen design. The hope is that thanks to these technologies, more diseases will be addressed in the 21st century by novel preventative and therapeutic vaccines. Graphical Abstract This novel review of the host‐pathogen interactions series highlights the scientific and practical challenges facing vaccine development: starting with a historical perspective, the authors illustrate the current novel technologies with a focus on vaccines for infectious diseases.

Bacterial infections have been traditionally controlled by antibiotics and vaccines, and these approaches have greatly improved health and longevity. However, multiple stakeholders are declaring that the lack of new interventions is putting our ability to prevent and treat bacterial infections at risk. Vaccine and antibiotic approaches still have the potential to address this threat. Innovative vaccine technologies, such as reverse vaccinology, novel adjuvants, and rationally designed bacterial outer membrane vesicles, together with progress in polysaccharide conjugation and antigen design, have the potential to boost the development of vaccines targeting several classes of multidrug-resistant bacteria. Furthermore, new approaches to deliver small-molecule antibacterials into bacteria, such as hijacking active uptake pathways and potentiator approaches, along with a focus on alternative modalities, such as targeting host factors, blocking bacterial virulence factors, monoclonal antibodies, and microbiome interventions, all have potential. Both vaccines and antibacterial approaches are needed to tackle the global challenge of antimicrobial resistance (AMR), and both areas have the underpinning science to address this need. However, a concerted research agenda and rethinking of the value society puts on interventions that save lives, by preventing or treating life-threatening bacterial infections, are needed to bring these ideas to fruition.

Infectious diseases are now emerging or reemerging almost every year. This trend will continue because a number of factors, including the increased global population, aging, travel, urbanization, and climate change, favor the emergence, evolution, and spread of new pathogens. The approach used so far for emerging infectious diseases (EIDs) does not work from the technical point of view, and it is not sustainable. However, the advent of platform technologies offers vaccine manufacturers an opportunity to develop new vaccines faster and to reduce the investment to build manufacturing facilities, in addition to allowing for the possible streamlining of regulatory processes. The new technologies also make possible the rapid development of human monoclonal antibodies that could become a potent immediate response to an emergency. So far, several proposals to approach EIDs have been made independently by scientists, the private sector, national governments, and international organizations such as the World Health Organization (WHO). While each of them has merit, there is a need for a global governance that is capable of taking a strong leadership role and making it attractive to all partners to come to the same table and to coordinate the global approach.

In the eleven months elapsed since the identification of the SARS-CoV-2 virus and its genome, an exceptional effort by the scientific community has led to the development of over 300 vaccine projects. Over 40 are now undergoing clinical evaluation, ten of these are in Phase III clinical trials, three of them have ended Phase III with positive results. A few of these new vaccines are being approved for emergency use. Existing data suggest that new vaccine candidates may be instrumental in protecting individuals and reducing the spread of pandemic. The conceptual and technological platforms exploited are diverse, and it is likely that different vaccines will show to be better suited to distinct groups of the human population. Moreover, it remains to be elucidated whether and to what extent the capacity of vaccines under evaluation and of unrelated vaccines such as BCG can increase immunological fitness by training innate immunity to SARS-CoV-2 and pathogen-agnostic protection. Due to the short development time and the novelty of the technologies adopted, these vaccines will be deployed with several unresolved issues that only the passage of time will permit to clarify. Technical problems connected with the production of billions of doses and ethical ones connected with the availably of these vaccines also in the poorest countries, are imminent challenges facing us. It is our tenet that in the long run more than one vaccine will be needed to ensure equitable global access, protection of diverse subjects and immunity against viral variants.

Vaccination is the most effective medical intervention ever introduced and, together with clean water and sanitation, it has eliminated a large part of the infectious diseases that once killed millions of people. A recent study concluded that since 1924 in the United States alone, vaccines have prevented 40 million cases of diphtheria, 35 million cases of measles, and a total of 103 million cases of childhood diseases. A report from the World Health Organization states that today vaccines prevent 2.5 million deaths per year: Every minute five lives are saved by vaccines worldwide. Overall, vaccines have done and continue to do an excellent job in eliminating or reducing the impact of childhood diseases. Furthermore, thanks to new technologies, vaccines now have the potential to make an enormous contribution to the health of modern society by preventing and treating not only communicable diseases in all ages, but also noncommunicable diseases such as cancer and neurodegenerative disorders. The achievement of these results requires the development of novel technologies and health economic models able to capture not only the mere cost–benefit of vaccination, but also the value of health per se.