Download PDF The Bridge: 50th Anniversary Issue January 7, 2021 Volume 50 Issue S This special issue celebrates the 50th year of publication of the NAE’s flagship quarterly with 50 essays looking forward to the next 50 years of innovation in engineering. How will engineering contribute in areas as diverse as space travel, fashion, lasers, solar energy, peace, vaccine development, and equity? The diverse authors and topics give readers much to think about! We are posting selected articles each week to give readers time to savor the array of thoughtful and thought-provoking essays in this very special issue. Check the website every Monday! Imagining the Future of Vaccine Development Monday, January 18, 2021 Author: Arup K. Chakraborty and Bernhardt L. Trout Human history is inextricably linked with infectious diseases. Smallpox and plague pandemics and epidemics have afflicted humans since antiquity. As recently as the 19th century, roughly one in 100 people living in New York City died of tuberculosis. To an inhabitant of the 19th century, the early 21st century would not be recognizable. The prevalence of common childhood diseases and infant mortality is dramatically lower, in many parts of the world infectious disease epidemics are rare, and common bacterial infections are no longer fatal. These dramatic changes were wrought by human ingenuity, which resulted in better sanitation, antibiotics, and vaccines. But the enormous human and economic toll of the covid-19 pandemic is a reminder that infectious disease–causing pathogens remain an existential threat to humanity. And this will not be the last pandemic. What if another virus emerges that is easily spreadable by casual human contact, is highly mutable, and causes a disease with a significant mortality rate? While vaccination has saved more lives than any other medical procedure, some pathogens defy successful vaccination using available strategies. For example, no vaccine exists for the human immunodeficiency virus (HIV) or malaria, nor is there a universal vaccine that can protect against the mutant strains of influenza that emerge every year. It is not hard, however, to imagine a future where a connected pipeline of discovery, design, delivery, and deployment makes the rapid development of vaccines against diverse pathogens routine. Discovery The human adaptive immune system enables the body to generate effective responses specifically tailored for pathogens to which it has not been previously exposed. Even more amazingly, a memory of past infections makes it possible to mount rapid and robust responses upon reinfection with the same pathogen. To stimulate the immune system to develop memory for a particular pathogen, a vaccine contains some form of the pathogen. But the pathogen-specific nature of the immune response is a challenge for the development of vaccines against highly mutable pathogens. If the vaccine contains only a single strain of a mutable virus, the immune response will be specific for that strain. A pipeline of discovery, design, delivery, and deployment will enable the rapid development of vaccines against diverse pathogens. This challenge can be addressed by bringing together approaches and people from the life and physical sciences and engineering. Machine learning (ML) approaches and mechanistic modeling of systemic immune responses can be applied to massive sets of data on virus sequences and structures and combined with clinical data to potentially identify regions of the virus’s proteome that cannot change without making the mutant strain unviable. Targeting these regions of the virus’s proteins with a vaccine-induced immune response will trap the virus between being killed by the immune response or evolving mutations that cripple the virus’s ability to replicate and propagate infection. Such discoveries could set the stage for developing pan-coronavirus vaccines, an HIV vaccine, a universal influenza vaccine, and vaccines that protect against new mutable viruses that could emerge and cause pandemics. Many members of families of viruses that infect humans also circulate in animals (e.g., coronaviruses in bats and influenza viruses in pigs and birds). If a virus that circulates in an animal species adapts to infect humans, no one has immunity and a pandemic can result. We imagine that 50 years from now, the knowledge gained from the research described above, along with global virus surveillance capabilities, may make it possible to anticipate the most likely types of pandemic-causing viruses. Such discoveries could enable the design of vaccines in advance. Design A key component of a vaccine is the immunogen, a form of a virus’s proteins. Pathogen-specific immune responses are mediated by antibodies and T cells. The immunogens required to induce antibodies that target the mutationally vulnerable regions of a pathogen are different from those required to elicit T cells. Antibodies target the proteins that make up a virus’s spike, while T cells attack short peptides derived from all viral proteins. Systematic approaches to design immunogens that elicit desired immune responses in humans with different genotypes are not available. We imagine that developments in systems immunology that bring together systems-level modeling of the immune response, machine learning, data from animal models, and immune monitoring of humans with diverse genotypes will overcome this challenge. This will enable the development of algorithms and tools that can reliably design effective immunogens. Delivery Vaccines that are composed of the whole pathogen, either weakened or killed, have existed since the advent of vaccination. The kinds of vaccines that we imagine are not the whole pathogen but immunogens carefully chosen to contain parts of the pathogen. If a pathogen’s proteins are simply injected into an animal, nothing much happens. How can they be delivered in a way that elicits strong immune responses? Immunoengineering is a rapidly developing field that, among other goals, aims to develop nanoparticle-based vaccine delivery modalities that can efficaciously induce strong immune responses to subunits of a pathogen’s proteins. Indeed, the vaccines being developed for covid-19 employ nanoparticles and engineered viruses to deliver RNA or DNA corresponding to the viral spike protein. The lessons learned from these and other ongoing efforts will provide the capability to design robust delivery vehicles for novel vaccines. Deployment Formulation and manufacturing of billions of doses of new vaccines usually takes many months, or years. Even the best of vaccines is useless if the formulation of its components is not stable and it cannot be manufactured at large scale in a reliable, robust, and cost-effective way. The current paradigm is batch manufacturing, in which individual steps are done separately without much integration. This is a recipe for slow scale-up times, inflexibility, and quality challenges, particularly when a rapid response is required. Fortunately, solutions are being developed to ensure speed and quality and reduce cost. Integrated continuous manufacturing includes model-based control, a systems approach, and end-to-end flow. The basic technologies exist, but there is a barrier to industrial adoption due to perceived regulatory risks. Given the obvious benefits of integrated continuous manufacturing, these challenges need to be addressed for the benefit of the world. The next 50 years will see not only integrated continuous manufacturing of vaccines but automated process development approaches based on ML technologies. Robots will systematically optimize processes, complementing the human creativity needed for the proper inputs to models and specifications into the algorithms. Ultimately, automated systems will both run the manufacturing equipment and enable process development. Advanced manufacturing approaches and compatible regulatory policies will enable large-scale manufacturing of vaccines and therapies to begin shortly after successful clinical trials. Data from the clinical trials being conducted for covid-19 vaccines and future studies will show how to optimally time and stage clinical trials for vaccines, and how some stages can be efficiently combined. Other valuable lessons will be learned about the infrastructure required to store, transport, and deploy billions of doses of a vaccine rapidly. Conclusion The connected pipeline of discovery, design, delivery, and deployment of vaccines that we imagine is not a fantasy. Building on current abilities and research activities, the future will likely be the present fairly soon. This will lead to a more pandemic-resilient world, and will be one more important step forward in the eternal quest to vanquish infectious disease–causing pathogens. Reference Chakraborty AK, Shaw AS. 2020. Viruses, Pandemics, and Immunity. Cambridge: MIT Press.  Some of the ideas discussed here are elaborated in Chakraborty and Shaw (2020). About the Author:Arup Chakraborty (NAE/NAS/NAM) is the Robert T. Haslam Professor of Chemical Engineering, professor of physics and chemistry, and was the founding director of the Institute for Medical Engineering and Science at the Massachusetts Institute of Technology, and a founding member of the Ragon Institute of Massachusetts General Hospital, MIT, and Harvard University. Bernhardt Trout is the Raymond F. Baddour, ScD, (1949) Professor of Chemical Engineering at MIT.