The sixth revolution in pediatric vaccinology: immunoengineering and delivery systems.

Infection is the predominant cause of mortality in early life, and immunization is the most promising biomedical intervention to reduce this burden. However, very young infants fail to respond optimally to most vaccines currently in use, especially neonates. In 2005, Stanley Plotkin proposed that new delivery systems would spur a new revolution in pediatric vaccinology, just as attenuation, inactivation, cell culture of viruses, genetic engineering, and adjuvantation had done in preceding decades. Recent advances in the field of immunoengineering, which is evolving alongside vaccinology, have begun to increasingly influence vaccine formulation design. Historically, the particulate nature of materials used in many vaccine formulations was empiric, often because of the need to stabilize antigens or reduce endotoxin levels. However, present vaccine delivery systems are rationally engineered to mimic the size, shape, and surface chemistry of pathogens, and are therefore often referred to as "pathogen-like particles". More than a decade from his original assessment, we re-assess Plotkin's prediction. In addition, we highlight how immunoengineering and advanced delivery systems may be uniquely capable of enhancing vaccine responses in vulnerable populations, such as infants. IMPACT: Immunoengineering and advanced delivery systems are leading to new developments in pediatric vaccinology.Summarizes delivery systems currently in use and development, and prospects for the future.Broad overview of immunoengineering's impact on vaccinology, catering to Pediatric Clinicians and Immunologists.Fig. 1THE FIVE REVOLUTIONS IN VACCINOLOGY.: Attenuation: 1800s onwards; live attenuated smallpox, rabies, tuberculosis (BCG), yellow fever, polio (oral polio vaccine (OPV)) vaccines. Inactivation: 1880s onwards; killed vaccines for typhoid, cholera, whole-cell pertussis, influenza, polio (inactivated polio vaccine (IPV)). Cell culture of viruses: 1950s; of the cornucopia of live vaccines made possible by passage in cell culture, the work by Enders, Robbins, and Weller lead to the Salk and Sabin polio vaccines. Genetic engineering: 1980s: Hepatitis B vaccine (HBV), the first recombinant-antigen-based vaccine, incorporated the viral surface proteins, derived from molecular biology production. Methods to induce cellular immune responses: 2000s; driving the immune system in the T helper 1 direction with stimuli such as vectors and adjuvants.Fig. 2CANDIDATES FOR THE SIXTH REVOLUTION IN VACCINOLOGY.: Combination vaccines: simultaneous administration of vaccines to target multiple diseases. The adjuvant toolbox: ranging from small-molecule adjuvants to combination adjuvants. Vaccines for non-infectious diseases: new treatments for tumors, allergy, or non-infectious disorders (e.g., prevention of drug overdose). Systems vaccinology: Systems biology approaches to identify predictors of vaccine efficacy and explore new insights about protective immunity. Reverse vaccinology: Bioinformatics aided vaccine design from pathogenic genetics. Immunoengineering and delivery systems: Delivering precise materials for specific activation of immune system (right time, right place, right size, right shape, etc.).Fig. 3RECENT ADVANCES IN VACCINE DESIGN TECHNOLOGIES ENABLED BY NOVEL DELIVERY SYSTEMS.: DNA: Plasmid contains DNA sequences encoding the pathogenic antigen(s). RNA: mRNA strand encodes for pathogenic antigen(s). Virus-like particles: multiprotein structures mimicking pathogenic virus however lacking their genome. Broadly neutralizing Abs: target conserved epitopes of the pathogen, regardless of mutation in pathogen (e.g. passive immunization with Palivizumab (RSV treatment)). Antigen display and delivery: antigen presentation on self-assembing nanoparticles to enhance humoral responses (e.g. multivalent display, co-display, immunomodulation, and genetic delivery). Structure-guided antigen design: structural manipulations of vaccine antigens (e.g. conformational stabilization, epitope focusing, epitope scaffolding, and antigenicity modification). Recombinant bacteria: recombinant bacterial vector/bacteria carries pieces of the pathogen. Viral vector: recombinant viral vector/another virus carries pieces of the pathogen.