Precision Vaccine Development: Cues From Natural Immunity

Abstract

Traditional vaccine development against infectious diseases has been guided by the overarching aim to generate efficacious vaccines normally indicated by an antibody and/or cellular response that correlates with protection. However, this approach has been shown to be only a partially effective measure, since vaccine- and pathogen-specific immunity may not perfectly overlap. Thus, some vaccine development strategies, normally focused on targeted generation of both antigen specific antibody and T cell responses, resulting in a long-lived heterogenous and stable pool of memory lymphocytes, may benefit from better mimicking the immune response of a natural infection. However, challenges to achieving this goal remain unattended, due to gaps in our understanding of human immunity and full elucidation of infectious pathogenesis. In this review, we describe recent advances in the development of effective vaccines, focusing on how understanding the differences in the immunizing and non-immunizing immune responses to natural infections and corresponding shifts in immune ontogeny are crucial to inform the next generation of infectious disease vaccines.

Keywords: adaptive immunity; adjuvants; antigens; immune system; innate immunity; natural infection; vaccines; vita-PAMP.

Figure 1

How precision vaccine design takes cues from natural immunity. Overview of the immune responses, portraying from the perspective of conventional T cell biology, induced by (A) natural infection, (B) pathogen specific vaccines along with their potential advantages and shortcomings and (C) possible hypothesis to overcoming the disadvantages by precision vaccine design. APC, antigen presenting cell, Th, T helper, IL, interleukin, TNF, tumor necrosis factor, T_FH, follicular helper T cell, Treg, regulatory T cells, CTL, cytotoxic CD8⁺ T cell, BCG, Bacille Calmette-Guérin, DTwP, Diphtheria and Tetanus Toxoids along with Whole Cell Pertussis, DTaP, Diphtheria and Tetanus Toxoids along with Acellular Pertussis, LAIV, live attenuated influenza virus, IM, intramuscular, ID, intradermal, IFN, interferon, PT, pertussis toxin, ACT, Adenylate Cyclase Toxin, FHA, filamentous hemagglutinin, LOS, lipo-oligosaccharide, PRN, pertactin, HA, haemagglutinin, NA, neuraminidase, NP, nucleoprotein, TEM, effector memory T cell, TRM, tissue resident memory T cells. Figure is created with BioRender.com.

Figure 2

Precision vaccines design. Overview of strategies to design precision vaccines which can effectively mimic immunity against pathogens as observed post natural infection. Natural infection often leads to immunological imprinting which provides long-term immunity and disease resistance to future exposure of pathogens. However, it can also lead to detrimental effects to the host as observed in disease outcomes. On the contrary, vaccination provides disease resistance but may be associated with waning immunity, insufficient protective immune response either in vulnerable populations or to prevent disease transmission, contraindications for immunocompromised hosts etc. Precision vaccines can guide the development of next generation vaccines by incorporating a toolkit for building vaccines to mimic natural immunity, which includes: i) immunogen design (such as antigens, small molecule TLR or other adjuvants, biological adjuvants such as cytokines); ii) optimizing formulations for targeted delivery to antigen presenting cells which can lead to subsequent long-lasting adaptive immune response (approaches such as hydrogels, cellular vehicles, nanocarriers and microparticles etc.); iii) optimizing delivery routes for enhancing immune response and mimicking the natural exposure to the pathogen (such as transdermal patch, injection site, sprayable gels for nasal routes) and iv) pre-clinical evaluation of vaccine formulations in appropriate animal models can be followed by clinical evaluation in distinct populations. System biology approaches from such clinical trials may be helpful to dissect age- and population specific vaccine-induced cellular and molecular signatures which correlate with protective immunity. Further, usage of human in vitro modelling may accelerate and/or expand hypothesis testing and selection of population specific adjuvants. These approaches can lead to precision vaccines tailored for long-term disease protection while abating disease outcomes associated with natural infection. Figure is created with BioRender.com.