Immunity to viruses: learning from successful human vaccines

Abstract

For more than a century, immunologists and vaccinologists have existed in parallel universes. Immunologists have for long reveled in using 'model antigens', such as chicken egg ovalbumin or nitrophenyl haptens, to study immune responses in model organisms such as mice. Such studies have yielded many seminal insights about the mechanisms of immune regulation, but their relevance to humans has been questioned. In another universe, vaccinologists have relied on human clinical trials to assess vaccine efficacy, but have done little to take advantage of such trials for studying the nature of immune responses to vaccination. The human model provides a nexus between these two universes, and recent studies have begun to use this model to study the molecular profile of innate and adaptive responses to vaccination. Such 'systems vaccinology' studies are beginning to provide mechanistic insights about innate and adaptive immunity in humans. Here, we present an overview of such studies, with particular examples from studies with the yellow fever and the seasonal influenza vaccines. Vaccination with the yellow fever vaccine causes a systemic acute viral infection and thus provides an attractive model to study innate and adaptive responses to a primary viral challenge. Vaccination with the live attenuated influenza vaccine causes a localized acute viral infection in mucosal tissues and induces a recall response, since most vaccinees have had prior exposure to influenza, and thus provides a unique opportunity to study innate and antigen-specific memory responses in mucosal tissues and in the blood. Vaccination with the inactivated influenza vaccine offers a model to study immune responses to an inactivated immunogen. Studies with these and other vaccines are beginning to reunite the estranged fields of immunology and vaccinology, yielding unexpected insights about mechanisms of viral immunity. Vaccines that have been proven to be of immense benefit in saving lives offer us a new fringe benefit: lessons in viral immunology.

Keywords: Toll-like receptors; dendritic cells; vaccination.

Figure 1

Systems biological approach to identifying molecular signatures of vaccination in humans. High throughput techniques such as transcriptomics (RNA-seq; microarrays), proteomics, CyTOF, luminex and metabolomics can be used to detect molecular signatures induced early after vaccination. Bioinformatics analyses of the data generated can be used to determine signatures that correlate with the ensuing adaptive immune response or protective immunity. The robustness of such signatures, and their ability to predict the immunogenicity and protective immunity to vaccination, can be tested in an independent “test trial,” (Trial 2).

Figure 2. Innate and adaptive responses to the live attenuated yellow fever vaccine YF-17D

Vaccination with YF-17D results in an acute viral infection during which viral replication peaks between days 5 and 7 becomes undetectable by 14 days post vaccination. Vaccination rapidly induces IgM neutralizing antibody titers which peak at 2 and then decline, but can be detected for as long as 18 months post vaccination. Virus-specific IgG neutralizing antibody titers develop more slowly and can persist for up to 40 years. Vaccination induces virus-specific CD8⁺ T cell responses, which develop rapidly after immunization, peaking at day 15 (with roughly 2-13% of CD8⁺ T cells being activated at day 15) but reaching near baseline levels by day 30. Vaccination also induces a mixed Th1 and Th2 CD4⁺ T cell response. A robust innate response develops within hours and seems to persist for more than 15 days, likely caused by persisting viral replication in the blood, during the first 7 days or so. YF-17D activates multiple subsets of DCs via several different PRRs. This results in a mixed Th1/Th2 response, and may also impact the persistence of the antibody response. YF-17D also activates mammalian target of rapamycin (mTOR) in plasmacytoid DCs, via a mechanism dependent on TLR7, and this leads to phosphorylation of interferon regulatory factor 7 (IRF7). This results in induction of IFNα which activate CD8⁺ T cells.

Figure 3. The integrated stress response

Mammalian cells have evolved at least four different sensors that can detect environmental stresses of various kinds. GCN2 (EIF2AK4) senses changes in amino acid concentrations, PKR senses viral infections, HRI senses heme deprivation oxidative stress and heat shock and PEK or PERK senses endoplasmic reticulum stress. Activation of any one of these sensors results in the phosphorylation of eIF2α, which leads to the shut down of housekeeping mRNA, and their compartmentalization in stress granules in the cytosol.