Live attenuated vaccines have proven to be the most efficient human vaccines for many serious infectiousdiseases. When compared to their dead counterparts, live vaccines induce superior immune protection andlasting memory. But despite the efficacy of live vaccines, concerns over their safety have led to vaccine refusalby some and withholding their administration to the very young, the elderly and immunocompromised.Preservation and delivery of live vaccines especially to impoverished areas in developing countries is difficultand expensive. Understanding the molecular basis for the efficacy of live vaccines is significant because itwould enable targeting of the relevant immune pathways that induce optimal and long-lasting protectiveimmunity. Importantly, it would set the stage for the development of vaccines that are safe and afford the sameprotection as live vaccines, alleviating public fears and increasing the segment of the population that isvaccinated. We began our work eight years ago with the hypothesis that innate immune cells sense microbialviability as a distinct set of pathogen associated molecular patterns (PAMPs), and we identified bacterialmessenger RNA (mRNA) as a vita-PAMP that signifies bacterial viability and mobilizes a tailored immuneresponse not warranted for dead microorganisms. The Toll-like receptor (TLR) signaling adaptor TRIF plays acentral role here upstream of inflammatory type I interferon and NLRP3 inflammasome pathways. Addingbacterial mRNA to dead bacteria recapitulates these innate responses, and supplementing a dead vaccine withbacterial mRNA (what we call a vita-vaccine) augments its performance in mice. A vita-vaccine performedsimilarly to a live vaccine in uniquely eliciting a follicular T helper cell response (that helps B cells), germinalcenter formation, and B cell isotype class switching, all in a TRIF-dependent manner. These studies providestrong evidence that vita-vaccine versions of existing vaccines could represent a significant advance in beingable to combine the efficacy of live vaccines with the safety of dead vaccines. The three overlapping areas wewill investigate in this project are:1. We will determine how adaptive immunity elicited by the supplementation of a dead bacterial vaccine withthe vita-PAMP bacterial mRNA compares to that elicited by PAMPs such as bacterial lipopeptides and others.2. We will investigate how bacterial mRNA impacts the performance of subunit vaccines. We will test vita-vaccine versions of the licensed anthrax subunit vaccine and Influenza A virus monovalent subunit vaccine.3. We will test a vita-vaccine version of a trivalent inactivated Influenza virus vaccine and compare it to thelive attenuated influenza vaccine. The completion of these studies should provide sufficient experimental evidence to warrant the use ofbacterial mRNAs as superior vita-adjuvants that restore the signatures of microbial viability to dead vaccinesand improve existing inactivated and subunit vaccines for protection against either bacterial or viral diseases.
PROPOSAL NARRATIVEVaccines comprised of live attenuated microorganisms are superior to their dead counterparts; yet concernsabout the safety of live vaccines have dampened their popularity. We discovered that bacterial messengerRNA signals microbial viability to the immune system and when used as an adjuvant augments theperformance of dead vaccines. Armed with bacterial RNA as a new adjuvant; the work we propose here willadvance the development of dead vaccines that work as well as live ones; improve the performance of existingvaccines; and salvage vaccines that may have been shelved due to inefficacy; all while achieving superiorprotection and maintaining desired safety.
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|García-Sastre, Adolfo (2017) Ten Strategies of Interferon Evasion by Viruses. Cell Host Microbe 22:176-184|
|Moretti, Julien; Blander, J Magarian (2017) Cell-autonomous stress responses in innate immunity. J Leukoc Biol 101:77-86|
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|Schotsaert, Michael; García-Sastre, Adolfo (2017) Inactivated influenza virus vaccines: the future of TIV and QIV. Curr Opin Virol 23:102-106|
|Blander, J Magarian (2017) The many ways tissue phagocytes respond to dying cells. Immunol Rev 277:158-173|
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