Research ArticleVACCINES

Amino acid starvation enhances vaccine efficacy by augmenting neutralizing antibody production

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Science Signaling  12 Nov 2019:
Vol. 12, Issue 607, eaav4717
DOI: 10.1126/scisignal.aav4717

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Starving for DENV vaccines

Nearly 50% of the world’s population is considered at risk of infection with dengue virus (DENV), a mosquito-borne RNA virus that can potentially cause lethal disease. The efficacy of currently approved vaccines is poor in people who have not previously encountered DENV. Afroz et al. found that pretreatment of mice with the amino acid starvation mimetic halofuginone (HF) increased the adaptive immune response to a DENV vaccine. Known to activate the nutrient-sensing kinase GCN2, HF promoted phosphorylation of the translation initiation factor eIF2α in immune cells, increased germinal center formation, and increased neutralizing antibody responses. These data demonstrate how activation of this stress-induced kinase improves vaccination.

Abstract

Specific reduction in the intake of proteins or amino acids (AAs) offers enormous health benefits, including increased life span, protection against age-associated disorders, and improved metabolic fitness and immunity. Cells respond to conditions of AA starvation by activating the amino acid starvation response (AAR). Here, we showed that mimicking AAR with halofuginone (HF) enhanced the magnitude and affinity of neutralizing, antigen-specific antibody responses in mice immunized with dengue virus envelope domain III protein (DENVrEDIII), a potent vaccine candidate against DENV. HF enhanced the formation of germinal centers (GCs) and increased the production of the cytokine IL-10 in the secondary lymphoid organs of vaccinated mice. Furthermore, HF promoted the transcription of genes associated with memory B cell formation and maintenance and maturation of GCs in the draining lymph nodes of vaccinated mice. The increased abundance of IL-10 in HF-preconditioned mice correlated with enhanced GC responses and may promote the establishment of long-lived plasma cells that secrete antigen-specific, high-affinity antibodies. Thus, these data suggest that mimetics of AA starvation could provide an alternative strategy to augment the efficacy of vaccines against dengue and other infectious diseases.

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