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Yellow fever virus vaccination: an emblematic model to elucidate robust human immune responses.

ABSTRACT: By preventing infectious diseases, vaccines contribute substantially to public health. Besides, they offer great opportunities to investigate human immune responses. This is particularly true for live-attenuated virus vaccines which cause resolving acute infections and induce robust immunity. The fact that one can precisely schedule the time-point of vaccination enables complete characterization of the immune response over time, short-term and over many years. The live-attenuated Yellow Fever virus vaccine strain YF-17D was developed in the 1930's and gave rise to the 17D-204 and 17DD vaccine sub-strains, administered to over 600 million individuals worldwide. YF vaccination causes a systemic viral infection, which induces neutralizing antibodies that last for a lifetime. It also induces a strong T cell response resembling the ones of acute infections, in contrast to most other vaccines. In spite of its use since 1937, learning how YF vaccination stimulates such strong and persistent immune responses has gained substantial knowledge only in the last decades. Here we summarize the current state of knowledge on the immune response to YF vaccination, and discuss its contribution as a human model to address complex questions on optimal immune responses.

SUBMITTER: Bovay A

PROVIDER: S-EPMC8475614 | biostudies-literature | 2021 Aug

REPOSITORIES: biostudies-literature

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Yellow fever virus vaccination: an emblematic model to elucidate robust human immune responses.

Bovay Amandine A Fuertes Marraco Silvia A SA Speiser Daniel E DE

Human vaccines & immunotherapeutics 20210428 8

By preventing infectious diseases, vaccines contribute substantially to public health. Besides, they offer great opportunities to investigate human immune responses. This is particularly true for live-attenuated virus vaccines which cause resolving acute infections and induce robust immunity. The fact that one can precisely schedule the time-point of vaccination enables complete characterization of the immune response over time, short-term and over many years. The live-attenuated Yellow Fever vi ...[more]

PMID: 33909542

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Project description:The non-human primate (NHP) model (specifically rhesus and cynomolgus macaques) has facilitated our understanding of the pathogenic mechanisms of yellow fever (YF) disease and allowed evaluation of safety and efficacy of YF-17D vaccines. However, the accuracy of this model in mimicking vaccine-induced immunity in humans remains to be fully determined. We used a system biology approach to compare hematological, biochemical, transcriptomic, innate and antibody-mediated immune responses in cynomolgus macaques and human participants following YF-17D vaccination. Immune response progression in cynomolgus macaques followed a similar course as in adult humans, but with slightly earlier onset. Yellow fever virus neutralizing antibody responses occurred earlier in cynomolgus macaques (by Day 7 [D7]), but titers >10 were reached in both species by D14 post-vaccination and were not significantly different by D28 (PRNT50 titers 3.6 Log vs 3.5 Log in cynomolgus macaques and human participants, respectively; p = 0.821). Changes in neutrophils, NK cells, monocytes, T and B cell frequency were higher in cynomolgus macaques and persisted for four weeks versus less than two weeks in humans. Low levels of systemic inflammatory cytokines (IL-1Ra, IL-8, MIP-1α, IP-10, MCP-1 or VEGF) were detected in either or both species, but with no or only slight changes versus baseline. Similar changes in gene expression profiles were elicited in both species. These included enriched and up-regulated type I IFN-associated viral sensing, antiviral innate response, and dendritic cell activation pathways D3–D7 post-vaccination in both species. Hematological and blood biochemical parameters remained relatively unchanged versus baseline in both species. Low level YF-17D viremia (RNAemia) was transiently detected in some cynomolgus macaques (28% [5/18]) but generally absent in humans (except one participant [5%; 1/20]). Importance: Cynomolgus macaques were confirmed as a valid surrogate model for replicating YF-17D vaccine-induced responses in humans, and suggest a key role for type I IFN.

Project description:IntroductionPrompted by recent amendments of Yellow Fever (YF) vaccination guidelines from boost to single vaccination strategy and the paucity of clinical data to support this adjustment, we used the profile of the YF-specific CD8+ T-cell subset profiles after primary vaccination and neutralizing antibodies as a proxy for potentially longer lasting immunity.Methods and findingsPBMCs and serum were collected in six individuals on days 0, 3, 5, 12, 28 and 180, and in 99 individuals >10 years after YF-vaccination. Phenotypic characteristics of YF- tetramer+ CD8+ T-cells were determined using class I tetramers. Antibody responses were measured using a standardized plaque reduction neutralization test (PRNT). Also, characteristics of YF-tetramer positive CD8+ T-cells were compared between individuals who had received a primary- and a booster vaccination. YF-tetramer+ CD8+ T-cells were detectable on day 12 (median tetramer+ cells as percentage of CD8+ T-cells 0.2%, range 0.07-3.1%). On day 180, these cells were still present (median 0.06%, range 0.02-0.78%). The phenotype of YF-tetramer positive CD8+ T-cells shifted from acute phase effector cells on day 12, to late differentiated or effector memory phenotype (CD45RA-/+CD27-) on day 28. Two subsets of YF-tetramer positive T-cells (CD45RA+CD27- and CD45RA+CD27+) persisted until day 180. Within all phenotypic subsets, the T-bet: Eomes ratio tended to be high on day 28 after vaccination and shifted towards predominant Eomes expression on day 180 (median 6.0 (day 28) vs. 2.2 (day 180) p = 0.0625), suggestive of imprinting compatible with long-lived memory properties. YF-tetramer positive CD8+ T-cells were detectable up to 18 years post vaccination, YF-specific antibodies were detectable up to 40 years after single vaccination. Booster vaccination did not increase titers of YF-specific antibodies (mean 12.5 vs. 13.1, p = 0.583), nor induce frequencies or alter phenotypes of YF-tetramer+ CD8+ T-cells.ConclusionThe presence of a functionally competent YF-specific memory T-cell pool 18 years and sufficient titers of neutralizing antibodies 35-40 years after first vaccination suggest that single vaccination may be sufficient to provide long-term immunity.

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Yellow fever virus vaccination: an emblematic model to elucidate robust human immune responses.

Publications

Yellow fever virus vaccination: an emblematic model to elucidate robust human immune responses.

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