A Randomized, Double-Blind, Controlled Trial of the 17D Yellow Fever Virus Vaccine Given in Combination with Immune Globulin or Placebo: Comparative Viremia and Immunogenicity

Edupuganti, Srilatha; Eidex, Rachel B.; Keyserling, Harry L.; Akondy, Rama; Lanciotti, Robert S.; Orenstein, Walter A.; Rı́o, Carlos del; Pan, Yi; Querec, Troy D.; Lipman, Harvey; Barrett, Alan D.T.; Ahmed, Rafi; Teuwen, Dirk E.; Cetron, Martín S.; Mulligan, Mark J.

doi:10.4269/ajtmh.2012.12-0179

Cited by 28 publications

(31 citation statements)

References 28 publications

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“…Yellow fever vaccine recipients received the Food and Drug Administration-approved 17D yellow fever vaccine (37). Plasma samples from HIV-uninfected candidate vaccine recipients from the HVTN068 trial (38) were analyzed for CXCL13 in plasma after a booster immunization (Ad5/HIV) given at the 6-mo time point.…”

Section: Methodsmentioning

confidence: 99%

“…Two separate cohorts were studied. The first cohort was a vaccine cohort immunized with the Food and Drug Administration-approved yellow fever virus vaccine (37). The second group comprised study participants in an HIV Vaccine Trials Network (HVTN) protocol testing a candidate HIV vaccine regimen (HVTN068) (38).…”

Section: Plasma Cxcl13 Is Correlated With Gc Activity In Macaques Aftermentioning

confidence: 99%

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CXCL13 is a plasma biomarker of germinal center activity

Havenar-Daughton

Lindqvist

Heit

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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282

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Significantly higher levels of plasma CXCL13 [chemokine (C-X-C motif) ligand 13] were associated with the generation of broadly neutralizing antibodies (bnAbs) against HIV in a large longitudinal cohort of HIV-infected individuals. Germinal centers (GCs) perform the remarkable task of optimizing B-cell Ab responses. GCs are required for almost all B-cell receptor affinity maturation and will be a critical parameter to monitor if HIV bnAbs are to be induced by vaccination. However, lymphoid tissue is rarely available from immunized humans, making the monitoring of GC activity by direct assessment of GC B cells and germinal center CD4 + T follicular helper (GC Tfh) cells problematic. The CXCL13-CXCR5 [chemokine (C-X-C motif) receptor 5] chemokine axis plays a central role in organizing both B-cell follicles and GCs. Because GC Tfh cells can produce CXCL13, we explored the potential use of CXCL13 as a blood biomarker to indicate GC activity. In a series of studies, we found that plasma CXCL13 levels correlated with GC activity in draining lymph nodes of immunized mice, immunized macaques, and HIV-infected humans. Furthermore, plasma CXCL13 levels in immunized humans correlated with the magnitude of Ab responses and the frequency of ICOS + (inducible T-cell costimulator) Tfh-like cells in blood. Together, these findings support the potential use of CXCL13 as a plasma biomarker of GC activity in human vaccine trials and other clinical settings.T he germinal center (GC) reaction is a critical immunological process that occurs in draining lymph nodes after immunization (1). The GC response consists of antigen-specific B cells undergoing affinity maturation through a process of somatic hypermutation (SHM) of the B-cell receptor. SHM is necessary for producing high-affinity Ab responses after immunizations and infections. Influenza neutralizing Abs have substantial SHM. Particularly high levels of SHM, 15-30% amino acid mutation (2, 3), are present and necessary for broad Ab neutralization of diverse HIV strains (4, 5). Therefore, as candidate influenza and HIV vaccines are evaluated for the ability to induce broadly neutralizing antibodies (bnAbs), the quantitation and functional characterization of GC responses will be a key parameter for study. Serological analysis of vaccine-specific Ab titers provides important information, but those data are limited. Serological outcomes are measured at time points long after initial immunizations. Neutralizing Ab responses are commonly only measurable after multiple boosts. Those outcomes likely depend on GC activity and affinity maturation at much earlier time points. Several state of the art HIV vaccine strategies rely on long, multistage immunization protocols (6, 7). With bnAb responses as the goal, means of early analysis of the immune response will be essential to understand and improve on vaccination schemes that may end in failure or only partial success. One critical parameter to assess will be the ability of each immunization to generate GC responses.Central to the GC re...

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Section: Methodsmentioning

confidence: 99%

Section: Plasma Cxcl13 Is Correlated With Gc Activity In Macaques Aftermentioning

confidence: 99%

CXCL13 is a plasma biomarker of germinal center activity

Havenar-Daughton

Lindqvist

Heit

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

282

310

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“…followed a large cohort of 80 individuals with intensive sampling at days 0, 1, 2, 3, 5, 7, 9, 11, 14, 30, and 90 postvaccination to quantify viral load in plasma (39). Additionally, we quantified the magnitude of the YFV-specific effector CD8 T-cell response at days 0, 3, 7, 14, 30, and 90 postvaccination using the Ki-67 + Bcl-2 lo phenotype.…”

mentioning

confidence: 99%

Initial viral load determines the magnitude of the human CD8 T cell response to yellow fever vaccination

Akondy

Johnson²,

Nakaya

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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106

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CD8 T cells are a potent tool for eliminating intracellular pathogens and tumor cells. Thus, eliciting robust CD8 T-cell immunity is the basis for many vaccines under development. However, the relationship between antigen load and the magnitude of the CD8 T-cell response is not well-described in a human immune response. Here we address this issue by quantifying viral load and the CD8 T-cell response in a cohort of 80 individuals immunized with the live attenuated yellow fever vaccine (YFV-17D) by sampling peripheral blood at days 0, 1, 2, 3, 5, 7, 9, 11, 14, 30, and 90. When the virus load was below a threshold (peak virus load < 225 genomes per mL, or integrated virus load < 400 genome days per mL), the magnitude of the CD8 T-cell response correlated strongly with the virus load (R 2 ∼ 0.63). As the virus load increased above this threshold, the magnitude of the CD8 T-cell responses saturated. Recent advances in CD8 T-cell-based vaccines have focused on replication-incompetent or single-cycle vectors. However, these approaches deliver relatively limited amounts of antigen after immunization. Our results highlight the requirement that T-cellbased vaccines should deliver sufficient antigen during the initial period of the immune response to elicit a large number of CD8 T cells that may be needed for protection.vaccines | human CD8 T cells | viral load | effector T cells | immune memory C D8 T cells provide a powerful mechanism for elimination of intracellular pathogens and tumor cells. Accordingly, a major thrust of current vaccine research focuses on stimulating robust T-cell immunity for defense against infections such as HIV, malaria, tuberculosis, Ebola virus, herpes viruses, and hepatitis C virus (HCV) (1-8). Inducing effective CD8 T-cell immunity is also an important goal for cancer vaccines (9, 10). However, how antigen load affects the CD8 T-cell response has not been quantified in a detailed manner during a human immune response. In this study we address this question using the human live attenuated yellow fever vaccine (YFV-17D) vaccine.The dynamics of CD8 T-cell responses to intracellular infection have been extensively studied in model systems. Infection typically stimulates a rapid burst of proliferation in antigenspecific CD8 T cells with division occurring as quickly as once in 4-6 h (11). This expansion results in a large population of effector CD8 T cells that aid in clearance of infected cells. Although most (90-95%) of the effector CD8 T cells die, a small fraction differentiate to form long-term memory CD8 T cells (12). Detailed quantitative measurements of the dynamics of virus and the CD8 T-cell response to the YFV-17D vaccine allow us to characterize these basic features of the CD8 T-cell responses in humans. Additionally, tracking the dynamics of both virus and CD8 T cells over time in a large cohort allows us to explore the relationship between amount of antigen and the magnitude of expansion and answer the following questions: Is there a threshold amount of virus required to generate a r...

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“…25,26 When the level of viremia is too high and persists for too long, unwanted adverse events may occur. In contrast, when viremia is absent the viral replication may be too limited to produce sufficient antigens to stimulate the magnitude of immune response required for protection.…”

Section: Yellow Fever and Yellow Fever Vaccinesmentioning

confidence: 99%

“…26 Many CD8 1 T cell epitopes have been mapped on the E protein and all of the NS proteins (NS1, NS2a, NS2b, NS3, NS4a, NS4b, and NS5) in vaccines with divergent HLA types who received YF-17D. 46 Some epitopes are preferentially associated with specific HLA types: HLA-B35-restricted cytotoxic T lymphocyte epitopes are mainly found on the NS1, NS2b, NS3, and E proteins, whereas a dominant HLA-A2-restricted epitope is found on the NS4b protein.…”

Section: Cd8mentioning

confidence: 99%

Guiding dengue vaccine development using knowledge gained from the success of the yellow fever vaccine

2015

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Flaviviruses comprise approximately 70 closely related RNA viruses. These include several mosquito-borne pathogens, such as yellow fever virus (YFV), dengue virus (DENV), and Japanese encephalitis virus (JEV), which can cause significant human diseases and thus are of great medical importance. Vaccines against both YFV and JEV have been used successfully in humans for decades; however, the development of a DENV vaccine has encountered considerable obstacles. Here, we review the protective immune responses elicited by the vaccine against YFV to provide some insights into the development of a protective DENV vaccine.

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A Randomized, Double-Blind, Controlled Trial of the 17D Yellow Fever Virus Vaccine Given in Combination with Immune Globulin or Placebo: Comparative Viremia and Immunogenicity

Cited by 28 publications

References 28 publications

CXCL13 is a plasma biomarker of germinal center activity

CXCL13 is a plasma biomarker of germinal center activity

Initial viral load determines the magnitude of the human CD8 T cell response to yellow fever vaccination

Guiding dengue vaccine development using knowledge gained from the success of the yellow fever vaccine

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