Case of Yellow Fever Vaccine–Associated Viscerotropic Disease with Prolonged Viremia, Robust Adaptive Immune Responses, and Polymorphisms in CCR5 and RANTES Genes

Pulendran, Bali; Miller, Joseph D.; Querec, Troy D.; Akondy, Rama; Moseley, Nelson B.; Laur, Oskar; Glidewell, John; Monson, Nathan D.; Zhu, Tuofu; Zhu, Haiying; Staprans, Sylvija; Lee, David; Brinton, Margo A.; Perelygin, Andrey A.; Vellozzi, Claudia; Brachman, Philip S.; Lalor, Susan; Teuwen, Dirk E.; Eidex, Rachel B.; Cetron, Martín S.; Priddy, Frances; Rı́o, Carlos del; Altman, John D.; Ahmed, Rafi

doi:10.1086/590187

Cited by 113 publications

(73 citation statements)

References 29 publications

(44 reference statements)

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“…In this case we might expect that the magnitude of the CD8 T-cell response will be proportional to the integral of stimulation (which saturates with virus load) over the duration of the acute infection. Indeed, in one of the rare cases where YFV-17D caused a severe (nonfatal) adverse reaction, a prolonged viremia occurring for more than 30 days after vaccination was seen, and it was coupled with large frequency (>50%) of activated CD8 T cells (41). The relationship between the virus and CD8 T-cell responses during persistent infections is more complex and brings into play many factors including the magnitude of the viral load, the duration of infection, and T-cell exhaustion.…”

Section: Discussionmentioning

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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Section: Discussionmentioning

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.

Self Cite

106

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“…In one well studied case there were minor genetic variations on the genes for OAS1 and OAS2 16 that could be responsible for the high virus levels, and this issue should be explored further. In another case, 17 anomalies in the innate immune response with possible disruption of the CCR5-RANTES axis were found. Such breakdown could impair migration of monocytes to sites of infection in tissues, with a milder innate response failing to limit early viral replication although the mounting of adaptive immune response was adequate.…”

Section: Vaccine-associated Viscerotropicmentioning

confidence: 95%

Serious adverse events associated with yellow fever vaccine

Martins

Leal²,

Homma³

2015

Human Vaccines & Immunotherapeutics

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“…1 In the past decade, there have been increased numbers of reports of systemic adverse events, namely YF vaccine-associated neurotropic (YF-AND) and viscerotropic (YF-AVD) disease in primary vaccinees. [2][3][4][5] A review of adverse events reported to the US Vaccine Adverse Event Reporting System (VAERS) from 2000 to 2006 estimated the risks of YF-AND and YF-AVD at 0.4 per 100,000 and 0.8 per 100,000 doses, respectively. 6 YF-AND has a bimodal distribution, with infants and elderly being at highest risk.…”

Section: Introductionmentioning

confidence: 99%

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

Eidex²,

Keyserling

et al. 2013

The American Journal of Tropical Medicine and Hygiene

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Abstract. We evaluated whether coadministration of the yellow fever (YF) virus vaccine with human immunoglobulin (Ig) that contained YF virus-neutralizing antibodies would reduce post-vaccination viremia without compromising immunogenicity and thus, potentially mitigate YF vaccine-associated adverse events. We randomized 80 participants to receive either YF vaccine and Ig or YF vaccine and saline placebo. Participants were followed for 91 days for safety and assessments of viremia and immunogenicity. There were no differences found between the two groups in the proportion of vaccinated participants who developed viremia, seroconversion, cluster of differentiation (CD)-8 + and CD4 + T-cell responses, and cytokine responses. These results argue against one putative explanation for the increased reporting of YF vaccine side effects in recent years (i.e., a change in travel clinic practice after 1996 when hepatitis A prophylaxis with vaccine replaced routine use of pre-travel Ig, thus potentially removing an incidental YF vaccineattenuating effect of anti-YF virus antibodies present in Ig) (ClinicalTrials.gov identifier: NCT00254826).

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Case of Yellow Fever Vaccine–Associated Viscerotropic Disease with Prolonged Viremia, Robust Adaptive Immune Responses, and Polymorphisms in CCR5 and RANTES Genes

Cited by 113 publications

References 29 publications

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

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

Serious adverse events associated with yellow fever vaccine

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

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