Case of yellow fever vaccine--associated viscerotropic disease with prolonged viremia, robust adaptive immune responses, and polymorphisms in CCR5 and RANTES genes

Abstract

Background: The live attenuated yellow fever vaccine 17D (YF-17D) is one of the most effective vaccines. Despite its excellent safety record, some cases of viscerotropic adverse events develop, which are sometimes fatal. The mechanisms underlying such events remain a mystery. Here, we present an analysis of the immunologic and genetic factors driving disease in a 64-year-old male who developed viscerotropic symptoms.

Methods: We obtained clinical, serologic, virologic, immunologic and genetic data on this case patient.

Results: Viral RNA was detected in the blood 33 days after vaccination, in contrast to the expected clearance of virus by day 7 after vaccination in healthy vaccinees. Vaccination induced robust antigen-specific T and B cell responses, which suggested that persistent virus was not due to adaptive immunity of suboptimal magnitude. The genes encoding OAS1, OAS2, TLR3, and DC-SIGN, which mediate antiviral innate immunity, were wild type. However, there were heterozygous genetic polymorphisms in chemokine receptor CCR5, and its ligand RANTES, which influence the migration of effector T cells and CD14+CD16bright monocytes to tissues. Consistent with this, there was a 200-fold increase in the number of CD14+CD16bright monocytes in the blood during viremia and even several months after virus clearance.

Conclusion: In this patient, viscerotropic disease was not due to the impaired magnitude of adaptive immunity but instead to anomalies in the innate immune system and a possible disruption of the CCR5-RANTES axis.

Figure 1

Analysis of yellow fever virus (YFV) loads and adaptive immune responses in a patient with yellow fever vaccine–associated viscerotropic disease and healthy vaccinees. A, Viral loads in the case patient and healthy vaccinees. White square with error bars, mean and standard error for viral loads in 5 healthy vaccinees. B, Neutralizing antibody (Ab) titers in the case patient and healthy vaccinees. White bar, mean and standard error of titers from 3 normal vaccinees. C and D, Evaluation of T cell function. Peripheral blood mononuclear cells from the case patient or 2 healthy vaccinees were cultured with multiple vesicular stomatitis virus constructs expressing different YFV proteins, and the frequency of interferon (IFN)-γ⁺CD3⁺ T cells was evaluated. The magnitude (C) and breadth (D) of the response is shown. Mean and standard error for the percentage of IFN-γ⁺ T cells for 2 normal vaccinees is shown. E, Flow cytometric analysis of activated HLA-DR+CD38+CD8⁺ effector T cells at day 34 after vaccination. F, Kinetics of activated T cell expansion in the case patient and healthy vaccinees (average from 5 vaccinees). White bar, mean and standard error for the percentage of HLA-DR⁺CD38⁺ CD8⁺ T cells from 5 healthy vaccinees.

Figure 2

Analysis of CD14⁺CD16^bright monocytes, inflammatory mediators, and genetic polymorphisms in a patient with yellow fever vaccine–associated viscerotropic disease and unvaccinated control subjects. A, Flow cytometric analysis of CD14⁺CD16^bright monocytes in case patient and in 6 unvaccinated control subjects matched for age and sex. B, Luminex analysis of proinflammatory cytokines and chemokines in case patient and 6 age and sex-matched, unvaccinated control subjects. C, Genetic polymorphisms in the case patient’s CCR5 and RANTES genes.