Characterization of main cytokine sources from the innate and adaptive immune responses following primary 17DD yellow fever vaccination in adults
Introduction
Yellow fever (YF) is a severe viral disease of humans caused by YF virus, a mosquito-transmitted member of the Flaviviridae family with clinical spectrum ranging from subclinical infection to overwhelming pansystemic disease [1], [2]. The disease is endemic in sub-Saharan Africa and tropical regions of South America and also in several Caribbean islands. In the past 20 years, the global epidemic arboviral activity has dramatically increased with more than 200,000 cases and 30,000 deaths registered a year [3], [4]. The disease can be prevented by a live attenuated vaccine, originally prepared from the 17D strain, and developed following successive passages of wild-type YF strain Asibi in mouse and chicken tissue. Two substrains are currently used worldwide, 17D-204 and 17DD, which are at passages 235–240 and 287–289, respectively, from wild-type Asibi virus [5], [6].
A single immunization induces seroconversion in more than 95% of recipients with long-lasting neutralizing antibody levels besides YF-specific T-cell responses with minimal incident of severe side effects [5], [7], [8], [9]. Since 1937, this vaccine has protected more than 400 million humans from YF and it is considered as one of the most successful live attenuated vaccines available [10], [11], [12]. Despite this outstanding efficacy, the mechanisms underlying the robust immunity triggered by the 17D-204 and 17DD YF vaccines are still poorly understood.
Although, the humoral immune response induced by the YF vaccine is generally considered as the main mediator of protection against infection with wild-type YF virus, the cellular immunity, both innate and adaptive, has been pointed out as an important event playing pivotal role to generate an effective protection following YF vaccination with YF-17DD (FIOCRUZ), YF-VAX (Aventis Pasteur) and YF-VAX (Connaught Laboratories) [9], [13], [14], [15], [16], [17], [18].
Recently, a novel proposal has been raised by the scientific community, suggesting that the induction of complex immune response, including activation/modulation events as well as a mixed cytokine profile, is in fact triggered by the YF-17D vaccination, which seems to play a pivotal role in inducing a protective immunity and in avoiding adverse reactions in primo-vaccinees [13], [14], [15], [16], [17], [19], [20].
In the current report, we have performed a detailed investigation of intracytoplasmic cytokine pattern of peripheral blood innate and adaptive leukocytes aiming to characterize the kinetics and the major sources of cytokines following first-time vaccination with YF-17DD. Our findings confirmed the existence of mixed pattern of cytokines following YF vaccination, highlighting in the innate immunity compartment the relevance of neutrophils and monocytes as an early source of TNF-α and NK-cells supplying IFN-γ, both counterbalanced by enhanced levels of IL-10+ monocytes. In the adaptive immunity environment the early and transient downregulation of cytokine synthesis by CD4+ T-cells were prompt changed toward a mixed profile characterized by enhanced frequency of IFN-γ+, TNF-α+ and IL-5+ CD4+ T-cells with CD8+ T-cells pointed as a late source of IL-12 and IL-5. B-cells were identified as the source of IL-10 at day 15, when seroconversion was observed in all vaccinees. The overall cytokine signature showed that the transient pro-inflammatory profile observed at day 7, mainly due to the innate immunity cells, draws back toward a mixed or modulated pattern at day 15 and day 30 in most vaccinees.
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Study population
This longitudinal investigation consisted of four consecutive analysis of 10 healthy volunteers, aged 21–51 years with no history of previous YF vaccination or infection with the wild-type YF virus, confirmed by negative plaque reduction neutralization test (PRNT), carried out at Laboratório de Virologia, Departamento de Microbiologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais under supervision of Dra. Erna Geessien Kroon.
Each volunteer was vaccinated subcutaneously
Prominent participation of innate immunity is observed in healthy adults after YF-17DD primo-vaccination
Aiming to characterize the pro- and anti-inflammatory cytokine profiles of innate immunity cells following YF-17DD vaccination, we have analyzed the ex vivo intracytoplasmic cytokine pattern of peripheral blood leukocytes after short-term culture of whole blood samples, particularly in the absence of exogenous stimuli, here referred as non-stimulated culture (Fig. 1). Our data showed a prominent involvement of innate immunity cells, as demonstrated by increased frequency of TNF-α+ neutrophils
Discussion
The major goal of this study was to identify the major sources of pro- and anti-inflammatory cytokines, aiming to add new elements to the complex cytokine network triggered by the YF-17DD primo-vaccination. These findings may help not only for the understanding of the immunological mechanism underlying the establishment of protective immunity but also supply new insights to support the investigation of severe adverse diseases following YF-17D vaccination. Moreover, considering the outstanding
Acknowledgments
This work was supported by Centro de Pesquisas René Rachou – FIOCRUZ-MG and Instituto Bio-manguinhos – FIOCRUZ-RJ by the grant # carta compromisso 05/05 05/08, CNPq (Grant #422782/09) and FAPEMIG (APQ 01183-08). The authors thank the program for technological development in tools for health – PDTIS – FIOCRUZ for the use of its facilities. EGK, ATC and OAMF thank CNPq for fellowships (PQ). ACCA acknowledge the FAPEMIG for the fellowship (PDJ 00265/09).
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