Human Effector and Memory CD8+ T Cell Responses to Smallpox and Yellow Fever Vaccines

Miller, Joseph D.; Most, Robbert G. van der; Akondy, Rama; Glidewell, John; Albott, Sophia; Masopust, David; Murali‐Krishna, Kaja; Mahar, Patryce L.; Edupuganti, Srilatha; Lalor, Susan; Germon, Stéphanie; Rı́o, Carlos del; Mulligan, Mark J.; Staprans, Silvija I.; Altman, John D.; Feinberg, Mark B.; Ahmed, Rafi

doi:10.1016/j.immuni.2008.02.020

Cited by 557 publications

(689 citation statements)

References 70 publications

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“…This molecule has recently been shown to be expressed together with HLA-DR, Ki-67 and a downregulated Bcl-2 on almost all YFV-17D-specific CD8 + T cells in the primary vaccination phase [9]. Similar to YFV-17D-specific CD4 + T cells (Fig.…”

Section: Cd8 + T Cellsmentioning

confidence: 69%

“…The systemic response to YFV-17D vaccination was analyzed on the molecular level in detail and the B-cell growth factor TNFRS17 has been identified as a predictor of height of neutralizing antibody titers [12]. Yet the early cellular events leading to such an accurate activation of all three branches of adaptive immunity have not yet been elucidated in detail, as so far most studies focused on later time points [7][8][9][10].In order to decipher the immunological processes inducing a robust and persistent protective immune response, we have performed a detailed analysis of the activation and differentiation kinetics of various cell types of both the innate and the adaptive immune system in the course of YFV-17D vaccination. We observed activation of DCs and polyfunctional YFV-specific CD4 + T cells at early time points after vaccination, correlating with the magnitude of the neutralizing antibody response specific for YFV-17D.…”

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confidence: 99%

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The early cellular signatures of protective immunity induced by live viral vaccination

et al. 2012

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Here, we have used primary vaccination of healthy donors with attenuated live yellow fever virus 17D (YFV-17D) as a model to study the generation of protective immunity. In short intervals after vaccination, we analyzed the induction of YFV-17D specific T-and B-cell immunity, bystander activation, dendritic cell subsets, changes in serum cytokine levels, and YFV-17D-specific antibodies. We show activation of innate immunity and a concomitant decline of numbers of peripheral blood T and B cells. An early peak of antigen-specific T cells at day 2, followed by mobilization of innate immune cells, preceded the development of maximal adaptive immunity against YFV-17D at day 14 after vaccination. Interestingly, potent adaptive immunity as measured by high titers of neutralizing YFV-17D-specific antibodies, correlated with early activation and recruitment of YFV-17D-specific CD4 + T cells and higher levels of sIL-6R. Thus our data might provide new insights into the interplay of innate and adaptive immunity for the induction of protective immunity. Keywords: Immune responses r Protective immunity r T cells r Vaccination r Yellow fever virus Supporting Information available online IntroductionVaccines were introduced into modern medicine about 300 years ago and are now administered to millions of people every year, conferring efficient protection against a variety of toxins as well as bacterial and viral diseases. However, the complex interplay of innate and adaptive immune cells, particularly in the first few Correspondence: Dr. Siegfried Kohler e-mail: siegfried.kohler@charite.de days after vaccination, leading to protective immunity after challenge with an innocuous agent is still incompletely understood. Yet this information might be crucial to developing new vaccines or improving current vaccinations with respect to efficiency, especially in risk groups and prevention of side effects.In order to assess early events in the course of a defined protective immune response, we studied vaccination of healthy * These authors contributed equally to this work. Eur. J. Immunol. 2012. 42: 2363-2373 humans with the 17D yellow fever virus vaccine (YFV-17D 5] and efficiently induce DC maturation, characterized by upregulation of CD86, CD80, MHC class II, and CD40. Barba-Spaeth et al. detected YFV-17D-dependent infection of human DCs irrespective of their maturation state but no infection of monocytes [6]. In vivo, the activation of B-and T cells has been shown to occur between day 4 and day 15 in YFV-17D vaccinated subjects, characterized by the expression of phenotypic markers such as CD69 or IL-10-R on CD8 + T and B cells and HLA-DR on CD4 + T cells [7]. A persistent, broadly reactive CD4 + T-cell response with a mixed TH1/TH2 phenotype was observed [8]. The maximal expansion of CD8 + T cells was detectable at day 30 with 0.5 to 17% of CD8 + T cells recognized by tetramers, yet activation determined by expression of HLA-DR + , CD38 + , KI-67 high , and BCL-2 low , among YFV-17D-specific CD8 + T cells was already detected at ...

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Section: Cd8 + T Cellsmentioning

confidence: 69%

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confidence: 99%

The early cellular signatures of protective immunity induced by live viral vaccination

et al. 2012

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“…Previous studies with two highly effective vaccines in humans, the yellow fever virus (YFV) vaccine and the smallpox vaccine, have indicated measurement of cytokine-producing T cells alone may vastly underestimate the total frequency and functional diversity of vaccine-induced T-cell responses (21). Moreover, these studies, using tetramers to detect specific cells, indicated measurement of activation markers can accurately identify vaccine-induced populations of effector CD8 T cells (21).…”

Section: Discussionmentioning

confidence: 99%

Induction and Regulation of T-Cell Immunity by the Novel Tuberculosis Vaccine M72/AS01 in South African Adults

Day

Tameris

Mansoor

et al. 2013

Am J Respir Crit Care Med

108

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Rationale: Tuberculosis (TB) is a major cause of morbidity and mortality worldwide, thus there is an urgent need for novel TB vaccines. Objectives: We investigated a novel TB vaccine candidate, M72/ AS01, in a phase IIa trial of bacille Calmette-Gué rin-vaccinated, HIV-uninfected, and Mycobacterium tuberculosis (Mtb)-infected and -uninfected adults in South Africa. Methods: Two doses of M72/AS01 were administered to healthy adults, with and without latent Mtb infection. Participants were monitored for 7 months after the first dose; cytokine production profiles, cell cycling, and regulatory phenotypes of vaccine-induced T cells were measured by flow cytometry. Measurements and Main Results: The vaccine had a clinically acceptable safety profile, and induced robust, long-lived M72-specific T-cell and antibody responses. M72-specific CD4 T cells produced multiple combinations of Th1 cytokines. Analysis of T-cell Ki67 expression showed that most vaccination-induced T cells did not express Th1 cytokines or IL-17; these cytokine-negative Ki67 1 T cells included subsets of CD4 T cells with regulatory phenotypes. PD-1, a negative regulator of activated T cells, was transiently expressed on M72-specific CD4 T cells after vaccination. Specific T-cell subsets were present at significantly higher frequencies after vaccination of Mtb-infected versus -uninfected participants. Conclusions: M72/AS01 is clinically well tolerated in Mtb-infected and -uninfected adults, induces high frequencies of multifunctional T cells, and boosts distinct T-cell responses primed by natural Mtb infection. Moreover, these results provide important novel insights into how this immunity may be appropriately regulated after novel TB vaccination of Mtb-infected and -uninfected individuals. Clinical trial registered with www.clinicaltrials.gov (NCT 00600782).Keywords: tuberculosis; vaccine; T cell; cytokine; proliferation Tuberculosis (TB) remains a major cause of morbidity and mortality, with approximately 9 million new cases and 1.5 million deaths worldwide each year (1). Bacille Calmette-Guérin (BCG) provides protection against miliary TB and TB meningitis in children (2); however, BCG provides variable efficacy against pulmonary TB in adults (3), the most common clinical manifestation of the disease. Mycobacterium tuberculosis (Mtb) is transmitted primarily by adults; therefore novel, effective TB vaccines are urgently needed to target this population, and thereby reduce the burden of TB disease worldwide.Phase I and II clinical trials of several novel candidate TB vaccines have either been completed or are currently ongoing (4). These vaccines include the candidate recombinant fusion protein vaccine M72, formulated with GlaxoSmithKline Vaccines Approximately one-third of the world's population is infected with Mycobacterium tuberculosis (Mtb), and despite the widespread use of the bacille Calmette-Guérin vaccine, tuberculosis (TB) remains a major cause of morbidity and mortality. There is an urgent need to develop novel TB vaccines that are safe,...

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“…Analysis of activated virus-specific and total CD8 T cells in 50 patients with acute HBV, dengue, influenza, and adenovirus infections show that HCMV-and EBV-specific CD8 T cells are activated, proliferate, and have increased production of IFN-ɣ during heterologous infection (Sandalova et al 2010). Conversely, vaccination for yellow fever or vaccinia virus did not induce activation or proliferation of EBVand HCMV-specific CD8 T cells, despite robust CD8 T cell responses (Miller et al 2008).…”

Section: Acute Co-infectionmentioning

confidence: 99%

A constant companion: immune recognition and response to cytomegalovirus with aging and implications for immune fitness

Souquette¹,

Frere²,

Smithey³

et al. 2017

GeroScience

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Approximately 50% of individuals aged 6-49 years in the United States are infected with cytomegalovirus (CMV), with seroprevalence increasing with age, reaching 85-90% by 75-80 years according to Bate et al. (Clin Infect Dis 50 (11): 1439-1447 and Pawelec et al. (Curr Opin Immunol 24:507-511, 2012). Following primary infection, CMV establishes lifelong latency with periodic reactivation. Immunocompetent hosts experience largely asymptomatic infection, but CMV can cause serious illness in immunocompromised populations, such as transplant patients and the elderly. Control of CMV requires constant immune surveillance, and recent discoveries suggest this demand alters general features of the immune system in infected individuals. Here, we review recent advances in the understanding of the immune response to CMV and the role of CMV in immune aging and fitness, while highlighting the importance of potential confounding factors that influence CMV studies. Understanding how CMV contributes to shaping Bbaseline^immunity has important implications for a host's ability to mount effective responses to diverse infections and vaccination.

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Human Effector and Memory CD8+ T Cell Responses to Smallpox and Yellow Fever Vaccines

Cited by 557 publications

References 70 publications

The early cellular signatures of protective immunity induced by live viral vaccination

The early cellular signatures of protective immunity induced by live viral vaccination

Induction and Regulation of T-Cell Immunity by the Novel Tuberculosis Vaccine M72/AS01 in South African Adults

A constant companion: immune recognition and response to cytomegalovirus with aging and implications for immune fitness

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