Preexisting influenza-specific CD4+ T cells correlate with disease protection against influenza challenge in humans

Wilkinson, Tom; Ckf., Li; Csc., Chui; Aky., Huang; Perkins, Molly R.; Liebner, Julia; Lambkin‐Williams, Robert; Gilbert, Anthony; Oxford, J. S.; Nicholas, Ben; Staples, Karl J.; Dong, Tao; Douek, Daniel C.; McMichael, Andrew J.; Xu, Xiao-Ning

doi:10.1038/nm.2612

Cited by 902 publications

(973 citation statements)

References 36 publications

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“…The CD8/CD4 bead depletion was validated by Wilkinson et al 32 We found both CD4-and CD8-dependent T-cell responses in the early phases of infection (Fig. 2b).…”

Section: Rdrp-specific T-cell Responses Detected In Healthy Adults Busupporting

confidence: 75%

“…44,45 Pre-existing influenza-specific CD4 + T cells were shown to correlate with disease protection in humans challenged with influenza infection. 32 HFMD is typically mild or even asymptomatic in adults, a large proportion of whom have come into contact with the virus and hence serve as a reservoir for EV71 transmission. 40 Among the most intriguing observations in the present study is that CD4-dependent EV71 RdRp-specific but not VP1-specific T-cell responses were predominantly found in healthy adults, together with the observation that there was no association between T-cell responses and disease severity.…”

Section: Discussionmentioning

confidence: 99%

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Dominant CD4‐dependent RNA‐dependent RNA polymerase‐specific T‐cell responses in children acutely infected with human enterovirus 71 and healthy adult controls

Dang

Gao

et al. 2014

Immunology

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SummaryHuman enterovirus 71 (EV71) is one of the major causes of hand, foot and mouth disease (HFMD), which leads to significant mortality in infected children. A prophylactic vaccine is urgently needed. However, little is known about the protective T-cell immunity in individuals infected with the EV71 virus. In this study, we performed a comprehensive ex vivo interferon-c ELISPOT analysis in 31 children infected with EV71 as well as in 40 healthy adult controls of the CD4 + and CD8 + T-cell responses to overlapping peptides spanning the VP1 structural protein and RNAdependent RNA polymerase (RdRp) non-structural protein. EV71-specific CD4 T-cell responses were detected in most of the acute patients and were mostly CD4-dependent RdRp-specific responses. CD8-dependent VP1 and RdRp-specific responses were also detected in a small proportion of recently infected children. There was no significant association between the strength of the T-cell responses and disease severity observed during the acute EV71 infection phase. Interestingly, an RdRp-specific, but no VP1-specific, CD4-dependent T-cell response was detected in 30% of the adult controls, and no T-cell responses were detected in healthy children. In addition, 24 individual peptides containing potential T-cell epitope regions were identified. The data suggest that CD4-dependent RdRp-specific T-cell responses may play an important role in protective immunity, and the epitopes identified in this study should provide valuable information for future therapeutic and prophylactic vaccine design as well as basic research.

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“…The CD8/CD4 bead depletion was validated by Wilkinson et al 32 We found both CD4-and CD8-dependent T-cell responses in the early phases of infection (Fig. 2b).…”

Section: Rdrp-specific T-cell Responses Detected In Healthy Adults Busupporting

confidence: 75%

Section: Discussionmentioning

confidence: 99%

Dominant CD4‐dependent RNA‐dependent RNA polymerase‐specific T‐cell responses in children acutely infected with human enterovirus 71 and healthy adult controls

Dang

Gao

et al. 2014

Immunology

Self Cite

View full text Add to dashboard Cite

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“…Most immune protection studies are carried out in animal models where challenge studies are feasible and mechanisms of protection can be identified by loss or gain of function. Human challenge studies are, however, becoming more frequent and have also demonstrated that cytokine‐producing memory CD4 T‐cells correlate with reduced symptoms following pathogen challenge 21, 22, 23…”

Section: Cytokine Production Is Key To Cd4 T‐cell Protective Immunitymentioning

confidence: 99%

The roles of resident, central and effector memory CD4 T‐cells in protective immunity following infection or vaccination

2018

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SummaryImmunological memory provides rapid protection to pathogens previously encountered through infection or vaccination. CD4 T‐cells play a central role in all adaptive immune responses. Vaccines must, therefore, activate CD4 T‐cells if they are to generate protective immunity. For many diseases, we do not have effective vaccines. These include human immunodeficiency virus (HIV), tuberculosis and malaria, which are responsible for many millions of deaths each year across the globe. CD4 T‐cells play many different roles during the immune response coordinating the actions of many other cells. In order to harness the diverse protective effects of memory CD4 T‐cells, we need to understand how memory CD4 T‐cells are generated and how they protect the host. Here we review recent findings on the location of different subsets of memory CD4 T‐cells that are found in peripheral tissues (tissue resident memory T‐cells) and in the circulation (central and effector memory T‐cells). We discuss the generation of these cells, and the evidence that demonstrates how they provide immune protection in animal and human challenge models.

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“…29 Similarly, mice exposed to pre-pandemic H1N1 develop memory CD4 + T cells that protect against pH1N1 infection. 30 In clinical vaccine studies, a single dose of monovalent pH1N1 vaccine generates neutralizing antibodies, suggesting that memory CD4 + T cells are able to support naïve B cell responses to a novel HA. 31–33 Importantly, it was shown that T cell epitopes common to pH1N1 and pre-pandemic HA stimulated memory CD4 + T cell responses; epitopes unique to pH1N1 HA failed to mount a significant CD4 + T cell response.…”

Section: Memory Cd4+ T Cells Contribute To Protection Against Influenzamentioning

confidence: 99%

T cell epitope engineering: an avian H7N9 influenza vaccine strategy for pandemic preparedness and response

Moise

Biron

Boyle

et al. 2018

Human Vaccines & Immunotherapeutics

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The delayed availability of vaccine during the 2009 H1N1 influenza pandemic created a sense of urgency to better prepare for the next influenza pandemic. Advancements in manufacturing technology, speed and capacity have been achieved but vaccine effectiveness remains a significant challenge. Here, we describe a novel vaccine design strategy called immune engineering in the context of H7N9 influenza vaccine development. The approach combines immunoinformatic and structure modeling methods to promote protective antibody responses against H7N9 hemagglutinin (HA) by engineering whole antigens to carry seasonal influenza HA memory CD4+ T cell epitopes – without perturbing native antigen structure – by galvanizing HA-specific memory helper T cells that support sustained antibody development against the native target HA. The premise for this vaccine concept rests on (i) the significance of CD4+ T cell memory to influenza immunity, (ii) the essential role CD4+ T cells play in development of neutralizing antibodies, (iii) linked specificity of HA-derived CD4+ T cell epitopes to antibody responses, (iv) the structural plasticity of HA and (v) an illustration of improved antibody response to a prototype engineered recombinant H7-HA vaccine. Immune engineering can be applied to development of vaccines against pandemic concerns, including avian influenza, as well as other difficult targets.

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Preexisting influenza-specific CD4+ T cells correlate with disease protection against influenza challenge in humans

Cited by 902 publications

References 36 publications

Dominant CD4‐dependent RNA‐dependent RNA polymerase‐specific T‐cell responses in children acutely infected with human enterovirus 71 and healthy adult controls

Dominant CD4‐dependent RNA‐dependent RNA polymerase‐specific T‐cell responses in children acutely infected with human enterovirus 71 and healthy adult controls

The roles of resident, central and effector memory CD4 T‐cells in protective immunity following infection or vaccination

T cell epitope engineering: an avian H7N9 influenza vaccine strategy for pandemic preparedness and response

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