Transcriptional atlas of the human immune response to 13 vaccines reveals a common predictor of vaccine-induced antibody responses

Hagan, Thomas; Gerritsen, Bram; Tomalin, Lewis; Fourati, Slim; Mulè, Matthew P.; Chawla, Daniel G.; Rychkov, Dmitri; Henrich, Evan; Miller, Helen; Diray‐Arce, Joann; Dunn, Patrick; Lee, Audrey; Deckhut-Augustine, Alison; Haddad, Elias K.; Hafler, David A.; Harris, Eva; Farber, Donna L.; McElrath, M. Juliana; Montgomery, Ruth R.; Peters, Bjoern; Rahman, Adeeb; Reed, Elaine F.; Rouphael, Nadine; Fernández-Sesma, Ana; Sette, Alessandro; Stuart, Ken; Togias, Alkis; Levy, Ofer; Gottardo, Raphaël; Sarwal, Minne M.; Tsang, John S.; Suárez‐Fariñas, Mayte; Sékaly, Rafick‐Pierre; Kleinstein, Steven H.; Pulendran, Bali

doi:10.1038/s41590-022-01328-6

Cited by 73 publications

(62 citation statements)

References 46 publications

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“…Overall, Fourati et al 2 and Hagan et al 4 have demonstrated the use of this compendium as a highly valuable tool to gain insight into the variation in antibody response observed between individuals, which provides an excellent resource for immunologists and vaccinologists to use in comparative studies to obtain further mechanistic insight into the effect of genetic factors (age, sex, ethnicity) and environmental factors (nutrition, geographical location, time of vaccination) that shape cellular and molecular mechanisms and underpin antibody responsiveness. Growing evidence points to adult females having better protective immune responses 9 , possibly due to increased innate immune responses; to pregnant women responding better to vaccination in the first and third trimesters; 10 to novel mRNA vaccines inducing a more potent monocyte response; 11 and to greater effectiveness of vaccination in the morning because of circadian rhythms 12 .…”

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confidence: 95%

“…Hagan et al applied the same approach to find common and unique features associated with antibody responses across vaccines in the early post-vaccination period 4 . Unsupervised analysis of gene profiles revealed four temporal expression patterns: on days 1-3, innate responses (predominant in live viral vectors) and lower natural killer cell (NK cell) responses; and on day 7, expansion of plasmablasts and stimulation of CD4 + T cells.…”

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confidence: 99%

“…Best studied is the effect of age on antibody responsiveness, with elderly individuals known to have lower antibody titers than younger people after vaccination 8 . Although Fourati et al did not address how age contributed to the primed endotype before vaccination 2 -possibly due to data scarcity in the datasets -Hagan et al used their dataset to compare blood modules after vaccination 4 . Consistent with previous results 8 , they found that elderly individuals had reduced transcriptional expression in modules associated with interferon responses and plasmablasts, but the kinetics of responses remained the same.…”

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confidence: 99%

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Immune signature atlas of vaccines: learning from the good responders

Pedroza-Pacheco

McMichael

2022

Nat Immunol

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Immune signature atlas of vaccines: learning from the good responders

Pedroza-Pacheco

McMichael

2022

Nat Immunol

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“…Recent studies have aimed to identify such biomarkers in the form of a transcriptional atlas of the human immune response to several vaccinations (56,57). While such studies have identified features of a vaccine induced immune response, they were heterogeneous at both the individual and vaccine level (56,57). To combat this, Hagan et al (57) proposed the development of a 'vaccine chip' devised to monitor plasmablast signatures as a biomarker to predict protective immune responses in vaccine trials.…”

Section: Expanded Ctfh Cells Reveal Potential Transcriptomic Signatur...mentioning

confidence: 99%

Tracking of activated cTfh cells following sequential influenza vaccinations reveals transcriptional profile of clonotypes driving a vaccine-induced immune response

et al. 2023

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IntroductionA vaccine against influenza is available seasonally but is not 100% effective. A predictor of successful seroconversion in adults is an increase in activated circulating T follicular helper (cTfh) cells after vaccination. However, the impact of repeated annual vaccinations on long-term protection and seasonal vaccine efficacy remains unclear.MethodsIn this study, we examined the T cell receptor (TCR) repertoire and transcriptional profile of vaccine-induced expanded cTfh cells in individuals who received sequential seasonal influenza vaccines. We measured the magnitude of cTfh and plasmablast cell activation from day 0 (d0) to d7 post-vaccination as an indicator of a vaccine response. To assess TCR diversity and T cell expansion we sorted activated and resting cTfh cells at d0 and d7 post-vaccination and performed TCR sequencing. We also single cell sorted activated and resting cTfh cells for TCR analysis and transcriptome sequencing.Results and discussionThe percent of activated cTfh cells significantly increased from d0 to d7 in each of the 2016-17 (p < 0.0001) and 2017-18 (p = 0.015) vaccine seasons with the magnitude of cTfh activation increase positively correlated with the frequency of circulating plasmablast cells in the 2016-17 (p = 0.0001) and 2017-18 (p = 0.003) seasons. At d7 post-vaccination, higher magnitudes of cTfh activation were associated with increased clonality of cTfh TCR repertoire. The TCRs from vaccine-expanded clonotypes were identified and tracked longitudinally with several TCRs found to be present in both years. The transcriptomic profile of these expanded cTfh cells at the single cell level demonstrated overrepresentation of transcripts of genes involved in the type-I interferon pathway, pathways involved in gene expression, and antigen presentation and recognition. These results identify the expansion and transcriptomic profile of vaccine-induced cTfh cells important for B cell help.

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“…Further complicating the study of correlates of protection against influenza is the substantial degree of baseline immune variation that exists across humans, which is now recognized as a key determinant in predicting efficacy of some vaccines and therapeutics, and modeling disease outcomes [14][15][16][17][18] . Differences in host genetics, environmental and demographic factors, and antigen exposure histories impact the composition of baseline innate, cellular, and humoral compartments, and may augment differing responses to influenza virus infection or vaccination 17,[19][20][21][22][23][24][25][26][27][28][29][30] .…”

Section: Introductionmentioning

confidence: 99%

Baseline innate and T cell populations are correlates of protection against symptomatic influenza virus infection independent of serology

Thomas

Mettelman

Souquette

et al. 2023

Preprint

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Influenza viruses remain a leading cause of global respiratory illness in humans. The suboptimal effectiveness of seasonal influenza vaccination underscores the need for a more comprehensive understanding of immune mediators of protection, especially in populations with diverse baseline immune profiles and exposure histories. While anti-influenza antibody titers are typically used to define correlates of protection, mounting evidence suggests a substantive role for innate and cellular immunity in determining tolerance and resistance during influenza virus infection. However, distinct cell subsets that correlate with protection against symptomatic influenza remain to be identified in humans. Here, we measured baseline cellular and serologic profiles in peripheral blood from 206 vaccinated or unvaccinated adult subjects enrolled in the 2018 SHIVERS-II cohort to determine how baseline variations in the cellular and humoral immune compartments contribute independently or synergistically to the risk of developing symptomatic influenza infection. Protection from symptomatic influenza correlated with increased individual frequencies of diverse and polyfunctional CD4 and CD8 T cells, cells associated with engagement of humoral responses including cTfh and mDCs, Th17 cells, and innate effector CD16-expressing cytotoxic and cytokine-producing NK cells. In contrast, increased susceptibility was predominantly attributed to nonspecific inflammatory populations including γδ T cells and activated CD16neg NK cells, as well as TNFα+ single-producing CD8 T cells. A trained random forest model categorizing symptomatic influenza cases identified that cellular covariates substantially improved model accuracy up to 86% over demographic and serologic factors alone (61%). A corresponding variable importance analysis showed cellular populations comprise 28 of the top 30 covariates (from 48 total), with the single most important factor being ICOS+ cTfh cells. Lastly, using a multivariate logistic regression model considering participant demographics, anti-influenza antibody titers, vaccination status, and cell population covariates, we quantified how these factors contribute to risk of symptomatic influenza infection. Protection was associated with a combination of lymphocyte populations including naïve, CD107a+, and Th17 CD4 T cells, and serologic factors including antibodies targeting neuraminidase. Increased risk of symptomatic influenza (95% subtype A) was associated with elevated anti-hemagglutinin antibodies against influenza B (Yamagata), along with γδ T cells and TNFα+ CD8 T cell single-cytokine producers. Together, these results demonstrate that the composition of pre-infection peripheral cell profiles is a stronger predictor of symptomatic influenza susceptibility than vaccination, demographics, or serology.

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Transcriptional atlas of the human immune response to 13 vaccines reveals a common predictor of vaccine-induced antibody responses

Cited by 73 publications

References 46 publications

Immune signature atlas of vaccines: learning from the good responders

Immune signature atlas of vaccines: learning from the good responders

Tracking of activated cTfh cells following sequential influenza vaccinations reveals transcriptional profile of clonotypes driving a vaccine-induced immune response

Baseline innate and T cell populations are correlates of protection against symptomatic influenza virus infection independent of serology

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