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Systems biology of vaccination for seasonal influenza in humans.

Nakaya HI, Wrammert J, Lee EK, Racioppi L, Marie-Kunze S, Haining WN, Means AR, Kasturi SP, Khan N, Li GM, McCausland M, Kanchan V, Kokko KE, Li S, Elbein R, Mehta AK, Aderem A, Subbarao K, Ahmed R, Pulendran B - Nat. Immunol. (2011)

Bottom Line: Here we have used a systems biology approach to study innate and adaptive responses to vaccination against influenza in humans during three consecutive influenza seasons.We studied healthy adults vaccinated with trivalent inactivated influenza vaccine (TIV) or live attenuated influenza vaccine (LAIV).Thus, systems approaches can be used to predict immunogenicity and provide new mechanistic insights about vaccines.

View Article: PubMed Central - PubMed

Affiliation: Emory Vaccine Center, Emory University, Atlanta, Georgia, USA.

ABSTRACT
Here we have used a systems biology approach to study innate and adaptive responses to vaccination against influenza in humans during three consecutive influenza seasons. We studied healthy adults vaccinated with trivalent inactivated influenza vaccine (TIV) or live attenuated influenza vaccine (LAIV). TIV induced higher antibody titers and more plasmablasts than LAIV did. In subjects vaccinated with TIV, early molecular signatures correlated with and could be used to accurately predict later antibody titers in two independent trials. Notably, expression of the kinase CaMKIV at day 3 was inversely correlated with later antibody titers. Vaccination of CaMKIV-deficient mice with TIV induced enhanced antigen-specific antibody titers, which demonstrated an unappreciated role for CaMKIV in the regulation of antibody responses. Thus, systems approaches can be used to predict immunogenicity and provide new mechanistic insights about vaccines.

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Related in: MedlinePlus

Molecular signatures that correlate with antibody titers to TIV. (a) Heat map of probe sets (in lines) whose baseline normalized expression at day 3 (top) or day 7 (bottom) correlates (Pearson, P-value < 0.05) to baseline-normalized antibody response at day 28 post-TIV vaccination. Blue and red bars on the right of the heat map indicate the probe sets with negative and positive correlation, respectively (number of probe sets shown). The colors represent the individual fold-change in gene expression at days 3 or 7 compared to day 0 in TIV vaccinees. Probe sets that correlate on both day 3 and 7 to HAI response were counted as “day 7” and the day7-day0 expression was used to represent the expression on heat map. (b) HAI response-correlated genes (Pearson, P-value < 0.05) associated with the Unfolded protein response (purple area), Antibody-secreting cell differentiation (light brown area) and/or regulated by the transcription factor XBP-1. Solid and dashed lines represent, respectively direct and indirect interactions reported for the genes. (c) Spider graph showing the fold enrichment of genes (among those highly expressed in any PBMC subset), whose expression on either day 3 or day 7 post-TIV vaccination is positively (red line) or negatively (blue line) correlated to HAI titers (Pearson, P-value < 0.05). Fold enrichment is calculated as described in Methods. Cell subsets with statistically significant enrichment (Fisher’s exact test two tailed P-value < 10−10) are marked with asterisks. (d) Heat map of probe sets highly expressed in B cells and antibody-secreting cells whose baseline normalized expression correlates (Pearson, P-value < 0.05) to baseline-normalized HAI response.
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Figure 4: Molecular signatures that correlate with antibody titers to TIV. (a) Heat map of probe sets (in lines) whose baseline normalized expression at day 3 (top) or day 7 (bottom) correlates (Pearson, P-value < 0.05) to baseline-normalized antibody response at day 28 post-TIV vaccination. Blue and red bars on the right of the heat map indicate the probe sets with negative and positive correlation, respectively (number of probe sets shown). The colors represent the individual fold-change in gene expression at days 3 or 7 compared to day 0 in TIV vaccinees. Probe sets that correlate on both day 3 and 7 to HAI response were counted as “day 7” and the day7-day0 expression was used to represent the expression on heat map. (b) HAI response-correlated genes (Pearson, P-value < 0.05) associated with the Unfolded protein response (purple area), Antibody-secreting cell differentiation (light brown area) and/or regulated by the transcription factor XBP-1. Solid and dashed lines represent, respectively direct and indirect interactions reported for the genes. (c) Spider graph showing the fold enrichment of genes (among those highly expressed in any PBMC subset), whose expression on either day 3 or day 7 post-TIV vaccination is positively (red line) or negatively (blue line) correlated to HAI titers (Pearson, P-value < 0.05). Fold enrichment is calculated as described in Methods. Cell subsets with statistically significant enrichment (Fisher’s exact test two tailed P-value < 10−10) are marked with asterisks. (d) Heat map of probe sets highly expressed in B cells and antibody-secreting cells whose baseline normalized expression correlates (Pearson, P-value < 0.05) to baseline-normalized HAI response.

Mentions: TIV vaccination induces a remarkable variation in the magnitude of the HAI response (Fig. 1a). To gain insight into the potential mechanisms underlying this variation, and to identify gene signatures capable of predicting the magnitude of the HAI response, we searched for early gene signatures that correlate with the B cell responses at day 7 and day 28 post-TIV vaccination. Pearson correlation analysis identified 600–1,100 probe sets that correlated, either directly or inversely, with the magnitude of the HAI antibody response (see Methods and Fig. 4a). Among these correlated genes, there were several genes known to be regulated by the transcription factor XBP-1 and involved in plasma cell differentiation and the unfolded protein response (Fig. 4b). The complete list of genes correlated with the HAI response is available (Supplementary Table 5).


Systems biology of vaccination for seasonal influenza in humans.

Nakaya HI, Wrammert J, Lee EK, Racioppi L, Marie-Kunze S, Haining WN, Means AR, Kasturi SP, Khan N, Li GM, McCausland M, Kanchan V, Kokko KE, Li S, Elbein R, Mehta AK, Aderem A, Subbarao K, Ahmed R, Pulendran B - Nat. Immunol. (2011)

Molecular signatures that correlate with antibody titers to TIV. (a) Heat map of probe sets (in lines) whose baseline normalized expression at day 3 (top) or day 7 (bottom) correlates (Pearson, P-value < 0.05) to baseline-normalized antibody response at day 28 post-TIV vaccination. Blue and red bars on the right of the heat map indicate the probe sets with negative and positive correlation, respectively (number of probe sets shown). The colors represent the individual fold-change in gene expression at days 3 or 7 compared to day 0 in TIV vaccinees. Probe sets that correlate on both day 3 and 7 to HAI response were counted as “day 7” and the day7-day0 expression was used to represent the expression on heat map. (b) HAI response-correlated genes (Pearson, P-value < 0.05) associated with the Unfolded protein response (purple area), Antibody-secreting cell differentiation (light brown area) and/or regulated by the transcription factor XBP-1. Solid and dashed lines represent, respectively direct and indirect interactions reported for the genes. (c) Spider graph showing the fold enrichment of genes (among those highly expressed in any PBMC subset), whose expression on either day 3 or day 7 post-TIV vaccination is positively (red line) or negatively (blue line) correlated to HAI titers (Pearson, P-value < 0.05). Fold enrichment is calculated as described in Methods. Cell subsets with statistically significant enrichment (Fisher’s exact test two tailed P-value < 10−10) are marked with asterisks. (d) Heat map of probe sets highly expressed in B cells and antibody-secreting cells whose baseline normalized expression correlates (Pearson, P-value < 0.05) to baseline-normalized HAI response.
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Related In: Results  -  Collection

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Figure 4: Molecular signatures that correlate with antibody titers to TIV. (a) Heat map of probe sets (in lines) whose baseline normalized expression at day 3 (top) or day 7 (bottom) correlates (Pearson, P-value < 0.05) to baseline-normalized antibody response at day 28 post-TIV vaccination. Blue and red bars on the right of the heat map indicate the probe sets with negative and positive correlation, respectively (number of probe sets shown). The colors represent the individual fold-change in gene expression at days 3 or 7 compared to day 0 in TIV vaccinees. Probe sets that correlate on both day 3 and 7 to HAI response were counted as “day 7” and the day7-day0 expression was used to represent the expression on heat map. (b) HAI response-correlated genes (Pearson, P-value < 0.05) associated with the Unfolded protein response (purple area), Antibody-secreting cell differentiation (light brown area) and/or regulated by the transcription factor XBP-1. Solid and dashed lines represent, respectively direct and indirect interactions reported for the genes. (c) Spider graph showing the fold enrichment of genes (among those highly expressed in any PBMC subset), whose expression on either day 3 or day 7 post-TIV vaccination is positively (red line) or negatively (blue line) correlated to HAI titers (Pearson, P-value < 0.05). Fold enrichment is calculated as described in Methods. Cell subsets with statistically significant enrichment (Fisher’s exact test two tailed P-value < 10−10) are marked with asterisks. (d) Heat map of probe sets highly expressed in B cells and antibody-secreting cells whose baseline normalized expression correlates (Pearson, P-value < 0.05) to baseline-normalized HAI response.
Mentions: TIV vaccination induces a remarkable variation in the magnitude of the HAI response (Fig. 1a). To gain insight into the potential mechanisms underlying this variation, and to identify gene signatures capable of predicting the magnitude of the HAI response, we searched for early gene signatures that correlate with the B cell responses at day 7 and day 28 post-TIV vaccination. Pearson correlation analysis identified 600–1,100 probe sets that correlated, either directly or inversely, with the magnitude of the HAI antibody response (see Methods and Fig. 4a). Among these correlated genes, there were several genes known to be regulated by the transcription factor XBP-1 and involved in plasma cell differentiation and the unfolded protein response (Fig. 4b). The complete list of genes correlated with the HAI response is available (Supplementary Table 5).

Bottom Line: Here we have used a systems biology approach to study innate and adaptive responses to vaccination against influenza in humans during three consecutive influenza seasons.We studied healthy adults vaccinated with trivalent inactivated influenza vaccine (TIV) or live attenuated influenza vaccine (LAIV).Thus, systems approaches can be used to predict immunogenicity and provide new mechanistic insights about vaccines.

View Article: PubMed Central - PubMed

Affiliation: Emory Vaccine Center, Emory University, Atlanta, Georgia, USA.

ABSTRACT
Here we have used a systems biology approach to study innate and adaptive responses to vaccination against influenza in humans during three consecutive influenza seasons. We studied healthy adults vaccinated with trivalent inactivated influenza vaccine (TIV) or live attenuated influenza vaccine (LAIV). TIV induced higher antibody titers and more plasmablasts than LAIV did. In subjects vaccinated with TIV, early molecular signatures correlated with and could be used to accurately predict later antibody titers in two independent trials. Notably, expression of the kinase CaMKIV at day 3 was inversely correlated with later antibody titers. Vaccination of CaMKIV-deficient mice with TIV induced enhanced antigen-specific antibody titers, which demonstrated an unappreciated role for CaMKIV in the regulation of antibody responses. Thus, systems approaches can be used to predict immunogenicity and provide new mechanistic insights about vaccines.

Show MeSH
Related in: MedlinePlus