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. 2021 Mar 25:12:639358.
doi: 10.3389/fimmu.2021.639358. eCollection 2021.

Transcriptional and Immunologic Correlates of Response to Pandemic Influenza Vaccine in Aviremic, HIV-Infected Children

Lesley R de Armas  1 , Varghese George  1 , Abdelali Filali-Mouhim  2 , Courtney Steel  3 , Anita Parmigiani  1 , Coleen K Cunningham  4 , Adriana Weinberg  5 , Lydie Trautmann  6 , Rafick-Pierre Sekaly  7 , Mark J Cameron  8 , Savita Pahwa  1
Affiliations

Transcriptional and Immunologic Correlates of Response to Pandemic Influenza Vaccine in Aviremic, HIV-Infected Children

Lesley R de Armas et al. Front Immunol. .

Abstract

People living with HIV (PWH) often exhibit poor responses to influenza vaccination despite effective combination anti-retroviral (ART) mediated viral suppression. There exists a paucity of data in identifying immune correlates of influenza vaccine response in context of HIV infection that would be useful in improving its efficacy in PWH, especially in younger individuals. Transcriptomic data were obtained by microarray from whole blood isolated from aviremic pediatric and adolescent HIV-infected individuals (4-25 yrs) given two doses of Novartis/H1N1 09 vaccine during the pandemic H1N1 influenza outbreak. Supervised clustering and gene set enrichment identified contrasts between individuals exhibiting high and low antibody responses to vaccination. High responders exhibited hemagglutination inhibition antibody titers >1:40 post-first dose and 4-fold increase over baseline. Baseline molecular profiles indicated increased gene expression in metabolic stress pathways in low responders compared to high responders. Inflammation-related and interferon-inducible gene expression pathways were higher in low responders 3 wks post-vaccination. The broad age range and developmental stage of participants in this study prompted additional analysis by age group (e.g. <13yrs and ≥13yrs). This analysis revealed differential enrichment of gene pathways before and after vaccination in the two age groups. Notably, CXCR5, a homing marker expressed on T follicular helper (Tfh) cells, was enriched in high responders (>13yrs) following vaccination which was accompanied by peripheral Tfh expansion. Our results comprise a valuable resource of immune correlates of vaccine response to pandemic influenza in HIV infected children that may be used to identify favorable targets for improved vaccine design in different age groups.

Keywords: HIV; influenza; microarray; pandemic; pediatric; systems vaccinology; vaccine.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
pH1N1 Serology for Study participants. pH1N1 Ab titers as determined by Hemagluttination Inhibition Assay (HAI) in study participants from Responder and Non-responder groups at each timepoint in the IMPAACT P1088 study. Responders (n=29, left panel) were defined as exhibiting a 4-fold increase at week 3 compared to week 0 and Non-responders (n=11right panel) failed to increase titers at least 4-fold between week 0 and 3. The red dashed line at titer 1:40 shows the accepted threshold for sero-protection.
Figure 2
Figure 2
Baseline Enriched Molecular Pathways Associated with Antibody Titer Response. (A) Heatmap representation of the top 1,000 significantly correlated transcripts by regressing baseline gene expression from all participants against V1 pH1N1 titer. The expression intensities are represented using a blue-white-red color scale. Rows correspond to probes and columns correspond to profiled samples (p ≤ 0.01). High responder and Low/non responder clusters were compared and subjected to gene set enrichment analysis using the IPA database (B) and MSigDB immunologic signature model (C).
Figure 3
Figure 3
Correlates of Vaccine-induced Antibody Responses Post-Vaccination. (A) Heatmap representation of the top significantly correlated transcripts from regressing baseline expression from all participants and fold change difference in pH1N1 antibody titers at V1 compared to BL. The expression intensities are represented using a blue-white-red color scale. Rows correspond to probes and columns correspond to profiled samples (p ≤ 0.05). “High” responder and “low/non” responder clusters were compared and subjected to gene set enrichment analysis using the IPA database (B) and MSigDB Immunologic signature model (C).
Figure 4
Figure 4
Gene Set Enrichment using Nakaya.NatImmunology Cell Specific Signatures. “High” responder and “low” responder clusters from regression analysis with baseline gene expression (A, C) and V1 gene expression (B, D) and fold change difference in pH1N1 titers (V1/BL) were subjected to gene set enrichment analysis using the Nakaya modules (21). (A, B) Radial plots illustrating selective enrichment in major PBMC cell types high responders compared to low/non-responders. (C, D) Genesets induced in a specific subset are significantly enriched (adjusted p-value <0.05 denoted by *) among genes upregulated or downregulated with respect to the enrichment score – (NES) between groups.
Figure 5
Figure 5
Pathway Analysis in two Age Groups at Baseline. Heatmap showing statistically significant canonical pathways (IPA) (both uniquely and commonly) regulated in high responders versus low/non-responders in the two age groups (4-12 years and 13-24 years) at baseline. Genes with an adjusted p-value <0.05, |FC|>1.3 and associated with canonical IPA pathway were used for analysis. Heat scaling refers to results from over-representation test performed using Fisher Exact Test (red indicating greater gene enrichment in the pathway). All pathways shown are statistically significant (p value < 0.05) in one or both groups.
Figure 6
Figure 6
Pathways Analysis in two Age Groups at Post-Vaccination. Top 10 (or top selected) significant pathways and their gene members enriched when comparing high responder versus low/non-responder at Visit 1 in 4-12yr group (A) and 13-24yr group (B). Each row is a regulated canonical pathway (ingenuity software); each column represents an up-(red) or down-(blue) regulated genes (p-value <= 0.05 and |FC|>1.3) induced in 1 or more pathways(s). Over representation test was performed using Fisher Exact Test; significance, displayed on the right, is achieved for p<0.05 (-log(p)1.3).
Figure 7
Figure 7
Increase in pTfh Frequency and Function Post-Vaccination in pH1N1 Responders. (A) Frequencies of CD4+CD45RO+CXCR5+ peripheral T follicular helper cells (pTfh) without stimulation and (B) IL-21+ pTfh after 12-hour stimulation with H1N1 from responders (n=14) and non-responders (n=14) at baseline (BL) and post vaccination (visit 1, V1). Pearson correlations between (C) IL-21+pTfh at V1 following H1N1 stimulation with HAI titers at V1 (D) IL-21+pTfh at V1 following H1N1 stimulation with baseline CD4 Immune activation (E) HAI titers at V1 with baseline CD4 Immune activation. P-values were calculated with Student’s t-test or Mann-Whitney test as appropriate. Box plots include median with 25th and 75th percentile borders, and error bars represent 10th and 90th percentiles. Stars indicate the level of significance: *p < 0.05, **p < 0.01.
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