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• W4317191808 abstract "Article Figures and data Abstract Editor's evaluation Introduction Materials and methods Results Discussion Data availability References Decision letter Author response Article and author information Metrics Abstract Background: Both sex and prior exposure to pathogens are known to influence responses to immune challenges, but their combined effects are not well established in humans, particularly in early innate responses critical for shaping subsequent outcomes. Methods: We employed systems immunology approaches to study responses to a replication-defective, herpes simplex virus (HSV) 2 vaccine in men and women either naive or previously exposed to HSV. Results: Blood transcriptomic and cell population profiling showed substantial changes on day 1 after vaccination, but the responses depended on sex and whether the vaccinee was naive or previously exposed to HSV. The magnitude of early transcriptional responses was greatest in HSV naive women where type I interferon (IFN) signatures were prominent and associated negatively with vaccine-induced neutralizing antibody titers, suggesting that a strong early antiviral response reduced the uptake of this replication-defective virus vaccine. While HSV seronegative vaccine recipients had upregulation of gene sets in type I IFN (IFN-α/β) responses, HSV2 seropositive vaccine recipients tended to have responses focused more on type II IFN (IFN-γ) genes. Conclusions: These results together show that prior exposure and sex interact to shape early innate responses that then impact subsequent adaptive immune phenotypes. Funding: Intramural Research Program of the NIH, the National Institute of Allergy and Infectious Diseases, and other institutes supporting the Trans-NIH Center for Human Immunology, Autoimmunity, and Inflammation. The vaccine trial was supported through a clinical trial agreement between the National Institute of Allergy and Infectious Diseases and Sanofi Pasteur. Clinical trial number: NCT01915212. Editor's evaluation This important study uses a systems immunology approach to disentangle the effect of sex and prior exposure on an individual's response to viral vaccines. This work brings an impressive data assortment and present compelling evidence to support the conclusions. The paper would be of interest to researchers working in human immunology and vaccine development. https://doi.org/10.7554/eLife.80652.sa0 Decision letter eLife's review process Introduction Systems vaccinology aims to improve understanding of vaccine outcomes, by using unbiased approaches to identify the major associated immune phenotypes, including peripheral blood cell population frequencies and gene expression (Pulendran et al., 2010). This has been particularly informative for dissecting the molecular and cellular correlates of natural human variation that can influence vaccine responses and outcomes in vivo (Tsang, 2015). Sex and prior exposure to the same or similar antigen are prominent examples of natural variation that influence vaccinee responses. However, immune response differences associated with sex and prior exposure have typically been defined and analyzed separately. These variables have not been examined together because vaccination studies often involve individuals who are either almost entirely previously exposed (e.g., influenza studies Bucasas et al., 2011; Nakaya et al., 2016; Nakaya et al., 2011; Tsang et al., 2014; Kotliarov et al., 2020) or naive (e.g., Ebola or yellow fever studies in US cohorts Gaucher et al., 2008; Querec et al., 2009; Rechtien et al., 2017) to the vaccine pathogen. Here, we utilize a unique cohort of herpes simplex virus (HSV) 2 vaccine recipients that includes both sexes, as well as naive and previously exposed subjects, thus allowing us to study the in vivo molecular and cellular response correlates of the joint effects of sex and prior exposure. Sex is a well-known variable that can influence vaccine and disease responses. Females typically develop higher antibody responses and report more adverse reactions following vaccination than males (Klein et al., 2015). These differences could be a result of multiple sex dimorphic traits, including sex hormones and increased expression of X-linked genes escaping inactivation. Females in particular have been observed to show higher levels of Toll-like receptor (TLR)/interferon (IFN)-associated gene expression in innate responses to vaccination (Klein et al., 2010). Systems immunology studies have identified prevaccination differences that predict antibody titer responses, such as CD20+CD38high B cell frequency and plasmacytoid dendritic cell activation (Kotliarov et al., 2020). Prior exposure to antigen is another dominant factor in immune response, but its effects have most often been analyzed focusing on adaptive, antigen-specific responses. An example of particular interest for innate responses involved vaccine vectors using replication-defective viruses: trials testing an experimental adenovirus vector-based HIV vaccine revealed increased inflammatory responses in subjects seropositive for a prevalent adenovirus subtype and showed an enhanced risk of HIV infection that was associated with prior adenovirus exposure (Zak et al., 2012; Buchbinder et al., 2008; Gray et al., 2011). Here, we analyzed a unique cohort receiving a multidose, replication-defective vaccine, to interrogate the interaction of sex and prior exposure to infection. Subjects received an experimental HSV2 vaccine in a phase 1 clinical trial where comparisons could be made between three groups of volunteers based on their HSV serostatus prior to vaccination: HSV1−/HSV2−, HSV1+/HSV2−, or HSV1±/HSV2+ (Dropulic et al., 2019). Each of these groups included subjects from both sexes. HSV2 is an important human pathogen. Persons infected with HSV2 have a threefold increased risk of acquiring HIV, and HSV2 infection causes genital herpes and severe disease in neonates, patients with AIDS, and transplant recipients (Koelle and Corey, 2008; Freeman et al., 2006). Prior attempts to produce an effective prophylactic vaccine for HSV2, including glycoprotein subunit or replication-competent vaccines, have been unsuccessful (Dropulic and Cohen, 2012). The replication-defective vaccine HSV529 studied here is deleted for two essential HSV genes, UL5 and UL29, and propagated in a cell line expressing these two proteins (Da Costa et al., 1999; Da Costa et al., 2000). Infection of cells not expressing these two essential genes results in expression of nearly all the viral genes, but viral DNA replication is abolished, and no virions are produced. The vaccine induced greater than fourfold increases in HSV-specific antibody titers in most HSV1−/HSV2− vaccine recipients, but lower increases in antibody responses were observed in volunteers in the other serogroups; T cell responses were modest in all three serogroups (Dropulic et al., 2019). We characterized immune responses longitudinally by analyzing blood transcriptomic profiles and high-dimensional immune cell phenotyping throughout the three-dose vaccine regimen (Dropulic et al., 2019). Vaccine-induced changes and correlates of outcomes such as neutralizing antibody titers and adverse reactions to the vaccine were determined. The transcriptomic responses were associated with both sex and prior exposure to HSV, but the responding genes and pathways also differed markedly based on the combination of both variables. Women showed stronger early inflammatory and type I IFN responses when compared to men, but this was only observed for HSV seronegative vaccine recipients. Thus, using unbiased systems immunology analyses, we show how prior exposure and sex interact to shape early, innate immune responses to a replication-defective vaccine, and identify transcriptional profiles that may shape the subsequent immune responses induced in vivo. Materials and methods Vaccine recipients and study design Request a detailed protocol All HSV529 vaccine recipients signed informed consent for a protocol (clinicaltrials.gov ID: NCT01915212) approved by the National Institute of Allergy and Infectious Diseases Institutional Review Board (Dropulic et al., 2019). The HSV529 vaccine was manufactured by Sanofi Pasteur. Peripheral blood was obtained at various timepoints and PBMCs were isolated by separation with Ficoll-Paque PLUS and cryopreserved. A web tool for visualization of experimental designs was used to summarize the samples and assays available at sampled timepoints (Cheung and CHI Consortium, 2020). RNA sequencing Request a detailed protocol Fresh PBMCs were collected and lysed in TRIzol (Thermo Fisher, Waltham, MA), and total RNA was isolated and purified with an miRNeasy kit (Qiagen, Hilden, Germany). All blood samples at different timepoints from the same subject were processed together. RNA quality and quantity were estimated using Nanodrop (Thermo Scientific, Wilmington, DE) and Agilent 2100 Bioanalyzer (Agilent Technologies, Palo Alto, CA). Before sequencing analysis, all samples were batched according to their age, sex, race, and immunization status, but assayed blindly. Two reference samples were simultaneously processed with the vaccine study samples in each batch. Stranded cDNA sequencing libraries were generated with a TruSeq Stranded mRNA Library Prep Kit (Illumina, San Diego, CA) following the manufacturer’s instructions. Briefly, 500 ng of total RNA was used for mRNA selection. After the reverse transcription to first strand cDNA, strand information was maintained with dUTP during second strand synthesis. A single nucleotide (containing adenine) was added to the dsDNA fragments and the products were ligated to an adapter. The products were then purified and amplified by PCR to create the final cDNA library. The library was qualified with an Agilent Bioanalyzer and quantified with a Qubit 2.0 fluorometer. The cluster generation and pair-end (2 × 75 bp) sequencing were performed on an Illumina HiSeq 3000. Up to 96 barcoded samples were pooled for one single run, which yielded at least 30 M passed filter paired reads per sample. Sequencing results were demultiplexed and converted to FASTQ format using Illumina bcl2fastq software. The sequencing reads were adapter and quality trimmed and then aligned to the human genome using STAR software, and read counts determined with HTSeqCount software. Raw read counts were normalized using the DESeq2, LIMMA packages, and R software. Cells and flow cytometry Request a detailed protocol Viable PBMCs were isolated and cryopreserved according to Center for Human Immunology (CHI) protocols (https://chi.niaid.nih.gov/web/new/our-research/sop.html). High parameter flow cytometry was performed using the Human Immunology Project Consortium (HIPC) panels as previously described (Maecker et al., 2012; Finak et al., 2016; Langweiler and McCoy, 2019). Briefly, 4 parallel 10-color panels with a total of 26 unique markers enabled detection of 70 subsets of PBMCs represented as a fraction of their parent population (Supplementary file 1A, B). Staining was performed using dedicated lyophilized antibody plates for each of compensation, fluorescence-minus-one controls, and study sample staining (all BD Biosciences). Sample staining plates included up to 10 study samples in addition to control PBMCs from a healthy donor, and staining was preceded by an additional incubation with LIVE/DEAD Fixable Blue Dead Cell Stain (Thermo Fisher Scientific). Acquisition was performed with a Becton Dickinson LSRFortessa, using DIVA 8 software, acquiring 250,000 cells for each sample. Subsequent analysis to determine population frequencies used FlowJo version 9.6.2. Compensation performed with unstained cells and Becton Dickinson compensation beads was used to aid acquisition monitoring. Subsequently a final compensation matrix was calculated using FlowJo during postacquisition analysis. Statistics and computational analysis Request a detailed protocol Batching of samples, quality control filtering, and statistical analyses were performed using R/Bioconductor as well as R-Shiny web tools similar to those previously published (Cheung et al., 2017; Cheung, 2023, copy archived at swh:1:rev:5480d6351a4740b56297f2470b24402bd1b676b9). Longitudinal changes in flow cytometry populations were evaluated by Wilcoxon’s signed-rank paired test, and p values were corrected for multiple comparisons using the Benjamini–Hochberg method, using an R webtool. For transcriptomic responses the most significantly responding genes were initially identified using Bioconductor package DESeq2 and then responses were further analyzed using linear models for microarray data (LIMMA) (Smyth, 2004; Love et al., 2014). Low expressed genes were removed and day 1 expression after subtraction of baseline values were used to fit models based on log counts per million, with an interaction term included when comparing the effect of sex between groups based on prior exposure. The tmod package in R was used for blood transcription module (BTM) analysis (Zyla et al., 2019). Each BTM is a set of genes which has been shown to show coherent expression across many biological samples in conditions including in vivo responses to interventions such as vaccines (Bar-Joseph et al., 2003; Chaussabel and Baldwin, 2014). BTM analysis can used to identify significant enrichment of a set of foreground genes, in predefined transcriptional modules compared against a reference set. The hypergeometric test devised in tmodHGtest was used to calculate enrichments and p values employing Benjamini–Hochberg correction for multiple sampling. All the statistical analyses and graphical presentations were performed in R. Gene set variation analysis (GSVA) was used to quantify subject-level variation in signatures of interest (Zyla et al., 2019; Hänzelmann et al., 2013). Reactions to HSV529 vaccination Request a detailed protocol Solicited systemic and local reactions to vaccine were graded based on a toxicity table as reported previously (Dropulic et al., 2019). Severity of disease, represented by aggregate symptom scores, wase determined by multiplying the severity of each symptom by the number of days it persisted. Welch’s unpaired t-test was used to determine statistically significant differences (two-tailed p < 0.05) in aggregate symptom scores between women and men after each vaccine dose. Results Vaccination strategy and study design Sixty subjects who comprised three groups based on their HSV serostatus prior to vaccination were studied: HSV1−/HSV2−, HSV1+/HSV2−, and HSV1±/HSV2+ (Dropulic et al., 2019). The three groups each consisted of 20 volunteers who received intramuscular injection with either HSV529 vaccine (15 participants) or placebo (5 participants), and 50% of the vaccine recipients were women. The mean age of vaccine recipients was 31 years (range 21–40) and did not differ significantly between the groups defined by serology and sex. The vaccine regimen consisted of three vaccinations and peripheral blood samples were obtained on the day before each of these vaccinations, and at follow-up timepoints for all 60 subjects (Figure 1A). Bulk RNA-seq was performed at nine timepoints and flow cytometry at seven timepoints including the day of each vaccination, 1 day after the first vaccination, and 7 days after each of the three vaccinations. Measurements were also obtained for neutralizing antibody titers to HSV, complete blood count tests, and adverse reactions to the vaccination at various timepoints (Figure 1A). Figure 1 with 1 supplement see all Download asset Open asset Prior exposure and sex affect neutralizing antibody responses after HSV529 vaccination. (A) Schematic outline of the vaccination strategy and study design. Each subject was randomized to receive three vaccinations with HSV529 or saline placebo on days 0, 30, and 180. Timepoints are marked at which blood was obtained for immune phenotyping assays, or when adverse events were scored. (B, C) Changes in HSV2 neutralizing antibody titer over time are shown for HSV529 vaccine recipients, plotted separately for subjects with no prior exposure to herpes simplex virus (HSV) (HSV1−/HSV2−) or for HSV1 seropositive subjects (HSV1+/HSV2−). Subjects are shown classified by sex and as slow or fast responders to vaccination based on the increase in HSV2 neutralizing titer by day 30. Rapid responders were defined by an increase in neutralizing antibody responses at day 30 for subjects who were HSV1−/HSV2− before vaccination. In subjects HSV1+/HSV2− prior to vaccination, in whom an increase in neutralizing antibody responses was observed by day 30 for most individuals, rapid responders were a distinct group marked by higher titer responses compared to slow responders at day 30. Significant changes are indicated for men and women separately (*p < 0.05, ***p < 0.001). Prior exposure and sex are associated with the kinetics of the antibody response and adverse events induced by vaccination The HSV529 vaccine induced increases in HSV-specific antibody titers in most recipients (Dropulic et al., 2019). These responses were most prominent in HSV1−/HSV2− vaccine recipients, while in subjects previously exposed to HSV the vaccine responses were more modest particularly at later timepoints. Kinetic analysis of the profiles of HSV2 neutralizing antibody titers showed clear differences based on prior exposure to HSV. In subjects who were HSV1−/HSV2− before vaccination, neutralizing antibody responses peaked at 1 month after the third dose of vaccine at day 210 (Wilcoxon’s signed-rank paired test, p < 0.05), and antibody titers declined significantly by day 360 regardless of sex (p < 0.001) (Figure 1B). In contrast, individuals seropositive for HSV1 prior to vaccination showed neutralizing antibody responses that peaked at day 60 or earlier for the majority of subjects (Figure 1C). Neutralizing antibodies were only tested at day 0 and 210 in HSV2+ vaccine recipients, so for this group kinetics of the response could not be assessed. Effects of sex were observed particularly when focusing on kinetics of the neutralizing antibody responses to the first vaccination dose. Neutralizing antibodies increased significantly by day 30 compared to baseline in HSV1−/HSV2− and HSV1+/HSV2− women, but not men; and this increase was most significant for HSV1−/HSV2− women (p = 0.022) (Figure 1B, C). Within both the HSV1−/HSV2− and HSV1+/HSV2− groups, subjects could be further separated into groups of approximately equal sizes of rapid and slow responders based on the neutralizing antibody responses observed by day 30 (Figure 1B, C). Women were more highly represented than men in the fast responder groups, with this most pronounced for HSV1−/HSV2− subjects in which women comprised 89% of fast responders (Figure 1B). Evaluation of adverse events observed in this cohort also indicated effects of both serostatus and sex. HSV1−/HSV2− women reported more systemic and local reactions to the vaccine than men. About 65% of HSV529 recipients had systemic reactions to the vaccine (compared with ~55% of placebo recipients), while ~90% of HSV529 recipients had local injection site reactions (compared with ~50% of placebo recipients) (Dropulic et al., 2019). Analysis of sex-specific differences in HSV1−/HSV2− vaccine recipients showed that women were more likely to have more severe systemic reactions within the first 7 days of the first dose of vaccine than men (Welch’s unpaired t-test, p = 0.015) and more severe local reactions within the first 7 days of the second dose of vaccine (p = 0.017) (Figure 1—figure supplement 1). However, differences in systemic or local reactions were not noted between women and men in the HSV1+/HSV2− or HSV1±/HSV2+ groups. Together, these results demonstrate that both sex and prior exposure to HSV1 markedly affect the response to this vaccine with HSV1−/HSV2− women showing the most robust early responses marked by a more rapid induction of HSV2 neutralizing antibody, and a higher frequency of adverse events. The magnitude of the response to vaccination is greatest at day one after the first vaccine dose For all 60 subjects, peripheral blood bulk RNA-seq and high parameter flow cytometry measurements were analyzed from seven matched timepoints, and at two further timepoints for RNA-seq (Figure 1A). Initially all subjects that received HSV529 were combined to identify genes differentially expressed longitudinally in response to vaccination, and gene set enrichment analysis was performed using BTMs to identify the highest responding biological pathways (Figure 2A, B; Subramanian et al., 2005; Li et al., 2014). Many of the responses previously observed in other vaccine studies were detected (Nakaya et al., 2011; Tsang et al., 2014; Querec et al., 2009; Kazmin et al., 2017). Inflammatory and IFN pathways, dendritic cell, T cell, and B cell responses were all detected at day 1 after the first vaccination. Cell cycling, T cell, and B cell responses were observed at day 7 after the first vaccination. A timepoint of 7 days after vaccination was chosen for analysis of the subsequent doses, and although after the first vaccine dose the magnitude of changes was reduced at the individual gene level, in terms of gene set enrichments the changes for subsequent doses resembled those after the first dose, particularly for dose 3. The individual genes most significantly upregulated on day 1 after the first dose of vaccine included those encoding IFN-induced proteins and Fc receptors (Supplementary file 1C). Figure 2 with 1 supplement see all Download asset Open asset Peripheral blood phenotypic responses are greatest on day 1 after vaccination with HSV529 and differ based on prior exposure to herpes simplex virus (HSV). (A) Transcriptomic phenotypes of PBMCs were characterized by RNA-seq and responses for all HSV529 recipients were defined by comparing observations at day 1 or 7 to day 0 (day of the first vaccination dose), and for subsequent doses by comparing between the day of the second or third vaccination dose and timepoints 7 days later (days 37 and 187). Functions represented by the genes differentially expressed were assessed by enrichment of blood transcription modules (BTMs), and all significantly enriched modules are shown (FDR adjusted p < 0.05) with plotted size and color indicating the normalized effect size and significance, respectively, for enrichments. (B) Volcano plots show the changes in individual genes for all HSV529 recipients, with significantly differentially expressed genes colored red (FDR adjusted p < 0.05), and the most significantly differentially expressed genes labeled. Note that the scale of the y axes differ between the days that were analyzed. (C) Flow cytometry was used to quantify the frequencies of 70 PBMC populations for all HSV529 recipients. Examples of populations that showed significant changes at either day 1 or 7 after the first vaccine dose compared to day 0 are shown (FDR adjusted p < 0.05). (D) Changes in gene expression between days 0 and 1 were next determined separately for subjects that received HSV529 and differed in their status in terms of prior exposure to HSV, or that received placebo and in which all groups of prior exposure were combined (y-axis). Jaccard index values and statistical significance, indicated by plotted size and color, respectively, are shown for overlap of these expression changes with the differentially expressed genes reported in previous studies of vaccine responses at day 1 to influenza (Tsang et al., 2014) and in two studies of yellow fever (x-axis) (Gaucher et al., 2008; Querec et al., 2009). Multi-parameter flow cytometry quantified 70 cell populations which were compared for the same timepoints as the transcriptomic analysis, for all subjects combined. Cell population changes occurring across broad lineages were observed as expected for vaccine responses (Figure 2C and Supplementary file 1D). Monocyte and NK cell frequencies significantly increased at day 1 after the first dose of vaccine, whereas the Th1 subset decreased, possibly reflecting polarization of the vaccine response. T follicular helper cells, T cells, and B cells were all significantly expanded by day 7 consistent with an activated adaptive response. Plasmablasts, defined as CD19+ CD20− CD27+ CD38high (Perez-Andres et al., 2010), were significantly expanded at both days 1 and 7 (Wilcoxon’s signed-rank paired test with Benjamini–Hochberg correction for multiple comparisons, p < 0.05) (Figure 2C). Although this analysis combined all subjects, the remarkably early rise in plasmablasts after vaccination may be related to the particularly rapid neutralizing antibody response to vaccination in HSV seronegative women described above. The number of genes showing significant changes (FDR corrected p < 0.05) in response to vaccination was higher at 1 day after the first dose of vaccine than at later timepoints and after subsequent vaccine doses (Figure 2B). This was also true for the changes in cell populations and might be expected for a replication-defective vaccine which presents antigens to the immune system immediately after vaccination, but is not amplified over time like a replication-competent attenuated virus or vector-based vaccine. Therefore, we further focused analyses on day 1 after the first dose of vaccine, to investigate how subjects differing in sex or prior exposure vary in their responses to HSV529 vaccination. Innate responses to HSV529 that differ based on prior exposure resemble differences between innate responses to yellow fever and influenza vaccinations We analyzed the differentially expressed genes (DEGs) observed after HSV529 vaccination to investigate the transcriptomic responses which were associated with prior exposure to HSV. We compared day 1 DEGs in each of the three HSV serogroups that received HSV529 vaccine, with the early transcriptomic responses that have been previously reported in recipients of either yellow fever or influenza vaccines (Tsang et al., 2014; Gaucher et al., 2008; Querec et al., 2009). In the previous studies, yellow fever is a pathogen for which vaccine recipients had no prior exposure, whereas all subjects receiving the influenza vaccine were expected to have some degree of immunity due to prior influenza infection and vaccine exposure. Jaccard index values, reflecting the size of the intersection relative to the size of the union for two sample sets, were determined to quantify the overlap in day 1 transcriptomic responses to these different vaccines (Figure 2D). DEGs in HSV seronegative HSV529 recipients were strikingly similar to those seen in yellow fever vaccine recipients (p < 1 × 10−90, Jaccard index >0.35). In contrast, DEGs in both HSV seropositive groups were more similar to those seen in influenza vaccine recipients (p < 1 × 10−30, Jaccard index >0.13). Thus, transcriptomic responses observed in HSV naive and seropositive subjects mirror the responses to yellow fever and influenza vaccine recipients, respectively. This indicates that the effect of prior HSV exposure on response to HSV529 is consistent with differences observed between the early responses to vaccines for other pathogens that represent either naive responses or those mounted by individuals with existing adaptive immunity. Network analysis of pathways that were enriched in overlap between HSV seronegative HSV529 recipients and yellow fever vaccine recipients, showed central roles for gene sets involved in type I IFN (IFN-α/β) and antiviral innate responses (Figure 2—figure supplement 1A). In contrast, network analysis of pathways that were enriched in overlap between HSV2 seropositive HSV529 recipients and influenza vaccine recipients, showed a more heterogenous pattern of relatedness that included type II IFN (IFN-γ) and IL-12 responses (Figure 2—figure supplement 1B). The 20 most significantly upregulated genes for HSV529 recipients in each of the 3 HSV serogroups emphasize the similarities in the two HSV2 seropositive groups and how different they are from the seronegative group (Table 1). GBP1, WARS, and IRF1, which are upregulated predominantly by IFN-γ (Megger et al., 2017; Sen et al., 2018) were among the genes most significantly upregulated in both of the HSV seropositive groups studied, while MX1 and ISG15, which are upregulated primarily by IFN-α (Megger et al., 2017; Taylor et al., 1996), were among the most significantly upregulated genes in HSV seronegative subjects. Table 1 Twenty most significantly upregulated genes at day 1 for HSV529 recipients divided into three groups based on prior exposure to herpes simplex virus (HSV). Changes in expression compared to day 0 were analyzed using Bioconductor package DESeq2, with log 2 fold changes reported and p values corrected for multiple comparisons. Genes marked in red are present in both HSV1+/HSV2− and HSV1±/HSV2+, but not HSV1−/HSV2− subjects. HSV1−/HSV2−HSV1+/HSV2−HSV1±/HSV2+GeneFold changep adjustedGeneFold changep adjustedGeneFold changep adjustedMX11.957.02 × 10−31GBP21.141.36 × 10−20ANKRD225.444.37 × 10−44EIF2AK21.283.99 × 10−28GBP12.062.60 × 10−19GBP51.946.39 × 10−41IFI442.013.99 × 10−28PSTPIP20.984.27 × 10−18WARS2.192.03 × 10−40ISG152.103.99 × 10−28ANKRD223.547.25 × 10−18ETV74.125.08 × 10−40IFI62.264.94 × 10−28FCGR1B2.324.39 × 10−17GBP12.861.64 × 10−39HERC51.663.52 × 10−27WARS1.449.49 × 10−17GBP41.861.93 × 10−38OAS31.953.52 × 10−27GBP41.242.28 × 10−16IDO14.024.50 × 10−38CMPK22.125.75 × 10−27LAP31.542.28 × 10−16CD2741.722.16 × 10−37HERC61.025.75 × 10−27GBP51.243.51 × 10−16LAP32.267.50 × 10−37IFI44L2.681.52 × 10−26GBP1P13.095.37 × 10−16GBP21.461.71 × 10−36LAMP31.942.86 × 10−26FCGR1" @default.
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• W4317191808 title "Author response: Sex and prior exposure jointly shape innate immune responses to a live herpesvirus vaccine" @default.
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