Blood transcriptome profiling reveals distinct gene networks induced by mRNA vaccination against COVID-19.

Messenger RNA (mRNA) vaccines represent a new class of vaccines that has been shown to be highly effective during the COVID-19 pandemic and that holds great potential for other preventative and therapeutic applications. While it is known that the transcriptional activity of various genes is altered following mRNA vaccination, identifying and studying gene networks could reveal important scientific insights that might inform future vaccine designs. In this study, we conducted an in-depth weighted gene correlation network analysis of the blood transcriptome before and 24 h after the second and third vaccination with licensed mRNA vaccines against COVID-19 in humans, following a prime vaccination with either mRNA or ChAdOx1 vaccines. Utilizing this unsupervised gene network analysis approach, we identified distinct modular networks of co-varying genes characterized by either an expressional up- or downregulation in response to vaccination. Downregulated networks were associated with cell metabolic processes and regulation of transcription factors, while upregulated networks were associated with myeloid differentiation, antigen presentation, and antiviral, interferon-driven pathways. Within this interferon-associated network, we identified highly connected hub genes such as STAT2 and RIGI and associated upstream transcription factors, potentially playing important regulatory roles in the vaccine-induced immune response. The expression profile of this network significantly correlated with S1-specific IgG levels at the follow-up visit in vaccinated individuals. Those findings could be corroborated in a second, independent cohort of mRNA vaccine recipients. Collectively, results from this modular gene network analysis enhance the understanding of mRNA vaccines from a systems immunology perspective. Influencing specific gene networks could lead to optimized vaccines that elicit augmented vaccine responses.

MPXV Infection Stimulates a More Robust and Durable Neutralizing Antibody Response Compared to MVA-BN Vaccination.

Monkeypox virus (MPXV) has recently caused a global disease outbreak in humans. Differences in the neutralizing antibody response to vaccination vs. MPXV infection remain poorly understood. Here, we examined the neutralization of MPXV and VACV by sera from a cohort of convalescent and vaccinated individuals at 1- and 8-months post-exposure. Convalescent individuals displayed higher neutralizing antibody titers against MPXV than vaccinated and MPXV-naïve persons at one-month post-exposure. Neutralizing antibody titers had waned significantly in both groups at 8 months. This study suggests additional vaccine strategies are needed to elicit a durable humoral response and prevent breakthrough infections.

Seroconversion in liver and intestine transplant patients after one, two or three doses of adenoviral vector vaccines against SARS-CoV-2. Single center experience in Argentina.

BACKGROUND: The capacity of different anti-SARS-CoV-2 vaccines to elicit immune response is not equivalent in the healthy population compared to chronically immunosuppressed patients. Most of the reports available to assess the effects of anti-SARS-CoV-2 vaccines on solid organ transplant recipients (SOTR) were performed using mRNA-based vaccines. OBJECTIVE: This study aims to assess the seroconversion rate in a cohort of liver and liver- intestinal transplant patients after vaccination with the non-replicative vector-based vaccines after transplantation used in our country, Argentina (rAd26-rAd5 (Sputnik V) and ChAdOx11 nCoV-19 (AZD1222) (Astra Zeneca-Oxford). METHODS: One hundred and three (103) liver and liver-intestinal transplant recipients were enrolled. Patients with previous PCR-confirmed COVID19 were excluded, therefore 77 were finally included for analysis; 75 were liver transplant recipients, 1 was a combined liver-intestine and 1 a multivisceral transplant. All received their first vaccine dose between March and June 2021; 66,2% males, and the mean age was 56,3 years. All patients have a post-transplant follow up longer than 1 year (mean 6.6 years, median 5 years, range 1-23 years). Immune response after first, second and third doses were determined using three different spike (S)-S commercial ELISA kits and an in-house made anti nucleocapsid-protein (N) ELISA. RESULTS: Following the three doses, 57.1 % (44/77) of the patients seroconverted, while 33/77 (42.9 %) did not present anti-SARS-CoV-2 antibodies. The seroconversion rate was different for each dose. We found that 5/27 (18.5 %) of transplant patients seroconverted after a single dose; 18/29 pts (62.0 %) had anti-SARS-Cov-2 antibodies after the second doses; and 18/21 pts (85.7 %) reached the seroconversion after the third doses. The proportion of seroconversion was significantly increased in the second doses regardless the response observed after the first doses (p = 0.012, Fisher's exact test), particularly when two doses of ChAdOx11 vaccine was administrated (p = 0.040, Chi-square). However, the comparisons of seroconversion rate between Sputnik V and ChAdOx11 vaccines showed no differences after the different vaccination doses. No significant statistical difference in patient́s gender, age, comorbidities, type of vaccine, post-transplant, or maintenance immunosuppressive therapy was found between responders and non-responders. CONCLUSION: Despite having a lower seroconversion rate compared to the general population, viral-vector vaccines benefit SOTR patients increasing the seroconversion rate using at least two doses of vaccine. These results support the concept of developing tailor-made vaccination guidelines for this specific population. This analysis provides further support to safety and efficacy of viral-vector vaccines in liver and liver-intestine transplant patients.

Variants in IGLL1 cause a broad phenotype from agammaglobulinemia to transient hypogammaglobulinemia.

BACKGROUND: Agammaglobulinemia due to variants in IGLL1 has traditionally been considered an exceedingly rare form of severe B-cell deficiency, with only 8 documented cases in the literature. Surprisingly, the first agammaglobulinemic patient identified by newborn screening (NBS) through quantification of kappa-deleting recombination excision circles harbored variants in IGLL1. OBJECTIVE: We comprehensively reviewed clinical and immunologic findings of patients with B-cell deficiency attributed to variants in IGLL1. METHODS: NBS programs reporting the use of kappa-deleting recombination excision circle assays, the European Society for Immunodeficiencies Registry, and authors of published reports featuring patients with B-cell deficiency linked to IGLL1 variants were contacted. Only patients with (likely) pathogenic variants, reduced CD19+ counts, and no alternative diagnosis were included. RESULTS: The study included 13 patients identified through NBS, 2 clinically diagnosed patients, and 2 asymptomatic siblings. All had severely reduced CD19+ B cells (< 0.1 × 109/L) at first evaluation, yet subsequent follow-up assessments indicated residual immunoglobulin production. Specific antibody responses to vaccine antigens varied, with a predominant reduction observed during infancy. Clinical outcomes were favorable with IgG substitution. Two patients successfully discontinued substitution therapy without developing susceptibility to infections and while maintaining immunoglobulin levels. The pooled incidence of homozygous or compound heterozygous pathogenic IGLL1 variants identified by NBS in Austria, Czechia, and Switzerland was 1.3:100,000, almost double of X-linked agammaglobulinemia. CONCLUSION: B-cell deficiency resulting from IGLL1 variants appears to be more prevalent than initially believed. Despite markedly low B-cell counts, the clinical course in some patients may be milder than reported in the literature so far.

The Impact of Lebrikizumab on Vaccine-Induced Immune Responses: Results from a Phase 3 Study in Adult Patients with Moderate-to-Severe Atopic Dermatitis.

INTRODUCTION: Lebrikizumab, a high-affinity IgG4 monoclonal antibody that selectively inhibits interleukin-13 with high binding affinity and slow dissociation rate, prevents the formation of the interleukin-4Rα/interleukin-13Rα1 heterodimer receptor signaling complex. Here we report the impact of lebrikizumab on responses to two non-live vaccines in adult patients with moderate-to-severe atopic dermatitis (AD). METHODS: ADopt-VA (NCT04626297) was a double-blind, placebo-controlled, parallel-group, 16-week, phase 3 randomized study to assess the impact of lebrikizumab treatment on non-live vaccine immune responses, and efficacy and safety of lebrikizumab compared with placebo. Eligible patients included adults from 18 to 55 years of age with moderate-to-severe chronic AD who were randomly assigned 1:1 to lebrikizumab 250 mg every 2 weeks or placebo and stratified according to disease severity. The primary endpoints were the development of a booster response to tetanus toxoid and a positive antibody response to meningococcal conjugate vaccine (MCV), 4 weeks after administration of the corresponding vaccine. RESULTS: At week 16, 73.6% of patients in the lebrikizumab group (n = 78/106) achieved Tdap booster response compared with 73.4% of patients in the placebo group (n = 58/79). MCV vaccine response was observed in 86.9% of patients in the lebrikizumab group (n = 86/99) and 75.0% of patients in the placebo group (n = 60/80). At week 16, IGA 0,1 with ≥ 2-point improvement from baseline was achieved by 40.6% (n = 51/125) of patients treated with lebrikizumab and 18.9% (n = 23/122) of patients who received placebo (p < 0.001). There was a higher proportion of patients achieving EASI 75 at week 16 in the lebrikizumab-treated patients (58.0%, n = 72/125) compared with placebo (32.7%, n = 40/122, p < 0.001). CONCLUSIONS: Treatment with lebrikizumab did not impact response to non-live vaccines Tdap and MCV in this study. Lebrikizumab treatment had a significant degree of efficacy compared to placebo across multiple endpoints. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT04626297.

Using Ex Vivo Tonsil Organoids to Study Memory B Cells.

Tools to study memory B cell (MBC) development and function are needed to understand their role in supporting sustained protection against recurrent infections. While human MBCs are traditionally measured using blood, there is a growing interest in elucidating their behavior within lymphoid tissues, which are the main sites where adaptive immune responses are orchestrated. In this chapter, we introduce a high-throughput organoid system that is derived from primary human lymphoid tissues. The approach can recapitulate many hallmarks of successful adaptive immune responses and capture inter-individual variation in response to a variety of stimuli. Lymphoid tissue organoids enable characterization of pre-existing antigen-specific MBCs within an entirely human system and can provide valuable insights into MBC dynamics.

Hospitalisations and humoral COVID-19 vaccine response in vaccinated rituximab-treated multiple sclerosis patients.

BACKGROUND: Patients with multiple sclerosis (MS) treated with anti-CD20 therapies such as rituximab may have increased risk of severe COVID-19 disease. Vaccination induces protective immunity, but humoral vaccine response is known to be attenuated in rituximab-treated MS-patients-patients, which has indicated a need for real world data on severe morbidity and mortality from COVID-19 after vaccination. METHODS: Rituximab-treated patients treated at Haukeland University Hospital were identified through the National MS Registry and invited to participate in the study by giving a consent and providing a blood sample 3 weeks or later after ordinary COVID-19- vaccination, i.e. 2 doses given with a standard interval of 3 weeks. Blood samples were analysed with Enzyme-Linked Immunosorbent assay (ELISA) to evaluate humoral vaccine response with screening test against receptor-binding domain (RBD) and confirmatory Spike IgG-specific ELISA. A haemagglutination test (HAT) was performed as a marker of neutralizing antibodies. Patient serum concentration of rituximab were quantified using liquid chromatography tandem mass spectrometry (LC-MS/MS). Registry data from the Norwegian MS registry and information on hospitalization from patient records were collected and linked to laboratory results. RESULTS: 111 patients were included in the study. A total of 7 (6.3%) were hospitalized due to COVID-19 disease during the observation period. No patient was admitted to ICU and there were no deaths. 34.2% did not have detectable titre of SARS CoV-2 Spike IgG antibodies, 72.1% did not have a detectable titre of SARS CoV-2 RBD antibodies, and 88.2% did not have a detectable HAT titre. There was a correlation between hospitalisation and the absence of SARS CoV-2 Spike IgG antibody titre, and between hospitalisation and MS disease duration, as well as between spike IgG antibody titre and CD19 B-cell count, time since last rituximab infusion, cumulative rituximab treatment time and total IgG level in the patients. CONCLUSION: A substantial proportion of rituximab-treated MS-patients-patients did not have detectable humoral vaccine responses after 2 doses of COVID-19 vaccination. Despite this, the cumulative percentage of patients hospitalized with COVID-19 disease throughout the observation period of 22 months was low, and no patients required ICU treatment. The results support that vaccinated MS-patients treated with rituximab have a protective effect against serious Covid-19 infection.

Evaluating patient immunocompetence through antibody response to pneumococcal polysaccharide vaccine using a newly developed 23 serotype multiplexed assay.

Assessing T-cell independent antibody response to polysaccharide vaccines is crucial for diagnosing humoral immune deficiencies. However, immunocompetence criteria based on S. pneumoniae vaccination remain unclear. We evaluated IgG antibody vaccine response in healthy individuals to establish interpretive criteria. Pre- and 4-week post-vaccination sera were collected from 79 adults. Antibody concentrations to PNEUMOVAX 23 serotypes were measured using a multiplexed platform. Immunocompetence was determined by fold increase in post-vaccination response, percentage of serotypes achieving 4- or 2-fold antibody ratio, and post-vaccination concentration ≥ 1.3 µg/mL. Immunogenicity varied widely across the 23 serotypes (26.6% to 94.9% for ≥4-fold increase, 51.9% to 98.7% for ≥2-fold increase). Immunocompetence based on historic criteria of ≥4-fold increase in antibody ratio to ≥70% of serotypes was low (72.2%), but increased to 98.7% with criteria of at least a 2-fold increase and/or post-vaccination concentration ≥ 1.3 µg/mL. Current criteria for assessing immunocompetence may be overly stringent and require updating.

Bacillus toyonensis amplifies the immunogenicity of an experimental recombinant tetanus vaccine in horses.

Probiotic microorganisms can stimulate an immune response and increase the efficiency of vaccines. For example, Bacillus toyonensis is a nonpathogenic, Gram-positive bacterium that has been used as a probiotic in animal supplementation. It induces immunomodulatory effects and increases the vaccine response in several species. This study aimed to evaluate the effect of B. toyonensis supplementation on the modulation of the immune response in horses vaccinated with recombinant Clostridium tetani toxin. Twenty horses were vaccinated twice, with an interval of 21 days between doses, and equally divided into two groups: the first group was supplemented orally for 42 days with feed containing viable spores of B. toyonensis (1 × 108) mixed with molasses (40 ml), starting 7 days before the first vaccination; the second (control) group received only feed mixed with molasses, starting 7 days before the first vaccination. Serum samples were collected to evaluate the humoral immune response using an in-house indirect enzyme-linked immunosorbent assay (ELISA), and peripheral blood mononuclear cells (PBMCs) were collected to evaluate cytokine transcription (qPCR). For the specific IgG-anti-rTENT titer, the supplemented group had ELISA values that were four times higher than those of the control group (p < 0.05). The supplemented group also showed higher ELISA values for the IgGa and IgGT sub-isotypes compared to the control group. In PBMCs stimulated with B. toyonensis, relative cytokine transcription of the supplemented group showed 15-, 8-, 7-, and 6-fold increases for IL1, TNFα, IL10 and IL4, respectively. When stimulated with a vaccine antigen, the supplemented group showed 1.6-, 1.8-, and 0.5-fold increases in IL1, TNFα, and IL4, respectively, compared to the control group. Horses supplemented with B. toyonensis had a significantly improved vaccine immune response compared to those in the control group, which suggests a promising approach for improving vaccine efficacy with probiotics.

An Exploratory Approach of Clinically Useful Biomarkers of Cvid by Logistic Regression.

Despite advancements in genetic and functional studies, the timely diagnosis of common variable immunodeficiency (CVID) remains a significant challenge. This exploratory study was designed to assess the diagnostic performance of a novel panel of biomarkers for CVID, incorporating the sum of κ+λ light chains, soluble B-cell maturation antigen (sBCMA) levels, switched memory B cells (smB) and the VISUAL score. Comparative analyses utilizing logistic regression were performed against established gold-standard tests, specifically antibody responses. Our research encompassed 88 subjects, comprising 27 CVID, 23 selective IgA deficiency (SIgAD), 20 secondary immunodeficiency (SID) patients and 18 healthy controls. We established the diagnostic accuracy of sBCMA and the sum κ+λ, achieving sensitivity (Se) and specificity (Spe) of 89% and 89%, and 90% and 99%, respectively. Importantly, sBCMA showed strong correlations with all evaluated biomarkers (sum κ+λ, smB cell and VISUAL), whereas the sum κ+λ was uniquely independent from smB cells or VISUAL, suggesting its additional diagnostic value. Through a multivariate tree decision model, specific antibody responses and the sum κ+λ emerged as independent, signature biomarkers for CVID, with the model showcasing an area under the curve (AUC) of 0.946, Se 0.85, and Spe 0.95. This tree-decision model promises to enhance diagnostic efficiency for CVID, underscoring the sum κ+λ as a superior CVID classifier and potential diagnostic criterion within the panel.

Effect of methotrexate hold on COVID-19 vaccine response in the patients with autoimmune inflammatory disorders: a systematic review and meta-analysis.

Immunosuppressants, such as methotrexate (MTX), can suppress the COVID-19 vaccine response in patients with autoimmune diseases. Thus, this study aims to evaluate the effects of MTX hold following COVID-19 vaccination on vaccine efficacy response. A systematic review and meta-analysis of relevant studies retrieved from Web of Science, SCOPUS, PubMed, and CENTRAL from inception until Oct 1, 2023, was conducted. Covidence was used to screen the eligible articles, and all relevant outcomes data were synthesized using risk ratios (RRs) or standardized mean differences (SMDs) with 95% confidence intervals (CIs) in meta-analysis models within RevMan 5.4. PROSPERO ID: CRD42024511628. Four studies with a total of 762 patients with autoimmune inflammatory disorders were included. Holding MTX following the COVID-19 vaccination for approximately 2 weeks was associated with significantly higher antibody titer (SMD: 0.70, 95% CI [0.54, 0.87], P < 0.00001). However, the flare rate was significantly higher in the MTX hold group based on CDAI > 10 or DAS28-CRP > 1.2 either after 1st dose (RR: 2.49 with 95% CI [1.39, 4.47], P = 0.002) or 2nd dose (RR: 2.16 with 95% CI [1.37, 3.41], P = 0.0009) and self-reported disease flare (RR: 1.71 with 95% CI [1.35, 2.17], P < 0.00001). Holding MTX for 2 weeks after the COVID-19 vaccination resulted in significantly higher antibody titer but also had a higher disease flare rate, necessitating cautious clinical monitoring during this period. There is still a need to investigate safer MTX hold duration, considering patients' vulnerability to COVID-19, disease status, and demographics while adopting this strategy.

The effect of oral probiotics on response to vaccination in older adults: a systematic review of randomised controlled trials.

This systematic review evaluated the impact of oral probiotics on the immune response to vaccination in older people. A literature search was performed in three electronic databases up to January 2023. Randomised controlled trials (RCTs) conducted in older people (age ≥ 60 years) investigating oral probiotics and vaccine response outcomes were included. Characteristics and outcome data of the included studies were extracted and analysed and study quality was assessed using the Cochrane Risk of Bias Tool for randomised trials. Ten RCTs involving 1,560 participants, reported in 9 papers, were included. Nine studies involved the seasonal influenza vaccine and one a COVID-19 vaccine. All studies used lactobacilli, some in combination with bifidobacteria. Studies reported outcomes including anti-vaccine antibody titres or concentrations, seroconversion and seroprotection. When comparing antibody titres, seroprotection rate and seroconversion rate between probiotic and placebo groups expressed as a response ratio, the weighted mean values were 1.29, 1.16 and 2.00, respectively. Meta-analysis showed that probiotics increase seroconversion rates to all three strains of the seasonal influenza vaccine: odds ratio (95% confidence interval) 2.74 (1.31, 5.70; P = 0.007) for the H1N1 strain; 1.90 (1.04, 3.44; P = 0.04) for the H3N2 strain; 1.72 (1.05, 2.80; P = 0.03) for the B strain. There was a low level of heterogeneity in these findings. Several studies were at high risk of bias due to missing outcome data. Lactobacilli may improve the vaccine response, but further research is needed to be more certain of this.

Immunogenicity of Recombinant Zoster Vaccine: A Systematic Review, Meta-Analysis, and Meta-Regression.

BACKGROUND: The adjuvanted recombinant zoster vaccine (RZV), consisting of varicella-zoster virus glycoprotein E (gE) and the AS01B adjuvant system, effectively prevents herpes zoster (HZ). In the absence of a well-defined correlate of protection, it is important to monitor the RZV immune response, as a proxy of clinical effectiveness. METHODS: This systematic review examined post-vaccination parameters: humoral and cell-mediated immunity, avidity index, geometric mean concentration of antibody (GMC), and immunity persistence. The meta-analysis used a random-effects model, and subgroup and meta-regression analyses were conducted. RESULTS: Among 37 included articles, after one month from RZV-dose 2, the pooled response rate for anti-gE humoral immunity was 95.2% (95%CI 91.9-97.2), dropping to 77.6% (95%CI 64.7-86.8) during immunosuppression. The anti-gE cell-mediated immunity-specific response reached 84.6% (95%CI 75.2-90.9). Varying factors, such as age, sex, coadministration with other vaccines, prior HZ, or live-attenuated zoster vaccine, did not significantly affect response rates. RZV induced a substantial increase in gE avidity. Immunity persistence was confirmed, with more rapid waning in the very elderly. CONCLUSIONS: This systematic review indicates that RZV elicits robust immunogenicity and overcomes immunocompromising conditions. The findings underscore the need for further research, particularly on long-term immunity, and have the potential to support HZ vaccination policies and programs.

Integrating population and single-cell variations in vaccine responses identifies a naturally adjuvanted human immune setpoint.

Multimodal single-cell profiling methods can capture immune cell variations unfolding over time at the molecular, cellular, and population levels. Transforming these data into biological insights remains challenging. Here, we introduce a framework to integrate variations at the human population and single-cell levels in vaccination responses. Comparing responses following AS03-adjuvanted versus unadjuvanted influenza vaccines with CITE-seq revealed AS03-specific early (day 1) response phenotypes, including a B cell signature of elevated germinal center competition. A correlated network of cell-type-specific transcriptional states defined the baseline immune status associated with high antibody responders to the unadjuvanted vaccine. Certain innate subsets in the network appeared "naturally adjuvanted," with transcriptional states resembling those induced uniquely by AS03-adjuvanted vaccination. Consistently, CD14+ monocytes from high responders at baseline had elevated phospho-signaling responses to lipopolysaccharide stimulation. Our findings link baseline immune setpoints to early vaccine responses, with positive implications for adjuvant development and immune response engineering.

Serological responses to immunization during nephrosis in infants with congenital nephrotic syndrome of the Finnish type.

Background: Pretransplant vaccination is generally recommended to solid organ transplant recipients. In infants with congenital nephrotic syndrome (CNS), the immune response is hypothetically inferior to other patients due to young age and urinary loss of immunoglobulins, but data on the immunization response in severely nephrotic children remain scarce. If effective, however, early immunization of infants with CNS would clinically be advantageous. Methods: We investigated serological vaccine responses in seven children with CNS who were immunized during nephrosis. Antibody responses to measles-mumps-rubella -vaccine (MMR), a pentavalent DTaP-IPV-Hib -vaccine (diphtheria, tetanus, acellular pertussis, inactivated poliovirus, Haemophilus influenzae type b), varicella vaccine, combined hepatitis A and B vaccine, and pneumococcal conjugate vaccine (PCV) were measured after nephrectomy either before or after kidney transplantation. Results: Immunizations were started at a median age of 7 months [interquartile range (IQR) 7-8], with a concurrent median proteinuria of 36,500 mg/L (IQR 30,900-64,250). Bilateral nephrectomy was performed at a median age of 20 months (IQR 14-25), and kidney transplantation 10-88 days after the nephrectomy. Antibody levels were measured at median 18 months (IQR 6-23) after immunization. Protective antibody levels were detected in all examined children for hepatitis B (5/5), Clostridium tetani (7/7), rubella virus (2/2), and mumps virus (1/1); in 5/6 children for varicella; in 4/6 for poliovirus and vaccine-type pneumococcal serotypes; in 4/7 for Haemophilus influenzae type B and Corynebacterium diphtheriae; in 1/2 for measles virus; and in 2/5 for hepatitis A. None of the seven children had protective IgG levels against Bordetella pertussis. Conclusion: Immunization during severe congenital proteinuria resulted in variable serological responses, with both vaccine- and patient-related differences. Nephrosis appears not to be a barrier to successful immunization.

Immune response stability to the SARS-CoV-2 mRNA vaccine booster is influenced by differential splicing of HLA genes.

Many molecular mechanisms that lead to the host antibody response to COVID-19 vaccines remain largely unknown. In this study, we used serum antibody detection combined with whole blood RNA-based transcriptome analysis to investigate variability in vaccine response in healthy recipients of a booster (third) dose schedule of the mRNA BNT162b2 vaccine against COVID-19. The cohort was divided into two groups: (1) low-stable individuals, with antibody concentration anti-SARS-CoV IgG S1 below 0.4 percentile at 180 days after boosting vaccination; and (2) high-stable individuals, with antibody values greater than 0.6 percentile of the range in the same period (median 9525 [185-80,000] AU/mL). Differential gene expression, expressed single nucleotide variants and insertions/deletions, differential splicing events, and allelic imbalance were explored to broaden our understanding of the immune response sustenance. Our analysis revealed a differential expression of genes with immunological functions in individuals with low antibody titers, compared to those with higher antibody titers, underscoring the fundamental importance of the innate immune response for boosting immunity. Our findings also provide new insights into the determinants of the immune response variability to the SARS-CoV-2 mRNA vaccine booster, highlighting the significance of differential splicing regulatory mechanisms, mainly concerning HLA alleles, in delineating vaccine immunogenicity.

A multi-omics systems vaccinology resource to develop and test computational models of immunity.

Systems vaccinology studies have identified factors affecting individual vaccine responses, but comparing these findings is challenging due to varying study designs. To address this lack of reproducibility, we established a community resource for comparing Bordetella pertussis booster responses and to host annual contests for predicting patients' vaccination outcomes. We report here on our experiences with the "dry-run" prediction contest. We found that, among 20+ models adopted from the literature, the most successful model predicting vaccination outcome was based on age alone. This confirms our concerns about the reproducibility of conclusions between different vaccinology studies. Further, we found that, for newly trained models, handling of baseline information on the target variables was crucial. Overall, multiple co-inertia analysis gave the best results of the tested modeling approaches. Our goal is to engage community in these prediction challenges by making data and models available and opening a public contest in August 2024.

Host genetics drives differences in cecal microbiota composition and immune traits of laying hens raised in the same environment.

Vaccination is one of the most effective strategies for preventing infectious diseases but individual vaccine responses are highly heterogeneous. Host genetics and gut microbiota composition are 2 likely drivers of this heterogeneity. We studied 94 animals belonging to 4 lines of laying hens: a White Leghorn experimental line genetically selected for a high antibody response against the Newcastle Disease Virus (NDV) vaccine (ND3) and its unselected control line (CTR), and 2 commercial lines (White Leghorn [LEG] and Rhode Island Red [RIR]). Animals were reared in the same conditions from hatching to 42 d of age, and animals from different genetic lines were mixed. Animals were vaccinated at 22 d of age and their humoral vaccine response against NDV was assessed by hemagglutination inhibition assay and ELISA from blood samples collected at 15, 19, and 21 d after vaccination. The immune parameters studied were the 3 immunoglobulins subtypes A, M, and Y and the blood cell composition was assessed by flow cytometry. The composition of the cecal microbiota was assessed at the end of the experiment by analyzing amplified 16S rRNA gene sequences to obtain amplicon sequence variants (ASV). The 4 lines showed significantly different levels of NDV vaccine response at the 3 measured points, with, logically, a higher response of the genetically selected ND3 line, and intermediate and low responses for the unselected CTR control line and for the 2 commercial lines, respectively. The ND3 line displayed also a higher proportion of immunoglobulins (IgA, IgM, and IgY). The RIR line showed the most different blood cell composition. The 4 lines showed significantly different microbiota characteristics: composition, abundances at all taxonomic levels, and correlations between genera and vaccine response. The tested genetic lines differ for immune parameters and gut microbiota composition and functions. These phenotypic differences can be attributed to genetic differences between lines. Causal relationships between both types of parameters are discussed and will be investigated in further studies.

Humoral immunogenicity of primary yellow fever vaccination in infants and children: a systematic review, meta-analysis and meta-regression.

BACKGROUND: Vaccination plays a critical role in mitigating the burden associated with yellow fever (YF). However, there is a lack of comprehensive evidence on the humoral response to primary vaccination in the paediatric population, with several questions debated, including the response when the vaccine is administered at early ages, the effect of co-administration with other vaccines, the duration of immunity and the use of fractional doses, among others. This study summarizes the existing evidence regarding the humoral response to primary YF vaccination in infants and children. METHODS: Studies on the humoral response to primary YF vaccination in children aged 12 years or younger were reviewed. The humoral vaccine response rate (VRR), i.e. the proportion of children who tested positive for vaccine-induced YF-specific neutralizing antibodies, was pooled through random-effects meta-analysis and categorized based on the time elapsed since vaccination. Subgroup, meta-regression and sensitivity analyses were performed. RESULTS: A total of 33 articles met the inclusion criteria, with all but one conducted in countries where YF is endemic. A total of 14 028 infants and children entered this systematic review. Within three months following vaccination, the pooled VRR was 91.9% (95% CI 89.8-93.9). A lower VRR was observed with the 17DD vaccine at the meta-regression analysis. No significant differences in immunogenicity outcomes were observed based on age, administration route, co-administration with other vaccines, or fractional dosing. Results also indicate a decline in VRR over time. CONCLUSIONS: Primary YF vaccination effectively provides humoral immunity in paediatric population. However, humoral response declines over time, and this decline is observable after the first 18 months following vaccination. A differential response according to the vaccine substrain was also observed. This research has valuable implications for stimulating further research on the primary YF vaccination in infants and children, as well as for informing future policies.