Background: Food allergy affects up to 8% of the pediatric population. Despite ongoing efforts, treatment options remain limited. Novel models of food allergy are needed to study response patterns downstream of IgE-crosslinking and evaluate drugs modifying acute events. Here, we report a novel human ex vivo model that displays acute, allergen-specific, IgE-mediated smooth muscle contractions using precision cut intestinal slices (PCIS). Methods: PCIS were generated using gut tissue samples from children who underwent clinically indicated surgery. Viability and metabolic activity were assessed from 0-24h. Distribution of relevant cell subsets was confirmed using single cell nuclear sequencing. PCIS were passively sensitized using plasma from peanut allergic donors or peanut-sensitized non-allergic donors, and exposed to various stimuli including serotonin, histamine, FcɛRI-crosslinker and food allergens. Smooth muscle contractions and mediator release functioned as readouts. A novel program designed to measure contractions was developed to quantify responses. The ability to demonstrate the impact of antihistamines and immunomodulation from peanut oral immunotherapy (OIT) was assessed. Results: PCIS viability was maintained for 24h. Cellular distribution confirmed the presence of key cell subsets including mast cells. The video analysis tool reliably quantified responses to different stimulatory conditions. Smooth muscle contractions were allergen-specific and reflected the clinical phenotype of the plasma donor. Tryptase measurement confirmed IgE-dependent mast cell-derived mediator release. Antihistamines suppressed histamine-induced contraction and plasma from successful peanut OIT suppressed peanut-specific PCIS contraction. Conclusion: PCIS represent a novel human tissue-based model to study acute, IgE-mediated food allergy and pharmaceutical impacts on allergic responses in the gut.

A document by Alessandro Farsi. Click on the document to view its contents.

There has been an important change in the clinical characteristics and immune profile of COVID-19 patients during the pandemic thanks to the extensive vaccination programs. Here, we highlight recent studies on COVID-19, from the clinical and immunological characteristics to the protective and risk factors for severity and mortality of COVID-19. The efficacy COVID-19 vaccines and potential allergic reactions after administration are also discussed. The occurrence of new variants of concerns such as Omicron BA.2, BA.4 and BA.5 and the global administration of COVID-19 vaccines have changed the clinical scenario of COVID-19. Multisystem inflammatory syndrome in children (MIS-C) has been identified as an important cause of death of children with COVID-19. Perturbations in immunity of T cells, B cells, and mast cells, as well as autoantibodies and metabolic reprogramming may contribute to the long-term symptoms of COVID-19. Atopic diseases, such as allergic asthma and rhinitis, have been shown to be associated with a lower susceptibility and better outcomes of COVID-19. At the beginning of pandemic, EAACI developed guidelines that provided timely information for the management of allergic diseases and preventive measures to reduce transmission in the allergic clinics. The global distribution of COVID-19 vaccines and emerging SARS-CoV-2 variants with reduced pathogenic potential dramatically decreased the morbidity, severity, and mortality of COVID-19. Nevertheless, breakthrough infection remains a challenge for disease control. Hypersensitivity reactions (HSR) to COVID-19 vaccines are low compared to other vaccines, and these were addressed in EAACI statements that provided indications for the management of allergic reactions, including anaphylaxis to COVID-19 vaccines. We have gained a depth knowledge and experience in the over 2 years since the start of the pandemic, and yet a full eradication of SARS-CoV-2 is not on the horizon. Novel strategies are warranted to prevent severe disease in high-risk groups, the development of MIS-C and long COVID.

Fenebrutinib is an orally administered, selective and reversible BTK inhibitor. Metz et al recently published a double-blind, placebo-controlled, phase 2 trial where fenebrutinib (50mg daily, 150mg daily or 200mg twice-daily) or placebo were randomly administered to 93 adults with CSU refractory to up-dosed H 1-antihistamines during 8 weeks. Fenebrutinib was more effective than placebo in reducing weekly Urticaria Activity Score (UAS7) after 8 weeks, achieving rates of well-controlled disease (UAS7≤6) of up to 57% (with a 200mg twice-daily dose).

Background: From early life, respiratory viruses are implicated in the development, exacerbation and persistence of respiratory conditions such as asthma. Complex dynamics between microbial communities and host immune responses, shape immune maturation and homeostasis, influencing health outcomes. We evaluated the hypothesis that the respiratory virome is linked to systemic immune responses, using peripheral blood and nasopharyngeal swab samples from preschool-age children in the PreDicta cohort. Methods: Peripheral blood mononuclear cells from 51 children (32 asthmatics, 19 healthy controls), participating in the 2-year multinational PreDicta cohort were cultured with bacterial (Bacterial-DNA, LPS) or viral (R848, Poly:IC, RV) stimuli. Supernatants were analyzed by Luminex for the presence of 22 relevant cytokines. Virome composition was obtained using untargeted high troughput sequencing of nasopharyngeal samples. The metagenomic data were used for the characterization of virome profiles and the presence of key viral families (Picornaviridae, Anelloviridae, Siphoviridae). These were correlated to cytokine secretion patterns, identified through hierarchical clustering and principal component analysis. Results: High spontaneous cytokine release was associated with increased presence of Prokaryotic virome profiles and reduced presence of Eukaryotic and Anellovirus profiles. Antibacterial responses did not correlate with specific viral families or virome profile, however, low antiviral responders had more Prokaryotic and less Eukaryotic virome profiles. Anelloviruses and Anellovirus-dominated profiles were equally distributed amongst immune response clusters. The presence of Picornaviridae and Siphoviridae was associated with low interferon-λ responses. Asthma or allergy did not modify these correlations. Conclusions: Antiviral cytokines responses at a systemic level reflect the upper airway virome composition. Individuals with low innate interferon responses have higher abundance of Picornaviruses (mostly Rhinoviruses) and bacteriophages. Bacteriophages, particularly Siphoviridae appear to be sensitive sensors of host antimicrobial capacity, while Anelloviruses are not affected by TLR-induced immune responses.

Title: Real-world evidence on the risk of cancer with anti-IL-5 and anti-IL-4Ra biologicalsAuthors : Diogo Mota1; Tiago Azenha Rama1, 2, 3, 4; André Moreira1, 2, 3, 4

Background Patients with severe asthma may present with characteristics representing overlapping phenotypes, making them eligible for more than one class of biologic. Our aim was to describe the profile of severe adult asthma patients eligible for both anti-IgE and anti-IL5/5R and to compare the effectiveness of both classes of treatment in real life. Methods This was a prospective cohort study that included adult severe asthma patients from 22 countries enrolled into the International Severe Asthma registry (ISAR) who were eligible for both anti-IgE and anti-IL5/5R. The effectiveness of anti-IgE and anti-IL5/5R was compared in a 1:1 matched cohort. Exacerbation rate was the primary effectiveness endpoint. Secondary endpoints included long-term-oral corticosteroid (LTOCS) use, asthma-related emergency room (ER) attendance and hospital admissions. Results In the matched analysis (n=350/group), the mean annualized exacerbation rate decreased by 47.1% in the anti-IL5/5R group and 38.7% in the anti-IgE group. Patients treated with anti-IL5/5R were less likely to experience a future exacerbation (adjusted IRR 0.76; 95% CI 0.64, 0.89; p<0.001) and experienced a greater reduction in mean LTOCS dose than those treated with anti-IgE (37.44% vs 20.55% reduction; p=0.023).) There was some evidence to suggest that patients treated with anti-IL5/5R experienced fewer asthma-related hospitalizations (IRR 0.64; 95% CI 0.38, 1.08), but not ER visits (IRR 0.94, 95% CI 0.61, 1.43). Conclusions In real life, both anti-IgE and anti-IL5/5R improve asthma outcomes in patients eligible for both biologic classes, however anti-IL5/5R was superior in terms of reducing asthma exacerbations and LTOCS use.

BACKGROUND Severe acute respiratory syndrome corona virus (SARS-CoV-2) infection frequently causes severe and prolonged disease but only few specific treatments are available. We aimed to investigate safety and efficacy of a SARS-CoV-2-specific siRNA-peptide dendrimer formulation (MIR 19 ®) targeting a conserved sequence in known SARS-CoV-2 variants for treatment of COVID-19. METHODS We conducted an open-label, randomized controlled multicenter phase II trial (NCT05184127) evaluating safety and efficacy of inhaled MIR 19 ® (3.7mg and 11.1 mg/day: groups 1 and 2, respectively) in comparison with standard etiotropic drug treatment (group 3) in patients hospitalized with moderate COVID-19. The primary endpoint was the time to clinical improvement according to predefined criteria within 14 days of randomization. RESULTS Patients from group1 had a significantly reduced (median 6 days (95% confidence interval [CI]: 5-7, HR 1.75, P=0.0005) time to clinical improvement compared to patients from group 3 (8 days (95% CI: 7-10). Normalized oxygen saturation (SpO 2>94%) occurred quicker in the group 1 (median 5 days (95% CI: 4–5, HR 1.59, P=0.0033) than in the group 3 (6 days, 95% CI: 5–8). Treatment with MIR 19® was well tolerated and safe. CONCLUSIONS MIR 19 ®, a SARS-CoV-2-specific siRNA-peptide dendrimer formulation is safe and significantly reduces time to clinical improvement in hospitalized moderate COVID-19 patients compared to standard therapy in a randomized controlled trial. MIR 19 ® treatment targets a sequence which is identical in all SARS-CoV-2 variants known so far and hence should be applicable for all of them.

As many other physicians and researchers, we have had the great pleasure to be fellows in the laboratory of Dean Metcalfe, the Laboratory of Allergic Diseases, National Institute of Allergic and Infectious Diseases (NIAID), NIH, Bethesda, USA (Figure [1](#fig-cap-0001)). The open atmosphere, research driven by curiosity, hypotheses originating from clinical observations, and mutual trust and respect are the cornerstones of Dean’s mentorship. Dean and his laboratory have made major contributions on mast cell biology, from basic studies on the regulation of mast cell development and functions, to clinical studies on mast cells in diseases, such as systemic mastocytosis. After more than 50 years of exploring human mast cells, Dean’s impact on what we know today about these cells, their biology and how they affect diseases is outstanding and unique.

The impact of exposure to air pollutants, such as fine particulate matter (PM), on the immune system and its consequences on pediatric asthma are not well understood. We investigated whether the ambient levels of fine PM with aerodynamic diameter ≤ 2.5 microns (PM 2.5) are associated with alterations in circulating monocytes in children with or without asthma. Increased exposure to ambient PM 2.5 was linked to specific monocyte subtypes, particularly in children with asthma. Mechanistically, we hypothesized that innate trained immunity is evoked by a primary exposure to fine PM and accounts for an enhanced inflammatory response after secondary stimulation in vitro. We determined that the trained immunity was induced in circulating monocytes by fine particulate pollutants, and it was characterized by upregulation of proinflammatory mediators, such as TNF, IL-6, and IL-8, upon stimulation with house dust mite or LPS. This phenotype was epigenetically controlled by enhanced H3K27ac marks in circulating monocytes. The specific alterations of monocytes after ambient pollution exposure suggest a possible prognostic immune signature for pediatric asthma, and pollution-induced trained immunity may provide a potential therapeutic target for asthmatic children living in areas with increased air pollution.

Title: Some OPA once told me “LKB1 is going to rule me”: the OPA1-LKB1 axis in immune responseAuthors: Contreras N1,2*, Macías-Camero A1,2*, Delgado-Dolset MI1,2.Affiliations: 1Centre for Metabolomics and Bioanalysis (CEMBIO), Department of Chemistry and Biochemistry, Facultad de Farmacia, Universidad San Pablo-CEU, CEU Universities, Urbanización Montepríncipe, 28660 Boadilla del Monte, Madrid, Spain.2Instituto de Medicina Molecular Aplicada Nemesio Díez (IMMA-NM), Departamento de Ciencias Médicas Básicas, Facultad de Medicina, Universidad San Pablo-CEU, CEU Universities, Urbanización Montepríncipe, 28660 Boadilla del Monte, Madrid, Spain.*These authors contributed equallyCorrespondence to: María Isabel Delgado-Dolset , Instituto de Medicina Molecular Aplicada Nemesio Díez (IMMA-NM), Departamento de Ciencias Médicas Básicas, Facultad de Medicina, Universidad San Pablo CEU, CEU Universities, Urbanización Montepríncipe, 28660 Boadilla del Monte, Madrid, Spain.Campus Montepríncipe. Crtra. Boadilla del Monte km 5.3.CP 28668 Boadilla del Monte. Madrid, Spain.Tlf: +34 91 372 47 00 ext. 15068E-mail: [email protected] of interest: The authors have no conflicts of interest to declare.Funding information: The authors received no specific funding for the elaboration of this article.Authorship: All the authors approved the final version of the manuscript as submitted and agreed to be accountable for all aspects of the work.Acknowledgments: The authors acknowledge the support by Instituto de Salud Carlos III (PI18/01467 and PI19/00044), co-funded by FEDER “Investing in your future” for the thematic network and co-operative research centres ARADyAL RD16/0006/0015 and RICORS Red de Enfermedades Inflamatorias (REI) RD21 0002 0008. Authors would also like to recognize the funding by the Ministry of Science and Innovation in Spain (PCI2018-092930), co-funded by the European program ERA HDHL—Nutrition and the Epigenome, project Dietary Intervention in Food Allergy: Microbiome, Epigenetic and Metabolomic interactions (DIFAMEM); and by Fundación Mutua Madrileña (AP177712021). N.C. and A.M.C. are supported by FPI-CEU predoctoral fellowships. The authors would like to thank Dr Domingo Barber, Dr María M Escribese and Dr Alma Villaseñor for their asserted comments.List of abbreviations : 2-HG: 2-HidroxyGlutarate, α-KG: α-KetoGlutarate, CD4: Cluster of Differentiation 4, ETC: Electron Transport Chain, IL17A: InterLeukin 17A, LKB1: Liver-associated Kinase B1, NET: Neutrophil Extracellular Trap, OPA1: Optic Atrophy 1, PHGDH: PHosphoGlycerate DeHydrogenase, Treg: Regulatory T Helper, TH: T HelperIn the last 20 years, increasing evidence has arisen challenging the belief that mitochondria are mere ATP-synthesizing machines, shedding light on their role in cell signaling (1). Metabolites, energy mediators, and physical interactions involving membrane rearrangements are some of the mechanisms involved in mitochondria-driven cell regulation (1). In this sense, energetics plays a role in the development and function of immune cells, and immunometabolism is a flourishing field. Nonetheless, how mitochondria signaling networks, including membrane dynamics, affect T cell development and differentiation remains unclear (2).In a recently published work, Baixauli et al (3) investigated how CD4+ T cell differentiation is influenced by mitochondrial membrane morphology. In vitro analysis showed that elongated mitochondria with tight cristae in TH17 cells correlated with higher levels of the long isoform protein of OPA1 (L-OPA1) when compared to TH1 and TH2 cells. Moreover, they developed an OPA1 knockout mouse model (Opa1Cd4-cre ) which showed that, besides controlling mitochondrial membrane dynamics, OPA1 also regulated IL17A production, suggesting its potential role in the regulation of TH17 cells effector function.To address this matter, a multi-omic approach, including epigenomics, transcriptomics, proteomics, and metabolomics, was applied. They found several changes in the mitochondria due to the lack of OPA1 that could lead to the loss of Il17a expression. First, as a result of a disrupted inner mitochondrial membrane, electron transport chain (ETC) subunits uncouple, leading to an increase in the NADH/NAD+ ratio. Higher levels of NADH, together with an increase in the oxidation of glutamine, promote α-ketoglutarate (α-KG) conversion towards 2-hidroxyglutarate (2-HG) by phosphoglycerate dehydrogenase (PHGDH). 2-HG accumulation increases histone and DNA methylation that lastly alters chromatin accessibility in immune response genes interfering with Il17a expression.Pathway analysis was performed to determine OPA1 intracellular biological mediators, raising LKB1 as its major upstream regulator. While LKB1 activity was increased inOpa1Cd4-cre mice, authors demonstrated thatLkb1 deletion restored cell carbon metabolism and Il17aexpression by reducing the production of PHGDH and other serine biosynthesis enzymes.This article provides a perspective of the OPA1-LKB1 axis and its role in immune regulation in TH17 cells, which grants a deep understanding on how the different types of molecules are intertwined in the disease (4). As for possible limitations, this work was done using solely a mouse model, which, despite being as extraordinary as it is, does not necessarily match the conditions and metabolic changes that take place in human cells (1). It would have been interesting to see some of these experiments being done in T cells from human donors to corroborate these findings, which would be possible by using CRISPR/Cas technology to delete OPA1 and/or LKB1 .Furthermore, it is still necessary to understand how, if at all, OPA1-LKB1 axis regulates other subsets of T cells, such as TH1 or Treg. It is known that LKB1 affects other immune cell types, even within the innate immune response. For example, LKB1 deficiency in mouse dendritic cells results in higher levels of Treg in vivo that promote an immune-suppressed phenotype through mTOR signaling, impairing tumor growth control and protecting against allergic asthma development (5). Moreover, deletion of Lkb1 in mice alveolar macrophages leads to more severe asthma and higher susceptibility to S. aureusinfection through the AMPK pathway (6); and an increased number of neutrophils. Additionally, it has been described that OPA1-dependent ATP production is needed for neutrophil extracellular trap (NET) formation and effective antibacterial defense both in human and mouse neutrophils (7). However, these studies fail to analyze the OPA1-LKB1 relation, which, to our knowledge, has been described for the first time by Baixauli et al. All in all, these authors have uncover the great potential of the OPA-LKB1 axis in the immunometabolism research field.REFERENCES1. Picard M, Shirihai OS. Mitochondrial signal transduction. Cell Metab 2022;34 :1620–1653.2. Shyer JA, Flavell RA, Bailis W. Metabolic signaling in T cells.Cell Res 2020;30 :649–659.3. Baixauli F, Piletic K, Puleston DJ, Villa M, Field CS, Flachsmann LJ et al. An LKB1–mitochondria axis controls TH17 effector function.Nature 2022;610 :555–561.4. Radzikowska U, Baerenfaller K, Cornejo-Garcia JA, Karaaslan C, Barletta E, Sarac BE et al. Omics technologies in allergy and asthma research: An EAACI position paper. Allergy2022;77 :2888–2908.5. Pelgrom LR, Patente TA, Sergushichev A, Esaulova E, Otto F, Ozir-Fazalalikhan A et al. LKB1 expressed in dendritic cells governs the development and expansion of thymus-derived regulatory T cells.Cell Res 2019;29 :406–419.6. Wang Q, Chen S, Li T, Yang Q, Liu J, Tao Y et al. Critical Role of Lkb1 in the Maintenance of Alveolar Macrophage Self-Renewal and Immune Homeostasis. Front Immunol 2021;12 :1–12.7. Amini P, Stojkov D, Felser A, Jackson CB, Courage C, Schaller A et al. Neutrophil extracellular trap formation requires OPA1-dependent glycolytic ATP production. Nat Commun 2018;9 :2958.

Background. Oral immunotherapy (OIT) is an emerging method for treating food allergy in children. However, data regarding adults undergoing this process is lacking. Methods. We retrospectively analyzed the medical records of patients with food allergy aged ≥17 years who completed OIT treatment between April 2010 to December 2020 at Shamir medical Center. Data was compared to that of children aged 4 to <11 years and adolescents aged ≥11 to 17 treated during the same time period. Results. A total of 96 adults at a median age of 22.3 years who underwent OIT for milk (n=53), peanut (n=18), sesame (n=7), egg (n=5) and tree nuts (n=13) were analyzed and compared to 1299 children and 309 adolescents. Adults experienced more adverse reactions requiring injectable epinephrine, both during in-clinic up-dosing (49% vs. 15.9% and 26.5% for children and adolescents respectively, p<0.0001) and during home treatment (22.9% vs. 10.5%, p=0.001 for children, and 14.2%, p=0.06 for adolescents). Most adults (61.5%) were fully desensitized, but rates of full desensitization were significantly lower compared to children (73.4%, p=0.013). Significantly more adults (28.3%) undergoing milk OIT failed treatment compared to children (14.3%, p=0.015) and adolescents (14.1%, p=0.022), while failure rates in adults undergoing OIT for other foods were low (9.3%) and comparable to children and adolescents. Conclusions. OIT is successful in desensitizing most adults with IgE-mediated food allergy. Adults undergoing milk OIT are at increased risk for severe reactions and for OIT failure while failure rates in adults undergoing OIT for other foods are low.

Adolescence is a critical stage of rapid biological, emotional and social change and development. Adolescents and young adults (AYA) with asthma and allergies need to develop the knowledge and skills to self-manage their health independently. Healthcare professionals (HCP), parents and their wider network play an essential role in supporting AYA in this process. Previous work showed significant limitations in transition care across Europe. In 2020, the first evidence-based guideline on effective transition for AYA with asthma and allergies was published by EAACI. We herein summarize practical resources to support this guideline’s implementation in clinical practice. For this purpose, multi-stakeholder Task Force members searched for resources in peer review journals and grey literature. These resources were included if relevant and of good quality, and were pragmatically rated for their evidence-basis and user friendliness. Resources identified covered a range of topics and targeted healthcare professionals, AYA, parents/carers, schools, workplace, and wider community. Most resources were in English, web-based and had limited evidence-basis. This position paper provides a valuable selection of practical resources for all stakeholders to support effective transitional care for AYA with asthma and allergies. Future research should focus on developing validated, patient-centred tools to further assist evidence-based transition care.

Background: Randomized controlled trials (RCTs) are the gold-standard for benefit-risk assessments during drug approval processes. Real-word data (RWD) and the resulting real-world evidence (RWE) are becoming increasingly important for assessing the effectiveness of drug products after marketing authorization showing how RCT results are transferred into real life care. The effectiveness of allergen immunotherapy (AIT) has been assessed in several RWE studies based on large prescription databases. Methods: We performed a literature search for retrospective cohort assessments of prescription databases in Europe to provide an overview on the methodology, long-term effectiveness outcomes and adherence to AIT. Results: 13 respective publications were selected. AIT was more effective in reducing the progression of allergic rhinitis (AR) compared to a non-AIT control group receiving only symptomatic treatment for AR for up to 6 years. The development and progression of asthma was hampered for most endpoints in patients treated with most preparations compared to the non-AIT group, receiving only anti-asthmatic medication. The results for “time to onset” of asthma were inconsistent. Adherence to AIT decreased during the recommended 3-years treatment period, however in most studies higher adherence to subcutaneous than to sublingual AIT was shown. Conclusion: The analysis of long-term effectiveness outcomes of the RWE studies based on prescription databases confirms the long-term efficacy of AIT demonstrated in RCTs. Progression of rhinitis and asthma symptoms as well as delayed onset of asthma triggered by different allergens, real life adherence to the treatment shows differences in particular application routes.

Immune-inflammatory proteome of elite ice hockey players before and after SARS-CoV-2 infection

LetterDelta or Omicron BA.1/2-neutralizing antibody levels and T-cell reactivity after triple-vaccination or infectionTo the editor,In Germany, SARS-CoV-2 infections in fall 2021 were caused by the Delta variant of concern (VOC B.1.617.2), which was completely replaced by the Omicron VOC (BA.1, B.1.529.1/BA.2, B.1.529.2) in winter. Meanwhile, the BA.2 sublineage dominates, apparently having a selection advantage1.We studied the kinetics of anti-spike (S) protein IgG and Delta neutralizing antibodies (NA) as well as the release of interferon-gamma (IFN-γ) from SARS-CoV-2-specific T-cells in 152 individuals (117 women, 35 men, median age 41 years) who received two doses of vector vaccine (AstraZeneca, AZD, N=34), mRNA vaccine (BioNTech or Moderna, mRNA, N=62), or a combination of both (N=56) followed by an mRNA vaccine boost (N=81). In a subset of 15 age- and gender-matched vaccinees and in ten triple-vaccinated and two unvaccinated patients with previous BA.1 infection, the Delta- and Omicron BA.1/BA.2 NAs and T-cell reactivity were examined. For comparison, variant-specific antibody responses of unvaccinated patients after infection with Alpha- (N=10) or Beta VOCs (N=1) were included.Within 279 days after the second vaccination, a decrease in anti-S IgG concentrations (Figures S 1A-C) and Delta NA titers (Figure 1A) was measured regardless of the immunization regimen. The booster vaccination led to a significant increase of anti-S IgG concentrations (Figures S1 D-F) and of Delta NA titers (Figure 1B). The IgG levels and Delta NAs reached four weeks after the mRNA vaccine booster were 1.3 - 1.7-fold higher than after the second mRNA dose, but this difference was significant only for IgG (Figures 1A, C; Figures S 1A-C, G-I). The release of IFN-γ as a measure of SARS-CoV-2 T-cell reactivity was demonstrated for months after second vaccination. In contrast to the Delta NA levels, IFN-γ concentrations were independent of the underlying vaccination schedule and increased slightly after the third immunization (Figures 1D, E). The parameters of humoral and cellular immunity decreased again after the booster vaccination (Figures 1C, F; Figures S 1G-I).As reported by others 1-4, NAs to Omicron BA.1 were induced by the mRNA vaccine booster, but also against the predominant BA.2 sublineage, which was previously unclear. The BA.2 NA geometric mean titer (GMT) was higher than the BA.1 NA GMT (Figure 2A). With respect to the results presented in Figures 1C and 2B, we suspect that NAs against the Omicron VOC will decline rapidly after booster vaccination alone. High NA titers against Omicron BA.1/BA.2 and against Delta VOC were exclusively observed in triple-vaccinated individuals two to three weeks after Omicron breakthrough infection (Figure 2A). This indicates broadened immunity covering additional viral variants and may also explain why few BA.2 infections have occurred in this group of individuals to date 5. Because Omicron is a distinct serotype 6, only NAs against this VOC were detectable in two unvaccinated BA.1-infected individuals (Figure 2A), while unvaccinated Alpha- and Beta VOC patients developed isolated NAs against the antigenically more related Delta VOC (Figure S 2A). Accordingly, both BA.1 patients had very low IgG levels against the receptor-binding domain (RBD) of a Wuhan-like virus (Figure S 2B), whereas IgGs against the higher preserved nucleocapsidprotein were barely affected (Figures S 2C, D). The results of a surrogate neutralization assay confirmed very limited humoral immunity after Omicron infection alone (Figure S 2E).The increase of IFN-γ release by mRNA booster vaccination was moderate (Figures 1D, E), while the breakthrough infection insignificantly increased IFN-γ release by a factor of 1.9 - 2.6 (Figure 2C).In conclusion, the importance of pre-existing vaccine-induced immunity is clearly demonstrated. The booster vaccination with the conventional mRNA vaccine resulted in measurable BA.1/BA.2 NAs. However, a multivalent vaccine could induce higher titers, which could provide better protection.

Article type: Editorial

A document by Carmen H. Li. Click on the document to view its contents.