The local and systemic symptoms that follow vaccination, collectively referred to as reactogenicity, are common, yet the mechanisms underlying individual variability remain poorly understood. Through longitudinal immune profiling of vaccinated individuals and mechanistic studies in mice, we identified key immunological determinants of reactogenicity induced by mRNA vaccines. Systemic adverse events were associated with stronger interferon and pro-inflammatory responses after the second dose of a COVID-19 mRNA vaccine, which were also correlated with the magnitude of the antigen-specific adaptive responses. This heightened inflammation occurred within 24 hours of vaccination, originated primarily from the injection site, and was characterized by enhanced recruitment and activation of myeloid cells, particularly monocytes. Two mechanisms contributed to this response: early interferon production by muscle T cells generated after the first dose and Fcγ receptor-dependent chemokine induction by vaccine antigen-specific antibodies. Consistently, serum antibody levels before vaccination correlated positively with reactogenicity. In addition to this local amplification mechanism, variability in reactogenicity was influenced by the baseline immune state, given that individuals with a preexisting interferon-stimulated gene signature in monocytes, detectable at both transcriptomic and epigenetic levels, were more prone to systemic symptoms. Together, our findings revealed molecular and cellular mechanisms driving vaccine reactogenicity, providing a framework for the design of less reactogenic vaccines.

Hepatitis B virus (HBV) infection remains a major driver of liver-related morbidity and mortality among people living with HIV (PLWH), yet vaccine-induced protection is frequently suboptimal. HIV-associated immune dysfunction, including CD4+ T-cell depletion, altered antigen presentation, impaired T follicular helper cell support, and B-cell dysregulation, reduces seroprotection after standard recombinant HBV vaccines and may limit durability of antibody responses. Vaccine response is further influenced by HIV viral suppression, age, comorbidities, prior vaccine history, and baseline HBV serologic status, including isolated hepatitis B core antibody (anti-HBc) and occult HBV infection (OBI) considerations. Although antiretroviral therapy (ART) improves vaccine responsiveness, many PLWH fail to achieve protective hepatitis B surface antibody (anti-HBs) titers (≥10 mIU/mL) after conventional schedules, or experience antibody waning over time. Current guidelines recommend HBV vaccination for all susceptible PLWH with post-vaccination serologic testing and revaccination for nonresponders. Persistent implementation barriers, including incomplete series, vaccine hesitancy, stigma, and logistical constraints, continue to limit real-world impact. Emerging clinical trial data support CpG-adjuvanted HBV vaccines (HepB-CpG/Heplisav-B) and intensified dosing and schedules (double-dose or four-dose regimens) to improve seroprotection and generate higher peak anti-HBs titers, which may enhance durability. This review synthesizes guideline recommendations, immunologic mechanisms of hyporesponsiveness, predictors of vaccine response, and practical strategies to optimize HBV vaccination in PLWH.

BackgroundTreatment with anti-CD20 antibodies (rituximab) is used in both adults and children to treat various autoimmune and oncological diseases. Rituximab depletes B CD20+ cells and, thereby, antibody response to vaccines. This study aimed to examine the antibody response to mRNA-based COVID-19 vaccines in children aged 5-18 years undergoing rituximab treatment compared to healthy matched children.MethodsBetween 31 January and 18 July 2022, we conducted a prospective observational study at the Geneva University Hospitals, enrolling children aged 5-18 years under rituximab treatment who had received two mRNA-based SARS-CoV-2 vaccine doses. Controls were healthy volunteers with no significant medical conditions. Exclusion criteria included a recent SARS-CoV-2 infection. Blood samples were collected at day 60 (+/- 30) and day 270 (+/- 90) after the second vaccination.ResultsThe rituximab-treated group exhibited significantly lower levels of antibodies specific to the anti-receptor binding domain (RBD) of the SARS-CoV-2 spike (S) protein than healthy controls at 60 (+/- 30) days after the second vaccine dose (geometric mean concentration: 868.3 IU/mL in patients and 11,393 IU/mL in controls; p = .008). However, patients with a rituximab-to-vaccine interval shorter than 6 months and with evidence of a past infection (based on positive anti-N antibody levels) had a high level of anti-RBD antibodies.ConclusionA past infection with SARS-CoV-2 may induce anti-RBD-specific memory B cells that can be re-activated by SARS-CoV-2 vaccination, even after rituximab-induced B-cell depletion. This suggests that it is possible to vaccinate earlier than 6 months after rituximab to develop a good antibody response, especially in the case of past SARS-CoV-2 infection.

The number of elderly people is constantly increasing in Switzerland. This population is often at higher risk of infections and concomitant decompensation of underlying comorbidities, in particular cardiac or respiratory diseases. Vaccines are some of the most effective preventive measures for limiting morbidity and mortality related to some of those infections, such as influenza or shingles. In order to improve vaccination coverage, it is essential to inform the patients of the benefits of vaccination, and to plan a catch-up vaccination consultation. The goal of this article is to offer a practical guide for the general practitioner detailing vaccines for the elderly recommended in Switzerland.

Since their emergence in late 2021, SARS-CoV-2 Omicron replaced earlier variants of concern and marked a new phase in the SARS-CoV-2 pandemic. Until the end of 2023, Omicron lineages continue to circulate and continue to evolve, with new lineages causing infection waves throughout 2022 and 2023. In the population, this leads to a complex immunological exposure background, characterized by immunity derived through vaccination, in the 5th year of the pandemic in the majority of individuals followed by at least one or even multiple infections or only natural infection in individuals that did not receive a vaccine.In this study, we use eight authentic SARS-CoV-2 isolates (ancestral lineage B.1 and the seven Omicron lineages BA.1, BA.2, BA.5.1, BQ.1, XBB.1.5, EG.5.1 and JN.1.1) in a live virus neutralization assay to study immune escape in 97 human sera or plasma of different immunological backgrounds (vaccination, hybrid immunity due to one or two natural infections and natural infection without vaccination in children and adults).We showed a gradually increasing immune escape after vaccination and hybrid immunity in from B.1 to BA.1/BA.2 to BA.5.1 to BQ.1 to XBB.1.5 to EG.5.1, but remarkably, no more enhanced immune escape of JN.1.1 compared to EG.5.1, with the latter two showing almost identical neutralization titers in individuals with hybrid immunity due to one or more infections. In vaccinated but never infected individuals, neutralization was markedly reduced or completely lost for XBB.1.5., EG.5.1 and JN.1.1, while in those with hybrid immunity, titers were reduced but almost all sera still showed some degree of neutralization. After a single infection without vaccination, reduced or complete loss of neutralization occurred for BQ.1, XBB.1.5, EG.5.1 and JN.1.1 compared to BA.1/BA.2. Furthermore, we observed that, although absolute titers differed between groups, the pattern of immune escape between the variants remains comparable across groups, with strongest loss of neutralization for BQ.1, XBB.1.5, EG.5.1 and JN.1.1 was observed across the different immunological backgrounds. Our results show gradually increasing antibody escape of evolving Omicron lineages over the last two years of Omicron circulation until variant EG.5.1, but not anymore for the currently dominant lineages JN.1.1, suggesting other mechanisms than immune escape to be behind the rapid global emergence of JN.1.### Competing Interest StatementIE has received research funding and speakers fees from Moderna for an unrelated research project (IIS). CSE received funding from Pfizer for an unrelated research project (IIS). All other authors: No conflict of interest.

ObjectiveImmune checkpoint inhibitors (ICI) that block the programmed cell death 1 (PD-1) pathway have shown promise with limited benefit. We and others have shown in small patient cohorts that an early proliferative CD8 T-cell response in the blood may be predictive of clinical response. However, these studies lack detailed analyses and comparisons between monotherapy and combination therapies.Methods and analysisWe analysed longitudinal blood samples from 103 patients with cancer who received αPD-1 monotherapy or combined with anti-cytotoxic T lymphocyte-associated protein 4 (αCTLA-4) or chemotherapy. Transcriptional analysis of CD8 T cells after the first treatment cycle with effector cells generated following yellow fever virus (YFV-17D) vaccine-induced infection was also compared.ResultsAn early proliferative (Ki-67+) CD8 T-cell response was observed after cycle 1 in 60 patients (58.3%). Patients with early-and-sustained proliferative responses (cycle 1 and beyond) had better clinical responses and survival than patients with an early-but-limited response (p=0.02). The proliferating cells had an effector-like phenotype. The transcriptional profiles of the effector-like CD8 T cells were similar irrespective of treatment type or clinical response but distinct from that of YFV-specific effector CD8 T cells.ConclusionsOur data suggest that early proliferative CD8 T-cell response in the blood is predictive, and that an early-and-sustained proliferative response may further identify patients with prolonged survival. The ICI-induced effector-like CD8 T cells are transcriptionally distinct from highly functional YFV-specific cells, suggesting opportunities for improved T-cell effector function with combination therapies for better clinical outcome.

The number of elderly people is constantly increasing in Switzerland. This population is often at higher risk of infections and concomitant decompensation of underlying comorbidities, in particular cardiac or respiratory diseases. Vaccines are some of the most effective preventive measures for limiting morbidity and mortality related to some of those infections, such as influenza or shingles. In order to improve vaccination coverage, it is essential to inform the patients of the benefits of vaccination, and to plan a catch-up vaccination consultation. The goal of this article is to offer a practical guide for the general practitioner detailing vaccines for the elderly recommended in Switzerland.

Patients on dialysis (PoD) are at high risk of severe morbidity and mortality from COVID-19. Characterizing long-term vaccine immune responses in these patients will help optimize vaccine schedule for PoD. This study aimed to determine whether long-term humoral and B and T cell-responses post 3rd and 4th dose of the BNT162b2 vaccine differed between PoD and controls. Non-infected PoD and controls vaccinated with BNT162b2 were recruited in Ziv Medical Center, Israel, between 2021 and 2022. Specimens were collected 1-2 months pre 3rd dose; 1-3 months post 3rd dose; 4-5 months post 3rd dose and 3-5 months post the 4th dose. Anti-SARS-CoV-2 spike (spike) specific antibodies, spike specific memory B cells, and spike specific CD154+ T cells as well as cytokines producing CD4+/CD8+ T cells were measured using standardized assays and compared between PoD and controls at each time point using Mann Whitney and Fisher's exact tests. We recruited 22 PoD and 20 controls. Antibody levels in PoD were lower compared to controls pre 3rd dose but not post 3rd and 4th doses. Frequencies of spike specific memory B cell populations were similar between PoD and controls overall. Frequencies of spike specific T cells, including those producing IFN gamma and TNF alpha, were not lower in PoD. B and T cell mediated immune response in PoD following a 3rd and a 4th dose of the BNT162b2 vaccine was not inferior to controls up to 5 months post vaccination. Our results suggest that standard BNT162b2 vaccination is suitable for this group.

Objectives To comprehensively analyze the quality of the antibody response between children with Multisystem inflammatory syndrome (MIS-C) and age-matched controls at one month after SARS-CoV-2 exposure, and infected in the same time-period. Methods Serum from 20 MIS-C children at admission, and 14 control children were analyzed. Antigen specific antibody isotypes and subclasses directed against various antigens of SARS-CoV-2 as well as against human common coronavirus (HCoVs) and commensal or pathogenic microorganisms were assessed by a bead-based multiplexed serological assay and by ELISA. The functionality of these antibodies was also assessed using a plaque reduction neutralization test, a RBD-specific avidity assay, a complement deposition assay and an antibody-dependent neutrophil phagocytosis (ADNP) assay. Results Children with MIS-C developed a stronger IgA antibody response in comparison to children with uncomplicated COVID-19, while IgG and IgM responses are largely similar in both groups. We found a typical class-switched antibody profile with high level of IgG and IgA titers and a measurable low IgM due to relatively recent SARS-CoV-2 infection (one month). SARS-CoV-2-specific IgG antibodies of MIS-C children had higher functional properties (higher neutralization activity, avidity and complement binding) as compared to children with uncomplicated COVID-19. There was no difference in the response to common endemic coronaviruses between both groups. However, MIS-C children had a moderate increase against mucosal commensal and pathogenic strains, reflecting a potential association between a disruption of the mucosal barrier with the disease. Conclusion Even if it is still unclear why some children develop a MIS-C, we show here that MIS-C children produce higher titers of IgA antibodies, and IgG antibodies with higher functionality, which could reflect the local gastro-intestinal mucosal inflammation potentially induced by a sustained SARS-CoV-2 gut infection leading to continuous release of SARS-CoV-2 antigens.

Methods for the analysis of cell secretions at the single-cell level only provide semiquantitative endpoint readouts. Here we describe a microwell array for the real-time spatiotemporal monitoring of extracellular secretions from hundreds of single cells in parallel. The microwell array incorporates a gold substrate with arrays of nanometric holes functionalized with receptors for a specific analyte, and is illuminated with light spectrally overlapping with the device's spectrum of extraordinary optical transmission. Spectral shifts in surface plasmon resonance resulting from analyte-receptor bindings around a secreting cell are recorded by a camera as variations in the intensity of the transmitted light while machine-learning-assisted cell tracking eliminates the influence of cell movements. We used the microwell array to characterize the antibody-secretion profiles of hybridoma cells and of a rare subset of antibody-secreting cells sorted from human donor peripheral blood mononuclear cells. High-throughput measurements of spatiotemporal secretory profiles at the single-cell level will aid the study of the physiological mechanisms governing protein secretion.

The timing of maternal pertussis vaccination influences the titers of cord-blood anti-pertussis antibodies. Whether it affects their avidity is unknown. We demonstrate in 298 term and 72 preterm neonates that antibody avidity is independent of the timing of maternal vaccination, whether comparing second with third trimester or intervals before birth.

ObjectiveTo comprehensively evaluate SARS-CoV-2 specific B-cell and antibody responses up to one year after mild COVID-19.MethodsIn 31 mildly symptomatic COVID-19 participants SARS-CoV-2-specific plasmablasts and antigen-specific memory B cells were measured by ELISpot. Binding antibodies directed against the proteins spike (S), domain S1, and nucleocapsid (N) were estimated using rIFA, ELISA, and commercially available assays, and avidity measured using thiocyanate washout. Neutralizing antibodies against variants of concern were measured using a surrogate-neutralization test.ResultsPlasmablast responses were assessed in all participants who gave sequential samples during the first two weeks after infection; they preceded the rise in antibodies and correlated with antibody titers measured at one month. S1 and N protein-specific IgG memory B-cell responses remained stable during the first year, whereas S1-specific IgA memory B-cell responses declined after 6 months. Antibody titers waned over time, whilst potent affinity maturation was observed for anti-RBD antibodies. Neutralizing antibodies against wild-type (WT) and variants decayed during the first 6 months but titers significantly increased for Alpha, Gamma and Delta between 6 months and one year. Therefore, near-similar titers were observed for WT and Alpha after one year, and only slightly lower antibody levels for the Delta variant compared to WT. Anti-RBD antibody responses correlated with the neutralizing antibody titers at all time points, however the predicted titers were 3-fold lower at one year compared to one month.ConclusionIn mild COVID-19, stable levels of SARS-CoV-2 specific memory B cells and antibodies neutralizing current variants of concern are observed up to one year post infection. Care should be taken when predicting neutralizing titers using commercial assays that measure binding antibodies.

Background and Aims : Auto-antibodies against apolipoprotein A-1 (AAA1) develop during SARS-CoV-2 infection and could be of concern as mediators of symptoms in the later stages of infection. We aimed at determining i) the duration and kinetics of AAA1 response over 12 months after a SARS-CoV-2 infection, and ii) whether AAA1 were associated with COVID-19 symptoms persistence.Methods: All serologies were measured by immunoassays at one, three, six, and twelve months in 193 COVID-19 positive hospital employees. LGM, ROC curve and LRM analyses were used to assess the clinical determinants of AAA1 levels and kinetics, their prognostic accuracy and the association between AAA1 levels and patient-reported COVID-19 symptoms persistence respectively.Results: AAA1 positivity rate was 92% declining to 14.5% at 12 months after infection. Significant correlation were retrieved between SARS-CoV-2 anti-S, anti-N and AAA1 IgG levels. Age was the only independent factor modulating AAA1 initial levels. Persistent symptoms at 12 months were observed in 45.1 % of participants, with a predominance of neurological (28.5 %), followed by general (15%) and respiratory symptoms (9.3%). AAA1 levels at 3 months after the infection, displayed significant prognostic accuracies and were independently associated with respiratory symptoms persistence (AUC ranging between 0.72 to 0.74; p<0.001; adjusted OR varying between 4.81-4.94; p=0.02), while anti-S and anti-N antibodies levels were not.Conclusions: SARS-CoV-2 infection induces a marked though transient AAA1 response, independently predicting one-year persistence of respiratory symptoms from the third month after infection. If and how AAA1 levels assessment could be of use for COVID-19 risk stratification remains to be determined. Background and Aims : Auto-antibodies against apolipoprotein A-1 (AAA1) develop during SARS-CoV-2 infection and could be of concern as mediators of symptoms in the later stages of infection. We aimed at determining i) the duration and kinetics of AAA1 response over 12 months after a SARS-CoV-2 infection, and ii) whether AAA1 were associated with COVID-19 symptoms persistence. Methods: All serologies were measured by immunoassays at one, three, six, and twelve months in 193 COVID-19 positive hospital employees. LGM, ROC curve and LRM analyses were used to assess the clinical determinants of AAA1 levels and kinetics, their prognostic accuracy and the association between AAA1 levels and patient-reported COVID-19 symptoms persistence respectively. Results: AAA1 positivity rate was 92% declining to 14.5% at 12 months after infection. Significant correlation were retrieved between SARS-CoV-2 anti-S, anti-N and AAA1 IgG levels. Age was the only independent factor modulating AAA1 initial levels. Persistent symptoms at 12 months were observed in 45.1 % of participants, with a predominance of neurological (28.5 %), followed by general (15%) and respiratory symptoms (9.3%). AAA1 levels at 3 months after the infection, displayed significant prognostic accuracies and were independently associated with respiratory symptoms persistence (AUC ranging between 0.72 to 0.74; p<0.001; adjusted OR varying between 4.81-4.94; p=0.02), while anti-S and anti-N antibodies levels were not. Conclusions: SARS-CoV-2 infection induces a marked though transient AAA1 response, independently predicting one-year persistence of respiratory symptoms from the third month after infection. If and how AAA1 levels assessment could be of use for COVID-19 risk stratification remains to be determined.

Background: Allogeneic hematopoietic stem cell transplantation (HSCT) recipents have a higher risk to develop severe forms of COVID-19 after infection with SARS-CoV2 compared to the general population. Aims: To gain further insights into the immune defects leading to increased severity of COVID-19 infection in allogeneic HSCT recipients, we evaluated B and T cells responses in convalescent healthy controls and allogeneic HSCT recipients after COVID-19 infection. Methods: Peripheral blood samples were obtained from allogeneic HSCT recipients (n=11) between 1 and 8 months after COVID-19 infection. Median time of COVID-19 infection since HSCT was 17 months (range 8-70). Healthy controls recruited by the Geneva Blood Transfusion Center 1 to 3 months after mild COVID-19 infection served as controls (n=11). None of the HSCT recipients nor healthy controls has received anti-SARS-Cov2 vaccination before infection. Antibody responses against the SARS-CoV-2 spike protein (anti-S) and nucleocapside phosphoprotein (anti-N) were measured in plasma using the semi-quantitative Elecsys® Anti-SARS-CoV-2 immunoassay (Roche). SARS-CoV-2-specific T cell responses were quantified based on IFN-γ release against a range of peptides from the SARS-CoV-2 Spike protein (S) as well as from the membrane glycoprotein (M) and the nucleocapside phosphoprotein (N) using an Enzyme-Linked ImmunoSpot (ELISpot) assay. SARS-CoV-2- specific T cell clonotypes were identified by genomic DNA T-cell receptor (TCR) sequencing (immunoSEQ® T-MAP™ COVID, Adaptive). Results: We observed no difference in anti-S and anti-N antibody titers between convalescent healthy controls and HSCT recipients (Figure 1A). We observed significantly lower numbers of IFN-γ spot forming units after stimulation with peptides from both the S protein (p=0.0068) and the M plus N proteins (p=0.0067; Figure 1B) in the transplant group as opposed to the control group. Importantly, such differences were not merely due to T cell lymphopenia in HSCT recipients as similar numbers of IFN-γ producing T cells after phytohemagglutinin (PHA) stimulation and similar percentages of CD3+ T cells among PBMCs were measured in PBMCs from HC and HSCT recipients. SARS-CoV-2- specific T cell clonotypes were detectable in both HC and HSCT recipients (Figure 1C). The degree of diversity of the SARS-CoV-2-specific T cell clonotypes differed between the two groups, with HSCT recipients displaying a significantly reduced number of SARS-CoV-2-specific T cell clonotypes compared with HC (p=0.0037; Figure 1D). Such a difference was maintained when T cell clonotypes specific for the S protein (p=0.0011) or the N and M proteins (p=0.036) were analyzed (Figure 1E). As predicted, HSCT recipients displayed a less diverse TCR repertoire compared with HC as revealed by higher Simpson clonality (p= 0.0079). Interestingly, the Simpson clonality negatively correlated with the number of different SARS-CoV-2-specific T cell clonotypes (R2=0.86, p=4.8e−06; Figure 1F). Summary/Conclusion: Our results indicate that allogeneic HSCT recipients display a defect in cellular but not humoral SARS-CoV-2-specific responses after COVID-19 infection. Such impairment was both quantitative, as revealed by reduced IFN-γ release upon stimulation with SARS-CoV-2 peptides, and qualitative as demonstrated by the reduced clonotypic diversity of SARS-CoV-2-specific T cell clonotypes. These findings provide insights into our understanding of post-HSCT immune-dysfunction and into the increased risk of HSCT recipients of developing severe forms of COVID-19 after infection by SARS-CoV-2.

During this global health crisis, COVID-19 unfortunately did not spare pregnant women, who are at greater risk of becoming infected, developing severe forms and having obstetric complications. In this article we will talk about the risks associated with COVID-19 during pregnancy and in particular the existing data on the drugs to be administered in the event of illness and how to avoid infection and its complications through vaccination.

Emerging SARS-CoV-2 variants raise questions about escape from previous immunity. As the population immunity to SARS-CoV-2 has become more complex due to prior infections with different variants, vaccinations or the combination of both, understanding the antigenic relationship between variants is needed. Here, we have assessed neutralizing capacity of 120 blood specimens from convalescent individuals infected with ancestral SARS-CoV-2, Alpha, Beta, Gamma or Delta, double vaccinated individuals and patients after breakthrough infections with Delta or Omicron-BA.1. Neutralization against seven authentic SARS-CoV-2 isolates (B.1, Alpha, Beta, Gamma, Delta, Zeta and Omicron-BA.1) determined by plaque-reduction neutralization assay allowed us to map the antigenic relationship of SARS-CoV-2 variants. Highest neutralization titers were observed against the homologous variant. Antigenic cartography identified Zeta and Omicron-BA.1 as separate antigenic clusters. Substantial immune escape in vaccinated individuals was detected for Omicron-BA.1 but not Zeta. Combined infection/vaccination derived immunity results in less Omicron-BA.1 immune escape. Last, breakthrough infections with Omicron-BA.1 lead to broadly neutralizing sera.