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Although we develop influenza immunity from an early age, it is insufficient to prevent future infection with antigenically novel strains. One proposed way to generate long-term protective immunity against a broad range of influenza virus strains is to boost responses to the conserved epitopes on the hemagglutinin, the major surface glycoprotein on the influenza virus. Influenza-specific humoral immunity comprises a large fraction of the overall immune memory in humans, and it has been long recognized that preexisting immunity to influenza shapes the response to subsequent influenza infections and vaccinations. However, the mechanisms by which preexisting immunity modulates the response to influenza vaccination are still not completely understood. Using a set of mathematical models, we explore several hypotheses that may contribute to diminished boosting of antibodies to conserved epitopes after repeated vaccinations.

The COVID-19 pandemic has presented a serious challenge to the hepatology community, particularly healthcare professionals and patients. While the rapid development of safe and effective vaccines and treatments has improved the clinical landscape, the emergence of the omicron variant has presented new challenges. Thus, it is timely that the European Association for the Study of the Liver provides a summary of the latest data on the impact of COVID-19 on the liver and issues guidance on the care of patients with chronic liver disease, hepatobiliary cancer, and previous liver transplantation, as the world continues to deal with the consequences of the COVID-19 pandemic.

IMPORTANCE: The SARS-CoV-2 variant B.1.1.529 (Omicron) escapes neutralizing antibodies elicited after COVID-19 vaccination, while T-cell responses might be better conserved. It is crucial to assess how a third vaccination modifies these responses, particularly for immunocompromised patients with readily impaired antibody responses. OBJECTIVE: To determine T-cell responses to the Omicron spike protein in anti-CD20–treated patients with multiple sclerosis (MS) before and after a third messenger RNA COVID-19 vaccination. DESIGN, SETTING, AND PARTICIPANTS: In this prospective cohort study conducted from March 2021 to November 2021 at the University Hospital Geneva, adults with MS receiving anti-CD20 treatment (ocrelizumab) were identified by their treating neurologists and enrolled in the study. A total of 20 patients received their third dose of messenger RNA COVID-19 vaccine and were included in this analysis. INTERVENTIONS: Blood sampling before and 1 month after the third vaccine dose. MAIN OUTCOMES AND MEASURES: Quantification of CD4 and CD8 (cytotoxic) T cells specific for the SARS-CoV-2 spike proteins of the vaccine strain as well as the Delta and Omicron variants, comparing frequencies before and after the third vaccine dose. RESULTS: Of 20 included patients, 11 (55%) were male, and the median (IQR) age was 45.8 (37.8-53.3) years. Spike-specific CD4 and CD8 T-cell memory against all variants were maintained in 9 to 12 patients 6 months after their second vaccination, albeit at lower median frequencies against the Delta and Omicron variants compared with the vaccine strain (CD8 T cells: Delta, 83.0%; 95% CI, 73.6-114.5; Omicron, 78.9%; 95% CI, 59.4-100.0; CD4 T cells: Delta, 72.2%; 95% CI, 67.4-90.5; Omicron, 62.5%; 95% CI, 51.0-89.0). A third dose enhanced the number of responders to all variants (11 to 15 patients) and significantly increased CD8 T-cell responses, but the frequencies of Omicron-specific CD8 T cells remained 71.1% (95% CI, 41.6-96.2) of the responses specific to the vaccine strain. CONCLUSIONS AND RELEVANCE: In this cohort study of patients with MS treated with ocrelizumab, there were robust T-cell responses recognizing spike proteins from the Delta and Omicron variants, suggesting that COVID-19 vaccination in patients taking B-cell–depleting drugs may protect them against serious complications from COVID-19 infection. T-cell response rates increased after the third dose, demonstrating the importance of a booster dose for this population.

T cells are important in tumour immunity but a better understanding is needed of the differentiation of antigen-specific T cells in human cancer1,2. Here we studied CD8 T cells in patients with human papillomavirus (HPV)-positive head and neck cancer and identified several epitopes derived from HPV E2, E5 and E6 proteins that allowed us to analyse virus-specific CD8 T cells using major histocompatibility complex (MHC) class I tetramers. HPV-specific CD8 T cells expressed PD-1 and were detectable in the tumour at levels that ranged from 0.1% to 10% of tumour-infiltrating CD8 T lymphocytes (TILs) for a given epitope. Single-cell RNA-sequencing analyses of tetramer-sorted HPV-specific PD-1+ CD8 TILs revealed three transcriptionally distinct subsets. One subset expressed TCF7 and other genes associated with PD-1+ stem-like CD8 T cells that are critical for maintaining T cell responses in conditions of antigen persistence. The second subset expressed more effector molecules, representing a transitory cell population, and the third subset was characterized by a terminally differentiated gene signature. T cell receptor clonotypes were shared between the three subsets and pseudotime analysis suggested a hypothetical differentiation trajectory from stem-like to transitory to terminally differentiated cells. More notably, HPV-specific PD-1+TCF-1+ stem-like TILs proliferated and differentiated into more effector-like cells after in vitro stimulation with the cognate HPV peptide, whereas the more terminally differentiated cells did not proliferate. The presence of functional HPV-specific PD-1+TCF-1+CD45RO+ stem-like CD8 T cells with proliferative capacity shows that the cellular machinery to respond to PD-1 blockade exists in HPV-positive head and neck cancer, supporting the further investigation of PD-1 targeted therapies in this malignancy. Furthermore, HPV therapeutic vaccination efforts have focused on E6 and E7 proteins; our results suggest that E2 and E5 should also be considered for inclusion as vaccine antigens to elicit tumour-reactive CD8 T cell responses of maximal breadth. An analysis of human papillomavirus (HPV)-specific CD8 T cells in patients with head and neck cancer identifies functional PD-1+TCF-1+CD8 T cells in the tumour with implications for therapeutic vaccination and PD-1 directed immunotherapy.

BACKGROUND SARS-CoV-2 infection triggers different auto-antibodies, including anti-apolipoprotein A-1 IgGs (AAA1), which could be of concern as mediators of persistent symptoms. We determined the kinetics of AAA1 response over after COVID-19, and the impact of AAA1 on the inflammatory response and symptoms persistence. METHODS All serologies were assessed at one, three, six, and twelve months in 193 hospital employees with COVID-19. ROC curve analyses and logistic regression models (LRM) were used to determine the prognostic accuracy of AAA1 and their association with patient-reported COVID-19 symptoms persistence at 12 months. Interferon (IFN)-α and-γ production by AAA1-stimulated human monocyte-derived macrophages (HMDM) was assessed in vitro. RESULTS AAA1 seropositivity was 93% at one month and declined to 15% at 12 months after COVID-19. 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%). Over time, strength of correlations between AAA1 and anti-SARS-COV2 serologies decreased, but remained significant. From the 3rd month on, AAA1 levels predicted persistent respiratory symptoms (area under the curves 0.72-0.74; p

Purpose of review Coronavirus disease 2019 (COVID-19) vaccination is considered one of the most promising and socioeconomically sustainable strategy to help control the pandemic and several vaccines are currently being distributed in nationwide mass immunization campaigns. Very limited data are available on benefits and risks of COVID-19 vaccination in immunocompromised patients and in particular in solid organ or hematopoietic stem cell transplant recipients as they were excluded from phase III trials. This review summarizes current knowledge, international guidelines and controversies regarding COVID-19 vaccination in these vulnerable populations. Recent findings Various COVID-19 vaccine platforms showed good efficacy in phase III trials in the immunocompetent and there are data arising on the safety and immunogenicity of these vaccines in the immunocompromised population. Summary Transplant recipients could benefit significantly from COVID-19 vaccination, both through active immunization provided they elicit protective vaccine responses, and probably through cocooning by immunization of caregivers and healthcare personnel and thus reducing the risk of SARS-coronavirus-2 exposure. Although awaiting more data on the safety and efficacy of COVID-19 vaccines to inform potential adaptations of vaccine regimens, we strongly recommend prioritizing COVID-19 vaccination of solid and hematopoietic stem cell transplant recipients to decrease COVID-19-related morbidity and mortality.

By the beginning of November 2020, almost 50 million cases of coronavirus disease 2019 (COVID-19) had been reported worldwide, with over 35 million people defined as recovering from the disease [1]. According to the Centers for Disease Control and Prevention (CDC), updated on 10 September 2020, there were no confirmed reports to date of a person being reinfected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) within 3 months of the initial infection [2]. In the absence of solid human data, Rhesus monkeys were challenged 28 days after first SARS-CoV-2 infection with same virus strain and did not establish reinfection [3]. However, on 21 September 2020 the European CDC issued a report addressing SARS-CoV-2 reinfection, citing several case studies and calling for a case definition [4]. Defining reinfection, relapsed infection and recurrence of positive (re-positive) nucleic acid detection might have clinical and epidemiological implications for treatment and infection control measures, respectively. In this commentary, we aimed to provide such definitions, including a microbiologically confirmed definition of reinfection, as well as clinical and epidemiological ones. Reinfections are observed with many respiratory viruses, including human coronaviruses. Reinfections with respiratory viruses may be due to weak or waning initial immune response (e.g. respiratory syncytial virus), reinfection with another genotype/species (e.g. rhinoviruses) or the high variability of the viruses (e.g. influenza virus). Following the SARS-CoV-1 and Middle East respiratory syndrome coronavirus (MERS-CoV) epidemics, specific antibodies were detected in survivors up to 24 and 34 months, respectively. The negligible risk of a second exposure to these viruses has not allowed for a clinical determination as to the immunity against reinfection [5,6]. For endemic coronaviruses, immunity was shown to be temporary, lasting from several months to a few years, and reinfection has been reported after experimental and natural infection [7]. It is assumed that the immune response following a natural viral infection is incomplete and reinfections are possible [8]. Currently tested COVID-19 vaccine platforms such as RNA and viral vector vaccines are designed to elicit antibody and T-cell responses, whereas subunit vaccines are more restricted to antibody responses, precluding the effect of active effector T cells and memory T cells. However, it is one of the subunit vaccine candidates that shows so far the highest neutralizing antibody titres and it is still unclear if a future COVID-19 vaccine will provide sustained and sterilizing immunity.

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Tumours often contain B cells and plasma cells but the antigen specificity of these intratumoral B cells is not well understood1-8. Here we show that human papillomavirus (HPV)-specific B cell responses are detectable in samples from patients with HPV-positive head and neck cancers, with active production of HPV-specific IgG antibodies in situ. HPV-specific antibody secreting cells (ASCs) were present in the tumour microenvironment, with minimal bystander recruitment of influenza-specific cells, suggesting a localized and antigen-specific ASC response. HPV-specific ASC responses correlated with titres of plasma IgG and were directed against the HPV proteins E2, E6 and E7, with the most dominant response against E2. Using intratumoral B cells and plasma cells, we generated several HPV-specific human monoclonal antibodies, which exhibited a high degree of somatic hypermutation, consistent with chronic antigen exposure. Single-cell RNA sequencing analyses detected activated B cells, germinal centre B cells and ASCs within the tumour microenvironment. Compared with the tumour parenchyma, B cells and ASCs were preferentially localized in the tumour stroma, with well-formed clusters of activated B cells indicating ongoing germinal centre reactions. Overall, we show that antigen-specific activated and germinal centre B cells as well as plasma cells can be found in the tumour microenvironment. Our findings provide a better understanding of humoral immune responses in human cancer and suggest that tumour-infiltrating B cells could be harnessed for the development of therapeutic agents.

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.Durant cette crise sanitaire mondiale, le Covid-19 n’a malheureusement pas épargné les femmes enceintes. Celles-ci sont plus à risque d’être infectées, de développer des formes sévères et d’avoir des complications obstétricales. Dans cet article, nous allons parler des risques liés au Covid-19 durant la grossesse et notamment des données existantes sur les médicaments à administrer en cas de maladie et comment éviter l’infection et ses complications grâce à la vaccination.

Emerging SARS-CoV-2 variants of concern/interest (VOC/VOI) raise questions about effectiveness of neutralizing antibodies derived from infection or vaccination. As the population immunity to SARS-CoV-2 has become more complex due to prior infection and/or vaccination, understanding the antigenic relationship between variants is needed. Here, we have assessed in total 104 blood specimens from convalescent individuals after infection with early-pandemic SARS-CoV-2 (pre-VOC) or with Alpha, Beta, Gamma or Delta, post-vaccination after double-dose mRNA-vaccination and break through infections due to Delta or Omicron. Neutralization against seven authentic SARS-CoV-2 isolates (B.1, Alpha, Beta, Gamma, Delta, Zeta, Omicron) was assessed by plaque-reduction neutralization assay. We found highest neutralization titers against the homologous (previously infecting) variant, with lower neutralization efficiency against heterologous variants. Significant loss of neutralization for Omicron was observed but to a varying degree depending on previously infecting variant (23.0-fold in Beta-convalescence up to 56.1-fold in Alpha-convalescence), suggesting that infection-derived immunity varies, but independent of the infecting variant is only poorly protective against Omicron. Of note, Zeta VOI showed also pronounced escape from neutralization of up to 28.2-fold in Alpha convalescent samples. Antigenic mapping reveals both Zeta and Omicron as separate antigenic clusters. Double dose vaccination showed robust neutralization for Alpha, Beta, Gamma, Delta and Zeta, with fold-change reduction of only 2.8 (for Alpha) up to 6.9 (for Beta). Escape from neutralization for Zeta was largely restored in vaccinated individuals, while Omicron still showed a loss of neutralization of 85.7-fold compared to pre-VOC SARS-CoV-2. Combined immunity from infection followed by vaccination or vaccine breakthrough infection showed highest titers and most robust neutralization for heterologous variants. Breakthrough infection with Delta showed only 12.5-fold reduced neutralization for Omicron, while breakthrough infection with Omicron showed only a 1.5-fold loss for Delta, suggests that infection with antigenically different variants can boost immunity for antigens closer to the vaccine strain. Antigenic cartography showed also a tendency towards broader neutralizing capacity for heterologous variants. We conclude that the complexity of background immunity needs to be taken into account when assessing new VOCs. Development towards separate serotypes such as Zeta was already observed before Omicron emergence, thus other factors than just immune escape must contribute to Omicrons rapid dominance. However, combined infection/vaccination immunity could ultimately lead to broad neutralizing capacity also against non-homologous variants.

Monocytes are known to play a critical role in dengue pathophysiology. However, which monocyte subset expresses what inflammatory mediator(s) and what transcriptional features distinguish each of the monocyte subset

Background Unravelling autoimmune targets triggered by SARS‐CoV‐2 infection may provide crucial insights into the physiopathology of the disease and foster the development of potential therapeutic candidate targets and prognostic tools. We aimed at determining (a) the association between anti‐SARS‐CoV‐2 and anti‐apoA‐1 humoral response and (b) the degree of linear homology between SARS‐CoV‐2, apoA‐1 and Toll‐like receptor 2 (TLR2) epitopes. Design Bioinformatics modelling coupled with mimic peptides engineering and competition experiments were used to assess epitopes sequence homologies. Anti‐SARS‐CoV‐2 and anti‐apoA‐1 IgG as well as cytokines were assessed by immunoassays on a case‐control (n = 101), an intensive care unit (ICU; n = 126) and a general population cohort (n = 663) with available samples in the pre and post‐pandemic period. Results Using bioinformatics modelling, linear sequence homologies between apoA‐1, TLR2 and Spike epitopes were identified but without experimental evidence of cross‐reactivity. Overall, anti‐apoA‐1 IgG levels were higher in COVID‐19 patients or anti‐SARS‐CoV‐2 seropositive individuals than in healthy donors or anti‐SARS‐CoV‐2 seronegative individuals (P

Patients treated with anti-CD20 therapy are particularly at risk of developing severe COVID-19, however little is known regarding COVID-19 vaccine effectiveness in this population. This study assesses humoral and T-cell responses to mRNA-based COVID-19 vaccines in patients treated with rituximab for rheumatic diseases or ocrelizumab for multiple sclerosis (n=37), compared to immunocompetent individuals (n=22). SARS-CoV-2-specific antibodies were detectable in only 69.4% of patients and at levels that were significantly lower compared to controls who all seroconverted. In contrast to antibodies, Spike (S)-specific CD4+ T cells were equally detected in immunocompetent and anti-CD20 treated patients (85-90%) and mostly of a Th1 phenotype. Response rates of S-specific CD8+T cells were higher in ocrelizumab (96.2%) and rituximab-treated patients (81.8%) as compared to controls (66.7%). Vaccine-specific CD4+and CD8+T cells were polyfunctional but expressed more IL-2 in patients than in controls. In summary, our study suggests that patients on anti-CD20 treatment are able to mount potent T-cell responses to mRNA COVID-19 vaccines, despite impaired humoral responses. This could play an important role in the prevention of severe COVID-19.

Emerging variants of concern (VOCs) are driving the COVID-19 pandemic1,2. Experimental assessments of replication and transmission of major VOCs and progenitors are needed to understand the mechanisms of replication and transmission of VOCs3. Here we show that the spike protein (S) from Alpha (also known as B.1.1.7) and Beta (B.1.351) VOCs had a greater affinity towards the human angiotensin-converting enzyme 2 (ACE2) receptor than that of the progenitor variant S(D614G) in vitro. Progenitor variant virus expressing S(D614G) (wt-S614G) and the Alpha variant showed similar replication kinetics in human nasal airway epithelial cultures, whereas the Beta variant was outcompeted by both. In vivo, competition experiments showed a clear fitness advantage of Alpha over wt-S614G in ferrets and two mouse models—the substitutions in S were major drivers of the fitness advantage. In hamsters, which support high viral replication levels, Alpha and wt-S614G showed similar fitness. By contrast, Beta was outcompeted by Alpha and wt-S614G in hamsters and in mice expressing human ACE2. Our study highlights the importance of using multiple models to characterize fitness of VOCs and demonstrates that Alpha is adapted for replication in the upper respiratory tract and shows enhanced transmission in vivo in restrictive models, whereas Beta does not overcome Alpha or wt-S614G in naive animals.

Emerging variants of concern (VOCs) drive the SARS-CoV-2 pandemic. We assessed VOC B.1.1.7, now prevalent in several countries, and VOC B.1.351, representing the greatest threat to populations with immunity to the early SARS-CoV-2 progenitors. B.1.1.7 showed a clear fitness advantage over the progenitor variant (wt-S614G) in ferrets and two mouse models, where the substitutions in the spike glycoprotein were major drivers for fitness advantage. In the “superspreader” hamster model, B.1.1.7 and wt-S614G had comparable fitness, whereas B.1.351 was outcompeted. The VOCs had similar replication kinetics as compared to wt-S614G in human airway epithelial cultures. Our study highlights the importance of using multiple models for complete fitness characterization of VOCs and demonstrates adaptation of B.1.1.7 towards increased upper respiratory tract replication and enhanced transmission in vivo.Summary sentenceB.1.1.7 VOC outcompetes progenitor SARS-CoV-2 in upper respiratory tract replication competition in vivo.

Zostavax is a live-attenuated varicella zoster virus (VZV) vaccine recommended for use in adults >50 years of age to prevent shingles. The main risk factor for the development of shingles is age, which correlates with decreasing cell-mediated immunity. These data suggest a predominant role of T cell immunity in controlling VZV latency. However, other components of the immune system may also contribute. In this review, we will discuss how the immune system responds to Zostavax, focusing on recent studies examining innate immunity, transcriptomics, metabolomics, cellular, and humoral immunity.

An immunocompetent adult received corticosteroids for chest pain, which later was clinically found to be herpes zoster (HZ). She developed severe disease and rapid viral dissemination that elicited an exceptionally strong varicella zoster virus–specific B-cell and CD8 T-cell response. Clinicians should consider atypical HZ presentation prior to corticosteroid administration.

To evaluate longitudinally the persistence of humoral immunity for up to 6 months in a cohort of hospital employees with mild coronavirus disease 2019 (COVID-19).We measured anti-RBD (receptor binding domain of viral spike protein), anti-N (viral nucleoprotein) and neutralizing antibodies at 1, 3 and 6 months after mostly mild COVID-19 in 200 hospital workers using commercial ELISAs and a surrogate virus neutralization assay.Antibodies specific for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) persisted in all participants for up to 6 months. Anti-RBD geometric mean concentrations (GMCs) progressively increased between months 1 (74.2 U/mL, 95%CI: 62.7-87.8), 3 (103.2 U/mL, 95%CI: 87.9-121.2; p 0.001), and 6 (123.3 U/mL, 95%CI: 103.4-147.0; p 0.001) in the whole cohort. Anti-N antibodies were detectable in97% at all times. Neutralizing antibodies were detectable in 99.5% of participants (195/196) at 6 months post infection. Their GMC progressively decreased between months 1 (20.1 AU/mL, 95%CI: 16.9-24.0), 3 (15.2 AU/mL, 95%CI: 13.2-17.6; p 0.001) and 6 (9.4 AU/mL, 95%CI: 7.7-11.4; p 0.001). RBD-ACE2-inhibiting antibody titres and anti-RBD antibody concentrations strongly correlated at each timepoint (all r 0.86, p 0.001). Disease severity was associated with higher initial anti-RBD and RBD-ACE2-inhibiting antibody titres, but not with their kinetics.Neutralizing antibodies persisted at 6 months in almost all participants, indicating more durability than initially feared. Anti-RBD antibodies persisted better and even increased over time, possibly related to the preferential detection of progressively higher-affinity antibodies.

Early life immunity is a complex field of research and there are still gaps in knowledge regarding the detailed mechanism of maternal antibody transfer, the impact of maternal antibodies on infant vaccine responses and the ontogeny of human early life immunity. A comprehensive understanding is necessary to identify requirements for early life vaccines and to improve early childhood immunization. New immunological methods have facilitated performing research in the youngest, however, some questions can only be addressed in animal models. To date, mostly murine models are used to study neonatal and infant immunity since they are well-described, easy to use and cost effective. Given their limitations especially in the transfer biology of maternal antibodies and the lack of infectivity of numerous human pathogens, this opinion piece discusses the potential and prerequisites of the nonhuman primate model in studying early life immunity and maternal antibody transfer.

Considerable efforts have been undertaken to quickly develop COVID-19 vaccines that protect vulnerable adults against severe disease and thus limit the socio-economic and public health impact of the current pandemic. To justify COVID-19 vaccination for the pediatric population, which rarely suffers from severe COVID-19, vaccines will need to have fully demonstrated safety and efficacy in preventing complications and viral transmission. This article summarizes the different vaccine platforms that are currently being tested and discusses practical and ethical aspects of childhood COVID-19 vaccination. It also examines the already deleterious effects of the pandemic on routine childhood vaccine coverage and insists on the imperative to vaccinate all children timely as recommended by national immunization programs.Des efforts considérables sont entrepris pour développer rapidement des vaccins contre le Covid-19 qui protègent les adultes vulnérables contre ses complications, limitant ainsi les impacts sanitaires et socio-économiques de cette pandémie. Pour justifier une vaccination des enfants, rarement atteints d’un Covid-19 sévère, les vaccins contre cette maladie devront avoir pleinement démontré leur sécurité et leur efficacité dans la prévention des complications et surtout dans la transmission virale. Cet article résume les types de vaccins actuellement testés et discute des aspects pratiques et éthiques d’une vaccination contre le Covid-19 pédiatrique. Il examine également l’effet déjà délétère de la pandémie sur la couverture vaccinale de routine des enfants et insiste sur la nécessité absolue de vacciner tous les enfants sans prendre de retard sur les recommandations.

Background SARS-CoV-2 infection leads to high viral loads in the upper respiratory tract that may be determinant in virus dissemination. The extent of intranasal antiviral response in relation to symptoms is unknown. Understanding how local innate responses control virus is key in the development of therapeutic approaches. Methods SARS-CoV-2-infected patients were enrolled in an observational study conducted at the Geneva University Hospitals, Switzerland, investigating virological and immunological characteristics. Nasal wash and serum specimens from a subset of patients were collected to measure viral load, IgA specific for the S1 domain of the spike protein, and a cytokine panel at different time points after infection; cytokine levels were analyzed in relation to symptoms. Results Samples from 13 SARS-CoV-2-infected patients and six controls were analyzed. We found an increase in CXCL10 and IL-6, whose levels remained elevated for up to 3 weeks after symptom onset. SARS-CoV-2 infection also induced CCL2 and GM-CSF, suggesting local recruitment and activation of myeloid cells. Local cytokine levels correlated with viral load but not with serum cytokine levels, nor with specific symptoms, including anosmia. Some patients had S1-specific IgA in the nasal cavity while almost none had IgG. Conclusion The nasal epithelium is an active site of cytokine response against SARS-CoV-2 that can last more than 2 weeks; in this mild COVID-19 cohort, anosmia was not associated with increases in any locally produced cytokines.

AimsUnravelling autoimmune targets triggered by SARS-CoV-2 infection may provide crucial insights in the physiopathology of the disease and foster the development of potential therapeutic candidate targets and prognostic tools. We aimed at determining i) the association between anti-SARS-CoV-2 and anti-apoA-1 humoral response, ii) their relationship to prognosis, and iii) the degree of linear homology between SARS-CoV-2, apoA-1, and Toll-like receptor-2 (TLR2) epitopes.Methods and ResultsImmunoreactivity against different engineered peptides as well as cytokines were assessed by immunoassays, on a case-control (n=101), an intensive care unit (ICU; n=126) with a 28-days follow-up, and a general population cohort (n=663) with available samples in the pre and post-pandemic period. Using bioinformatics modelling a linear sequence homologies between apoA-1, TLR2, and Spike epitopes were identified. Overall, anti-apoA-1IgG levels were higher in COVID-19 patients or anti-SARS-CoV-2 seropositive individuals than in healthy donors or anti-SARS-CoV-2 seronegative individuals (pConclusionCOVID-19 induces a marked humoral response against the major protein of high-density lipoproteins. As a correlate of poorer prognosis in other clinical settings, such autoimmunity signatures may relate to long-term COVID-19 prognosis assessment and warrant further scrutiny in the current COVID-19 pandemic.

According to a recent World Health Organization estimate, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic, which originated in China in 2019, has spread globally, infecting nearly 100 million people worldwide by January 2021. Patients with chronic liver diseases (CLD), particularly cirrhosis, hepatobiliary malignancies, candidates for liver transplantation, and immunosuppressed individuals after liver transplantation appear to be at increased risk of infections in general, which in turn translates into increased mortality. This is also the case for SARS-CoV-2 infection, where patients with cirrhosis, in particular, are at high risk of a severe COVID-19 course. Therefore, vaccination against various pathogens including SARS-CoV-2, administered as early as possible in patients with CLD, is an important protective measure. However, due to impaired immune responses in these patients, the immediate and long-term protective response through immunisation may be incomplete. The current SARS-CoV-2 pandemic has led to the exceptionally fast development of several vaccine candidates. A small number of these SARS-CoV-2 vaccine candidates have already undergone phase III, placebo-controlled, clinical trials in healthy individuals with proof of short-term safety, immunogenicity and efficacy. However, although regulatory agencies in the US and Europe have already approved some of these vaccines for clinical use, information on immunogenicity, duration of protection and long-term safety in patients with CLD, cirrhosis, hepatobiliary cancer and liver transplant recipients has yet to be generated. This review summarises the data on vaccine safety, immunogenicity, and efficacy in this patient population in general and discusses the implications of this knowledge on the introduction of the new SARS-CoV-2 vaccines.

Objectives To report a case of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) reinfection 6 months after the first infection in a young healthy female physician. Both episodes led to mild coronavirus disease 2019 (COVID-19). Methods SARS-CoV-2 infections were detected by real-time reverse transcriptase PCR (RT-PCR) on nasopharyngeal specimens. Reinfection was confirmed by whole-genome sequencing. Kinetics of total anti-S receptor binding domain immunoglobulins (Ig anti–S RBD), anti-nucleoprotein (anti-N) and neutralizing antibodies were determined in serial serum samples retrieved during both infection episodes. Memory B-cell responses were assessed at day 12 after reinfection. Results Whole-genome sequencing identified two different SARS-CoV-2 genomes both belonging to clade 20A, with only one nonsynonymous mutation in the spike protein and clustered with viruses circulating in Geneva (Switzerland) at the time of each of the corresponding episodes. Seroconversion was documented with low levels of total Ig anti–S RBD and anti-N antibodies at 1 month after the first infection, whereas neutralizing antibodies quickly declined after the first episode and then were boosted by the reinfection, with high titres detectable 4 days after symptom onset. A strong memory B-cell response was detected at day 12 after onset of symptoms during reinfection, indicating that the first episode elicited cellular memory responses. Conclusions Rapid decline of neutralizing antibodies may put medical personnel at risk of reinfection, as shown in this case. However, reinfection leads to a significant boosting of previous immune responses. Larger cohorts of reinfected subjects with detailed descriptions of their immune responses are needed to define correlates of protection and their duration after infection.

[no abstract available]

Tremendous efforts are undertaken to quickly develop COVID-19 vaccines that protect vulnerable individuals from severe disease and thereby limit the health and socioeconomic impacts of the pandemic. Potential candidates are tested in adult populations, and questions arise of whether COVID-19 vaccination should be implemented in children. Compared to adults, the incidence and disease severity of COVID-19 are low in children, and despite their infectiveness, their role in disease propagation is limited. Therefore, COVID-19 vaccines will need to have fully demonstrated safety and efficacy in preventing not only complications but transmission to justify childhood vaccination. This work summarizes currently tested vaccine platforms and debates practical and ethical considerations for their potential use in children. It also discusses the already deleterious effect of the pandemic on routine childhood vaccine coverage, calling for action to limit the risks for a rise in vaccine-preventable diseases.

Acute respiratory distress syndrome (ARDS) is an important condition associated with significant morbidity and mortality in both adults and children. Chapter 6 begins by explaining the definition of paediatric ARDS (PARDS), its severity stratification, risk factors for its development, and its pathophysiology. The evidence base for lung-protective ventilation strategies is covered, with recommended goals given permissive hypoxaemia and hypercapnia. Different modes of ventilation for ARDS are examined: non-invasive ventilation, conventional mechanical ventilation, high-frequency oscillatory ventilation, and neutrally-adjusted ventilator assist, and the relative merits of pressure and volume limitation for lung protection in adults and children. Adjuvant therapies for PARDS are explored: fluid restriction; neuromuscular blocking agents; prone positioning; steroids; inhaled nitric oxide; and surfactant therapy. The chapter concludes by addressing the challenges that remain in defining and managing ARDS, and suggests how patients should be followed up following discharge.

BackgroundRadiotherapy (RT) has been shown to stimulate an antitumor immune response in irradiated tumors as well as unirradiated distant sites (abscopal effect). Previous studies have demonstrated a role for the tumor-draining lymph node (LN) in mediating an anti-programmed death-1 (PD-1)/programmed death ligand-1 (PD-L1) stimulated antitumor immune response. Here, we investigated whether the LN is also important in mediating a RT alone stimulated abscopal response.MethodsWe used a subcutaneous modified B16F10 flank tumor model injected bilaterally. Our B16F10 cell line has an inserted viral glycoprotein which facilitated identification of tumor-specific T-cells. RT was directed at one flank tumor alone or one flank tumor and the tumor-draining LN. We evaluated response by tumor growth measurements and flow cytometry of both tumor-infiltrating and LN T-cells.ResultsWe show that local tumor irradiation improves distant tumor control (abscopal effect). Depletion of CD8+ T-cells significantly reduced this abscopal response. We have previously shown, in a chronic lymphocytic choriomeningitis virus (LCMV) infection, that the T-cell proliferative burst following blockade of PD-1/L1 is provided by a ‘stem-like’ CD8+ T-cell subset which then differentiate into terminally differentiated effectors. These terminally differentiated effectors have the potential to kill virally infected or tumor cells following PD-1/L1 blockade. In the chronic LCMV infection, stem-like CD8+ T-cells were found exclusively in secondary lymphoid organs. Similarly, here we found these cells at high frequencies in the tumor-draining LN, but at low frequencies within the tumor. The effect of RT on this T-cell subset in unknown. Interestingly, tumor irradiation stimulated total CD8+ and stem-like CD8+ T-cell proliferation in the LN. When the LN and the tumor were then targeted with RT, the abscopal effect was reduced, and we found a concomitant reduction in the number of total tumor-specific CD8+ T-cells and stem-like CD8+ T-cells in both the irradiated and unirradiated tumor.ConclusionsThese correlative results suggest the tumor-draining LN may be an important mediator of the abscopal effect by serving as a stem-like CD8+ T-cell reservoir, a site for stem-like T-cell expansion, and a site from which they can populate the tumor.

BackgroundViral shedding patterns and its correlation with the immune responses of mildly symptomatic COVID-19 patients are still poorly characterized.MethodsWe enrolled the first five COVID-19 patients quarantined in our institution; none received immunomodulatory treatment. We monitored shedding of viral RNA and infectious virus by RT-PCR and cell culture from the upper respiratory tract, and characterized the kinetics of systemic innate and adaptive immune responses.ResultsDespite mild clinical disease, high viral loads and shedding of infectious virus were observed from the respiratory tract, with isolation of infectious virus and prolonged positivity by PCR up to day 7 and 19 post onset of symptoms, respectively. Robust innate responses characterized by an increase in activated CD14+CD16+ monocytes and cytokine responses were observed as early as 2 days after symptoms onset. Cellular and humoral SARS-CoV-2 specific adaptive responses were detectable in all patients.ConclusionInfectious virus shedding was limited to the first week of symptom onset in mild cases. A strong innate response, characterized by the mobilization of activated monocytes during the first days of infection, as well as SARS-CoV-2 specific antibodies were detectable, even in patients with mild disease.SummaryWe describe viral and immune profiles of the first five SARS-CoV-2 patients in our institution, showing high viral loads and infectious viral shedding in early acute disease. Mild patients mount an innate response sufficient for viral control and specific immunity.

BackgroundSARS-CoV-2 test kits are in critical shortage in many countries. This limits large-scale population testing and hinders the effort to identify and isolate infected individuals.ObjectivesHerein, we developed and evaluated multi-stage group testing schemes that test samples in groups of various pool sizes in multiple stages. Through this approach, groups of negative samples can be eliminated with a single test, avoiding the need for individual testing and achieving considerable savings of resources.Study designWe designed and parameterized various multi-stage testing schemes and compared their efficiency at different prevalence rates using computer simulations.ResultsWe found that three-stage testing schemes with pool sizes of maximum 16 samples can test up to three and seven times as many individuals with the same number of test kits for prevalence rates of around 5% and 1%, respectively. We propose an adaptive approach, where the optimal testing scheme is selected based on the expected prevalence rate.ConclusionThese group testing schemes could lead to a major reduction in the number of testing kits required and help improve large-scale population testing in general and in the context of the current COVID-19 pandemic.

Childhood immunization with the live-attenuated varicella-zoster virus (VZV) vaccine induces protective immune responses. Routine VZV vaccination started only 2 decades ago, and thus, there are few studies examining the longevity of vaccine-induced immunity. Here, we analyzed the quantity of VZV-specific plasma cells (PCs) and CD4 T cells in the bone marrow (BM) of healthy young adults (n = 15) following childhood VZV immunization. Long-lived BM resident plasma cells constitutively secrete antibodies, and we detected VZV-specific PCs in the BM of all subjects. Anti-VZV plasma antibody titers correlated positively with the number of VZV-specific BM PCs. Furthermore, we quantified the number of interferon gamma (IFN-γ)-producing CD4 T cells specific for VZV glycoprotein E and all other structural and nonstructural VZV proteins in both BM and blood (peripheral blood mononuclear cells [PBMCs]). The frequency of VZV-specific IFN-γ-producing CD4 T cells was significantly higher in PBMCs than BM. Our study shows that VZV-specific PCs and VZV-specific CD4 memory T cells persist up to 20 years after vaccination. These findings indicate that childhood VZV vaccination can elicit long-lived immune memory responses in the bone marrow. IMPORTANCE Childhood varicella-zoster virus (VZV) immunization induces immune memory responses that protect against primary VZV infection, chicken pox. In the United States, routine childhood VZV vaccination was introduced only 2 decades ago. Hence, there is limited information on the longevity of B and CD4 T cell memory, which are both important for protection. Here, we showed in 15 healthy young adults that VZV-specific B and CD4 T cell responses are detectable in bone marrow (BM) and blood up to 20 years after vaccination. Specifically, we measured antibody-secreting plasma cells in the BM and VZV-specific CD4 T cells in BM and blood. These findings suggest that childhood VZV vaccination induces long-lived immunity.

Background: Little is known about the duration and breadth of humoral immunity against SARS-CoV-2 to better inform appropriate pandemic control measures. Methods: We measured anti-RBD, -N and neutralizing antibodies at one, three and six months after mostly mild COVID-19 in 200 hospital workers using commercial ELISAs and a surrogate virus neutralization assay. Findings: Anti-RBD antibodies were detected in all participants at each timepoint. Geometric mean concentrations (GMCs) progressively increased between month one (74 . 2 U/ml [95%CI 62 . 7-87 . 8), three (103 . 2 U/ml [95%CI 87 . 9-121 . 2]; p 97% at all times. Neutralizing antibodies were detectable in 92 . 5% (184/199), 94 . 4% (185/196) and 76 . 5% (150/196) participants at one, three and six months, respectively. Their GMC progressively decreased between months one (20 . 1 AU/ml [95%CI 16 . 9-24 . 0]), three (15 . 2 AU/ml [95%CI 13 . 2-17 . 6]; p 0 . 86, p

Pertussis remains a serious global health issue in infants aged less than 6 months. Neonates and young infants have the highest risk of developing pertussis as they are too young to be vaccinated and thus are more likely to develop more severe pertussis-related complications, including death. Protecting this vulnerable age population from pertussis is considered a main priority in many national health programs. Two vaccine strategies exist to protect infants from pertussis: "cocooning" and maternal vaccination during pregnancy. The latter is the more recent and preferred strategy, which protects newborns by passive transplacental transfer of pertussis antibodies. We review the reported evidence on the safety, effectiveness, timing and implementation of this antenatal immunization strategy.

Preterm infants are most vulnerable to pertussis. Whether they might benefit from maternal immunization is unknown. Extending our previous results in term neonates, this observational study demonstrates that second- rather than third-trimester maternal vaccination results in higher birth anti–pertussis toxin titers in preterm neonates.

Summary: Maternal antibodies (MatAbs) protect offspring from infections but limit their responses to vaccination. The mechanisms of this inhibition are still debated. Using murine early-life immunization models mimicking the condition prevailing in humans, we observed the induction of CD4-T, T follicular helper, and germinal center (GC) B cell responses even when early-life antibody responses were abrogated by MatAbs. GC B cells induced in the presence of MatAbs form GC structures and exhibit canonical GC changes in gene expression but fail to differentiate into plasma cells and/or memory B cells in a MatAb titer-dependent manner. Furthermore, GC B cells elicited in the presence or absence of MatAbs use different VH and Vk genes and show differences in genes associated with B cell differentiation and isotype switching. Thus, MatAbs do not prevent B cell activation but control the output of the GC reaction both quantitatively and qualitatively, shaping the antigen-specific B cell repertoire. : Maternal antibodies (MatAbs) protect offspring from infections but limit their vaccine responses through still poorly known mechanisms. Vono et al. report that MatAbs do not prevent B cell activation or germinal center formation but control plasma cell and memory B cell differentiation, shaping the long-term antigen-specific B cell repertoire. Keywords: immunization, maternal antibodies, neonates, repertoire, germinal centers, epitope masking