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Background: A significant proportion of the global population has been infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) at some point since the onset of the pandemic. Although most individuals who develop coronavirus disease 2019 (COVID-19) recover without complications, about 6% have persistent symptoms, referred to as post-COVID-19 condition (PCC). Intervention studies investigating treatments that potentially alleviate PCC-related symptoms and thus aim to mitigate the global public health burden and healthcare costs linked to PCC are desperately needed. The PYCNOVID trial investigates the effects of Pycnogenol®, a French maritime pine bark extract with anti-inflammatory and antioxidative properties, versus placebo on patient-reported health status in people with PCC., Methods: This is a single-center, placebo-controlled, quadruple blind, randomized trial. We aim to randomly assign 150 individuals with PCC (1:1 ratio) to receive either 200 mg Pycnogenol® or placebo daily for 12 weeks. Randomization is stratified for duration of PCC symptoms (≤ 6 months versus > 6 months) and presence of symptomatic chronic disease(s). The primary endpoint is perceived health status at 12 weeks (EuroQol-Visual Analogue Scale) adjusted for baseline values and stratification factors. Secondary endpoints include change in self-reported PCC symptoms, health-related quality of life, symptoms of depression and anxiety, cognitive function, functional exercise capacity, physical activity measured with accelerometry, and blood biomarkers for endothelial health, inflammation, coagulation, platelet function, and oxidative stress. Investigators, study participants, outcome assessors, and data analysts are blinded regarding the intervention assignment. Individuals with PCC were involved in the design of this study., Discussion: This is the first trial to investigate the effects of Pycnogenol® versus placebo on patient-reported health status in people with PCC. Should the trial proof clinical effectiveness, Pycnogenol® may serve as a therapeutic approach to mitigate symptoms associated with PCC., Trial Registration: The study is registered at ClinicalTrials.gov. :NCT05890534, June 6, 2023., (© 2024. The Author(s).)

BackgroundTick-borne encephalitis (TBE) is a severe, vaccine-preventable viral infection of the central nervous system. Symptoms are generally milder in children and adolescents than in adults, though severe disease does occur. A better understanding of the disease burden and duration of vaccine-mediated protection is important for vaccination recommendations.AimTo estimate TBE vaccination coverage, disease severity and vaccine effectiveness (VE) among individuals aged 0-17 years in Switzerland.MethodsVaccination coverage between 2005 and 2022 was estimated using the Swiss National Vaccination Coverage Survey (SNVCS), a nationwide, repeated cross-sectional study assessing vaccine uptake. Incidence and severity of TBE between 2005 and 2022 were determined using data from the Swiss disease surveillance system and VE was calculated using a case-control analysis, matching TBE cases with SNVCS controls.ResultsOver the study period, vaccination coverage increased substantially, from 4.8% (95% confidence interval (CI): 4.1-5.5%) to 50.1% (95% CI: 48.3-52.0%). Reported clinical symptoms in TBE cases were similar irrespective of age. Neurological involvement was less likely in incompletely (1-2 doses) and completely (≥ 3 doses) vaccinated cases compared with unvaccinated ones. For incomplete vaccination, VE was 66.2% (95% CI: 42.3-80.2), whereas VE for complete vaccination was 90.8% (95% CI: 87.7-96.4). Vaccine effectiveness remained high, 83.9% (95% CI: 69.0-91.7) up to 10 years since last vaccination.ConclusionsEven children younger than 5 years can experience severe TBE. Incomplete and complete vaccination protect against neurological manifestations of the disease. Complete vaccination offers durable protection up to 10 years against TBE.

Tick-borne Encephalitis (TBE) is a severe disease of the Central Nervous System (CNS) caused by the tick-borne encephalitis virus (TBEV). The generation of protective immunity after TBEV infection or TBE vaccination relies on the integrated responses of many distinct cell types at distinct physical locations. While long-lasting memory immune responses, in particular, form the basis for the correlates of protection against many diseases, these correlates of protection have not yet been clearly defined for TBE. This review addresses the immune control of TBEV infection and responses to TBE vaccination. Potential correlates of protection and the durability of protection against disease are discussed, along with outstanding questions in the field and possible areas for future research., Competing Interests: PL reports honoraria for lectures and/or research grants from Pfizer. RA-G and KZ report honoraria for lectures and/or research grants from Pfizer and Bavarian Nordic. This work was supported by a grant from Pfizer awarded to RA-G and KZ. The funder had the following involvement in the study: conceptualization of the study and review of the manuscript., (Copyright © 2024 Ackermann-Gäumann, Lang and Zens.)

Objectives: The correlate(s) of protection against SARS-CoV-2 remain incompletely defined. Additional information regarding the combinations of antibody and T cell-mediated immunity which can protect against (re)infection is needed., Methods: We conducted a population-based, longitudinal cohort study including 1044 individuals of varying SARS-CoV-2 vaccination and infection statuses. We assessed spike (S)- and nucleocapsid (N)-immunoglobulin(Ig)G and wildtype, Delta, and Omicron-neutralizing antibody (N-Ab) activity. In a subset of 328 individuals, we evaluated S, membrane (M), and N-specific T cells. Three months later, we reassessed Ab (n = 964) and T cell (n = 141) responses and evaluated factors associated with protection from (re)infection., Results: At the study start, >98% of participants were S-IgG seropositive. N-IgG and M/N-T-cell responses increased over time, indicating viral (re)exposure, despite existing S-IgG. Compared to N-IgG, M/N-T cells were a more sensitive measure of viral exposure. High N-IgG titers, Omicron-N-Ab activity, and S-specific-T-cell responses were all associated with a reduced likelihood of (re)infection over time., Conclusion: Population-level SARS-CoV-2 immunity is S-IgG-dominated, but heterogeneous. M/N-T-cell responses can distinguish previous infection from vaccination, and monitoring a combination of N-IgG, Omicron-N-Ab, and S-T-cell responses may help estimate protection against SARS-CoV-2 (re)infection., Competing Interests: Declarations of competing interest The authors have no competing interests to declare., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Tick-Borne Encephalitis - Viral Transmission and Considerations for Vaccination Abstract. Tick-Borne encephalitis virus (TBEV) is a flavivirus transmitted to humans primarily through the bite of infected Ixodes ticks. Infection with TBEV results in Tick-Borne Encephalitis (TBE), an acute disease of the Central Nervous System (CNS) that can lead to significant long-term sequalae. Over the last decades the geographic range of TBEV and the incidence of TBE have substantially increased. TBEV is now endemic through much of Central Europe, including parts of Germany, Austria, and Switzerland, and is recognized as an increasing public health problem. While there are no specific therapies for TBE, two vaccines are licensed and available in Europe, Encepur ® and FSME-Immun ® . Both are considered safe and effective. Following vaccination, the generation of virus-neutralizing antibodies is often considered an indicator of protection against disease. While recent evidence suggests that cell-mediated immune responses likely also play important roles in protection, cell-mediated immunity following infection and vaccination remains poorly characterized. As with many vaccines, the initial response to TBE vaccination is influenced by several factors. Here, we review how age, immunosuppression, adherence to recommended vaccination schedules, and the use of single vaccine type during priming may impact immunity following TBE vaccination. We further discuss vaccination coverage and disease prevention, as well as factors impacting individual vaccine uptake.

To better understand the development of SARS-CoV-2-specific immunity over time, a detailed evaluation of humoral and cellular responses is required. Here, we characterize anti-Spike (S) IgA and IgG in a representative population-based cohort of 431 SARS-CoV-2-infected individuals up to 217 days after diagnosis, demonstrating that 85% develop and maintain anti-S responses. In a subsample of 64 participants, we further assess anti-Nucleocapsid (N) IgG, neutralizing antibody activity, and T cell responses to Membrane (M), N, and S proteins. In contrast to S-specific antibody responses, anti-N IgG levels decline substantially over time and neutralizing activity toward Delta and Omicron variants is low to non-existent within just weeks of Wildtype SARS-CoV-2 infection. Virus-specific T cells are detectable in most participants, albeit more variable than antibody responses. Cluster analyses of the co-evolution of antibody and T cell responses within individuals identify five distinct trajectories characterized by specific immune patterns and clinical factors. These findings demonstrate the relevant heterogeneity in humoral and cellular immunity to SARS-CoV-2 while also identifying consistent patterns where antibody and T cell responses may work in a compensatory manner to provide protection., (© 2022. The Author(s).)

Objective: To estimate effectiveness of tickborne encephalitis (TBE) vaccination by time interval (<5, 5-10 and 10+years) postvaccination., Design: A retrospective, matched case-control study PARTICIPANTS: Cases-all adult (age 18-79) TBE cases in Switzerland reported via the national mandatory disease reporting surveillance system from 2006 to 2020 (final n=1868). Controls-community controls from a database of randomly selected adults (age 18-79) participating in a 2018 cross-sectional study of TBE vaccination in Switzerland (final n=4625)., Primary Outcome Measures: For cases and controls, the number of TBE vaccine doses received and the time since last vaccination were determined. Individuals were classified as being 'unvaccinated' (0 doses), 'incomplete' (1-2 doses) or 'complete' (3+ doses). Individuals with 'complete' vaccination were further classified by time since the last dose was received (<5 years, 5-10 years or 10+ years). A conditional logistic regression model was used to calculate vaccine effectiveness (VE: 100 × [1-OR]) for each vaccination status category., Results: VE for incomplete vaccination was 76.8% (95% CI 69.0% to 82.6%). For complete vaccination, overall VE was 95.0% (95% CI 93.5% to 96.1%). When the most recent dose was received <5 years prior VE was 91.6% (95% CI 88.4% to 94.0%), 95.2% (95% CI 92.4% to 97.0%) when the most recent dose was received 5-10 years prior, and 98.5% (95% CI 96.8% to 99.2%) when the most recent dose was received 10+ years prior., Conclusions: That VE does not decrease among completely vaccinated individuals over 10+ years since last vaccination supports the longevity of the protective response following complete TBE vaccination. Our findings support the effectiveness of 10-year TBE booster intervals currently used in Switzerland., Competing Interests: Competing interests: The authors declare no competing interests., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Streptococcus pneumoniae , or pneumococcus, is a common, opportunistic pathogen which can cause severe disease, particularly in adults 65+. In Switzerland, vaccination is recommended for children under 5 and for adults with health predispositions; vaccination of healthy adults 65+ is not recommended. In 2020 we conducted a nationwide, cross-sectional survey of vaccination records to evaluate pneumococcal vaccination coverage and factors affecting uptake among adults 18-85. We found that nationwide coverage was 4.5% without significant regional differences. Coverage was comparable between men and women and between those aged 18-39 (3.0%) and 40-64 (3.2%). Coverage was significantly higher among those 65-85 (9.6%). While 2.7% of individuals reporting no health predisposition were vaccinated, 14.8% with asthma or chronic pulmonary disease, 27.1% with immunosuppression, 12.9% with diabetes, 11.6% with heart, liver, or kidney disease, and 25.9% with >1 health risk were vaccinated. Adjusted odds of vaccination for all health predispositions except heart, liver, or kidney disease were significantly increased. Among unvaccinated individuals "not enough information about the topic" and "not suggested by a doctor/healthcare provider" were the major reasons for abstaining from vaccination. Respondents reporting a health predisposition were significantly less likely to report "not at increased risk due to chronic health conditions or age" as a reason for not being vaccinated (3.7% vs. 29.1%) and were more likely to report willingness to be vaccinated in the future compared to those not-at-risk (54.2% vs. 39.9%). Our results indicate that pneumococcal vaccination coverage in Switzerland is low among both individuals 65-85 and among those with predisposing health risks. It appears that at-risk individuals are aware of their increased risk, but feel they do not have enough information on the topic to seek vaccination, or have not been recommended a vaccination by their physician., Competing Interests: PL declares compensation for a presentation at a Pfizer training workshop in 2019. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Zens, Baroutsou, Fehr and Lang.)

The goal of this study was to evaluate timeliness of Tick-borne Encephalitis vaccination uptake among adults in Switzerland. In this cross-sectional survey, we collected vaccination records from randomly selected adults 18-79 throughout Switzerland. Of 4,626 participants, data from individuals receiving at least 1 TBE vaccination (n = 1875) were evaluated. We determined year and age of first vaccination and vaccine compliance, evaluating dose timeliness. Participants were considered "on time" if they received doses according to the recommended schedule ± a 15% tolerance period. 45% of participants received their first TBE vaccination between 2006 and 2009, which corresponds to a 2006 change in the official recommendation for TBE vaccination in Switzerland. 25% were first vaccinated aged 50+ (mean age 37). More than 95% of individuals receiving the first dose also received the second; ~85% of those receiving the second dose received the third. For individuals completing the primary series, 30% received 3 doses of Encepur, 58% received 3 doses of FSME-Immun, and 12% received a combination. According to "conventional" schedules, 88% and 79% of individuals received their second and third doses "on time", respectively. 20% of individuals receiving Encepur received their third dose "too early". Of individuals completing primary vaccination, 19% were overdue for a booster. Among the 31% of subjects receiving a booster, mean time to first booster was 7.1 years. We estimate that a quarter of adults in Switzerland were first vaccinated for TBE aged 50+. Approximately 80% of participants receiving at least one vaccine dose completed the primary series. We further estimate that 66% of individuals completing the TBE vaccination primary series did so with a single vaccine type and adhered to the recommended schedule., Competing Interests: Dr. Lang reports grants and personal fees from Pfizer during the conduct of the study. Pfizer had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Background: The incidence of influenza and influenza-like illnesses in Switzerland is generally high. Although related direct medical costs can be substantial, especially if hospitalisations occur, several studies suggested that indirect costs due to the loss of productivity may represent an even higher economic burden. The aim of this study was to assess the costs arising from lost productivity due to influenza and influenza-like illnesses in Switzerland., Methods: Analyses were based on data collected in 2016 and 2017 by the Swiss Sentinel Surveillance Network of the Swiss Federal Office of Public Health (SFOPH). The available information covered details on the physicians collecting the data, patients' characteristics, symptoms, treatments, and inability to work (in terms of physician-recorded workdays lost for own sickness or caregiving). The cost of lost productivity, estimated using the human capital approach, was calculated as the number of workdays lost due to influenza-like illnesses multiplied by the mean salary for one working day. Salary differences across sex, age and region were considered. Extrapolation to the national level was performed by adjusting for the size of the Swiss population, the age and sex distribution, the regional distribution, the number of Sentinel general physician contacts and the specialisation of the physician., Results: At the Swiss national level, the estimated total yearly number of cases of inability to work due to influenza and influenza-like illnesses was 101,287 in 2016 and 86,373 in 2017. In subgroups defined by year, gender, region and age class, numbers of cases per 100,000 inhabitants ranged from 12 to 2396. The total number of workdays lost in Switzerland, considering degree of employment and visit day, were estimated to be 324,118 in 2016 and 278,121 in 2017. The number of workdays lost was generally higher in men (53.7% of the total in 2016 and 55.6% of the total in 2017) than women. The estimated total costs due to inability to work, calculated using a human capital approach and including the caregiving costs, were CHF 115 million in 2016 and CHF 103 million in 2017, equivalent to CHF 1.4 million per 100,000 inhabitants., Conclusion: The costs of lost productivity due to influenza and influenza-like illnesses in Switzerland are substantial and may vary considerably between different years, regions and age classes. As the present analyses could not consider all causes of lost productivity (e.g., short-term inability to work not requiring a physician consultation, hospitalisations, early retirement, premature death), the total indirect costs due to influenza or influenza-like illnesses can be expected to be higher than the presented estimates.

Objectives: In 2019, there were 29 reported cases of measles in the Canton of Zurich, with two cases occurring among university students. In collaboration with the University of Zurich Travel Clinic, the Health Department of the Canton of Zurich offered free measles vaccination to all employees and students at the University of Zurich (UZH) and the Swiss Federal Institute of Technology (ETH). This short communication shares the results of this large measles vaccination campaign., Study Design: Vaccination intervention campaign., Methods: All employees and students at the UZH and ETH were informed via an email distribution list that they were eligible for cost-free consultation and measles vaccination (when indicated). Consultations and immunizations took place over the course of 3 days in June 2019 at the UZH Travel Clinic. All those who were missing one or two doses of measles vaccination, and had no contraindications, were vaccinated. Booster immunizations were offered until December 2019., Results: A total of 411 individuals participated in the campaign. Thirty-five individuals (8.5%) were found to have sufficient measles vaccination on consultation and received no additional vaccination. A total of 376 individuals (91.5%) met the eligibility criteria and were vaccinated; 83 individuals (20.2% of all participants and 22.1% of those vaccinated) returned for a second vaccination. In total, the campaign saw 494 visits (including consultations without immunization and visits for second immunization). Demographic data were collected for 439 visits where measles vaccination was administered. From these, 51.7% were for an individual's first measles vaccine dose, 27.3% for a second dose, 18.9% for a booster immunization and 2.1% were unknown. 54.7% of campaign visits were made by females; and 45.0% of visits were made by those aged 18-29 years, 27.9% by those 30-39 years, 14.6% by those 40-49 years, and 12.6% by those 50+ years. 49.8% of visits were made by students and 48.5% by employees. More students needed the first dose (54.2% of first-dose visits), whereas more employees received booster immunization (57.8% of booster visits)., Conclusions: The measles vaccination campaign was well attended, particularly by the younger age group 18-29 years and females. Coupled with intense media attention, such a campaign immediately following an outbreak may be an effective method to increase vaccination coverage., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Immunological memory equips our immune system to respond faster and more effectively against reinfections. This acquired immunity was originally attributed to long-lived, memory T and B cells with body wide access to peripheral and secondary lymphoid tissues. In recent years, it has been realized that both innate and adaptive immunity to a large degree depends on resident immune cells that act locally in barrier tissues including tissue-resident memory T cells (Trm). Here, we will discuss the phenotype of these Trm in mice and humans, the tissues and niches that support them, and their function, plasticity, and transcriptional control. Their unique properties enable Trm to achieve long-lived immunological memory that can be deposited in nearly every organ in response to acute and persistent infection, and in response to cancer. However, Trm may also induce substantial immunopathology in allergic and autoimmune disease if their actions remain unchecked. Therefore, inhibitory and activating stimuli appear to balance the actions of Trm to ensure rapid proinflammatory responses upon infection and to prevent damage to host tissues under steady state conditions., (© 2021 Wiley-VCH GmbH.)

Background: Overall incidence and geographic range of Tick-borne Encephalitis (TBE), a vaccine preventable infection, have steadily increased in Switzerland over the last 50 years. While fully subsidized vaccination has been recommended in many areas for well over a decade, vaccine coverage and variables associated with vaccination compliance among Swiss adults are poorly understood., Methods: In 2018 we conducted a national, cross-sectional survey of vaccination cards evaluating TBE vaccination coverage and compliance among adults (18-79) in Switzerland., Results: Nationwide TBE vaccination coverage was 41.7% (range 14.3% to 60.3%) for 1 dose and 32.9% (range 8.4% to 50.4%) for a complete primary series (3 doses). There was a significant correlation between average disease incidence by canton (2009-2018) and vaccine coverage at both 1 and 3 doses. Of the overall population, 9.5% had received at least one TBE booster vaccination with large regional coverage variation. We estimated that 23% of adults in Switzerland would be protected from infection based on their vaccination history and 135 (95% CI: 112-162) TBE cases were prevented in 2018. Individuals reporting previous experience with tick-associated health problems, those frequently in nature or those with "high" perceived risk of contracting TBE, were significantly more likely to have received at least one vaccine dose, indicating a positive impact of awareness on vaccination compliance. We also calculated a TBE incidence rate of 6.83/100,000 among the unvaccinated adult population in Switzerland and estimated vaccine effectiveness at 91.5% (95% CI: 90.9-92.0%)., Conclusions: These findings provide an important reference for TBE vaccination levels in Switzerland and further suggest that public health interventions promoting knowledge of TBE health impacts and risk factors may be beneficial in improving TBE vaccination coverage but should be tailored to account for heterogeneity in vaccine uptake., Competing Interests: Declaration of Competing Interest PL received monetary compensation for a presentation at a Pfizer training workshop; Pfizer also covered her cost to attend the ISW-TBE meeting ( International Scientific Working group on TBE) in 2019. All other authors have no other conflicts of interest to declare., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Tick-borne encephalitis (TBE) is increasing in Europe. We aimed to evaluate the immunogenicity and safety of TBE-vaccination., Methods: This systematic review was registered at PROSPERO (#CRD42020155737) and conducted in accordance with PRISMA guidelines. We searched CINAHL, Cochrane, Embase, PubMed, and Scopus using specific terms. Original articles, case reports and research abstracts in English, French, German and Italian were included for screening and extracting (JER; PS)., Results: Of a total of 2464 records, 49 original research publications were evaluated for immunogenicity and safety. TBE-vaccines showed adequate immunogenicity, good safety and interchangeability in adults and children with some differences in long-term protection (Seropositivity in 90.6-100% after primary vaccination; 84.9%-99.4% at 5 year follow up). Primary conventional vaccination schedule (days 0, 28, and 300) demonstrated the best immunogenic results (99-100% of seropositivity). Mixed brand primary vaccination presented adequate safety and immunogenicity with some exceptions. After booster follow-ups, accelerated conventional and rapid vaccination schedules were shown to be comparable in terms of immunogenicity and safety. First booster vaccinations five years after primary vaccination were protective in adults aged <50 years, leading to protective antibody levels from at least 5 years up to 10 years after booster vaccination. In older vaccinees, > 50 years, lower protective antibody titers were found. Allergic individuals showed an adequate response and immunosuppressed individuals a diminished response to TBE-vaccination., Conclusions: The TBE-vaccination is generally safe with rare serious adverse events. Schedules should, if possible, use the same vaccine brand (non-mixed). TBE-vaccines are immunogenic in terms of antibody response but less so when vaccination is started after the age of 50 years. Age at priming is a key factor in the duration of protection., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Dysregulated signaling via the epidermal growth factor receptor (EGFR)-family is believed to contribute to the progression of a diverse array of cancers. The most common variant of EGFR is EGFRvIII, which results from a consistent and tumor-specific in-frame deletion of exons 2-7 of the EGFR gene. This deletion generates a novel glycine at the junction and leads to constitutive ligand-independent activity. This junction forms a novel shared tumor neo-antigen with demonstrated immunogenicity in both mice and humans. A 21-amino acid peptide spanning the junctional region was selected, and then one or five copies of this 21-AA neo-peptide were incorporated into live-attenuated Listeria monocytogenes-based vaccine vector. These vaccine candidates demonstrated efficient secretion of the recombinant protein and potent induction of EGFRvIII-specific CD8+ T cells, which prevented growth of an EGFRvIII-expressing squamous cell carcinoma. These data demonstrate the potency of a novel cancer-specific vaccine candidate that can elicit EGFRvIII-specific cellular immunity, for the purpose of targeting EGFRvIII positive cancers that are resistant to conventional therapies., Competing Interests: P. Lauer and B. Hanson have ownership interest (including patents) in Aduro Biotech. Patents relevant to this manuscript held by authors include Patent# US20070207170A1 (Lauer), US9161974B2 (Bahjat), WO2007022511A2 (Bahjat), WO2012068360A1 (Lauer, Bahjat), US10105427B2 (Lauer, Hanson). This does not alter our adherence to PLOS ONE policies on sharing data and materials. All other authors declare that no competing interests exist.

Viral respiratory tract infections (VRTI) remain a leading cause of morbidity and mortality among infants and young children. In mice, optimal protection to VRTI is mediated by recruitment of effector T cells to the lungs and respiratory tract, and subsequent establishment of tissue resident memory T cells (Trm), which provide long-term protection. These critical processes of T cell recruitment to the respiratory tract, their role in disease pathogenesis, and establishment of local protective immunity remain undefined in pediatric VRTI. In this study, we investigated T cell responses in the upper respiratory tract (URT) and lower respiratory tract (LRT) of infants and young children with VRTI, revealing developmental regulation of T cell differentiation and Trm generation in situ. We show a direct concurrence between T cell responses in the URT and LRT, including a preponderance of effector CD8 + T cells that was associated with disease severity. During infant VRTI, there was an accumulation of terminally differentiated effector cells (effector memory RA + T cells) in the URT and LRT with reduced Trm in the early neonatal period, and decreased effector memory RA + T cell and increased Trm formation with age during the early years of childhood. Moreover, human infant T cells exhibit increased expression of the transcription factor T-bet compared with adult T cells, suggesting a mechanism for preferential generation of effector over Trm. The developmental regulation of respiratory T cell responses as revealed in the present study is important for diagnosing, monitoring, and treating VRTI in the critical early life stages., (Copyright © 2018 by The American Association of Immunologists, Inc.)

The immune system in early life is tasked with transitioning from a relatively protected environment to one in which it encounters a wide variety of innocuous antigens and dangerous pathogens. The immaturity of the developing immune system, and particularly the distinct functionality of T lymphocytes in early life, has been implicated in increased susceptibility to infection. Previous work has demonstrated that immune responses in early life are skewed toward limited inflammation and atopy; however, there is mounting evidence that such responses are context- and tissue-dependent. The regulation, differentiation, and maintenance of infant T cell responses, particularly as it relates to tissue compartmentalization, remains poorly understood. How the tissue environment impacts early-life immune responses and whether the development of localized protective immune memory cell subsets are established is an emerging area of research. As infectious diseases affecting the respiratory and digestive tracts are a leading cause of morbidity and mortality worldwide in infants and young children, a deeper understanding of site-specific immunity is essential to addressing these challenges. Here, we review the current paradigms of T cell responses during infancy as they relate to tissue localization and discuss implications for the development of vaccines and therapeutics.

Infants suffer disproportionately from respiratory infections and generate reduced vaccine responses compared with adults, although the underlying mechanisms remain unclear. In adult mice, lung-localized, tissue-resident memory T cells (TRMs) mediate optimal protection to respiratory pathogens, and we hypothesized that reduced protection in infancy could be due to impaired establishment of lung TRM. Using an infant mouse model, we demonstrate generation of lung-homing, virus-specific T effectors after influenza infection or live-attenuated vaccination, similar to adults. However, infection during infancy generated markedly fewer lung TRMs, and heterosubtypic protection was reduced compared with adults. Impaired TRM establishment was infant-T cell intrinsic, and infant effectors displayed distinct transcriptional profiles enriched for T-bet-regulated genes. Notably, mouse and human infant T cells exhibited increased T-bet expression after activation, and reduction of T-bet levels in infant mice enhanced lung TRM establishment. Our findings reveal that infant T cells are intrinsically programmed for short-term responses, and targeting key regulators could promote long-term, tissue-targeted protection at this critical life stage., (© 2017 Zens et al.)

Upon infection, an activated CD4 + T cell produces terminally differentiated effector cells and renews itself for continued defense. In this study, we show that differentiation and self-renewal arise as opposing outcomes of sibling CD4 + T cells. After influenza challenge, antigen-specific cells underwent several divisions in draining lymph nodes (LN; DLNs) while maintaining expression of TCF1. After four or five divisions, some cells silenced, whereas some cells maintained TCF1 expression. TCF1-silenced cells were T helper 1-like effectors and concentrated in the lungs. Cells from earliest divisions were memory-like and concentrated in nondraining LN. TCF1-expressing cells from later divisions in the DLN could self-renew, clonally yielding a TCF1-silenced daughter cell as well as a sibling cell maintaining TCF1 expression. Some TCF1-expressing cells in DLNs acquired an alternative, follicular helper-like fate. Modeled differentiation experiments in vitro suggested that unequal PI3K/mechanistic target of rapamycin signaling drives intraclonal cell fate heterogeneity. Asymmetric division enables self-renewal to be coupled to production of differentiated CD4 + effector T cells during clonal selection., (© 2017 Nish et al.)

Tissue-resident memory T cells (TRM) are a recently defined, noncirculating subset with the potential for rapid in situ protective responses, although their generation and role in vaccine-mediated immune responses is unclear. Here, we assessed TRM generation and lung-localized protection following administration of currently licensed influenza vaccines, including injectable inactivated influenza virus (IIV, Fluzone) and i.n. administered live-attenuated influenza virus (LAIV, FluMist) vaccines. We found that, while IIV preferentially induced strain-specific neutralizing antibodies, LAIV generated lung-localized, virus-specific T cell responses. Moreover, LAIV but not IIV generated lung CD4 + TRM and virus-specific CD8 + TRM, similar in phenotype to those generated by influenza virus infection. Importantly, these vaccine-generated TRM mediated cross-strain protection, independent of circulating T cells and neutralizing antibodies, which persisted long-term after vaccination. Interestingly, intranasal administration of IIV or injection of LAIV failed to elicit T cell responses or provide protection against viral infection, demonstrating dual requirements for respiratory targeting and a live-attenuated strain to establish TRM. The ability of LAIV to generate lung TRM capable of providing long-term protection against nonvaccine viral strains, as demonstrated here, has important implications for protecting the population against emergent influenza pandemics by direct fortification of lung-specific immunity.

Influenza A virus is a significant cause of morbidity and mortality worldwide, particularly among young children and the elderly. Current vaccines induce neutralizing antibody responses directed toward highly variable viral surface proteins, resulting in limited heterosubtypic protection to new viral serotypes. By contrast, memory CD4 T cells recognize conserved viral proteins and are cross-reactive to multiple influenza strains. In humans, virus-specific memory CD4 T cells were found to be the protective correlate in human influenza challenge studies, suggesting their key role in protective immunity. In mouse models, memory CD4 T cells can mediate protective responses to secondary influenza infection independent of B cells or CD8 T cells, and can influence innate immune responses. Importantly, a newly defined, tissue-resident CD4 memory population has been demonstrated to be retained in lung tissue and promote optimal protective responses to an influenza infection. Here, we review the current state of results regarding the generation of memory CD4 T cells following primary influenza infection, mechanisms for their enhanced efficacy in protection from secondary challenge including their phenotype, localization, and function in the context of both mouse models and human infection. We also discuss the generation of memory CD4 T cells in response to influenza vaccines and its future implications for vaccinology.

For both targeted and non-targeted exposures, the cellular responses to ionizing radiation have predominantly been measured in two-dimensional monolayer cultures. Although convenient for biochemical analysis, the true interactions in vivo depend upon complex interactions between cells themselves and the surrounding extracellular matrix. This study directly compares the influence of culture conditions on radiation induced cytotoxicity following exposure to low-LET ionizing radiation. Using a three-dimensional (3D) human mammary epithelial tissue model, we have found a protective effect of 3D cell culture on cell survival after irradiation. The initial state of the cells (i.e., 2D versus 3D culture) at the time of irradiation does not alter survival, nor does the presence of extracellular matrix during and after exposure to dose, but long term culture in 3D which offers significant reduction in cytotoxicity at a given dose (e.g. approximately 4-fold increased survival at 5Gy). The cell cycle delay induced following exposure to 2 and 5Gy was almost identical between 2D and 3D culture conditions and cannot account for the observed differences in radiation responses. However the amount of apoptosis following radiation exposure is significantly decreased in 3D culture relative to the 2D monolayer after the same dose. A likely mechanism of the cytoprotective effect afforded by 3D culture conditions is the down regulation of radiation induced apoptosis in 3D structures., (Copyright 2010. Published by Elsevier B.V.)