Defining the “Correlate(s) of Protection” to tick-borne encephalitis vaccination and infection – key points and outstanding questions

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

Pneumococcal Vaccination Coverage and Uptake Among Adults in Switzerland: A Nationwide Cross-Sectional Study of Vaccination Records

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

Retrospective, matched case-control analysis of tickborne encephalitis vaccine effectiveness by booster interval, Switzerland 2006-2020

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. Keywords: Breakthrough Infection; Duration; Prevention; Protection; TBE

A microbial-based cancer vaccine for induction of EGFRvIII-specific CD8+ T cells and anti-tumor immunity.

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

Diagnosis of latent tuberculosis infection is associated with reduced HIV viral load and lower risk for opportunistic infections in people living with HIV.

Approximately 28% of the human population have been exposed to Mycobacterium tuberculosis (MTB), with the overwhelming majority of infected individuals not developing disease (latent TB infection (LTBI)). While it is known that uncontrolled HIV infection is a major risk factor for the development of TB, the effect of underlying LTBI on HIV disease progression is less well characterized, in part because longitudinal data are lacking. We sorted all participants of the Swiss HIV Cohort Study (SHCS) with at least 1 documented MTB test into one of the 3 groups: MTB uninfected, LTBI, or active TB. To detect differences in the HIV set point viral load (SPVL), linear regression was used; the frequency of the most common opportunistic infections (OIs) in the SHCS between MTB uninfected patients, patients with LTBI, and patients with active TB were compared using logistic regression and time-to-event analyses. In adjusted models, we corrected for baseline demographic characteristics, i.e., HIV transmission risk group and gender, geographic region, year of HIV diagnosis, and CD4 nadir. A total of 13,943 SHCS patients had at least 1 MTB test documented, of whom 840 (6.0%) had LTBI and 770 (5.5%) developed active TB. Compared to MTB uninfected patients, LTBI was associated with a 0.24 decreased log HIV SPVL in the adjusted model (p &lt; 0.0001). Patients with LTBI had lower odds of having candida stomatitis (adjusted odds ratio (OR) = 0.68, p = 0.0035) and oral hairy leukoplakia (adjusted OR = 0.67, p = 0.033) when compared to MTB uninfected patients. The association of LTBI with a reduced HIV set point virus load and fewer unrelated infections in HIV/TB coinfected patients suggests a more complex interaction between LTBI and HIV than previously assumed

Heterogenous humoral and cellular immune responses with distinct trajectories post-SARS-CoV-2 infection in a population-based cohort

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

A cross-sectional study evaluating tick-borne encephalitis vaccine uptake and timeliness among adults in Switzerland

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

Analysis of Tick-borne Encephalitis vaccination coverage and compliance in adults in Switzerland, 2018

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

Pneumococcal Vaccination Coverage and Uptake Among Adults in Switzerland: A Nationwide Cross-Sectional Study of Vaccination Records

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% versus 29.1%) and were more likely to report willingness to be vaccinated in the future compared to those not-at-risk (54.2% versus 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

T-cell memory in tissues

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