Invasive pneumococcal disease among the elderly in the later era of paediatric pneumococcal conjugate vaccination-A longitudinal study over 10 years based on public surveillance data in the Nordics.

BACKGROUND: Pneumococcal conjugate vaccines (PCVs) have proven effective in preventing both non-invasive and invasive pneumococcal disease (IPD) in small children and in older age groups. However, long-term observations and country comparisons of IPD incidence in the elderly following introduction of PCVs in paediatric national immunisation programmes (NIPs) are scarce. We aimed to estimate and compare incidence of IPD in the elderly in Denmark, Finland, Norway, and Sweden over a 10-year time span. During the study period Denmark and Norway used PCV13 in their paediatric NIP, Sweden both PCV10 and PCV13 and Finland used PCV10. Uptake of pneumococcal vaccines for the elderly was low. METHOD: We collected longitudinal data on confirmed IPD cases and their serotypes among elderly people (aged ≥65 years) 2010-2019 in the four countries of interest. Annual IPD incidence rates were calculated per country, by vaccine-associated serotypes (PCV10, PCV13, PCV15, PCV20 and PPV23) and for non-vaccine serotypes. A regression model was used to estimate average annual change in incidence in each country. RESULTS: Incidence rates of IPD in the elderly in 2019 ranged from 31.4 to 41.8 per 100,000 people across the countries. Denmark and Norway showed an annual average decline in IPD incidence (-3.3; 95% CI: -5.6 to -1.1; p<0.01) and (-3.3; 95% CI: -5.5 to -1.0; p<0.01) respectively from 2010 to 2019, whereas no change was seen for Sweden (-0.5; 95% CI: -1.9 to 0.8; p = 0.39) or Finland (0.9; 95% CI: -1.0 to 2.7; p = 0.32). IPD incidence due to emerging serotypes, e.g., serotypes 8 and 12F, has increased. Serotype 19A remained a major cause of IPD in countries with PCV10 in paediatric NIPs. CONCLUSION: Despite paediatric PCV programmes, a considerable vaccine preventable IPD burden remains in the elderly. Further, choice of PCV in paediatric programs was associated with differences in serotype distribution and incidence amongst the elderly. Direct vaccination of the elderly with recently approved broad coverage PCVs holds promise for meaningful impact on disease burden with PCV20 covering a majority of IPD amongst the elderly in the four studied countries. Effectiveness of new vaccines in real-life clinical practice should be followed.

Radiographically confirmed community-acquired pneumonia in hospitalized adults due to pneumococcal vaccine serotypes in Sweden, 2016-2018-The ECAPS study.

Objectives: In Sweden, pneumococcal serotype distribution in adults with community-acquired pneumonia (CAP) and potential coverage of currently licensed pneumococcal conjugate vaccines (PCVs) is unknown. Methods: During 2016-2018, patients aged ≥18 years hospitalized with radiologically confirmed (RAD+) CAP were enrolled at Skåne University Hospital in a study on the etiology of CAP in Sweden (ECAPS). Urine samples and blood cultures were collected per-protocol. Streptococcus pneumoniae (Spn) culture isolates were serotyped and urine samples tested for the pan-pneumococcal urinary antigen (PUAT) and multiplex urine antigen detection (UAD) assay, detecting 24 serotypes. Results: Analyses included 518 participants with RAD+CAP; 67.4% were ≥65 years of age, 73.4% were either immunocompromised or had an underlying chronic medical condition. The proportion of CAP due to Spn identified by any method was 24.3% of which 9.3% was detected by UAD alone. The most frequently identified serotypes were 3 (26 cases, 5.0% of all CAP), and 8, 11A and 19A (10 cases each, 1.9%). In individuals aged 18-64 and ≥65 years, respectively, PCV20 serotypes contributed to 35 of 169 (20.7%) and 53 of 349 cases of all CAP (15.2%), and PCV13 serotypes caused 21 of 169 (12.4%) and 35 of 349 (10.0%) cases. PCV15 coverage was 23 of 169 (13.6%) and 42 of 349 (12.0%) in individuals aged 18-64 and ≥65 years, respectively. Overall, PCV20 increases the coverage of all CAP from 10.8% (PCV13) to 17.0%. Conclusion: Compared to earlier pneumococcal vaccines, PCV20 expands the coverage of all-cause CAP. Routine diagnostic tests underestimate the proportion of CAP caused by Spn.

Recommendations to Improve Tick-Borne Encephalitis Surveillance and Vaccine Uptake in Europe.

There has been an increase in reported TBE cases in Europe since 2015, reaching a peak in some countries in 2020, highlighting the need for better management of TBE risk in Europe. TBE surveillance is currently limited, in part, due to varying diagnostic guidelines, access to testing, and awareness of TBE. Consequently, TBE prevalence is underestimated and vaccination recommendations inadequate. TBE vaccine uptake is unsatisfactory in many TBE-endemic European countries. This review summarizes the findings of a scientific workshop of experts to improve TBE surveillance and vaccine uptake in Europe. Strategies to improve TBE surveillance and vaccine uptake should focus on: aligning diagnostic criteria and testing across Europe; expanding current vaccine recommendations and reducing their complexity; and increasing public education of the potential risks posed by TBEV infection.

Acceptance and application of a broad population health perspective when evaluating vaccine.

The traditional health economic analysis is limited to estimating the impact on the treated patient. As vaccines are usually aimed at preventing infectious diseases, they may be associated with additional values for the non-treated wider population. Although there are valid reasons for treating vaccines differently, and a wide support for a broader perspective in the literature (i.e., beyond the net costs and health gain related to the outcome for the vaccinated individual), it remains unclear to what extent the Health Technology Assessment (HTA) agencies accept and apply a broader perspective. The purpose of this study is to examine and discuss what type of consequences are relevant for a health economic analysis of vaccines and which consequences are considered by HTA agencies. The study includes a strategic review of literature and HTA decisions in Sweden and other countries, online round-table discussions with stakeholders in Sweden, and a basic estimation of the value of a COVID-19 vaccination in Sweden. The study shows that, other than herd effect, broader economic consequences for the population are generally not included in the economic evaluation of vaccines. Also, all economic consequences for the treated patient (production loss) and caregiver (health loss) are not always considered. The perspective chosen can have a major impact on the outcome of the analysis. A vaccine for COVID-19 is estimated to provide a value of €744-€956 per dose when using a societal perspective including broader consequences for the population. Providing a complete and appropriate picture of the value of vaccination is of importance to allocate resources efficiently, to provide incentives for vaccine development, and to show the cost of delaying decisions to implement a new vaccine.

TBE Vaccination Breakthrough Cases-Does Age Matter?

Tick-borne encephalitis (TBE) vaccines are highly effective in preventing TBE and vaccine failures (VF) are rare events. In this study, we compared the age distribution of TBE cases and TBE VF in three endemic countries: Sweden, Southern Germany, and Latvia. While the age distribution of TBE cases was similar for those <50 years versus those ≥50 years in all three countries, in Sweden, a higher proportion of VF cases was ≥50 years, whereas most VF cases in Latvia were <50 years of age and more evenly distributed between those <50 years versus those ≥50 in Southern Germany. Here, theoretical explanations were provided, including differences in diagnostic practices, vaccine uptake between age groups, behavioral patterns and underlying medical conditions, as to why VF were generally older in Sweden than the other countries. There is no scientific rationale to give an extra priming dose of TBE vaccine to subjects ≥50 years of age.

HIV drug therapy duration; a Swedish real world nationwide cohort study on InfCareHIV 2009-2014.

BACKGROUND: As HIV infection needs a lifelong treatment, studying drug therapy duration and factors influencing treatment durability is crucial. The Swedish database InfCareHIV includes high quality data from more than 99% of all patients diagnosed with HIV infection in Sweden and provides a unique opportunity to examine outcomes in a nationwide real world cohort. METHODS: Adult patients who started a new therapy defined as a new 3rd agent (all antiretrovirals that are not N[t]RTIs) 2009-2014 with more than 100 observations in treatment-naive or treatment-experienced patients were included. Dolutegravir was excluded due to short follow up period. Multivariate Cox proportional hazards models were used to estimate hazard ratios for treatment discontinuation. RESULTS: In treatment-naïve 2541 patients started 2583 episodes of treatments with a 3rd agent. Efavirenz was most commonly used (n = 1096) followed by darunavir (n = 504), atazanavir (n = 386), lopinavir (n = 292), rilpivirine (n = 156) and raltegravir (n = 149). In comparison with efavirenz, patients on rilpivirine were least likely to discontinue treatment (adjusted HR 0.33; 95% CI 0.20-0.54, p<0.001), while patients on lopinavir were most likely to discontinue treatment (adjusted HR 2.80; 95% CI 2.30-3.40, p<0.001). Also raltegravir was associated with early treatment discontinuation (adjusted HR 1.47; 95% CI 1.12-1.92, p = 0.005). The adjusted HR for atazanavir and darunavir were not significantly different from efavirenz. In treatment-experienced 2991 patients started 4552 episodes of treatments with a 3rd agent. Darunavir was most commonly used (n = 1285), followed by atazanavir (n = 806), efavirenz (n = 694), raltegravir (n = 622), rilpivirine (n = 592), lopinavir (n = 291) and etravirine (n = 262). Compared to darunavir all other drugs except for rilpivirine (HR 0.66; 95% CI 0.52-0.83, p<0.001) had higher risk for discontinuation in the multivariate adjusted analyses; atazanavir (HR 1.71; 95% CI 1.48-1.97, p<0.001), efavirenz (HR 1.86; 95% CI 1.59-2.17, p<0.001), raltegravir (HR 1.35; 95% CI 1.15-1.58, p<0.001), lopinavir (HR 3.58; 95% CI 3.02-4.25, p<0.001) and etravirine (HR 1.61; 95% CI 1.31-1.98, p<0.001).Besides the 3rd agent chosen also certain baseline characteristics of patients were independently associated with differences in treatment duration. In naive patients, presence of an AIDS-defining diagnosis and the use of other backbone than TDF/FTC or ABC/3TC increased the risk for early treatment discontinuation. In treatment-experienced patients, detectable plasma viral load at the time of switch or being highly treatment experienced increased the risk for early treatment discontinuation. CONCLUSIONS: Treatment durability is dependent on several factors among others patient characteristics and ART guidelines. The choice of 3rd agent has a strong impact and significant differences between different drugs on treatment duration exist.

Presence and specificity of tumor associated lymphocytes from ascites fluid in prostate cancer.

BACKGROUND: In the present study, we had the rare opportunity to study immunological responses of TAL from ascites fluid in a patient with hormone-refractory prostate cancer. METHODS: We evaluated tumor antigen-specific T-cell responses, induced by either prostate specific antigen (PSA) pulsed dendritic cells (DCs) or PSA peptides, in TAL and peripheral blood lymphocytes. RESULTS: DC stimulation with PSA protein induced recognition of naturally processed PSA epitopes by both blood and ascites T cells. In contrast, only ascites T cells recognized the PSA-3 peptide, after stimulation with PSA-pulsed DCs or peptides. Finally, although IFNgamma secreting T cells were detectable in both blood and ascites by ELISPOT, multiplex cytokine assay detected the presence of predominantly Th2 cytokines. CONCLUSIONS: Although tumor antigen-specific TAL were detected in ascites fluid, these cells were producing immunosuppressive cytokines which may contribute to tumor escape from recognition and/or destruction by the immune system.

Mature dendritic cells induce tumor-specific type 1 regulatory T cells.

The aim of this study was to compare the tumor antigen-specific T-cell repertoire generated by transduced, human dendritic cells (DCs). The transductions were three commonly used antigen delivery procedures: adenovirus (AdV) infection, RNA electroporation, and liposome-mediated protein transfection. The DCs in each experimental group were transfected with similar efficacy and matured using TNF-alpha, anti-CD40, or lipopolysaccharide. Regardless of the gene transfer method or the maturation stimuli used, the DCs were indistinguishable with regard to surface phenotype and allostimulatory capacity. With the exception of the Adv transduced group, the T cells generated were tumor antigen specific, as characterized by high IFN-gamma production. The T cells generated upon stimulation with DCs subjected to AdV infection, and subsequently treated with TNF-alpha, exhibited tumor antigen specificity, but accompanied by reduced proliferation and IFNgamma production and increased IL-10 production. Moreover, these T cells exerted a suppressive effect on both autologous and allogeneic lymphocytes resembling type 1 regulatory T cells (Tr1). The authors show that mature DCs may induce tumor antigen-specific Tr1 cells by the appearance of high IL-10 and low IL-12. Similar results were also obtained with AdV-infected and TNF-matured DCs regardless of the transgene used. This work supports the conclusion that it can no longer be assumed that mature DCs induce only antitumor reactive T cells.

Allogeneic tumor-dendritic cell fusion vaccines for generation of broad prostate cancer T-cell responses.

Antigen-loaded dendritic cells (DC) are considered potent stimulators of protective immunity. In some studies, DC hybridized with tumor cells have shown promising antitumor responses in mice as well as in humans. A practical drawback of this approach is the limited availability of autologous tumor samples. We investigated the possibility of hybridizing allogeneic prostate cancer cells with human-monocyte-derived DC, and thereby combine the wide repertoire of antigens from the tumor cells with the costimulatory features of the autologous antigen-presenting cells. Three tumor cell lines were used for hybridization using polyethylene glycol (PEG). We show that all three cell lines formed hybrids with DC to the same extent and without significant loss of viability. Restimulation of autologous T cells with these hybrids resulted in generation of tumor-specific IFNgamma-producing T cells with all three tumor cell lines. Similar tumor specificity could not be obtained if T cells were stimulated using a mixture of non-PEG-fused tumor cells and DC. Moreover, these T cells were capable of specific recognition of other tumor cells of prostate cancer origin and autologous DC pulsed with lysate from these prostate cancer cell lines, while a panel of unrelated EBV-transformed B cell lines were not recognized. These results are strongly indicative of the true tumor specificity of these T cells. Our results suggest that DC hybridized with allogeneic prostate cancer cell lines are potent stimulators of a broad prostate-tumor-specific response.