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PLAIN LANGUAGE SUMMARY What is the context? After haematopoletic stem cell transplantation, patlents have impaired immunity from conditioning chemotherapy regimens, often exacerbated by underlying diseases, putting them at high risk of developing herpes zoster. In this population, antiviral prophylaxis is the current standard of care to reduce herpes zoster risk. Vaccination provides an additional means to prevent herpes zoster. Live-attenuated vaccines are generally contraindicated in immuonocompromised patients. A non-live, adjuvanted recombinant zoster vaccine (RZV, Shingrix, GSK), has been approved for use in adults 250 years of age in the European Union, United States, Canada, Australia, Japan, and China. This vaccine is highly efficacious at preventing herpes zoster in adults over 50 years of age, as demonstrated in large, placebo-controlled randomised trials. Importantly, Shingrix use is not contraindicated in immunocompromised conditions, and was found to be highly efficacious in adults who had recently undergone autologous haematopoleticstem cell transplant. What is new? In autologous haematopoietic stem cell transplant recipients in whom Shingrix has demonstrated efficacy, two doseselicited high and persistent immune responses. Date presented here further support our understanding of the impact of specific factors such as age or underlying diseases on the vaccine's effect in the population studies, as well as the characteristics of the elicited cell-mediated immune responses. What is the impact? These results indicate that Shingrix, given shortly after haematopoletic stem cell transplant, can induce robust immune responses and reduce the risk of herpes zoster, even in individuals with immunosuppression due to underlying disease and/or use of immunosuppressive therapies, regardless of age or underlying disease. Immunocompromised individuals, particularly autologous hematopoietic stem cell transplant (auHSCT) recipients, are at high risk for herpes zoster (HZ). We provide an in-depth description of humoral and cell-mediated immune (CMI) responses by age (protocol-defined) or underlying disease (post-hoc) as well as efficacy by underlying disease (post-hoc) of the adjuvanted recombinant zoster vaccine (RZV) in a randomized observer-blind phase III trial (ZOE-HSCT, NCT01610414). 1846 adult auHSCT recipients were randomized to receive a first dose of either RZV or placebo 50-70 days post-auHSCT, followed by the second dose at 1-2 months (M) later. In cohorts of 114-1721 participants, at 1 M post-second vaccine dose: Anti-gE antibody geometric mean concentrations (GMCs) and median gE-specific CD4[2+] T-cell frequencies (CD4 T cells expressing >= 2 of four assessed activation markers) were similar between 18-49 and >= 50-year-olds. Despite lower anti-gE antibody GMCs in non-Hodgkin B-cell lymphoma (NHBCL) patients, CD4[2+] T-cell frequencies were similar between NHBCL and other underlying diseases. The proportion of polyfunctional CD4 T cells increased over time, accounting for 79.6% of gE-specific CD4 T cells at 24 M post-dose two. Vaccine efficacy against HZ ranged between 42.5% and 82.5% across underlying diseases and was statistically significant in NHBCL and multiple myeloma patients. In conclusion, two RZV doses administered early post-auHSCT induced robust, persistent, and polyfunctional gE-specific immune responses. Efficacy against HZ was also high in NHBCL patients despite the lower humoral response., GlaxoSmithKline Biologicals SA, This work was sponsored by GlaxoSmithKline Biologicals SA in all stages of the study conduct and analysis. GlaxoSmithKline Biologicals SA also took responsibility for all costs associated with the development and publishing of the present manuscript.

The authors report interim results of the WHO Solidarity trial of four repurposed antiviral drugs - remdesivir, hydroxychloroquine, lopinavir, and interferon beta-1a - in patients hospitalized with Covid-19. Effects on overall mortality, initiation of ventilation, and duration of hospital stay are compared. Background World Health Organization expert groups recommended mortality trials of four repurposed antiviral drugs - remdesivir, hydroxychloroquine, lopinavir, and interferon beta-1a - in patients hospitalized with coronavirus disease 2019 (Covid-19). Methods We randomly assigned inpatients with Covid-19 equally between one of the trial drug regimens that was locally available and open control (up to five options, four active and the local standard of care). The intention-to-treat primary analyses examined in-hospital mortality in the four pairwise comparisons of each trial drug and its control (drug available but patient assigned to the same care without that drug). Rate ratios for death were calculated with stratification according to age and status regarding mechanical ventilation at trial entry. Results At 405 hospitals in 30 countries, 11,330 adults underwent randomization; 2750 were assigned to receive remdesivir, 954 to hydroxychloroquine, 1411 to lopinavir (without interferon), 2063 to interferon (including 651 to interferon plus lopinavir), and 4088 to no trial drug. Adherence was 94 to 96% midway through treatment, with 2 to 6% crossover. In total, 1253 deaths were reported (median day of death, day 8; interquartile range, 4 to 14). The Kaplan-Meier 28-day mortality was 11.8% (39.0% if the patient was already receiving ventilation at randomization and 9.5% otherwise). Death occurred in 301 of 2743 patients receiving remdesivir and in 303 of 2708 receiving its control (rate ratio, 0.95; 95% confidence interval [CI], 0.81 to 1.11; P=0.50), in 104 of 947 patients receiving hydroxychloroquine and in 84 of 906 receiving its control (rate ratio, 1.19; 95% CI, 0.89 to 1.59; P=0.23), in 148 of 1399 patients receiving lopinavir and in 146 of 1372 receiving its control (rate ratio, 1.00; 95% CI, 0.79 to 1.25; P=0.97), and in 243 of 2050 patients receiving interferon and in 216 of 2050 receiving its control (rate ratio, 1.16; 95% CI, 0.96 to 1.39; P=0.11). No drug definitely reduced mortality, overall or in any subgroup, or reduced initiation of ventilation or hospitalization duration. Conclusions These remdesivir, hydroxychloroquine, lopinavir, and interferon regimens had little or no effect on hospitalized patients with Covid-19, as indicated by overall mortality, initiation of ventilation, and duration of hospital stay. (Funded by the World Health Organization; ISRCTN Registry number, ; ClinicalTrials.gov number, .)

Patients with chronic lymphocytic leukemia (CLL) are at a high risk for infections caused by Streptococcus pneumoniae. A pneumococcal conjugate vaccine (PCV) can induce a significant antibody response for some CLL patients. In this study we investigated antibody persistence after PCV7 in patients with CLL. The study material comprised 24 patients with CLL and 8 immunocompetent controls. The median antibody concentrations five years after PCV7 were lower for six pneumococcal serotypes in patients with CLL compared to controls, but the difference was not statistically significant. Depending on the serotype, the percentage of the CLL patients with antibody levels suggested to provide protection against invasive pneumococcal disease (IPD) varied from 29 to 71% five years after vaccination. This data suggests that PCV could result in antibody persistence at least five years in CLL patients.

BACKGROUND: The adjuvanted recombinant zoster vaccine (Shingrix) can prevent herpes zoster in older adults and autologous haemopoietic stem cell transplant recipients. We evaluated the safety and immunogenicity of this vaccine in adults with haematological malignancies receiving immunosuppressive cancer treatments. METHODS: In this phase 3, randomised, observer-blind, placebo-controlled study, done at 77 centres worldwide, we randomly assigned (1:1) patients with haematological malignancies aged 18 years and older to receive two doses of the adjuvanted recombinant zoster vaccine or placebo 1-2 months apart during or after immunosuppressive cancer treatments, and stratified participants according to their underlying diseases. The co-primary objectives of the study were the evaluation of safety and reactogenicity of the adjuvanted recombinant zoster vaccine compared with placebo from the first vaccination up to 30 days after last vaccination in all participants; evaluation of the proportion of participants with a vaccine response in terms of anti-glycoprotein E humoral immune response to the adjuvanted recombinant zoster vaccine at month 2 in all participants, excluding those with non-Hodgkin B-cell lymphoma and chronic lymphocytic leukaemia; and evaluation of the anti-glycoprotein E humoral immune responses to the vaccine compared with placebo at month 2 in all participants, excluding those with non-Hodgkin B-cell lymphoma and chronic lymphocytic leukaemia. We assessed immunogenicity in the per-protocol cohort for immunogenicity and safety in the total vaccinated cohort. The study is registered with ClinicalTrials.gov, number NCT01767467, and with the EU Clinical Trials Register, number 2012-003438-18. FINDINGS: Between March 1, 2013, and Sept 10, 2015, we randomly assigned 286 participants to adjuvanted recombinant zoster vaccine and 283 to placebo. 283 in the vaccine group and 279 in the placebo group were vaccinated. At month 2, 119 (80·4%, 95% CI 73·1-86·5) of 148 participants had a humoral vaccine response to adjuvanted recombinant zoster vaccine, compared with one (0·8%, 0·0-4·2) of 130 participants in the placebo group, and the adjusted geometric mean anti-glycoprotein E antibody concentration was 23 132·9 mIU/mL (95% CI 16 642·8-32 153·9) in the vaccine group and 777·6 mIU/mL (702·8-860·3) in the placebo group (adjusted geometric mean ratio 29·75, 21·09-41·96; p

The 23-valent pneumococcal polysaccharide vaccine (PPV23) given alone is ineffective in patients with chronic lymphocytic leukemia (CLL) and better antibody response is achieved with pneumococcal conjugate vaccines (PCVs). In this study, we determine whether CLL patients would achieve a significant antibody response and broaden their serotype coverage against invasive pneumococcal disease (IPD) with PPV23 given five years after the 7-valent conjugate vaccine (PCV7). A total of 24 patients with CLL and eight controls were vaccinated with PPV23 five years after PCV7. Blood samples for evaluation of antibody response to PCV7 serotypes and PPV23 serotypes 5 and 7 were taken before vaccination and one month after it. Post-vaccination samples were available from 20 patients. IgG antibodies were measured with ELISA. Antibody concentrations after PPV23 were significantly lower in CLL patients for six of the PCV7 serotypes and for both PPV23 serotypes. Only 10% to 15% of CLL patients achieved an antibody response suggested to be protective against IPD. Hence, PCV7 given five years before PPV23 did not improve antibody response in patients with CLL. Based on our results, PPV23 given after a PCV primer is not useful against IPD in CLL patients.

Outcomes for patients with multiple myeloma (MM) have improved with the advent of novel therapies, however, real-world evidence of outcomes in clinical practice is scarce. We conducted a multi-center registry study to build a reliable picture of treatment and patient outcomes in Finland. The aim of this study was also to understand any methodological challenges in assessing treatment outcomes using disease registry data. Methods: We carried out a retrospective, observational study using data from the national Finnish Hematology Registry (FHR) to provide real-world evidence of outcomes for all adult patients diagnosed with and treated for MM between 2009-2013 at one of the six regional hospitals, with at least six months of recorded follow-up. Patients were identified within the FHR by applying eligibility criteria of a diagnosis of MM and verifiable records of medical treatment and lines of treatment during the study period. Patients receiving allogenic stem cell transplantation were excluded from the cohort, as were individuals who only had monoclonal gammopathy of undetermined significance diagnosis and patients who had not initiated treatment during this period. Kaplan Meier curves were used to calculate overall survival and time to next treatment. Stratification was carried out by drug status (conventional/novel) and by autologous stem cell transplant (ASCT) status. Results: A total of 321 patients met the inclusion criteria and were included in this study. Overall survival (OS) was longest in patients who received first-line novel therapy and ASCT (median not reached during 60-month follow-up) versus 46.2 months for novel first-line therapy without ASCT and 25.6 months for first-line conventional therapy without ASCT. Similarly, median time to next treatment were 33.9 months, 12.6 months and 7.8 months, respectively. Conclusions: The adoption of novel treatments in MM in Finland has had substantial impact on patient outcomes. Given the reality of complex treatment combinations for MM and relatively low patient numbers, assessing individual treatment effectiveness will require substantial cohort sizes and advanced, collaborative analytics on an international scale.

Cerebral venous thrombosis (CVT) covers up to a third of all venous thromboses (VTs) detected in patients with acute lymphoblastic leukemia (ALL). It usually hampers patients' lives and may also endanger efficient leukemia treatment. Although many factors have been suggested to account for an elevated risk of VTs in patients with ALL, there still is a lack of studies focusing on CVTs and especially in the setting of adult ALL patients. We studied in our retrospective population-based cohort the occurrence, characteristics, as well as risk factors for VTs in 186 consecutively diagnosed Finnish adult ALL patients treated with a national pediatric-inspired treatment protocol ALL2000. In the risk factor analyses for VTs we found a distinction of the characteristics of the patients acquiring CVT from those with other kinds of VTs or without thrombosis. In contrast to previous studies we were also able to compare the effects of asparaginase in relation to CVT occurrence. Notably, more than half of the CVTs were diagnosed prior the administration of asparaginase which accentuates the role of other risk factors on the pathophysiology of CVT compared to truncal or central venous line (CVL) VTs in adult ALL patients.

Krooninen lymfaattinen leukemia (KLL) on länsimaiden yleisin pahanlaatuinen verisairaus. Sitä sairastavat potilaat saavat herkästi infektioita. Infektioherkkyyttä lisäävät sekä taudin aiheuttamat muutokset vastustuskyvyssä että myös taudin hoidossa käytettävät solunsalpaajat ja vasta-aineet. Infektiot ovat merkittävin KLL-potilaiden kuolinsyy. Potilaat saavat erityisen herkästi hengitystieinfektioita, kuten keuhkokuumeita (pneumonioita) ja nenän sivuonteloiden tulehduksia (sinuiitteja). Näitä infektioita esiintyy jo KLL:n varhaisvaiheessa. Streptococcus pneumoniae (pneumokokki) on merkittävin yksittäinen taudinaiheuttaja. Taudin myöhäisemmässä vaiheessa myös soluvälitteisen immuniteetin häiriöt lisääntyvät ja opportunistiset taudinaiheuttajat, kuten herpesvirukset ja sienet, tulevat yleisiksi. Keinoja infektioiden ehkäisemiseksi on ollut vähän. Aktiivinen immunisaatio rokotuksilla on osoittautunut tehokkaaksi terveen väestön infektiosairauksien hävittämisessä, mutta sen teho KLL-potilailla on epäselvää. Yleisimmin käytettyjä rokotteita ovat bakteeripolysakkaridit. Ne toimivat kuitenkin huonosti jos immuunisysteemi on häiriintynyt. Konjugaattirokotteessa bakteeripolysakkaridi liitetään kuljettajaproteiiniin jolloin sen vaikutusmekanismi muuttuu niin, että myös immunologinen muisti kehittyy. Tässä tutkimuksessa selvitimme KLL-potilaiden vasta-ainereaktioita erityyppisille rokoteantigeeneille. Selvitimme tekijöitä, jotka ennustivat rokotteen aiheuttamaa vastetta. Erityisen mielenkiinnon kohteena olivat konjugaattirokotteet ja pneumokokki vakavimpien infektioiden aiheuttajana. Potilaina oli KLL:aa sairastavia henkilöitä, joista suurimmalla osalla oli varhaisvaiheen tauti, eivätkä he olleet saaneet voimakkaita hoitoja. Vertailuryhmän muodostivat immunologialtaan terveet henkilöt. Polysakkaridirokotteena tutkimuksessa oli 23 serotyypin pneumokokkirokote (Pnu-Immune®), ja proteiinirokote oli tetanustoksoidi (Tetanus-d-rokote®). Konjugaattirokotteet olivat Haemophilus influenzae tyyppi b (HibTITER®) ja 7 serotyypin pneumokokkikonjugaattirokote (Prevenar®). Pneumokokkipolysakkaridirokotteen aiheuttama nousu vasta-aineissa jäi suurimmalla osalla KLL-potilaista olemattoman heikoksi kontrollihenkilöihin verrattuna. Ainoastaan muutamalla yksittäisellä potilaalla oli mitattavia vasteita kuukausi rokotuksen jälkeen. Sen sijaan molemmat konjugaattirokotteet olivat immunogeenisiä KLL-potilailla. Suuri osa KLL-potilaista saavutti rokotuksella vasta-ainetason, jota pidetään suojaavana. Konjugaattirokotteet olivat tehokkaampia nuoremmilla KLL-potilailla, joilla oli normaalit veren immunoglobuliinitasot ja varhaisemman vaiheen tauti. Kuitenkin myös monet potilaat, joilla oli pitkälle edennyt tauti ja huonon ennusteen tekijöitä, reagoivat konjugaattirokotteeseen. Tutkimustulokset viittaavat siihen, että KLL-potilaat tulisi rokottaa konjugaattirokotteilla ja että rokotukset pitäisi tehdä taudin alkuvaiheessa. Chronic lymphocytic leukemia (CLL) is the most common malignant blood disorder in the western world. It is characterized by an accumulation of malignant, mature-appearing but functionally incompetent B-lymphocytes in blood, bone marrow and lymphoid tissues. Patients with CLL are susceptible to infections, this arising from humoral and cell-mediated immunodeficiency associated with CLL itself as well as from treatment of the malignancy. Infections are the most frequent cause of death in these patients. They are especially prone to infections in the respiratory tract, for example pneumonias and sinusitis. Streptococcus pneumoniae is the most prominent single pathogen. In advanced stages of the disease opportunistic pathogens such as herpes viruses and fungi also become more prevalent. Treatment of CLL does not improve humoral immunity, and many new effective treatments - for example monoclonal antibodies - also disturb cell-mediated immunity. Prophylactic antimicrobials or intravenous immunoglobulins have not solved the problem of infections. Active immunization by vaccines has effectively eradicated many infections among the healthy population, but their impact in CLL patients has remained unclear. The vaccines mostly used are bacterial polysaccharides, which are, however, weak immunogens, especially when the immune system is compromised. Conjugation of polysaccharides to protein carrier renders them more immunogenic, and they act like T-cell-dependent antigens and also induce an immunological memory. In this series we evaluated the specific antibody responses to different types of vaccine antigens in CLL patients, and sought factors predictive of vaccination-induced antibody responses. Special interest focused on conjugate vaccines, and Streptococcus pneumoniae, which is the main pathogen underlying serious infection in patients with CLL. The study cohorts comprised CLL patients from Tampere and Turku University Hospitals. The majority had early-stage disease without a heavy treatment history. The control groups consisted of immunologically healthy persons. The polysaccharide vaccine used in the studies was 23-valent pneumococcal vaccine (Pnu-Immune®), the protein vaccine tetanus toxoid (Tetanus-d-rokote®). The conjugate vaccines were Haemophilus influenzae type b (HibTITER®) and 7-valent pneumococcal conjugate vaccine (Prevenar®). We measured concentrations of specific serum antibodies to vaccine antigens before and one month after vaccination. Vaccination responses to plain polysaccharide pneumococcal antigens were very weak in CLL patients compared to controls, only a few in fact evincing any response at all. In turn, both Haemophilus influenzae type b (Hib) and 7-valent pneumococcal conjugate vaccines were more immunogenic in CLL patients. A high proportion of patients reached the concentrations considered protective after vaccination with conjugate vaccines. The response rates were compromised by advanced disease state, chemotherapy and hypogammaglobulinemia. Every fourth CLL patient mounted a significant response to at least 6 pneumococcal antigens after 7-valent pneumococcal conjugate vaccine. Almost 40% of them developed a significant response to at least six pneumococcal antigens out of the seven included in the vaccine if the vaccine had been administered at an early stage in the disease. Similar rates were reached with Hib conjugate vaccine, where one in five CLL patients developed a significant response. Pneumococcal polysaccharide vaccine did not significantly increase antibody concentrations in CLL patients after vaccination. Pneumococcal and Hib conjugate vaccines, in turn, proved considerably more immunogenic. Conjugate vaccines appeared to be more effective in younger CLL patients with normal serum immunoglobulin concentrations and less advanced stage of disease. In any case, even many patients with advanced CLL disease and poor prognostic factors such as unmutated CLL responded to both conjugate vaccines. According to the present findings it seems reasonable to vaccinate all CLL patients with conjugate vaccines, and the vaccination should be delivered early in the course of the disease.