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© 2022 The Authors. Annals of Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.562 This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made., Objective: Cerebral venous thrombosis (CVT) caused by vaccine-induced immune thrombotic thrombocytopenia (VITT) is a rare adverse effect of adenovirus-based severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) vaccines. In March 2021, after autoimmune pathogenesis of VITT was discovered, treatment recommendations were developed. These comprised immunomodulation, non-heparin anticoagulants, and avoidance of platelet transfusion. The aim of this study was to evaluate adherence to these recommendations and its association with mortality. Methods: We used data from an international prospective registry of patients with CVT after the adenovirus-based SARS-CoV-2 vaccination. We analyzed possible, probable, or definite VITT-CVT cases included until January 18, 2022. Immunomodulation entailed administration of intravenous immunoglobulins and/or plasmapheresis. Results: Ninety-nine patients with VITT-CVT from 71 hospitals in 17 countries were analyzed. Five of 38 (13%), 11 of 24 (46%), and 28 of 37 (76%) of the patients diagnosed in March, April, and from May onward, respectively, were treated in-line with VITT recommendations (p < 0.001). Overall, treatment according to recommendations had no statistically significant influence on mortality (14/44 [32%] vs 29/55 [52%], adjusted odds ratio [OR] = 0.43, 95% confidence interval [CI] = 0.16-1.19). However, patients who received immunomodulation had lower mortality (19/65 [29%] vs 24/34 [70%], adjusted OR = 0.19, 95% CI = 0.06-0.58). Treatment with non-heparin anticoagulants instead of heparins was not associated with lower mortality (17/51 [33%] vs 13/35 [37%], adjusted OR = 0.70, 95% CI = 0.24-2.04). Mortality was also not significantly influenced by platelet transfusion (17/27 [63%] vs 26/72 [36%], adjusted OR = 2.19, 95% CI = 0.74-6.54). Conclusions: In patients with VITT-CVT, adherence to VITT treatment recommendations improved over time. Immunomodulation seems crucial for reducing mortality of VITT-CVT. ANN NEUROL 2022;92:562-573., This research was funded by The Netherlands Organisation for Health Research and Development (ZonMw, grant number 10430072110005) and the Dr. C. J. Vaillant Foundation.

[eng] Cellular senescence is a response to stress and damage, ant it is known to activate innate immune cells. However, the mechanisms by which senescent cells interact with the adaptive arm of the immune system and their potential ability to trigger adaptive immune responses remain largely unexplored. In this doctoral work, we report that senescent cells combine several characteristics that render them highly immunogenic and thus very efficient in promoting the activation of adaptive immune responses driven by antigen-presenting cells (APCs) and antigen-specific CD8 T cells. These properties include the release of alarmin molecules that can recruit and activate APCs; enhanced delivery of antigens to APCs; activation of interferon signaling; upregulated MHC class I (MHC-I) antigen processing and presentation; and an altered MHC- I immunopeptidome that includes senescence-associated self-peptides, some of which are recognized by specific CD8 T cells. In the context of cancer, the immunization of murine models with viable senescent cancer cells elicits strong anti-tumor protection mediated by adaptive immunity, specifically APCs and CD8 T cells. Interestingly, the anti-tumor protection promoted by senescent cells is superior to that of immunization with dying senescent cells or with those cancer cells undergoing immunogenic cell death. The latter being the gold standard method to boost the immunogenicity of cancer cells and elicit anti-tumor immune protection in both cancer therapy and whole-cell vaccination approaches. Finally, the induction of senescence in patient-derived primary cancer cells also enhances their ability to activate autologous antigen-specific CD8 tumor-infiltrating lymphocytes (TILs), with no effect on autologous non-tumor-reactive TILs. We conclude that senescent cells are provided with combined adjuvanticity and antigenicity that can strongly activate adaptive immunity. In this regard, we propose that the properties of senescent cancer cells can be harnessed to trigger efficient and protective CD8- dependent anti-tumor immune responses.

BackgroundThe COVID-19 pandemic highlighted the fragmented nature of governmental policy decisions in Europe. However, the extent to which COVID-19 vaccination policies differed between European countries remains unclear. Here, we mapped the COVID-19 vaccination policies that were in effect in January 2022 as well as booster regulations in April 2022 in Austria, Denmark, England, France, Germany, Ireland, Italy, the Netherlands, Poland, and Spain.MethodsNational public health and health policy experts from these ten European nations developed and completed an electronic questionnaire. The questionnaire included a series of questions that addressed six critical components of vaccine implementation, including (1) authorization, (2) prioritization, (3) procurement and distribution, (4) data collection, (5) administration, and (6) mandate requirements.ResultsOur findings revealed significant variations in COVID-19 vaccination policies across Europe. We observed critical differences in COVID-19 vaccine formulations authorized for use, as well as the specific groups that were provided with priority access. We also identified discrepancies in how vaccination-related data were recorded in each country and what vaccination requirements were implemented.ConclusionEach of the ten European nations surveyed in this study reported different COVID-19 vaccination policies. These differences complicated efforts to provide a coordinated pandemic response. These findings might alert policymakers in Europe of the need to coordinate their efforts to avoid fostering divergent and socially disruptive policies. Background: The COVID-19 pandemic highlighted the fragmented nature of governmental policy decisions in Europe. However, the extent to which COVID-19 vaccination policies differed between European countries remains unclear. Here, we mapped the COVID-19 vaccination policies that were in effect in January 2022 as well as booster regulations in April 2022 in Austria, Denmark, England, France, Germany, Ireland, Italy, the Netherlands, Poland, and Spain. Methods: National public health and health policy experts from these ten European nations developed and completed an electronic questionnaire. The questionnaire included a series of questions that addressed six critical components of vaccine implementation, including (1) authorization, (2) prioritization, (3) procurement and distribution, (4) data collection, (5) administration, and (6) mandate requirements. Results: Our findings revealed significant variations in COVID-19 vaccination policies across Europe. We observed critical differences in COVID-19 vaccine formulations authorized for use, as well as the specific groups that were provided with priority access. We also identified discrepancies in how vaccination-related data were recorded in each country and what vaccination requirements were implemented. Conclusion: Each of the ten European nations surveyed in this study reported different COVID-19 vaccination policies. These differences complicated efforts to provide a coordinated pandemic response. These findings might alert policymakers in Europe of the need to coordinate their efforts to avoid fostering divergent and socially disruptive policies.

The development of vaccines against SARS-CoV2 brought about several challenges, including the management of hypersensitivity reactions to these formulations. The search for underlying mechanisms involved in these adverse events initially focused on excipients which may trigger mast cell activation responses via non-IgE pathways: polyethylene glycol and trometamol. We sought to determine whether these components, in their pure form, were capable of stimulating mast cells directly. To test this hypothesis, we used an in vitro model for non-IgE-mediated activation that has previously shown degranulation responses induced via MRGPRX2 with known drug agonists of the receptor. Human LAD2 mast cells were incubated with different concentrations (1, 10, 50 mg/ml) of trometamol and of purified polyethylene glycol/Macrogol (molecular weights: 2,000, 3,350, 4,000, and 6,000). Mast cell degranulation was assessed using a beta-hexosaminidase read-out. Interestingly, degranulation responses for all reagents tested showed no significant differences from those obtained from the negative control (basal degranulation). Receptor-silencing assays were therefore not conducted. In summary, purified PEG and trometamol did not induce mast cell degranulation in this in vitro model for the study of non-IgE mechanisms of drug hypersensitivity, previously shown to be useful in the investigation of MRGPRX2 ligands. Studies using complete vaccine formulations, lipid conjugates, and receptor gene variants are needed to further clarify mechanisms of vaccine hypersensitivity.

Recently, oncolytic vaccinia viruses (VACVs) have shown their potential to provide for clinically effective cancer treatments. The reason for this clinical usefulness is not only the direct destruction of infected cancer cells but also activation of immune responses directed against tumor antigens. For eliciting a robust antitumor immunity, a dominant T helper 1 (Th1) cell differentiation of the response is preferred, and such polarization can be achieved by activating the Toll-like receptor 3 (TLR3)-interferon regulatory factor 3 (IRF3) signaling pathway. However, current VACVs used as oncolytic viruses to date still encode several immune evasion proteins involved in the inhibition of this signaling pathway. By inactivating genes of selected regulatory virus proteins, we aimed for a candidate virus with increased potency to activate cellular antitumor immunity but at the same time with a fully maintained replicative capacity in cancer cells. The removal of up to three key genes (C10L, N2L, and C6L) from VACV did not reduce the strength of viral replication, both in vitro and in vivo, but resulted in the rescue of IRF3 phosphorylation upon infection of cancer cells. In syngeneic mouse tumor models, this activation translated to enhanced cytotoxic T lymphocyte (CTL) responses directed against tumor-associated antigens and neo-epitopes and improved antitumor activity., Graphical abstract, The corresponding author and colleagues constructed and tested a replication-competent vaccinia virus with an improved capacity to activate the interferon regulatory factor 3 (IRF3) pathway as a candidate cancer therapeutic, showing increased antitumor immune responses and the ability to destroy tumors in mouse models.

Myeloproliferative disease Enfermedad mieloproliferativa Malaltia mieloproliferativa The study was supported by a research grant by the COVID “3 × 1 project”, BREMBO S.p.A., Bergamo, Italy (T.B.) and by AIRC 5 × 1000 call “Metastatic disease: the key unmet need in oncology” to MYNERVA project, #21267 (MYeloid NEoplasms Research Venture AIRC). A detailed description of the MYNERVA project is available at https://progettomynerva.it (A.M.V., P.G.). The study was also supported by HARMONY PLUS, which is funded through the Innovative Medicines Initiative (IMI), Europe’s largest public–private initiative aiming to speed up the development of better and safer medicines for patients. The HARMONY Alliance has received funding from IMI 2 Joint Undertaking and is listed under grant agreement No. 945406. This Joint Undertaking receives support from the European Union’s Horizon 2020 Research and Innovation Programme and the European Federation of Pharmaceutical Industries and Associations (EFPIA). IMI supports collaborative research projects and builds networks of industrial and academic experts in order to boost pharmaceutical innovation in Europe.

BackgroundAs management and prevention strategies against COVID-19 evolve, it is still uncertain whether prior exposure to immune checkpoint inhibitors (ICIs) affects COVID-19 severity in patients with cancer.MethodsIn a joint analysis of ICI recipients from OnCovid (NCT04393974) and European Society for Medical Oncology (ESMO) CoCARE registries, we assessed severity and mortality from SARS-CoV-2 in vaccinated and unvaccinated patients with cancer and explored whether prior immune-related adverse events (irAEs) influenced outcome from COVID-19.FindingsThe study population consisted of 240 patients diagnosed with COVID-19 between January 2020 and February 2022 exposed to ICI within 3 months prior to COVID-19 diagnosis, with a 30-day case fatality rate (CFR30) of 23.6% (95% CI 17.8 to 30.7%). Overall, 42 (17.5%) were fully vaccinated prior to COVID-19 and experienced decreased CFR30(4.8% vs 28.1%, p=0.0009), hospitalization rate (27.5% vs 63.2%, pOverall, 38 patients (15.8%) experienced at least one irAE of any grade at any time prior to COVID-19, at a median time of 3.2 months (range 0.13–48.7) from COVID-19 diagnosis. IrAEs occurred independently of baseline characteristics except for primary tumor (p=0.0373) and were associated with a significantly decreased CFR30(10.8% vs 26.0%, p=0.0462) additionally confirmed by the IPTW-fitted multivariable analysis (aOR 0.47, 95% CI 0.33 to 0.67). Patients who experienced irAEs also presented a higher median absolute lymphocyte count at COVID-19 (1.4 vs 0.8 109 cells/L, p=0.0098).ConclusionAnti-SARS-CoV-2 vaccination reduces morbidity and mortality from COVID-19 in ICI recipients. History of irAEs might identify patients with pre-existing protection from COVID-19, warranting further investigation of adaptive immune determinants of protection from SARS-CoV-2.

BackgroundVaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are highly effective. Nevertheless, immunocompromised participants were excluded from randomized controlled clinical trials. This study evaluates the efficacy and safety of the Pfizer/BioNTech BNT162b2 (BNT162b2) vaccine in patients with breast and gynecological cancer treated with active anticancer therapy versus a control cohort of healthy participants.MethodsImmune responses to the BNT162b2 vaccine in patients with breast cancer (n = 44) or a gynecological malignancy (n = 6) on active anticancer therapy (28 on chemotherapy, mostly anthracycline- or taxane-based, and 22 on target therapy) and in a control cohort of participants without cancer (n = 67) were investigated by SARS-CoV-2 neutralizing antibody titers measured by S1-binding immunoglobulin G (IgG) concentrations assessed using the LIAISON XL tools (DiaSorin S.p.A.). Response was assessed after a second dose of the BNT162b2 vaccine administered before and at least 3 weeks after the vaccine dose.ResultsOverall, 43/50 (86%) patients of the cancer cohort (74% in the breast cancer group and 100% in the gynecological malignancy group) developed IgG antibodies after the second dose of the BNT162b2 vaccine. There were no statistically significant differences in responder rates between patients treated with chemotherapy and those on target therapy. The majority of patients who received chemotherapy with or without target therapy, 21/28 (75%), developed a reliable antibody titer after a vaccine. All seven non-responder patients were undergoing an anthracycline-based regimen. Based on IgG levels (0–400 AU/ml), patients were classified as negative (‘non-responders’), weakly positive, or strongly positive (‘responders’). No delay in cancer therapy schedule or reported side effects were recorded after BNT162b2 vaccine administration. All healthy participants were strongly positive. Responder rates differed significantly between the two study cohorts (p < 0.001).ConclusionsMost patients develop antibody titers after the second immunization. However, given the persistence of non-responders or weak responders, additional immunization booster seems to be required, along with proactive planning in the vaccination schedule, with vaccine administration spaced out over time with respect to chemotherapy.

Additional support from ISGlobal’s Antoni Plasència and Josep M. Antó, Circulation of the Omicron BA.5 subvariant has led to a considerable increase in cases and also in hospitalisations (but not severe cases or deaths) in recent weeks in Catalonia, the rest of Spain and many other countries. Based on scientific evidence and the current epidemiological situation, the Multidisciplinary Collaborative Group for the Scientific Monitoring of COVID-19 (GCMSC) has conducted an analysis of the impact of the BA-5 subvariant in Catalonia and, with the support of the COVID-19 Scientific Advisory Committee (CCAC) attached to the Department of Health of the Government of Catalonia, has issued a series of recommendations for booster vaccination strategies.

The recent emergence of multiple SARS-CoV-2 variants has caused considerable concern due to reduced vaccine efficacy and escape from neutralizing antibody therapeutics. It is therefore paramount to develop therapeutic strategies that inhibit all known and future SARS-CoV-2 variants. Here we report that all SARS-CoV-2 variants analyzed, including variants of concern (VOC) Alpha, Beta, Gamma, and Delta, exhibit enhanced binding affinity to clinical grade and phase 2 tested recombinant human soluble ACE2 (APN01). Importantly, soluble ACE2 neutralized infection of VeroE6 cells and human lung epithelial cells by multiple VOC strains with markedly enhanced potency when compared to reference SARS-CoV-2 isolates. Effective inhibition of infections with SARS-CoV-2 variants was validated and confirmed in two independent laboratories. These data show that SARS-CoV-2 variants that have emerged around the world, including current VOC and several variants of interest, can be inhibited by soluble ACE2, providing proof of principle of a pan-SARS-CoV-2 therapeutic.

La COVID-19 és la malaltia causada pel virus SARS-CoV-2 el qual és responsable l’actual pandèmia. Malgrat els països del primer món aparentment han superat l’emergència sanitària que ha comportat la malaltia en qüestió, els països en vies de desenvolupament encara estan patint la malaltia i les seves conseqüències socioeconòmiques. Per tant, per tal d’acabar amb la transmissió del virus i prevenir mutacions d’aquest que podrien comprometre l’efectivitat de les actuals vacunes, cal que la humanitat proporcioni vacunes i tests de diagnosi de la malaltia a aquests països. La biotecnologia vegetal ofereix una solució adequada per a complir aquest objectiu: a més de proporcionar sistemes de baix cost i escalabilitat, els antígens del SARS-CoV-2 es poden emmagatzemar in planta sense el requisit d’una cadena de fred. Degut a aquests avantatges, moltes empreses han invertit en el desenvolupament de vacunes contra el SARS-CoV-2 produïdes en plantes. La primera vacuna comercial contra la COVID-19 fabricada en plantes es va produir mitjançant expressió transitòria en Nicotiana benthamiana, de la família del tabac, per la farmacèutica canadenca Medicago Inc. Aquesta vacuna rebé l’aprovació del govern del Canadà al febrer de 2022. A més a més, s’ha dut a terme una recerca extensiva en la matèria, la qual ha demostrat que els antígens del SARS-CoV-2 fabricats en plantes poden ser produïts eficient i econòmicament. Diversos experiments in vitro i in vivo han demostrat una activitat d’unió a la cèl·lula hoste dels antígens produïts en plantes comparable als antígens produïts en mamífers i són capaços de induir immunogenicitat. Així doncs, els sistemes d’expressió vegetals proporcionen una opció viable i rentable per als països en vies de desenvolupament.

Introducción: Las vacunas pertenecen al primer nivel de prevención, siendo una de las estrategias más efectivas de reducir los casos de morbi-mortalidad de enfermedades infecciosas. Para poder proporcionar todas las vacunas a la población se han establecido unos calendarios vacunales específicos de cada país. En España existen calendarios acelerados para la población inmigrante que no dispone de carnet vacunal o no haber sido vacunados en su país. Sin embargo, existen problemas en la armonización del calendario vacunal. La función de enfermería en este proceso es fundamental. Objetivos: Crear un protocolo de conciliación vacunal para población inmigrante atendida en centros de atención primaria de Cataluña. Metodología: Se ha realizado una búsqueda bibliográfica en base de datos como Web of Science, Pubmed. Además, se ha hecho una búsqueda en las páginas de ministerio de sanidad de los países tratados para identificar los calendarios vacunales. Resultados: Se ha diseñado un protocolo basado en la literatura reciente sobre la conciliación vacunal para la población inmigrante en España. Este protocolo es de aplicación en los centros de Atención primaria, para población pediátrica y adulta. Es importante destacar que el calendario vacunal no es algo establecido, es decir, se cambia anualmente, por lo que se tiene que ir actualizando el protocolo. Conclusiones: Es importante la creación de este protocolo, ya que facilitará el proceso de vacunación a población inmigrante que acude a la consulta de atención primaria, armonizando el calendario de origen con el del país de acogida. De esta forma se mejorará el nivel de inmunidad frente a enfermedades infecciosas en la población adulta y pediátrica. Introducció: Les vacunes pertanyen al primer nivell de prevenció, sent una de les estratègies més efectives de reduir els casos de morbiditat i mortalitat de les malalties infeccioses. Per a poder proporcionar totes les vacunes a la població s'han establert uns calendaris vacunals específics de cada país. A Espanya existeixen calendaris accelerats per a la població immigrant que no disposa de carnet vacunal o no haver estat vacunats al seu país. No obstant això, existeixen problemes en l'harmonització del calendari vacunal. La funció d'infermeria en aquest procés és fonamental. Objectius: Crear un protocol de conciliació vacunal per a població immigrant atesa en centres d'atenció primària de Catalunya. Metodologia: S'ha realitzat una cerca bibliogràfica en base de dades com a Web of Science, Pubmed. A més, s'ha fet una cerca en les pàgines de ministeri de sanitat dels països tractats per a identificar els calendaris vacunals. Resultats: S'ha dissenyat un protocol basat en la literatura recent sobre la conciliació vacunal per a la població immigrant a Espanya. Aquest protocol és aplicable en els centres d'Atenció primària, per a població pediàtrica i adulta. És important destacar que el calendari vacunal no és una cosa establerta, és a dir, es canvia anualment, per la qual cosa s'ha d'anar actualitzant el protocol. Conclusions: És important la creació d'aquest protocol, ja que facilitarà el procés de vacunació a població immigrant que acudeix a la consulta d'atenció primària, harmonitzant el calendari d'origen amb el del país d'acolliment. D'aquesta manera es millorarà el nivell d'immunitat enfront de malalties infeccioses en la població adulta i pediàtrica. Introduction: Vaccines belong to the first level of prevention, being one of the most effective strategies to reduce morbidity and mortality from infectious diseases. In order to provide all vaccines to the population, specific vaccination schedules have been established for each country. In Spain there are accelerated schedules for the immigrant population that does not have a vaccination card or has not been vaccinated in their country. However, there are problems in the harmonisation of the vaccination schedule. The role of nurses in this process is fundamental. Objectives: To create a vaccination reconciliation protocol for the immigrant population attending primary care centres in Catalonia. Methodology: A bibliographic search was carried out in databases such as Web of Science and Pubmed. In addition, a search was carried out on the pages of the health ministries of the countries concerned to identify the vaccination schedules. Results: A protocol has been designed based on recent literature on vaccine reconciliation for the immigrant population in Spain. This protocol is applicable in primary care centres, for paediatric and adult populations. It is important to note that the vaccination schedule is not established, it is changed annually, so the protocol needs to be updated. Conclusions: The creation of this protocol is important, as it will facilitate the vaccination process for the immigrant population attending primary care consultations, harmonising the calendar of origin with that of the host country. This will improve the level of immunity against infectious diseases in the adult and paediatric population.

The rapid spread of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) emerging variants raises concerns about their capacity to evade immune protection provided by natural infection or vaccination. The receptor-binding domain (RBD) of the viral spike protein is the major target of neutralizing antibodies, and viral variants accumulate mutations in this region. In this study, we determined the antibody neutralization capacity against the RBD of SARS-CoV-2 variants Alpha (B.1.1.7), Gamma (P.1), Epsilon (B.1.427), Kappa (B.1.617.1), and Delta (B.1.617.2) in a cohort of healthcare workers naturally infected or receiving COVID-19 mRNA vaccines from Moderna or Pfizer-BioNTech. We show that the five RBD variants displayed an augmented binding to ACE2 compared to the original Wuhan strain. The most significant increase was observed in variants Epsilon and Delta, containing mutation L452R. Using a flow cytometry cell-based assay, we found that SARS-CoV-2-infected subjects presented low levels of RBD-specific neutralizing antibodies against all variants analyzed, except Alpha. However, the neutralizing activity incremented considerably after a subsequent mRNA-vaccine dose, to levels significantly higher than those in naïve individuals receiving two vaccine doses. Importantly, we observed partially impaired neutralizing responses against most variants in fully vaccinated individuals. Variants Gamma and Kappa encompassing RBD E484K/Q mutations presented the highest neutralizing resistance. Furthermore, a wide heterogeneity in the magnitude of RBD-specific neutralizing responses against all tested SARS-CoV-2 variants following both mRNA vaccines was detected. Altogether, our findings provide important knowledge regarding SARS-CoV-2 vaccine-induced immunity, and should be very useful to guide future vaccination regimens and personalized vaccine approaches.

Background: The BCN02-trial combined therapeutic vaccination with a viral latency reversing agent (romidepsin, RMD) in HIV-1-infected individuals and included a monitored antiretroviral pause (MAP) as an efficacy read-out identifying individuals with an early or late (< or > 4weeks) viral-rebound. Integrated -omics analyses were applied prior treatment interruption to identify markers of virus control during MAP. Methods: PBMC, whole-genome DNA methylation and transcriptomics were assessed in 14 BCN02 participants, including 8 Early and 4 Late viral-rebound individuals. Chromatin state, histone marks and integration analysis (histone-3 acetylation (H3Ac), viral load, proviral levels and HIV-specific T cells responses) were included. REDUC-trial samples (n = 5) were included as a control group for RMD administration alone. Findings: DNA methylation imprints after receiving the complete intervention discriminated Early versus Late viral-rebound individuals before MAP. Also, differential chromatin accessibility and histone marks at DNA methylation level were detected. Importantly, the differential DNA methylation positions (DMPs) between Early and Late rebounders before MAP were strongly associated with viral load, proviral levels as well as the HIV-specific T-cell responses. Most of these DMPs were already present prior to the intervention and accentuated after RMD infusion. Interpretation: This study identifies host DNA methylation profiles and epigenetic cascades that are predictive of subsequent virus control in a kick-and-kill HIV cure strategy. Funding: European Union Horizon 2020 Framework Programme for Research and Innovation under Grant Agreement N°681137-EAVI2020 and N°847943-MISTRAL, the Ministerio de Ciencia e Innovación (SAF2017_89726_R), and the National Institutes of Health–National Institute of Allergy and Infectious Diseases Program Grant P01-AI131568.

La administración de dosis de refuerzo con vacuna distinta a la utilizada para la primovacunación es segura y la persona vacunada queda mejor protegida.

La tuberculosi (TB) és una malaltia infecciosa causada per diferents membres del complex Mycobacterium tuberculosis (MTBC), que pot afectar un ampli ventall d'hostes, inclosos els éssers humans i diferents espècies d'animals domèstics i salvatges. La TB continua sent un problema important de salut animal amb un elevat impacte econòmic a tot el món. En animals domèstics, com ara les cabres, els programes de control de la tuberculosi basats en la prova i el sacrifici dels animals positius no sempre són factibles. Per tant, en les últimes dècades s'ha renovat l'interès en la investigació sobre la vacunació contra la tuberculosi i les proves diagnòstiques associades a la vacuna per al control de la malaltia en els animals. En aquest sentit, la present tesi aporta informació sobre l'eficàcia de diferents estratègies de vacunació contra la TB caprina i les proves diagnòstiques associades a la vacuna en cabres. En el primer estudi es va avaluar l'eficàcia en el camp de la vacunació a llarg termini de cabres amb la vacuna atenuada viva Mycobacterium bovis Bacil Calmette-Guérin (BCG) (soca danesa 1331) en cinc granges caprines amb diferents característiques i maneig. La vacunació sistemàtica de cabrits per a la reposició amb BCG va contribuir a una reducció progressiva de la incidència i de la prevalença de TB en els ramats de cabres. El segon estudi va tractar la durada de les respostes immunes induïdes per la BCG en cabres i l'eficàcia de la vacunació i revacunació amb BCG al cap d'un any. La durada de les respostes immunes induïdes per la vacunació amb BCG va ser inferior a un any i no va conferir una protecció significativa després del desafiament experimental amb M. Caprae, ans el contrari, la revacunació amb BCG després d'un any de la primera vacunació va proporcionar una millor protecció contra la infecció amb M. caprae. En el tercer estudi es va avaluar l'eficàcia d'un candidat vacunal basat en Mycobacterium bovis inactivat per calor (HIMB) en cabres desafiades experimentalment amb M. caprae. La vacunació parenteral amb HIMB va conferir una protecció similar a la vacunació parenteral amb BCG, obrint el camí per a la seva avaluació en condicions de camp. En el quart estudi es va avaluar el complex antigènic P22 (obtingut per immunopurificació de la tuberculina del M. bovis) com a eina per al diagnòstic immunològic (humoral i mediat per cèl·lules) de la TB en cabres. L'estudi es va dur a terme en diferents contextos de vacunació: vacunació amb BCG i contra la paratuberculosi (Mycobacterium avium subesp. paratuberculosis - MAP) i vacuna MAP sola. En animals vacunats amb BCG i MAP, la interpretació combinada del diagnòstic serològic mitjançant P22 i proves cutànies va resultar en una bona estratègia de diagnòstic de la TB en termes d'especificitat i sensibilitat. En tots els estudis de la present tesi, el còctel d'antigen basat en les proteïnes ESAT-6 i CFP-10, aplicat per a l'assaig d'alliberament d'interferó-gamma, es va utilitzar per diferenciar els animals infectats dels vacunats (DIVA). No es va detectar cap reacció d'interferència diagnòstica en els animals vacunats i revacunats amb BCG ,ni en cabres vacunades amb HIMB, fet que confirma la idoneïtat del còctel antigènic ESAT-6 i CFP-10 com a prova diagnòstica DIVA. En síntesi, les troballes de la present tesi encoratgen a l'ús de vacunes contra la TB i de les proves diagnòstiques associades a la vacunació com a estratègia útil per al control de la TB en cabres. La tuberculosis (TB) es una enfermedad infecciosa causada por diferentes miembros del complejo Mycobacterium tuberculosis (MTBC), la cual puede afectar a una amplia variedad de huéspedes, incluidos los seres humanos y diferentes especies de animales domésticos y salvajes. La TB sigue siendo un importante problema de salud animal con un alto impacto económico en todo el mundo. En los animales domésticos, como por ejemplo las cabras, los programas de control de la TB basados en la prueba y el sacrificio de los animales positivos no siempre se pueden llevar a cabo. Por este motivo, durante las últimas décadas se ha renovado el interés por la investigación sobre la vacunación antituberculosa y las pruebas de diagnóstico asociadas a la vacuna para el control de la TB animal. En este sentido, la presente tesis aporta información sobre la eficacia de diferentes estrategias de vacunación contra la tuberculosis en cabras y las pruebas de diagnóstico asociadas a la vacuna en esta especie. El primer estudio evaluó la eficacia en el campo de una vacunación a largo plazo de cabras con la vacuna viva atenuada de Mycobacterium bovis Bacilo Calmette-Guérin (BCG) (cepa danesa 1331) en cinco granjas de cabras con diferentes características y manejo. La vacunación sistemática de cabritos de la reposición con BCG contribuyó a una reducción progresiva de la incidencia y de la prevalencia de la TB en los rebaños de cabras. El segundo estudio abordó la duración de las respuestas inmunes provocadas por la BCG en cabras, así como la eficacia de la vacunación y revacunación con BCG después de un año. La duración de la respuesta inmunitaria inducida por la vacunación con BCG fue inferior a un año y no confirió una protección significativa frente a la infección experimental con M. caprae. Por el contrario, la revacunación con BCG después de un año de la primera vacunación proporcionó una mejor protección contra el desafío con M. caprae. En el tercer estudio se evaluó la eficacia de un candidato vacunal basado en Mycobacterium bovis inactivado por calor (HIMB) en cabras desafiadas experimentalmente con M. caprae. La vacunación parenteral con HIMB mostró una protección similar a la conferida por la vacuna BCG parenteral. Estos hallazgos abren el camino para su evaluación en condiciones de campo. El cuarto estudio evaluó el desempeño del complejo antigénico P22 (obtenido por inmunopurificación de la tuberculina de M. bovis) para el inmunodiagnóstico (serológico y mediado por células) de la TB en cabras. Este estudio se llevó a cabo en diferentes contextos de vacunación: vacuna BCG y vacuna contra la paratuberculosis (Mycobacterium avium subesp. paratubercuclosis - MAP) y vacunación contra MAP sola. En animales vacunados con BCG y MAP, la interpretación combinada del diagnóstico serológico utilizando P22 y pruebas cutáneas fue una estrategia de diagnóstico eficaz en términos de especificidad y sensibilidad. En todos los estudios de la presente tesis se utilizó el cóctel de antígenos basado en las proteínas ESAT-6 y CFP-10, aplicado para el ensayo de liberación de interferón-gamma, para la diferenciación de animales infectados de vacunados (DIVA). No se detectó ninguna reacción de interferencia diagnóstica ni en cabras vacunadas ni revacunadas con BCG, así como tampoco en cabras vacunadas con HIMB, lo que confirma la idoneidad del cóctel antigénico ESAT-6 y CFP-10 como prueba de diagnóstico DIVA. Los hallazgos generales de la presente tesis apoyan el uso de vacunas contra la tuberculosis y de las pruebas de diagnóstico asociadas a la vacunación como una estrategia útil para el control de la TB en cabras. Tuberculosis (TB) is an infectious disease caused by different members of the Mycobacterium tuberculosis complex (MTBC) which can affect a wide range of hosts, including different species of domestic and wild animals and humans. TB is still an important animal health issue with a high economic impact worldwide. In domestic animals, such as goats, TB control programs based on test-and-slaughter of positives are not always feasible. Therefore, the interest in the research on TB vaccination and vaccine-associated diagnostic tests for the disease control in animals has been renewed. In this regard, the present thesis provided insights into the efficacy of different vaccination strategies against caprine TB and vaccine-associated diagnostic tests in goats. The first study evaluated the efficacy in the field of a long-term vaccination of goats with the live-attenuated Bacilli Calmette-Guérin (BCG) vaccine (Danish 1331 strain) in five goat farms with different characteristics and management. The systematic vaccination of replacement goat kids with BCG contributed to a progressive reduction of TB incidence and prevalence in goat herds. The second study addressed the duration of immune responses elicited by BCG in goats and the efficacy of BCG vaccination and revaccination after one year. The lifespan of immune responses evoked by BCG vaccination was lower than one year and did not confer significant protection after M. caprae experimental challenge. On the contrary, BCG revaccination after one year of first vaccination provided better protection against M. caprae challenge. The third study evaluated the efficacy of the Heat-Inactivated Mycobacterium bovis (HIMB) vaccine candidate in experimentally M. caprae infected goats. Parenteral vaccination with HIMB showed similar protection to parenteral BCG vaccination, paving the way for its evaluation under field conditions. The fourth study assessed the performance of the antigen complex P22 (obtained by immunopurification of M. bovis tuberculin) for cell-mediated and serological immunodiagnosis of TB in goats under different vaccination contexts: BCG and Mycobacterium avium subesp. paratuberculosis (MAP) vaccination and MAP vaccination alone. In BCG and MAP vaccinated animals, combined interpretation of serological diagnostic using P22 and skin tests was a performant TB diagnostic strategy in terms of specificity and sensitivity. In all studies of the present thesis, the antigen cocktail based on ESAT-6 and CFP-10 proteins, applied for the Interferon-gamma release assay, was used for Differentiating infected from vaccinated animals (DIVA). Any diagnostic interference reaction was detected neither in BCG nor in BCG revaccinated, nor in HIMB vaccinated goats, confirming the suitability of ESAT-6 and CFP-10 antigen cocktail as a DIVA diagnostic test. Overall findings of the present thesis encourage the use of vaccines against TB and the vaccine-associated diagnostic tests as a useful strategy for control of TB in goats.

La tuberculosi (TB) és una malaltia infecciosa causada per diferents membres del complex Mycobacterium tuberculosis (MTBC), que pot afectar un ampli ventall d’hostes, inclosos els éssers humans i diferents espècies d’animals domèstics i salvatges. La TB continua sent un problema important de salut animal amb un elevat impacte econòmic a tot el món. En animals domèstics, com ara les cabres, els programes de control de la tuberculosi basats en la prova i el sacrifici dels animals positius no sempre són factibles. Per tant, en les últimes dècades s’ha renovat l’interès en la investigació sobre la vacunació contra la tuberculosi i les proves diagnòstiques associades a la vacuna per al control de la malaltia en els animals. En aquest sentit, la present tesi aporta informació sobre l’eficàcia de diferents estratègies de vacunació contra la TB caprina i les proves diagnòstiques associades a la vacuna en cabres. En el primer estudi es va avaluar l’eficàcia en el camp de la vacunació a llarg termini de cabres amb la vacuna atenuada viva Mycobacterium bovis Bacil Calmette-Guérin (BCG) (soca danesa 1331) en cinc granges caprines amb diferents característiques i maneig. La vacunació sistemàtica de cabrits per a la reposició amb BCG va contribuir a una reducció progressiva de la incidència i de la prevalença de TB en els ramats de cabres. El segon estudi va tractar la durada de les respostes immunes induïdes per la BCG en cabres i l’eficàcia de la vacunació i revacunació amb BCG al cap d’un any. La durada de les respostes immunes induïdes per la vacunació amb BCG va ser inferior a un any i no va conferir una protecció significativa després del desafiament experimental amb M. Caprae, ans el contrari, la revacunació amb BCG després d’un any de la primera vacunació va proporcionar una millor protecció contra la infecció amb M. caprae. En el tercer estudi es va avaluar l’eficàcia d’un candidat vacunal basat en Mycobacterium bovis inactivat per calor (HIMB) en cabres desafiades experimentalment amb M. caprae. La vacunació parenteral amb HIMB va conferir una protecció similar a la vacunació parenteral amb BCG, obrint el camí per a la seva avaluació en condicions de camp. En el quart estudi es va avaluar el complex antigènic P22 (obtingut per immunopurificació de la tuberculina del M. bovis) com a eina per al diagnòstic immunològic (humoral i mediat per cèl·lules) de la TB en cabres. L’estudi es va dur a terme en diferents contextos de vacunació: vacunació amb BCG i contra la paratuberculosi (Mycobacterium avium subesp. paratuberculosis - MAP) i vacuna MAP sola. En animals vacunats amb BCG i MAP, la interpretació combinada del diagnòstic serològic mitjançant P22 i proves cutànies va resultar en una bona estratègia de diagnòstic de la TB en termes d’especificitat i sensibilitat. En tots els estudis de la present tesi, el còctel d’antigen basat en les proteïnes ESAT-6 i CFP-10, aplicat per a l’assaig d’alliberament d’interferó-gamma, es va utilitzar per diferenciar els animals infectats dels vacunats (DIVA). No es va detectar cap reacció d’interferència diagnòstica en els animals vacunats i revacunats amb BCG ,ni en cabres vacunades amb HIMB, fet que confirma la idoneïtat del còctel antigènic ESAT-6 i CFP-10 com a prova diagnòstica DIVA. En síntesi, les troballes de la present tesi encoratgen a l’ús de vacunes contra la TB i de les proves diagnòstiques associades a la vacunació com a estratègia útil per al control de la TB en cabres. La tuberculosis (TB) es una enfermedad infecciosa causada por diferentes miembros del complejo Mycobacterium tuberculosis (MTBC), la cual puede afectar a una amplia variedad de huéspedes, incluidos los seres humanos y diferentes especies de animales domésticos y salvajes. La TB sigue siendo un importante problema de salud animal con un alto impacto económico en todo el mundo. En los animales domésticos, como por ejemplo las cabras, los programas de control de la TB basados en la prueba y el sacrificio de los animales positivos no siempre se pueden llevar a cabo. Por este motivo, durante las últimas décadas se ha renovado el interés por la investigación sobre la vacunación antituberculosa y las pruebas de diagnóstico asociadas a la vacuna para el control de la TB animal. En este sentido, la presente tesis aporta información sobre la eficacia de diferentes estrategias de vacunación contra la tuberculosis en cabras y las pruebas de diagnóstico asociadas a la vacuna en esta especie. El primer estudio evaluó la eficacia en el campo de una vacunación a largo plazo de cabras con la vacuna viva atenuada de Mycobacterium bovis Bacilo Calmette-Guérin (BCG) (cepa danesa 1331) en cinco granjas de cabras con diferentes características y manejo. La vacunación sistemática de cabritos de la reposición con BCG contribuyó a una reducción progresiva de la incidencia y de la prevalencia de la TB en los rebaños de cabras. El segundo estudio abordó la duración de las respuestas inmunes provocadas por la BCG en cabras, así como la eficacia de la vacunación y revacunación con BCG después de un año. La duración de la respuesta inmunitaria inducida por la vacunación con BCG fue inferior a un año y no confirió una protección significativa frente a la infección experimental con M. caprae. Por el contrario, la revacunación con BCG después de un año de la primera vacunación proporcionó una mejor protección contra el desafío con M. caprae. En el tercer estudio se evaluó la eficacia de un candidato vacunal basado en Mycobacterium bovis inactivado por calor (HIMB) en cabras desafiadas experimentalmente con M. caprae. La vacunación parenteral con HIMB mostró una protección similar a la conferida por la vacuna BCG parenteral. Estos hallazgos abren el camino para su evaluación en condiciones de campo. El cuarto estudio evaluó el desempeño del complejo antigénico P22 (obtenido por inmunopurificación de la tuberculina de M. bovis) para el inmunodiagnóstico (serológico y mediado por células) de la TB en cabras. Este estudio se llevó a cabo en diferentes contextos de vacunación: vacuna BCG y vacuna contra la paratuberculosis (Mycobacterium avium subesp. paratubercuclosis - MAP) y vacunación contra MAP sola. En animales vacunados con BCG y MAP, la interpretación combinada del diagnóstico serológico utilizando P22 y pruebas cutáneas fue una estrategia de diagnóstico eficaz en términos de especificidad y sensibilidad. En todos los estudios de la presente tesis se utilizó el cóctel de antígenos basado en las proteínas ESAT-6 y CFP-10, aplicado para el ensayo de liberación de interferón-gamma, para la diferenciación de animales infectados de vacunados (DIVA). No se detectó ninguna reacción de interferencia diagnóstica ni en cabras vacunadas ni revacunadas con BCG, así como tampoco en cabras vacunadas con HIMB, lo que confirma la idoneidad del cóctel antigénico ESAT-6 y CFP-10 como prueba de diagnóstico DIVA. Los hallazgos generales de la presente tesis apoyan el uso de vacunas contra la tuberculosis y de las pruebas de diagnóstico asociadas a la vacunación como una estrategia útil para el control de la TB en cabras. Tuberculosis (TB) is an infectious disease caused by different members of the Mycobacterium tuberculosis complex (MTBC) which can affect a wide range of hosts, including different species of domestic and wild animals and humans. TB is still an important animal health issue with a high economic impact worldwide. In domestic animals, such as goats, TB control programs based on test-and-slaughter of positives are not always feasible. Therefore, the interest in the research on TB vaccination and vaccine-associated diagnostic tests for the disease control in animals has been renewed. In this regard, the present thesis provided insights into the efficacy of different vaccination strategies against caprine TB and vaccine-associated diagnostic tests in goats. The first study evaluated the efficacy in the field of a long-term vaccination of goats with the live-attenuated Bacilli Calmette-Guérin (BCG) vaccine (Danish 1331 strain) in five goat farms with different characteristics and management. The systematic vaccination of replacement goat kids with BCG contributed to a progressive reduction of TB incidence and prevalence in goat herds. The second study addressed the duration of immune responses elicited by BCG in goats and the efficacy of BCG vaccination and revaccination after one year. The lifespan of immune responses evoked by BCG vaccination was lower than one year and did not confer significant protection after M. caprae experimental challenge. On the contrary, BCG revaccination after one year of first vaccination provided better protection against M. caprae challenge. The third study evaluated the efficacy of the Heat-Inactivated Mycobacterium bovis (HIMB) vaccine candidate in experimentally M. caprae infected goats. Parenteral vaccination with HIMB showed similar protection to parenteral BCG vaccination, paving the way for its evaluation under field conditions. The fourth study assessed the performance of the antigen complex P22 (obtained by immunopurification of M. bovis tuberculin) for cell-mediated and serological immunodiagnosis of TB in goats under different vaccination contexts: BCG and Mycobacterium avium subesp. paratuberculosis (MAP) vaccination and MAP vaccination alone. In BCG and MAP vaccinated animals, combined interpretation of serological diagnostic using P22 and skin tests was a performant TB diagnostic strategy in terms of specificity and sensitivity. In all studies of the present thesis, the antigen cocktail based on ESAT-6 and CFP-10 proteins, applied for the Interferon-gamma release assay, was used for Differentiating infected from vaccinated animals (DIVA). Any diagnostic interference reaction was detected neither in BCG nor in BCG revaccinated, nor in HIMB vaccinated goats, confirming the suitability of ESAT-6 and CFP-10 antigen cocktail as a DIVA diagnostic test. Overall findings of the present thesis encourage the use of vaccines against TB and the vaccine-associated diagnostic tests as a useful strategy for control of TB in goats. Universitat Autònoma de Barcelona. Programa de Doctorat en Medicina i Sanitat Animals

Severe COVID-19 disease requiring ICU admission is possible in the fully vaccinated population, especially in those with immunocompromised status and other comorbidities. Interventions to improve vaccine response might be necessary in this population. Peer Reviewed "Article signat per 23 autors/es: Anna Motos, Alexandre López-Gavín, Jordi Riera, Adrián Ceccato, Laia Fernández-Barat, Jesús F. Bermejo-Martin, Ricard Ferrer, David de Gonzalo-Calvo, Rosario Menéndez, Raquel Pérez-Arnal, Dario García-Gasulla, Alejandro Rodriguez, Oscar Peñuelas, José Ángel Lorente, Raquel Almansa, Albert Gabarrus, Judith Marin-Corral, Pilar Ricart, Ferran Roche-Campo, Susana Sancho Chinesta, Lorenzo Socias, Ferran Barbé, Antoni Torres on behalf of the CIBERESUCICOVID Project (COV20/00110, ISCIII)"

Breast milk is a vehicle to transfer protective antibodies from the lactating mother to the neonate. After SARS-CoV-2 infection, virus-specific IgA and IgG have been identified in breast milk, however, there are limited data on the impact of different COVID-19 vaccine types in lactating women. This study is aimed to evaluate the time course of induction of SARS-CoV-2-specific IgA and IgG in breast milk after vaccination., This work was supported by the research grant from LaMarató-TV3 (MilkCORONA, ref. 202106). The funders played no role in the conduct of this work, review, analysis, or interpretation of findings and were not involved in the preparation of this manuscript. We also acknowledge support from the CSIC Open Access Publication Initiative through its Unit of Information Resources for Research (URICI).

Breastfeeding is key for infant development and growth. Breast milk contains different bioactive compounds including antibodies. Recent studies have demonstrated the presence of breast milk SARS-CoV-2 antibodies after maternal infection and vaccination. However, the potential impact on the infant has not been explored yet. As a first step, we aimed at assessing the potential persistence of SARS-CoV-2 IgA and IgG antibodies from infected and vaccinated women in the gastrointestinal tract of the infants by means of an in vitro-simulated gastrointestinal digestion approach. Breast milk samples from 10 lactating women receiving mRNA vaccination against SARS-CoV-2 (n = 5 with BNT162b2 mRNA and n = 5 with mRNA-1273) and also, COVID-19 infected (n = 5) were included. A control group with women with no exposure to the virus (n = 10 pre-pandemic) were also studied. The presence of IgA and IgG SARS-CoV-2 antibody levels was determined by ELISA after the gastric and intestinal stages. The impact of digested antibodies on infant gut microbiota was tested by simulating colonic fermentation with two different fecal inoculums: infants from vaccinated and non-vaccinated mothers. Specific gut microbial groups were tested by targeted qPCR. In vitro infant gastrointestinal digestion significantly decreased the levels of both anti-SARS-CoV-2 IgA and IgG. However, both remained resistant in all the study groups except in that evaluating breast milk samples from infected women, in which IgG was degraded below the cut-off values in the intestinal phase. No effect of the antibodies on microbiota were identified after digestion. In conclusion, antibody levels against SARS-CoV-2 are reduced after in vitro-simulated gastrointestinal tract but remain present, so a positive biological effect could be expected from this infant immunization pathway., This work was supported by the research grant from LaMarató-TV3 (MilkCORONA, No. 31/109/202106). The funders played no role in the conduct of this work, review, analysis or interpretation of findings and were not involved in the preparation of this manuscript.

COVID-19; Encuesta en línea; Resistencia COVID-19; Online survey; Resistance COVID-19; Enquesta en línia; Resistència COVID-19 vaccines are essential to limit and eliminate the infectious disease. This research aims to identify strong vaccination resistance profiles and/or hesitation considering health, psychosocial, and COVID-related variables. A cross-sectional online survey (N = 300) was conducted in the context of strict COVID-related gathering and mobility restrictions (January–March 2021). Data collected were vaccine acceptance, hesitancy and resistance rates, general psychosocial status, and preventive practices and beliefs regarding COVID-19 and its vaccination, among other factors. Logistic regression was applied to a real-world data set and a significant model (χ2 (7, N = 278) = 124.548, p < 0.001) explaining 51.3% (R2 Nagelkerke) of attitudes towards vaccination was obtained, including the following predictors for acceptance: to have greater confidence in the COVID vaccine security (OR = 0.599) and effectiveness (OR = 0.683), older age (OR = 0.952), to be a healthcare professional (OR = 0.363), to have vulnerable individuals in charge (OR = 0.330), and sustain the belief that the vaccine will end the pandemic situation (OR = 0.346) or not being sure but give some credence to that belief (OR = 0.414). Findings could help understand the rate and determinants of COVID-19 vaccine resistance/hesitancy among a Spanish population sample and facilitate multifaceted interventions to enhance vaccine acceptance. This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

We studied changes in serotype distribution and antimicrobial susceptibility in adult pneumococcal pneumonia in Spain (2011-2019). Among 895 pneumococci collected (433 bacteremic [BPP] and 462 non-bacteremic [non-BPP]), serotypes 3 (17%), 19A (10%), 8 (6.7%) and 11A (6.7%) were the most frequent. Serotypes 16F, 19A and 24F were associated with old people (≥65) and serotypes 4, 7F, 8, 12F and 19F to young adults. Serotypes 12F, 24F and 1 were significantly more frequent in BPP and serotypes 11A, 23A and 19F in non-BPP. Amoxicillin resistance was higher in non-BPP (17% vs. 11%) while penicillin non-susceptibility (37% vs. 24%) and macrolide resistance (29% vs. 14%) were higher in older adults. In the period 2017-2019, the vaccine coverages were: 32% (PCV13), 39% (PCV15), 65% (PCV20) and 69% (PPV23). Differences were found in serotype composition and antimicrobial resistance by age and type of infection. The maintenance of serotype 3 as a leading cause of adult pneumococcal pneumonia and the increase in highly invasive (serotype 8) or antimicrobial-resistant (serotype 11A) serotypes is worrisome. Further studies will be required to analyse the impact of the upcoming broader conjugate vaccines. This work was supported by grants from the Fondo de Investigaciones Sanitarias de la Seguridad Social [PI (PI14/00627; PI18/00339, and by CIBER de Enfermedades Respiratorias, CIBERES; [CB06/06/0037], run by the Instituto de Salud Carlos III (ISCIII), Madrid, Spain. Financial support was also provided by the European Regional Development Fund/European Social Fund (ERDF/ESF, “Investing in your future”). We thank CERCA Programme/Generalitat de Catalunya for institutional support. Sí

Vaccines against the severe acute respiratory coronavirus 2, which are the first to be used in humans against any coronavirus, were developed and produced in record time. Dermatologic adverse effects appeared during clinical trials and have also been described in the population since approval. Just as descriptions and categorization of skin manifestations of the coronavirus disease 2019 proved important for understanding the disease itself, characterizing the effects of vaccines may also further that goal. This paper reviews the properties of the different types of vaccines currently available and under development and describes how they interact with the immune system and the clinical signs they may cause. We focus on dermatologic adverse effects reported to date and recommendations for managing them.Las vacunas contra el SARS-CoV-2 son las primeras vacunas que han sido usadas en humanos contra coronavirus y su desarrollo se ha producido en un tiempo récord. En los análisis de seguridad de los ensayos clínicos previos a su aprobación y en la fase postautorización en la población, se han descrito efectos secundarios dermatológicos. La descripción y categorización de las manifestaciones cutáneas de la COVID-19 fueron importantes para el conocimiento de la enfermedad y de la misma forma pueden serlo las generadas por las vacunas. En este artículo hacemos un repaso a las características de los diferentes tipos de vacunas disponibles y en desarrollo, su modo de interacción con el sistema inmune, las consecuentes manifestaciones clínicas que pueden generar, con especial interés en los efectos secundarios dermatológicos hasta el momento descritos, y las actitudes terapéuticas recomendadas ante cada una de estas reacciones.

The COVID-19 pandemic has raised questions among individuals who are breastfeeding, both because of the possibility of viral transmission to infants during breastfeeding and, more recently, of the potential risks and benefits of vaccination in this specific population. Previous studies have reported the presence of anti–SARS-CoV-2 antibodies in breast milk of COVID-19–infected lactating women,1 and recently several studies have demonstrated the passage of postvaccine antibodies through breast milk in women vaccinated with novel mRNA-based vaccines.1,2 In the present study, conducted between February and March 2021 at Parc Sanitari Sant Joan de Deu, an urban hospital in Spain, we sought to characterize the levels of specific SARS-CoV-2 antibodies in the breast milk of mRNA-vaccinated women across time, as well as their correlation with serum antibody levels.

Influenza A virus is one of the most outstanding human viruses. The major treatments against influenza are small analogues, monoclonal antibodies and vaccines, however, due to the fast mutation of the seasonal influenza strain, these methods are easily outdated, so vaccine production and antiviral development need to be in continuous growth and study to improve immunity and fight against influenza disease. The characterization of the viral structure and the identification of the mechanisms of action of newly synthesized antivirals are crucial to develop fast and powerful treatments, nonetheless, due to the small size of viruses, conventional fluorescence techniques are lacking the resolution power to resolve individual viral structures. In this context, super-resolution microscopy has positioned in the last decade as a powerful technique to characterize viral constructs by achieving resolutions up to 10 nm. Here, we have optimized and established a type of super-resolution microscopy technique entitled single-molecule localization microscopy (SMLM) to study viral structures at single-particle level by characterizing several viral structures, antivirals and vaccines. Firstly, we could characterize the filament formation of influenza virus and described how monoclonal antibodies disturbed the development of those filaments, deforming them. Further, we could relate this malformation with an inhibition of the infectivity, suggesting the crucial role of filament formation in the infectivity of influenza. Moreover, we optimized and implemented a novel SMLM called DNA-PAINT in the study of the target distribution and quantification in the nanoscale, validating this method using commercial nanoparticles for its further implementation in the study of the expression of recombinant proteins of influenza and the corresponding virus-like particle produced. In addition, we studied and identified several other viral structures and antivirals interactions using SMLM such as the distribution of Hepatitis B and Hepatitis Delta on paraffin tissues, the interaction of analogues of sialic acid on four strains of influenza and the uptake of nanovaccines from antigen-presenting cells, obtaining features on how these viruses and antivirals interact in order to produce a smart design of antivirals and vaccines, corroborating how SMLM could increase the knowledge of the mechanism of action of viruses.

Therapeutic vaccines based on dendritic cells offer a good approach to HIV-specific T-cell responses and partial control of the viral load after antiretroviral therapy interruption. The aim of the present study was to identify mRNA expression profiles and to assess the impact of the gut microbiome composition for predicting the viral load control after antiretroviral therapy interruption. We enrolled 29 patients to receive either placebo or a monocyte-derived dendritic cell vaccine. Patients with a decrease in their viral load of &gt, 0.5 log10 copies/mL by 12 weeks after antiretroviral therapy interruption were considered responders. In total, 66 genes were considered differentially expressed between responders and non-responders. Enrichment analysis revealed several upregulated pathways involved in the host defense response to a virus via the type I interferon signaling pathway. Regarding the gut microbiota, responders showed enriched levels of Bacteroidetes (p &lt, 0.005) and Verrucomicrobia (p = 0.017), while non-responders were enriched with Tenericutes (p = 0.049) and Actinobacteria (p &lt, 0.005). We also found important differences at the genus level. However, we did not discover any effect of the dendritic cell vaccine on the transcriptome or the gut microbiota. An alternative analysis did characterize that the microbiota from responders were associated with the metabolic production of short-chain fatty acids, which are key metabolites in the regulation of intestinal homeostasis. The evidence now consistently shows that short-chain fatty acid depletion occurs in HIV-infected individuals receiving antiretroviral treatment.

The Ninth Interactive Infectious Disease workshop TIPICO was held on November 22–23, 2018, in Santiago de Compostela, Spain. This 2-day academic experience addressed current and topical issues in the field of infectious diseases and vaccination. Summary findings of the meeting include: cervical cancer elimination will be possible in the future, thanks to the implementation of global vaccination action plans in combination with appropriate screening interventions. The introduction of appropriate immunization programs is key to maintain the success of current effective vaccines such as those against meningococcal disease or rotavirus infection. Additionally, reduced dose schedules might improve the efficiency of some vaccines (i.e., PCV13). New vaccines to improve current preventive alternatives are under development (e.g., against tuberculosis or influenza virus), while others to protect against infectious diseases with no current available vaccines (e.g., enterovirus, parechovirus and flaviviruses) need to be developed. Vaccinomics will be fundamental in this process, while infectomics will allow the application of precision medicine. Further research is also required to understand the impact of heterologous vaccine effects. Finally, vaccination requires education at all levels (individuals, community, healthcare professionals) to ensure its success by helping to overcome major barriers such as vaccine hesitancy and false contraindications FMT and AS research activities received support from the Instituto de Salud Carlos III (Proyecto de Investigación en Salud, Acción Estratégica en Salud): project GePEM ISCIII/PI16/01478/Cofinanciado FEDER, and project ReSVinext ISCIII/PI16/01569/Cofinanciado FEDER; Consellería de Sanidade, Xunta de Galicia (RHI07/2-intensificación actividad investigadora, PS09749 and 10PXIB918184PR), Instituto de Salud Carlos III (Intensificación de la actividad investigadora 2007–2012, PI16/01569), Fondo de Investigación Sanitaria (FIS; PI070069/PI1000540) del plan nacional de I+D+I and ‘fondos FEDER’, and 2016-PG071 Consolidación e Estructuración REDES 2016GI-1344 G3VIP (Grupo Gallego de Genética Vacunas Infecciones y Pediatría, ED341D R2016/021). Research on flaviviruses at the AG-S laboratory is partially funded by NIAID grants R21AI129486, R21AI142337 and U19AI118610 Research on influenza virus vaccines and immunity at the AG-S laboratory is partly funded by NIAID grants U19AI117873, U01AI124297, R01AI127658, P01AI097092, U19AI135972, and R01 AI141226-01, by the Bill and Melinda Gates Foundations (OPP1084518), by a research contract from GSK and by CRIP (Center for Research on Influenza Pathogenesis), an NIAID funded Center of Excellence for Influenza Research and Pathogenesis (CEIRS, contract number HHSN272201400008C) SI

Vaccine hesitancy is considered as one of the leading causes for the resurgence of vaccine preventable diseases. A non-negligible minority of parents does not fully adhere to the recommended vaccination schedule, leading their children to be partially immunized and at higher risk of contracting vaccine preventable diseases. Here, we leverage more than one million comments of 201,986 users posted from March 2008 to April 2019 on the public online forum BabyCenter US to learn more about such parents. For 32% with geographic location, we find the number of mapped users for each US state resembling the census population distribution with good agreement. We employ Natural Language Processing to identify 6884 and 10,131 users expressing their intention of following the recommended and alternative vaccination schedule, respectively RSUs and ASUs. From the analysis of their activity on the forum we find that ASUs have distinctly different interests and previous experiences with vaccination than RSUs. In particular, ASUs are more likely to follow groups focused on alternative medicine, are two times more likely to have experienced adverse events following immunization, and to mention more serious adverse reactions such as seizure or developmental regression. Content analysis of comments shows that the resources most frequently shared by both groups point to governmental domains (.gov). Finally, network analysis shows that RSUs and ASUs communicate between each other (indicating the absence of echo chambers), however with the latter group being more endogamic and favoring interactions with other ASUs. While our findings are limited to the specific platform analyzed, our approach may provide additional insights for the development of campaigns targeting parents on digital platforms., Author summary The importance and effectiveness of vaccines is generally high, but concerns toward vaccination contribute to eroding confidence in vaccination. Recently, alternative vaccination schedules are becoming popular as they allow parents to selectively delay or refuse certain vaccines depending on their specific concerns. Not being expressly anti-vaccination, these parents are challenging to identify on social media, however understanding the determinants of their hesitancy toward vaccines could help addressing parents’ concerns through targeted interventions. In this work, we create a Natural Language Processing pipeline to automatically identify parents who state their adherence to the recommended or alternative vaccination schedule on a popular parenting forum, BabyCenter US. We find that these users have distinct interests and different experiences with vaccination, although they frequently share similar sources of information (e.g., .gov websites). Differently from what is observed on most popular digital platforms like Facebook or Twitter, where users communicate mainly with like-minded users, Babycenter users communicate between each other independently of the vaccination schedule they adopt. These observations suggest that parenting fora may be a more suitable medium to develop intervention aiming to influence positively the vaccination behavior of parents.

Streptococcus pneumoniae serotype 1 (ST1) was an important cause of invasive pneumococcaldisease (IPD) globally before the introduction of pneumococcal conjugate vaccines (PCVs) containingST1 antigen. The Pneumococcal Serotype Replacement and Distribution Estimation (PSERENADE)project gathered ST1 IPD surveillance data from sites globally and aimed to estimatePCV10/13 impact on ST1 IPD incidence. We estimated ST1 IPD incidence rate ratios (IRRs) comparingthe pre‐PCV10/13 period to each post‐PCV10/13 year by site using a Bayesian multi‐level, mixedeffectsPoisson regression and all‐site IRRs using a linear mixed‐effects regression (N = 45 sites).Following PCV10/13 introduction, the incidence rate (IR) of ST1 IPD declined among all ages. Aftersix years of PCV10/13 use, the all‐site IRR was 0.05 (95% credibility interval 0.04–0.06) for all ages,0.05 (0.04–0.05) for &lt, 5 years of age, 0.08 (0.06–0.09) for 5–17 years, 0.06 (0.05–0.08) for 18–49 years,0.06 (0.05–0.07) for 50–64 years, and 0.05 (0.04–0.06) for ≥65 years. PCV10/13 use in infant immunizationprograms was followed by a 95% reduction in ST1 IPD in all ages after approximately 6years. Limited data availability from the highest ST1 disease burden countries using a 3+0 scheduleconstrains generalizability and data from these settings are needed.

Vaccination is the most effective method to date to prevent viral diseases. It intends to mimic a naturally occurring infection while avoiding the disease, exposing our bodies to viral antigens to trigger an immune response that will protect us from future infections. Among different strategies for vaccine development, recombinant vaccines are one of the most efficient ones. Recombinant vaccines use safe viral vectors as vehicles and incorporate a transgenic antigen of the pathogen against which we intend to generate an immune response. These vaccines can be based on replication-deficient viruses or replication-competent viruses. While the most effective strategy involves replication-competent viruses, they must be attenuated to prevent any health hazard while guaranteeing a strong humoral and cellular immune response. Several attenuation strategies for adenoviral-based vaccine development have been contemplated over time. In this paper, we will review them and discuss novel approaches based on the principle that protein synthesis from individual genes can be modulated by codon usage bias manipulation. We will summarize vaccine approaches that consider recoding of viral proteins to produce adenoviral attenuation and recoding of the transgene antigens for both viral attenuation and efficient viral epitope expression.

VPH; Pichia pastoris; Purificación VPH; Pichia pastoris; Purificació HPV; Pichia pastoris; Purification Currently, three human papillomavirus (HPV) vaccines are already licensed and all of them are based on virus-like particles (VLPs) of HPV L1 capsid protein but not worldwide accessible. While about 38.0 million people were living with HIV in 2019, only 68% of HIV-infected individuals were accessing antiretroviral therapy as of the end of June 2020 and there is no HIV vaccine yet. Therefore, safe, effective, and affordable vaccines against those two viruses are immediately needed. Both HPV and HIV are sexually transmitted infections and one of the main access routes is the mucosal genital tract. Thus, the development of a combined vaccine that would protect against HPV and HIV infections is a logical effort in the fight against these two major global pathogens. In this study, a recombinant Pichia pastoris producing chimeric HPV-HIV L1P18 protein intracellularly was constructed. After cell disruption, the supernatant was collected, and the VLPs were purified by a combination of ammonium sulfate precipitation, size exclusion chromatography, ultracentrifugation, and ultrafiltration. At the end of purification process, the chimeric VLPs were recovered with 96% purity and 9.23% overall yield, and the morphology of VLPs were confirmed by transmission electron microscopy. This work contributes towards the development of an alternative platform for production of a bivalent vaccine against HPV and HIV in P. pastoris. This project has received funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement No. 681137. In addition, we acknowledge support by Instituto de Salud Carlos III (RETIC-RIS RD12/0017, FIS PI14/00494, and FIS PI20/00217), Direcció General de Recerca i Innovació en Salut (DGRIS), Catalan Health Ministry Generalitat de Catalunya, and Centro para el Desarrollo Tecnológico Industrial (CDTI) from the Spanish Ministry of Economy and Business, grant number IDI-20200297.

(1) Background: In epidemiological terms, it has been possible to calculate the savings in health resources and the reduction in the health effects of COVID vaccines. Conducting an economic evaluation, some studies have estimated its cost-effectiveness; the vaccination shows highly favorable results, cost-saving in some cases. (2) Methods: Cost–benefit analysis of the vaccination campaign in the North Metropolitan Health Region (Catalonia). An epidemiological model based on observational data and before and after comparison is used. The information on the doses used and the assigned resources (conventional hospital beds, ICU, number of tests) was extracted from administrative data from the largest primary care provider in the region (Catalan Institute of Health). A distinction was made between the social perspective and the health system. (3) Results: the costs of vaccination are estimated at 137 million euros (€48.05/dose administered). This figure is significantly lower than the positive impacts of the vaccination campaign, which are estimated at 470 million euros (€164/dose administered). Of these, 18% corresponds to the reduction in ICU discharges, 16% to the reduction in conventional hospital discharges, 5% to the reduction in PCR tests and 1% to the reduction in RAT tests. The monetization of deaths and cases that avoid sequelae account for 53% and 5% of total savings, respectively. The benefit/cost ratio is estimated at 3.4 from a social perspective and 1.4 from a health system perspective. The social benefits of vaccination are estimated at €116.67 per vaccine dose (€19.93 from the perspective of the health system). (4) Conclusions: The mass vaccination campaign against COVID is cost-saving. From a social perspective, most of these savings come from the monetization of the reduction in mortality and cases with sequelae, although the intervention is equally widely cost-effective from the health system perspective thanks to the reduction in the use of resources. It is concluded that, from an economic perspective, the vaccination campaign has high social returns.

Introducció : A dia d’avui la vacunació és una de les eines més efectives de prevenció de malalties. Les vacunes ens han ajudat a reduir la incidència de moltes malalties i fins i tot en alguns casos han aconseguit eradicar-les. Cal destacar també, que la majoria deles vacunes estan incloses dins del calendari de vacunacions sistemàtiques i que s’ofereixen de forma gratuïta i universal a tota la població. A priori tot semblen avantatges, però malgrat tots aquests beneficis, s’ha observat com durant l’última dècada han augmentat els brots de malalties prevenibles, com el xarampió, la diftèria o la tos ferina a causa de la reticència d'alguns pares a la vacunació. N’és un bon exemple el cas del nen de sis anys d’Olot que va morir a causa de la diftèria i que si hagués estat vacunat s’hauria pogut evitar. Objectius: A conseqüència d’aquests brots no desitjats, s’ha vist com ha augmentat l’interès de la població en general i especialment dels professionals de la salut, per tal d’esbrinar quines són les causes que fan que hi hagi una part de la població que rebutgi o dubti sobre la vacunació. L’objectiu principal d’aquest estudi és conèixer quina és la opinió que tenen els pares envers la vacunació sistemàtica de la infància i en conseqüència esbrinar quins són els motius de la reticència. Juntament amb altres objectius específics sobre l'atenció sanitària, els coneixements generals sobre vacunes i les fonts d'informació. Metodologia: L'instrument de mesura utilitzat és un qüestionari amb preguntes tancades que avalua els coneixements i actituds dels pares respecte les vacunes.Es tracta d'explorar a través d'aquesta eina quina és la opinió que tenen els pares sobre la vacunació, a fi de poder entendre millor quines són les seves preocupacions i necessitats. Conclusions: La reticència vacunal és un concepte complex i no existeix col.lectiu clarament definit, els dubtes vacunals van de menor a major grau. Els pares necessiten rebre informació actual i contrastada per part dels professionals de salut i és necessari ajudar a les famílies a entendre la importància de rebre les vacunes. Atès que les persones que rebutgen o retarden la vacunació, suposen un risc tant per si mateixes com per els seus fills i de forma paral·lela afecten també a la immunització col·lectiva. Introducción: A día de hoy, la vacunación es una de las herramientas más efectivas de prevención de enfermedades. Las vacunas nos han ayudado a reducir la incidencia de muchas enfermedades e incluso en algunos casos han conseguido erradicarlas. Cabe destacar también, que la mayoría de las vacunas están incluidas dentro del calendario de vacunaciones sistemáticas y se ofrecen de forma gratuita y universal a toda la población. A priori todo parecen ventajas, pero a pesar de todos estos beneficios, se ha observado como durante la última década han aumentado los brotes de enfermedades prevenibles, como el sarampión, la difteria o la tos ferina debido a la reticencia de algunos padres a la vacunación. Un buen ejemplo es el caso del niño de seis años de Olot que murió debido a la difteria y que si hubiera sido vacunado se hubiera podido evitar. Objetivos: A consecuencia de estos brotes no deseados, se ha visto como ha aumentado el interés de la población en general y especialmente de los profesionales de la salud, con el fin de averiguar cuáles son las causas que hacen que haya una parte de la población que rechace o dude sobre la vacunación. El objetivo principal de este estudio es conocer cuál es la opinión que tienen los padres hacia la vacunación sistemática de la infancia y en consecuencia averiguar cuáles son los motivos de la reticencia. Junto con otros objetivos específicos sobre la atención sanitaria, los conocimientos generales sobre vacunas y las fuentes de información. Metodología: El instrumento de medida utilizado es un cuestionario con preguntas cerradas que evalúa los conocimientos y actitudes de los padres respecto a las vacunas. Se trata de explorar a través de esta herramienta cuál es la opinión que tienen los padres sobre la vacunación, a fin de poder entender mejor cuáles son sus preocupaciones y necesidades. Conclusiones: La reticencia vacunal es un concepto complejo y no existe colectivo claramente definido, las dudas vacunales van de menor a mayor grado. Los padres necesitan recibir información actual y contrastada por parte de los profesionales de salud y es necesario ayudar a las familias a entender la importancia de la vacunación. Dado que las personas que rechazan o retrasan la vacunación, suponen un riesgo tanto para sí mismas como para sus hijos y de forma paralela afectan también a la inmunización colectiva. Introduction: Vaccination is one of the most effective tools for disease prevention today. Vaccines have helped us reduce the incidence of many diseases and even in some cases have managed to eradicate them. It should also be noted that most vaccines are included in the schedule of systematic vaccinations and are offered free of charge and universally to the entire population. A priori, everything seems to be an advantage, but despite all these benefits, it has been observed that outbreaks of preventable diseases, such as measles, diphtheria or whooping cough, have increased over the last decade due to the reluctance of some parents to vaccination. A good example is the case of a six-year-old boy from Olot who died of diphtheria and who, if he had been vaccinated, could have been prevented. Objectives: As a result of these unwanted outbreaks, it has been seen how the interest of the general population and especially of health professionals has increased, in order to find out what are the causes that make a part of the population that rejects or doubts the vaccination. The main objective of this study is to find out what parents think about the systematic vaccination of children and, consequently, to find out the reasons for the reluctance. Along with other specific goals on health care, general knowledge about vaccines, and sources of information. Methodology: The measuring instrument used is a closed-ended questionnaire that assesses parents' knowledge and attitudes about vaccines.The aim is to explore through this tool what parents think about vaccination, in order to better understand their concerns and needs. Conclusions: Vaccine reluctance is a complex concept and there is no clearly defined collective, vaccine doubts range from lower to higher. Parents need to receive current and verified information from health professionals and it is necessary to help families understand the importance of receiving vaccines. Since people who reject or delay vaccination pose a risk to both themselves and their children and in parallel also affect collective immunization.

Treballs Finals de Grau de Farmàcia, Facultat de Farmàcia i Ciències de l'Alimentació, Universitat de Barcelona, 2021. Tutores: Malen Massot i Margarida Castell, Hepatitis A (HA) is a viral disease caused by the hepatitis A virus (HAV) that occurs all over the world. It is transmitted by the faecal–oral route, and it is known that poor sanitary conditions increase the risk of HAV transmission. As no specific treatment for HA is available, prevention with vaccination strategies is the key to controlling the infection. Most of the available vaccines are inactivated vaccines adjuvanted with aluminium hydroxide. The slow growth of HAV and the need for an adjuvant make the vaccines’ economic cost relatively high and, what is more, there have been periods of vaccine shortages as demand has exceeded the production capacity. Recently, it has been demonstrated that HAV can be found encapsulated in a lipid membrane that resembles exosomes. Exosomes have been suggested to take part in Tcell stimulation and can induce an immune response without the need of an adjuvant. This study includes the preliminary experiments that will conclude with immunization with encapsulated HAV (eHAV) without adjuvant. In particular, herein we set up techniques to check an immunization protocol with HAV particles (with adjuvant) in two mouse strains (BALB/c and C75BL/6). These techniques include the proliferative capacity of spleen lymphocytes (ELISA), the antibody-secreting cells (ELISPOT) and the changes in the cell phenotype (flow cytometry). Although further studies remain to be done, the results obtained in the present study allow the defining of the mouse strain and obtention techniques to establish the immunization process.

[eng] Infectious diseases are one of the main causes of mortality in newborns born in Mozambique. Transplacental transfer of antibodies is essential for conferring protection during the first months of life against these diseases. In this doctoral thesis, we have assessed the impact of maternal HIV infection and malaria during pregnancy on cord blood levels of antibodies and on the efficiency of placental transfer of IgG subclasses. The effect of other maternal factors and pregnancy outcomes has also been assessed. We have measured total IgG and IgG subclass levels in maternal and cord blood by quantitative suspension array technology against (i) pathogens of high burden and health impact in southern Mozambique, including Plasmodium falciparum, and (ii) antigens from vaccines used for maternal immunization and included in the Expanded Program of Immunization. Our results have shown that maternal antibody levels are the main determinants of cord antibody levels and the efficiency of IgG subclass transfer differs depending on the antigen and may vary with maternal antigen exposure. We have associated maternal HIV infection with a reduction in cord blood antibodies and with a decrease in placental transfer, mainly IgG1, against a wide range of pathogens and vaccine antigens. We have also associated malaria exposure with a reduction of cord antibody levels and with a decrease in placental transfer in an antigen-antibody dependent manner. Placental malaria has also been associated with a decrease in total IgG levels in the cord. Finally, we have assessed the effect of prematurity and low birth weight and we have found an association of prematurity with lower levels of total IgG against some antigens. We have not observed any negative effect of low birth weight, although we have found an increase in cord IgG2 levels against P. falciparum antigens that could be associated with a higher risk of severe malaria. In summary, in this thesis we have provided evidence that maternal HIV infection and malaria have negative implications in maternal and infant health, with special importance in sub-Saharan Africa where the prevalence and transmission of these pathogens are high. Our results point out that these infections should be further considered during vaccine development and evaluation, in particular with regards to maternal immunization strategies that are key in public health., [spa] Las enfermedades infecciosas son unas de las causas principales de mortalidad en recién nacidos en Mozambique. La transferencia placentaria de anticuerpos es fundamental para conferir protección durante los primeros meses de vida contra estas enfermedades. En esta tesis doctoral se ha evaluado el impacto de la infección materna por VIH y la malaria durante el embarazo en los niveles de IgG totales y subclases de IgG en el cordón umbilical y en la transferencia placentaria. También se ha estudiado el efecto de otros factores maternos y complicaciones del embarazo. Nuestros resultados muestran que la eficacia de la transferencia de subclases de IgG es diferente según el antígeno y puede variar con la exposición materna a los antígenos. Hemos asociado la infección materna por VIH con una reducción de anticuerpos en el cordón umbilical y con una disminución de la transferencia placentaria, principalmente IgG1, contra una gama amplia de patógenos y antígenos de vacunas. También hemos asociado la exposición a malaria con una reducción en los niveles de anticuerpos en el cordón umbilical y con una disminución de la transferencia placentaria de una manera antígeno-anticuerpo dependiente. Asimismo, la malaria placentaria también se ha asociado con una disminución de los niveles de IgG totales en cordón. Finalmente, hemos evaluado el efecto de la prematuridad y el bajo peso al nacer. Únicamente hemos encontrado una asociación de la prematuridad con menores niveles de IgG totales contra algunos antígenos. Tampoco hemos observado ningún efecto negativo del bajo peso al nacer, aunque sí un aumento de los niveles IgG2 en cordón contra antígenos de P. falciparum que podría estar asociado con mayor riesgo de sufrir malaria severa. En resumen, en esta tesis hemos proporcionado evidencia de que la infección materna por VIH y la malaria tienen implicaciones negativas en la salud maternoinfantil, con especial importancia en África subsahariana donde la prevalencia y transmisión de estos patógenos es alta. Nuestros resultados señalan que estas infecciones deben considerarse más a fondo durante el desarrollo y la evaluación de vacunas, en particular respecto a las estrategias de inmunización materna que son clave para la salud pública.

espanolAntecedentes y objetivos El aumento de la reticencia vacunal amenaza los avances logrados en salud publica y causa brotes de enfermedades inmunoprevenibles en comunidades infra vacunadas. El objetivo de este estudio es explorar y comparar las actitudes y percepciones hacia la vacunacion de los usuarios de farmacia, los estudiantes de farmacia y los farmaceuticos comunitarios. Metodos Se realizo un estudio observacional transversal mediante encuestas sobre las actitudes hacia la vacunacion en la provincia de Barcelona (Espana) durante marzo-abril de 2020. El analisis estadistico se llevo a cabo mediante la prueba χ2 y una regresion multivariable. El nivel de significacion estadistica se considero cuando P Resultados Los resultados obtenidos muestran un 44% de reticencia en la poblacion a pesar de tener una cobertura vacunal del 80%. Se observo desconfianza en el Sistema de Salud (23,3%) y se asocio experiencia negativa previa con la vacunacion y reticencia (OR: 3,04; IC 95% de 1,16 a 7,93; P = 0,02). Del total de encuestados, los mayores de 44 anos mostraron una principal reticencia a las vacunas (OR: 2,63; IC 95% de 1,11 a 6,19; P = 0,03). Un 40% de los encuestados infravaloraron la vacuna antigripal. Los estudiantes de farmacia y los farmaceuticos comunitarios mostraron una actitud positiva hacia la vacunacion. Aunque solo el 14% estaban vacunados contra la gripe, la mayoria considero que su vacunacion es importante. Conclusiones Una promocion activa, educacion poblacional y comunicacion especializada sobre vacunas son algunas de las necesidades que el farmaceutico comunitario puede resolver, reafirmado asi su papel como profesional de la salud altamente calificado en contacto constante con la poblacion. EnglishBackground and objectives The increase in vaccine hesitancy threatens advances in public health and causes vaccine-preventable diseases outbreaks in infra-vaccinated communities. This study aims to determine and compare the perception and attitudes towards vaccination among pharmacy users, pharmacy students and community pharmacists. Methods A cross-sectional observational study was conducted during March and April 2020, surveying perceptions and attitudes towards vaccination in Barcelona (Spain). Statistical analysis was assessed by chi2 test and multivariate regression. Statistical significance when P Results A high percentage of hesitant opinions (44%) among pharmacy users was observed, despite high vaccine coverage (80%). Some showed mistrust in the health system (23.3%) and a statistically significant association was found between previous negative experiences with vaccination and hesitant attitudes (OR: 3.04; 95%CI 1.16 to 7.93; P = .02). Of all surveyed pharmacy users, those over 44 years old showed a stronger hesitant attitude towards vaccines (OR: 2.63; 95%CI 1.11 to 6.19; P = .03), and 40% undervalued influenza vaccine, including risk groups. Both pharmacy students and community pharmacists had a positive attitude towards vaccination. While only 16% of surveyed pharmacists vaccinated against influenza during the 2019/2020 influenza seasonal campaign, most of them considered their vaccination important to the profession (61%). Conclusions Active promotion and education of the population and reliable communication on vaccines are some of the needs that community pharmacists can solve, claiming their role as highly qualified health professionals in daily contact with the population.

Migration to the European Union (EU)/European Economic Area (EEA) affects the epidemiology of infectious diseases, including tuberculosis (TB), HIV, hepatitis B/C, and parasitic diseases. Some sub-populations of migrants are also considered to be an under-immunised group and thus at risk of vaccine-preventable diseases. Providing high-risk migrants access to timely and efficacious screening and vaccination, and understanding how best to implement more integrated screening and vaccination programmes into European health systems ensuring linkage to care and treatment, is key to improving the health of migrants and their communities, alongside meeting national and regional targets for infection surveillance, control, and elimination. The European Centre for Disease Prevention and Control (ECDC) has responded to calls to action to improve migrant health and strengthen universal health coverage by developing evidence-based guidance for policy makers, public health experts, and front-line healthcare professionals on how to approach screening and vaccination in newly arrived migrants within the EU/EEA. In this Commentary, we provide a perspective towards developing efficacious screening and vaccination of newly arrived migrants, with a focus on defining implementation challenges and evidence gaps in high-migrant receiving EU/EEA countries. There is a need now to leverage the increasing momentum around migrant health to both strengthen the evidence-base and to advocate for universal access to health care for all migrants in the EU/ EEA, including undocumented migrants. This should include voluntary, confidential, and non-stigmatising screening and vaccination that should be free of charge and facilitate linkage to appropriate care and treatment.

S'ofereix un recull d'actuacions dutes a terme el 2020 per les institucions i organismes europeus, com a resposta a una crisi sense precedentes.El treball es divideix en dues parts. La primera, presenta una visió general en els diversos àmbits i s'adreça a tots els públics. La segona, composta per documentació de referència i webs, s'orienta cap a un públic especialitzat que es proposi aprofundir en la matèria.

Laboratoris Hipra és una empresa familiar que ha aconseguit posicionar-se entre les 20 empreses que més facturen del món en el sector farmacèutic en prevenció de Salut Animal. Aquesta companyia és cada cop més visible als mitjans de comunicació per les inversions noves instal·lacions i també a les borses de treball on cerquen personal especialitzat que posa de manifest la voluntat de l'empresa de créixer i assolir objectius més ambiciosos. Aquest estudi explica aquells aspectes que han sigut i continuen sent determinants en aquest procés de creixement que està experimentant Laboratoris Hipra en un sector dominat per grans empreses multinacionals. L'encert estratègic concretat en l'especialització de vacunes per animals de producció a través de potenciar la investigació, el control de totes les fases de la cadena de valor i l'expansió internacional són fonamentals per comprendre l'evolució de l'empresa, com també ho és la responsabilitat social i ètica amb què opera, i l'equilibri econòmic i financer que es desprèn de l'anàlisi dels comptes anuals del període analitzat (2015-2019) i la seva comparació sectorial. En base a l'anàlisi intern i extern de l'empresa, se n'extreuen unes conclusions i recomanacions futures. Presteu molta atenció a la gran finestra d'oportunitat que se li presenta a Laboratoris Hipra amb la situació pandèmica de la COVID-19. Laboratoris Hipra is a family business that has managed to position itself among the 20 companies with the highest turnover in the world in the pharmaceutical sector in animal health prevention. This company is increasingly visible in the media for its investment in new facilities and also in the job market, headhunting skilled staff, which shows the company¿s desire to grow and achieve more ambitious goals. This study explains aspects that have been and continue to be decisive in its growth, which Laboratoris Hipra is experiencing in a sector dominated by large multinational companies. The strategic success lies in vaccine specialization in livestock through enhanced research, control of all phases of the value chain and international expansion are essential to understand the evolution of the company, as is the social and ethical responsibility with which it operates, and the economic and financial balance that emerges from the analysis of the annual accounts for the period analyzed (2015-2019) and the comparison within its sector. Based on the internal and external analysis of the company, future conclusions and recommendations are made. Attention is drawn to the large window of opportunity presented to Laboratoris Hipra with the pandemic situation of COVID-19. Laboratorios Hipra es una empresa familiar que ha conseguido posicionarse entre las 20 empresas que más facturan del mundo en el sector farmacéutico en prevención de Salud Animal. Esta compañía es cada vez más visible a los medios de comunicación por las inversiones nuevas instalaciones y también a las bolsas de trabajo donde buscan personal especializado que pose de manifiesto la voluntad de la empresa de crecer y lograr objetivos más ambiciosos. Este estudio explica aquellos aspectos que han sido y continúan siendo determinantes en este proceso de crecimiento que está experimentando Laboratorios Hipra en un sector dominado por grandes empresas multinacionales. El acierto estratégico concretado en la especialización de vacuna por animales de producción a través de potenciar la investigación, el control de todas las fases de la cadena de valor y la expansión internacional son fundamentales para comprender la evolución de la empresa, como también lo es la responsabilidad social y ética con que opera, y el equilibrio económico y financiero que se desprende del análisis de las cuentas anuales del periodo analizado (2015-2019) y su comparación sectorial. En base en el análisis interno y externo de la empresa, se extraen unas conclusiones y recomendaciones futuras. Prestáis mucha atención a la gran ventana de oportunidad que se le presenta a Laboratorios Hipra con la situación pandémica de la COVID-19.