Seguridad de la vacuna de la gripe en el receptor de trasplante de órgano sólido

La infección por influenza en los pacientes receptores de trasplante de órgano sólido (TOS) se ha asociado con altas tasas de morbilidad y mortalidad, especialmente en los primeros tres meses tras el trasplante. La vacunación de la gripe se ha propuesto como una medida eficaz para la prevención de la infección en estos pacientes. La mayoría de los estudios realizados para evaluar la eficacia de la vacunación en este grupo de pacientes han reflejado una respuesta humoral óptima en el receptor de TOS tras la vacunación, aunque inferior a la descrita en la población inmunocompetente (99), con un porcentaje variable de pacientes, entre el 1 y el 47% que no responde a la vacunación. En base a estos resultados se han propuesto diferentes estrategias para aumentar la efectividad de la vacunación en este grupo como la utilización de una vacuna adyuvantada, la administración de la vacuna en los primeros meses desde el trasplante o la administración de una segunda dosis de vacuna. Aunque la vacunación antigripal ha demostrado aportar efectos beneficiosos en la protección frente a la infección en estos pacientes receptores de TOS, algunos autores se mantienen reticentes a la vacunación, debido al riesgo hipotético de que la vacunación pudiera producir una hiperactivación del sistema inmune generando una respuesta aloinmune, incrementando la producción de anticuerpos anti-HLA frente al órgano trasplantado y desencadenando el rechazo, especialmente en los primeros tres a seis meses post-trasplante. No hay datos en la bibliografía acerca de la relación entre la vacunación temprana, en los primeros tres a seis meses desde el trasplante, la composición de la vacuna, o el aumento del número de dosis con la producción de anticuerpos anti-HLA, estrategias vacunales cuya eficacia ha sido descrita previamente en nuestro grupo. Pensamos que es necesario el análisis de cohortes numerosas de pacientes que permitan obtener conclusiones firmes acerca de este importante aspecto de la seguridad de la vacunación gripal, tan necesaria en el receptor de TOS dado el alto riesgo de desarrollar complicaciones al que se exponen por su estado de inmunosupresión. El objetivo de esta tesis fue evaluar en la población de receptores TOS la eficacia y seguridad de las posibles estrategias de mejora de la vacunación gripal tales como la administración precoz de la vacuna en los primeros meses desde el trasplante, la utilización de una composición vacunal adyuvantada, o la administración de una segunda dosis de vacuna. Nuestros resultados en esta tesis, tras analizar la mayor cohorte de receptores de TOS publicada hasta la fecha para analizar la efectividad y seguridad de la vacuna de la gripe en estos pacientes, muestran que la vacunación gripal administrada dentro de los primeros seis meses post-trasplante es tan inmunógena como cuando se administra más allá del sexto mes del trasplante. Dada la respuesta inmunológica y la falta de efectos adversos tras la vacunación así como la alta tasa de complicaciones producidas como consecuencia de la infección por influenza en los primeros seis meses tras el trasplante, la administración de la vacuna antigripal debería ser recomendada a partir primer mes post-trasplante. Además, debería recomendarse la vacunación anual de la gripe a los pacientes con enfermedad de órgano terminal para promover la presencia de títulos de anticuerpos neutralizantes y una mejor protección inmunológica en los primeros momentos tras el trasplante. Además, los resultados mostrados en esta tesis demuestran que la vacunación gripal en el receptor de TOS es segura y no está relacionada con la producción de aloanticuerpos anti-HLA relacionados con el rechazo de órgano, desde el primer mes post-trasplante independientemente del órgano trasplantado, del régimen de inmunosupresión o las comorbilidades diagnosticadas en el paciente

Immunological features beyond CD4/CD8 ratio values in older individuals

The CD4/CD8 T-cell ratio is emerging as a relevant marker of evolution for many pathologies and therapies. We aimed to explore immunological features beyond CD4/CD8 ratio values in older subjects (>65 years old) who were classified as having lower (2) ratio values. The lower group showed a lower thymic output (sj/β-TREC ratio) and frequency of naïve T-cells, concomitant with increased mature T-cells. In these subjects, the CD4 T-cell subset was enriched in CD95+ but depleted of CD98+ cells. The regulatory T-cell (Treg) compartment was enriched in CTLA-4+ cells. The CD8 T-cell pool exhibited increased frequencies of CD95+ cells but decreased frequencies of integrin-β7+ cells. Interestingly, in the intermediate group, the CD4 pool showed greater differences than the CD8 pool, mostly for cellular senescence. Regarding inflammation, only hsCRP was elevated in the lower group; however, negative correlations between the CD4/CD8 ratio and β2-microglobulin and sCD163 were detected. These subjects displayed trends of more comorbidities and less independence in daily activities. Altogether, our data reveal different thymic output and immune profiles for T-cells across CD4/CD8 ratio values that can define immune capabilities, affecting health status in older individuals. Thus, the CD4/CD8 ratio may be used as an integrative marker of biological age.This work was supported by grants from the Fondo de Investigación Sanitaria (FIS; PI18/01216), which is co-funded by Fondos Europeos para el Desarrollo Regional (FEDER) “Una manera de hacer Europa” and the Junta de Andalucía, Consejería de Economía, Innovación, Ciencia y Empleo (Proyecto de Investigación de Excelencia; CTS2593). The Spanish AIDS Research Network of Excellence also supported this study (RD16/0025/0019). V G-R, I O-M and A B-R were supported by Instituto de Salud Carlos III (FI19/00298, CM19/00051 and CD19/00143, respectively). YM. P was supported by the Consejería de Salud y Familias of Junta de Andalucía through the ‘‘Nicolás Monardes’’ program (C-0013-2017).Peer reviewe

Factors associated with the humoral response after three doses of COVID-19 vaccination in kidney transplant recipients

[Introduction] Kidney transplant recipients showed a weak humoral response to the mRNA COVID-19 vaccine despite receiving three cumulative doses of the vaccine. New approaches are still needed to raise protective immunity conferred by the vaccine administration within this group of high-risk patients.[Methods] To analyze the humoral response and identify any predictive factors within these patients, we designed a prospective monocentric longitudinal study of Kidney transplant recipients (KTR) who received three doses of mRNA-1273 COVID-19 vaccine. Specific antibody levels were measured by chemiluminescence. Parameters related to clinical status such as kidney function, immunosuppressive therapy, inflammatory status and thymic function were analyzed as potential predictors of the humoral response.[Results] Seventy-four KTR and sixteen healthy controls were included. One month after the administration of the third dose of the COVID-19 vaccine, 64.8% of KTR showed a positive humoral response. As predictive factors of seroconversion and specific antibody titer, we found that immunosuppressive therapy, worse kidney function, higher inflammatory status and age were related to a lower response in KTR while immune cell counts, thymosin-a1 plasma concentration and thymic output were related to a higher humoral response. Furthermore, baseline thymosin-a1 concentration was independently associated with the seroconversion after three vaccine doses.[Discussion] In addition to the immunosuppression therapy, condition of kidney function and age before vaccination, specific immune factors could also be relevant in light of optimization of the COVID-19 vaccination protocol in KTR. Therefore, thymosin-a1, an immunomodulatory hormone, deserves further research as a potential adjuvant for the next vaccine boosters.This study was supported by a grant from the Fondo de Investigación Sanitaria (FIS/PI21/00357), which is co-founded by Fondos Europeos para el Desarrollo Regional (FEDER) “Una manera de hacer Europa”. VG-R, IO-M and AB-R were supported by Instituto de Salud Carlos III (CD19/00143, FI19/00298 and CM19/00051, respectively). MP-B was supported by the Consejería de Transformación Económica, Industria, Conocimiento y Universidades [DOC_01646 to MP-B] and YP was supported by the Consejería de Salud y Familias of Junta de Andalucía through the “Nicolás Monardes” [RC-0006-2021].Peer reviewe

Effect of influenza vaccination inducing antibody mediated rejection in solid organ transplant recipients

Introduction: Our goal was to study whether influenza vaccination induced antibody mediated rejection in a large cohort of solid organ transplant recipients (SOTR). Methods: Serum anti-Human Leukocyte Antigen (HLA) antibodies were determined using class I and class II antibody-coated latex beads (FlowPRATM Screening Test) by flow cytometry. Anti-HLA antibody specificity was determined using the single-antigen bead flow cytometry (SAFC) assay and assignation of donor specific antibodies (DSA) was performed by virtual-crossmatch. Results: We studied a cohort of 490 SOTR that received an influenza vaccination from 2009 to 2013: 110 (22.4%) received the pandemic adjuvanted vaccine, 59 (12%) within the first 6 months post-transplantation, 185 (37.7%) more than 6 months after transplantation and 136 (27.7%) received two vaccination doses. Overall, no differences of anti-HLA antibodies were found after immunization in patients that received the adjuvanted vaccine, within the first 6 months post-transplantation, or based on the type of organ transplanted. However, the second immunization dose increased the percentage of patients positive for anti-HLA class I significantly compared with patients with one dose (14.6% vs. 3.8%; P = 0.003). Patients with pre-existing antibodies before vaccination (15.7% for anti-HLA class I and 15.9% for class II) did not increase reactivity after immunization. A group of 75 (14.4%) patients developed de novo anti HLA antibodies, however, only 5 (1.02%) of them were DSA, and none experienced allograft rejection. Only two (0.4%) patients were diagnosed with graft rejection with favorable outcomes and neither of them developed DSA. Conclusion: Our results suggest that influenza vaccination is not associated with graft rejection in this cohort of SOTR.Junta de Andalucía, Consejería de Salud PI-0119-2012Ministerio de Economía y Competitividad, Instituto de Salud Carlos III GR09/0041Ministerio de Economía y Competitividad, Instituto de Salud Carlos III PI14-00165Ministerio de Economía y Competitividad, Instituto de Salud Carlos III MPY110/18European Development Regional Fund “A way to achieve Europe” ERDF, Spanish Network for the Research in Infectious Diseases REIPI RD12/0015/000

Dysregulation of iron metabolism modulators in virologically suppressed HIV-infected patients

[Background] Iron metabolism plays an essential role in cellular functions. Since virologically suppressed chronic HIV-infected subjects under effective antiretroviral treatment (ART) exhibit a persistent immune dysfunction that leads to comorbidities, iron homeostasis may be relevant in this context. We aimed to explore iron metabolism in virologically suppressed chronic HIV infected subjects under a successful ART.[Methods] In this retrospective study, traditional iron metabolism biomarkers (total iron, ferritin, transferrin, and transferrin saturation index), as well as soluble transferrin receptor (sTfR), hepcidin, and inflammatory markers were determined in virologically suppressed chronic HIV-infected subjects under at least 2 years of ART (HIV) who also had >350 CD4-T-cells/mm3 (N=92) from Spain. As controls, we collected non-HIV age-matched healthy donors (Young, N=25) and elderly subjects (>65 years old; Elderly; N=25). Additionally, an external group of non-HIV patients with ferritin<50 ng/mL diagnosed with absolute iron deficiency (Ferropenic group; N=84) was included. Comparisons between groups were performed using Kruskal-Wallis or Mann-Whitney U-tests, while associations between variables were explored by Spearman’s rho correlation coefficient.[Results] We selected samples from HIV-infected subjects (aged 42[34-47], 95% males), young age-matched (aged 40[30-58], 60% males), and elderly controls (aged 82[78-88], 100% males). Compared to both healthy (Young and Elderly) groups, HIV exhibited decreased iron, transferrin saturation, and sTfR, and increased ferritin, but similar hepcidin levels. Notably, associations between sTfR and iron (Young, r=-0.587, p=0.002; Elderly, r=-0.496, p=0.012) or transferrin saturation index (Young, r=-0.581, p=0.002; Elderly, r=-0.489, p=0.013) were negative in both controls while positive in HIV (r=0.464, p<0.0001 and r=0.421, p<0.0001, respectively). Moreover, the expected negative correlation between hepcidin and sTfR, observed in controls (Young, r=-0.533, p=0.006; Elderly, r=-0.473, p=0.017), was absent in HIV (r=0.082; p=0.438). Interestingly, the HIV inflammatory profile differed from the Elderly one, who despite their inflammaging-related profile, succeed in maintaining these associations. Furthermore, subjects from the ferropenic group (aged 42[32-51], 5% males), showing significantly lower levels of hepcidin and higher sTfR, as expected, reflected similar correlations as those Young and Elderly, in contrast to HIV.[Conclusions] Virologically suppressed chronic HIV-infected patients under successful ART exhibit altered levels of iron metabolism modulators suggesting a complex functional iron deficiency.This work was supported by grants from the Fondo de Investigación Sanitaria [FIS; PI18/01216 and PI21/00357] which is co-funded by Fondos Europeos para el Desarrollo Regional (FEDER) “Una manera de hacer Europa”, the Instituto de Salud Carlos III [FI19/00298 to VG-R, CM19/00051 to IO-M and CD19/00143 to AB-R], the Consejería de Transformación Económica, Industria, Conocimiento y Universidades [DOC_01646 to MP-B] and the Consejería de Salud y Familias of Junta de Andalucía through the “Nicolás Monardes” [C-0013-2017 to YMP]. The HIV BioBank, integrated in the Spanish AIDS Research Network, is supported by Instituto de Salud Carlos III, Spanish Health Ministry (Grant n° RD06/0006/0035, RD12/0017/0037 and RD16/0025/0019) as part of the Plan Nacional I+D+i and cofinanced by ISCIII- Subdirección General de Evaluación y el Fondo Europeo de Desarrollo Regional (FEDER)”. The RIS Cohort (CoRIS) was funded by the Instituto de Salud Carlos III through the Red Temática de Investigación Cooperativa en SIDA (RIS C03/173, RD12/0017/0018 and RD16/0002/0006) as part of the Plan Nacional I+D+i and cofinanced by ISCIII-Subdirección General de Evaluación and the Fondo Europeo de Desarrollo Regional (FEDER).Peer reviewe

Longitudinal age differences in humoral responses to the COVID-19 vaccine in the elderly are lost after the third dose

Nursing home residents constitute an especially frail population at a high risk for severe COVID-19 disease,1 mainly due to multiple comorbid conditions and immunesenescence.2 Hence, many countries have considered the administration of booster doses of vaccines due to the lower levels of anti-S IgG antibodies achieved by elderly adults after two doses of vaccine and a faster waning immunity thereafter.3 A recent work published in this journal by Dimeglio et al.,4 showing anti-SARS-CoV-2 antibodies before and after the third dose of the vaccine, reported that elderly adults achieved similar levels of anti-S IgG titers after the booster dose than those achieved by younger participants, shedding light on the benefit of the administration of such vaccine booster. Here, we present additional longitudinal data reinforcing this concept.This work was supported by the Instituto de Salud Carlos III through the project “PI21/00357” (Co-funded byEuropean Regional Development Fund/European Social Fund “A way to make Europe”/“Investing in your future”). MMPB was supported by a postdoctoral contract from Consejería de Transformación Económica, Industria, Conocimiento y Universidades, Junta de Andalucía (DOC_01646). ABR, IOM and VGR were supported by Instituto de Salud Carlos III (Sara Borrell program CD19/00143, Rio Hortega program CM19/00051, and PFIS program FI19/00298, respectively). YMP was supported by the Consejería de Salud y Familias of Junta de Andalucía through the ‘‘Nicolás Monardes’’ program (RC‐0006-2021).Peer reviewe