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Adenoviral and mRNA vaccines encoding the viral spike (S) protein have been deployed globally to contain severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Older individuals are particularly vulnerable to severe infection, probably reflecting age-related changes in the immune system, which can also compromise vaccine efficacy. It is nonetheless unclear to what extent different vaccine platforms are impacted by immunosenescence. Here, we evaluated S protein-specific immune responses elicited by vaccination with two doses of BNT162b2 or ChAdOx1-S and subsequently boosted with a single dose of BNT162b2 or mRNA-1273, comparing age-stratified participants with no evidence of previous infection with SARS-CoV-2. We found that aging profoundly compromised S protein-specific IgG titers and further limited S protein-specific CD4+ and CD8+ T cell immunity as a probable function of progressive erosion of the naive lymphocyte pool in individuals vaccinated initially with BNT162b2. Our results demonstrate that primary vaccination with ChAdOx1-S and subsequent boosting with BNT162b2 or mRNA-1273 promotes sustained immunological memory in older adults and potentially confers optimal protection against coronavirus disease 2019.
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The mucosal immune response is recognized to be important in the early control of infection sustained by viruses with mucosal tissues as the primary site of entry and replication, such as SARS-CoV-2. Mucosal IgA has been consistently reported in the mouth and eye of SARS-CoV-2 infected subjects, where it correlated inversely with COVID-19 symptom severity. Yet, there is still scarce information on the comparative ability of the diverse SARS-CoV-2 vaccines to induce local IgA responses at the virus entry site. Thus, the aim of this study was to assess the presence of anti-SARS-CoV-2 IgA in the saliva of 95 subjects vaccinated with a booster dose and different combinations of vaccines, including mRNA-1273 (Moderna), BNT162b2 (Pfizer-BioNTech), and Vaxzevria (AstraZeneca). The results showed the presence of a mucosal response in 93.7% of vaccinated subjects, with a mean IgA titer of 351.5 ± 31.77 U/mL, strongly correlating with the serum anti-SARS-CoV-2 IgG titer (p < 0.0001). No statistically significant differences emerged between the vaccine types, although the salivary IgA titer appeared slightly higher after receiving a booster dose of the mRNA-1273 vaccine (Moderna) following two doses of BNT162b2 (Pfizer-BioNTech), compared to the other vaccine combinations. These data confirm what was previously reported at the eye level and suggest that monitoring salivary IgA may be a useful tool for driving forward vaccine design and surveillance strategies, potentially leading to novel routes of vaccine administration and boosting.
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Vacinas contra COVID-19 , COVID-19 , Humanos , Vacina BNT162 , Vacina de mRNA-1273 contra 2019-nCoV , SARS-CoV-2 , COVID-19/prevenção & controle , Imunização , Anticorpos Antivirais , Vacinas de mRNA , Imunoglobulina ARESUMO
Inhibitors of the mammalian target of rapamycin (mTOR) have been proposed to improve vaccine responses, especially in the elderly. Accordingly, testing mTOR inhibitors (such as Sirolimus) and other geroprotective drugs might be considered a key strategy to improve overall health resilience of aged populations. In this respect, Sirolimus (also known as rapamycin) is of great interest, in consideration of the fact that it is extensively used in routine therapy and in clinical studies for the treatment of several diseases. Recently, Sirolimus has been considered in laboratory and clinical studies aimed to find novel protocols for the therapy of hemoglobinopathies (e.g. ß-Thalassemia). The objective of the present study was to analyse the activity of CD4+ and CD8+ T cells in ß-Thalassemia patients treated with Sirolimus, taking advantages from the availability of cellular samples of the NCT03877809 clinical trial. The approach was to verify IFN-γ releases following stimulation of peripheral blood mononuclear cells (PBMCs) to stimulatory CEF and CEFTA peptide pools, stimulatory for CD4+ and CD8+ T cells, respectively. The main results of the present study are that treatment of ß-Thalassemia patients with Sirolimus has a positive impact on the biological activity and number of memory CD4+ and CD8+ T cells releasing IFN-γ following stimulation with antigenic stimuli present in immunological memory. These data are to our knowledge novel and in our opinion of interest, in consideration of the fact that ß-Thalassemia patients are considered prone to immune deficiency.
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Sirolimo , Talassemia beta , Idoso , Humanos , Talassemia beta/tratamento farmacológico , Linfócitos T CD4-Positivos , Linfócitos T CD8-Positivos , Leucócitos Mononucleares , Sirolimo/farmacologia , Sirolimo/uso terapêutico , Serina-Treonina Quinases TORRESUMO
Age-related changes in the immune system are thought to underlie the vulnerability of elderly individuals to emerging viral diseases, such as coronavirus disease 2019 (COVID-19). In this study, we used a fully validated in vitro approach to determine how age impacts the generation of de novo CD8+ T cell responses against severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), the causative agent of COVID-19. Our data revealed a generalized deficit in the ability of elderly individuals to prime the differentiation of naïve precursors into effector CD8+ T cells defined by the expression of interferon (IFN)-γ and the transcription factor T-bet. As a consequence, there was an age-related decline in the diversity of newly generated CD8+ T cell responses targeting a range of typically immunodominant epitopes derived from SARS-CoV-2, accompanied by an overall reduction in the expression frequency of IFN-γ. These findings have potential implications for the development of new strategies to protect the elderly against COVID-19.
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The increasing life expectancy leads to more older adults suffering from infectious diseases. Vaccines are available against diverse infections such as influenza, pneumococcal disease, herpes zoster and tetanus. However, vaccine acceptance is crucial for optimal preventive effect. The objective of the study is to perform a cross-country analysis of the perceptions and decision-making behaviour of older adults regarding vaccinations and their information needs. Focus groups with older adults were conducted in four countries: France, Hungary, Italy and the Netherlands. Data were analysed using thematic analysis. Demographic characteristics of participants were gathered with a questionnaire. Influenza and tetanus vaccines were commonly known, as was the disease influenza. On the contrary, the awareness of the vaccines against pneumococcal disease and herpes zoster were low. Participants also expressed a need for more information on vaccines, such as possible side effects, contra-indications and duration of protection, emphasizing that information is a condition for decision-making on vaccination. General practitioners were found to be the most important in information provision on vaccines. Perceptions on vaccines, such as effectiveness, side effects and safety, as well as perceptions on infectious diseases, such as severity, susceptibility and experiencing an infectious disease, played a role in the decision-making of older adults on vaccines. More awareness of the information needs among older adults with regard to vaccines should be raised among general practitioners and other healthcare providers. This requires appropriate knowledge about the vaccines among healthcare providers as well as communication skills to meet the information needs of older adults.
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Doenças Transmissíveis , Herpes Zoster , Influenza Humana , Infecções Pneumocócicas , Tétano , Vacinas , Humanos , Idoso , Influenza Humana/prevenção & controle , Grupos Focais , Infecções Pneumocócicas/prevenção & controleRESUMO
Uncontrolled inflammatory response arising from the tumor microenvironment (TME) significantly contributes to cancer progression, prompting an investigation and careful evaluation of counter-regulatory mechanisms. We identified a trimeric complex at the mitochondria-associated membranes (MAMs), in which the purinergic P2X7 receptor - NLRP3 inflammasome liaison is fine-tuned by the tumor suppressor PML. PML downregulation drives an exacerbated immune response due to a loss of P2X7R-NLRP3 restraint that boosts tumor growth. PML mislocalization from MAMs elicits an uncontrolled NLRP3 activation, and consequent cytokines blast fueling cancer and worsening the tumor prognosis in different human cancers. New mechanistic insights are provided for the PML-P2X7R-NLRP3 axis to govern the TME in human carcinogenesis, fostering new targeted therapeutic approaches.
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Proteína 3 que Contém Domínio de Pirina da Família NLR , Proteína da Leucemia Promielocítica , Receptores Purinérgicos P2X7 , Microambiente Tumoral , Humanos , Citocinas , Inflamassomos , Mitocôndrias , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Receptores Purinérgicos P2X7/metabolismo , Proteína da Leucemia Promielocítica/metabolismoRESUMO
The COVID-19 pandemic has brought forward myriad challenges to public policy, central of which is understanding the different contextual factors that can influence the effectiveness of policy responses across different systems. In this article, we explore how trust in government can influence the ability of COVID-19 policy responses to curb excess mortality during the pandemic. Our findings indicate that stringent policy responses play a central role in curbing excess mortality. They also indicate that such relationship is not only influenced by systematic and structural factors, but also by citizens' trust in government. We leverage our findings to propose a set of recommendations for policymakers on how to enhance crisis policymaking and strengthen the designs of the widely used underlying policy learning processes.
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Adult vaccination programs are receiving increasing attention however, little is known regarding the impact of age on the maintenance of the immune response. We investigated this issue in the context of a human papillomavirus (HPV) vaccination program collecting real-world data on the durability of humoral immunity in 315 female subjects stratified according to vaccination age (adolescents and adults) and sampled at early or late time points after the last vaccine dose. HPV-specific IgGs, but not memory B cells, were induced and maintained at higher levels in subjects vaccinated during adolescence. Nonetheless, antibody functions waned over time to a similar degree in adolescents and adults. To shed light on this phenomena, we analyzed quantitative and qualitative properties of lymphocytes. Similar biochemical features were observed between B-cell subsets from individuals belonging to the two age groups. Long term humoral responses toward vaccines administered at an earlier age were comparably maintained between adolescents and adults. The percentages of naïve B and CD4+ T cells were significantly higher in adolescents, and the latter directly correlated with IgG titers against 3 out of 4 HPV types. Our results indicate that age-specific HPV vaccine responsiveness is mostly due to quantitative differences of immune cell precursors rather than qualitative defects in B cells. In addition, our results indicate that adults also have a good humoral immunogenic profile, suggesting that their inclusion in catch-up programmes is desirable.
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BACKGROUND: Advanced age is accompanied by a decline of immune functions, which may play a role in increased vulnerability to emerging pathogens and low efficacy of primary vaccinations in elderly people. The capacity to mount immune responses against new antigens is particularly affected in this population. However, its precise determinants are not fully understood. We aimed here at establishing the influence of persistent viral infections on the naive T-cell compartment and primary immune responsiveness in older adults. METHODS: We assessed immunological parameters, related to CD8+ and CD4+ T-cell responsiveness, according to the serological status for common latent herpesviruses in two independent cohorts: 1) healthy individuals aged 19y to 95y (n = 150) and 2) individuals above 70y old enrolled in a primo-vaccination clinical trial (n = 137). FINDINGS: We demonstrate a prevalent effect of age and CMV infection on CD8+ and CD4+ naive T cells, respectively. CMV seropositivity was associated with blunted CD4+ T-cell and antibody responses to primary vaccination. INTERPRETATION: These data provide insights on the changes in adaptive immunity over time and the associated decline in vaccine efficacy with ageing. This knowledge is important for the management of emerging infectious diseases in elderly populations. FUNDING: This work was supported by the ANR (Project ANR-14-CE14-0030-01) and by Universita ItaloFrancese/Univeriste FrancoItalienne (Galileo Project G10-718; PHC Galilee Project 39582TJ), by the Swiss National Science Foundation (grant PP0033-110737 to UK), by the Heuberg Foundation (Zurich, Switzerland), by the AETAS Foundation (Geneva, Switzerland) and by a Senior IdEx Chair of the University of Bordeaux (France). EC, VB, CA, MA, DD and AT were supported by the French Government's Investissement d'Avenir Program, Laboratoire d'Excellence "Milieu Interieur" Grant ANR-10-LABX-69-01. EC and AT are supported by the Agence Nationale de la Recherche (Project RANKLthym ANR-19- CE18-0021-02).
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Infecções por Citomegalovirus , Herpesviridae , Adulto , Idoso , Formação de Anticorpos , Voluntários Saudáveis , Humanos , Vacinação , Adulto JovemRESUMO
Aging is associated with functional deficits in the naive T cell compartment, which compromise the generation of de novo immune responses against previously unencountered Ags. The mechanisms that underlie this phenomenon have nonetheless remained unclear. We found that naive CD8+ T cells in elderly humans were prone to apoptosis and proliferated suboptimally in response to stimulation via the TCR. These abnormalities were associated with dysregulated lipid metabolism under homeostatic conditions and enhanced levels of basal activation. Importantly, reversal of the bioenergetic anomalies with lipid-altering drugs, such as rosiglitazone, almost completely restored the Ag responsiveness of naive CD8+ T cells. Interventions that favor lipid catabolism may therefore find utility as adjunctive therapies in the elderly to promote vaccine-induced immunity against targetable cancers and emerging pathogens, such as seasonal influenza viruses and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).
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Envelhecimento/imunologia , Linfócitos T CD8-Positivos/imunologia , Imunocompetência/efeitos dos fármacos , Metabolismo dos Lipídeos , Adulto , Idoso , Idoso de 80 Anos ou mais , Apoptose , Linfócitos T CD8-Positivos/metabolismo , COVID-19/imunologia , Vacinas Anticâncer/imunologia , Divisão Celular , Feminino , Fenofibrato/farmacologia , Glucose/metabolismo , Antígeno HLA-A2/imunologia , Humanos , Hipolipemiantes/farmacologia , Hipolipemiantes/uso terapêutico , Influenza Humana/imunologia , Metabolismo dos Lipídeos/efeitos dos fármacos , Ativação Linfocitária , Antígeno MART-1/química , Antígeno MART-1/imunologia , Masculino , Pessoa de Meia-Idade , Neoplasias/imunologia , Fragmentos de Peptídeos/imunologia , Rosiglitazona/farmacologia , Método Simples-Cego , Vacinação , Vacinas Virais/imunologia , Adulto JovemRESUMO
The pandemic caused by the severe acute respiratory syndrome coronavirus (SARSCoV2), responsible for coronavirus disease 2019 (COVID19) has posed a major challenge for global health. In order to successfully combat SARSCoV2, the development of effective COVID19 vaccines is crucial. In this context, recent studies have highlighted a high COVID19 mortality rate in patients affected by ßthalassemia, probably due to their coexistent immune deficiencies. In addition to a role in the severity of SARSCoV2 infection and in the mortality rate of COVID19infected patients with thalassemia, immunosuppression is expected to deeply affect the effectivity of antiCOVID19 vaccines. In the context of the interplay between thalassemiaassociated immunosuppression and the effectiveness of COVID19 vaccines, the employment of immunomodulatory molecules is hypothesized. For instance, shortterm treatment with mammalian target of rapamycin inhibitors (such as everolimus and sirolimus) has been found to improve responses to influenza vaccination in adults, with benefits possibly persisting for a year following treatment. Recently, sirolimus has been considered for the therapy of hemoglobinopathies (including ßthalassemia). Sirolimus induces the expression of fetal hemoglobin (and this may contribute to the amelioration of the clinical parameters of patients with ßthalassemia) and induces autophagy (thereby reducing the excessive levels of αglobin). It may also finally contribute to the mobilization of erythroid cells from the bone marrow (thereby reducing anemia). In the present study, the authors present the hypothesis that sirolimus treatment, in addition to its beneficial effects on erythroidrelated parameters, may play a crucial role in sustaining the effects of COVID19 vaccination in patients with ßthalassemia. This hypothesis is based on several publications demonstrating the effects of sirolimus treatment on the immune system.
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Vacinas contra COVID-19/uso terapêutico , Sirolimo/uso terapêutico , Talassemia beta/terapia , COVID-19/complicações , COVID-19/mortalidade , COVID-19/patologia , COVID-19/prevenção & controle , Terapia Combinada , Humanos , SARS-CoV-2/efeitos dos fármacos , SARS-CoV-2/imunologia , Índice de Gravidade de Doença , Sirolimo/farmacologia , Resultado do Tratamento , Vacinação/métodos , Talassemia beta/complicações , Talassemia beta/imunologiaRESUMO
A current trend of research in the health field is toward the discovery of multifunctional compounds, capable of interacting with multiple biological targets, thus simplifying multidrug therapies and improving patient compliance. The aim of this work was to synthesize new multifunctional chemical entities bearing a benzothiazole nucleus, a structure that has attracted increasing interest for the great variety of biological actions that it can perform, and already used as a scaffold in several multifunctional drugs. Compounds are reported, divided into two distinct series, synthetized and tested in vitro for the antioxidant, and include UV-filtering and antitumor activities. DPPH and FRAP tests were chosen to outline an antioxidant activity profile against different radical species. The UV-filtering activity was investigated, pre- and post-irradiation, through evaluation of a O/W sunscreen standard formulation containing 3% of the synthetic compounds. The antitumor activity was investigated both on human melanoma cells (Colo-38) and on immortalized human keratinocytes as a control (HaCat). A good antiproliferative profile in terms of IC50 was chosen as a mandatory condition to further investigate apoptosis induction as a possible cytotoxicity mechanism through the Annexin V test. Compound BZTcin4 was endowed with excellent activity and a selectivity profile towards Colo-38, supported by a good antioxidant capacity and an excellent broad-spectrum photoprotective profile.
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Antineoplásicos , Antioxidantes , Humanos , Antioxidantes/química , Linhagem Celular Tumoral , Antineoplásicos/química , Protetores Solares/farmacologia , Protetores Solares/química , Benzotiazóis/química , Relação Estrutura-Atividade , Ensaios de Seleção de Medicamentos Antitumorais , Proliferação de CélulasRESUMO
People living with HIV, even under therapy, have a high burden of age-related co-morbidities including an increased risk of dyslipidemia (which often predisposes to cardiovascular diseases) and immune-aging. In this study, lipid profiles and antibody responses to measles and pertussis toxin vaccines were compared between ART experienced HIV+ children (n=64) aged 5-10 years, and their age- and sex-matched HIV- controls (n=47). Prevalence of high-density lipoprotein cholesterol (HDL-c) and triglyceride-driven dyslipidemia was higher among treated HIV+ children than in controls (51.6% vs 27.7% respectively, p < 0.019). In a multivariate Poisson regression model adjusted for age, sex and BMI, the association between low HDL-c, hypertriglyceridemia and HIV remained significantly high (for HDL-c: ARR: 0.89, 95% CI: 0.82 - 0.96, p = 0.003; for triglycerides: ARR: 1.54, 95% CI: 1.31 - 1.81, p < 0.001). Among HIV+ children, the use of lopinavir/ritonavir, a protease-based antiretroviral therapy was also associated elevation of triglyceride levels (p = 0.032). Also, HIV+ children had a 2.8-fold reduction of anti-measles IgG titers and 17.1-fold reduction of anti-pertussis toxin IgG levels when compared to HIV- children. Our findings suggest that dyslipidemia and inadequate vaccine-induced antibody responses observed in this population of young African HIV+ children might increase their risk for premature onset of cardiovascular illnesses and acquisition of preventable diseases.
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Infecções por HIV , Vacinas , Terapia Antirretroviral de Alta Atividade , Criança , Infecções por HIV/complicações , Infecções por HIV/tratamento farmacológico , Humanos , Lipídeos , Tanzânia/epidemiologiaRESUMO
Advanced age is associated with severe symptoms and death upon SARS-CoV-2 infection. Virus-specific CD8+ T-cell responses have shown to be protective toward critical COVID-19 manifestations, suggesting that suboptimal cellular immunity may contribute to the age-pattern of the disease. The induction of a CD8+ T-cell response against an emerging pathogen like SARS-CoV-2 relies on the activation of naive T cells. To investigate whether the primary CD8+ T-cell response against this virus is defective in advanced age, we used an in vitro approach to prime SARS-CoV-2-specific naive CD8+ T cells from healthy, unexposed donors of different age groups. Compared to younger adults, older individuals display a poor SARS-CoV-2-specific T-cell priming capacity in terms of both magnitude and quality of the response. In addition, older subjects recognize a lower number of epitopes. Our results implicate that immune aging is associated with altered primary SARS-CoV-2-specific CD8+ T-cell responses.
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Envelhecimento/imunologia , Linfócitos T CD8-Positivos/imunologia , COVID-19/imunologia , SARS-CoV-2/imunologia , Adulto , Idoso , Antígenos Virais/imunologia , Células Cultivadas , ELISPOT , Epitopos de Linfócito T/imunologia , Regulação da Expressão Gênica , Voluntários Saudáveis , Humanos , Interferon gama/genética , Interferon gama/metabolismo , Ativação Linfocitária , Pessoa de Meia-Idade , Peptídeos/imunologia , Adulto JovemRESUMO
Peptide vaccines incorporating B- and T-cell epitopes have shown promise in the context of various cancers and infections. These vaccines are relatively simple to manufacture, but more immunogenic formulations are considered a priority. We developed tetrabranched derivatives for this purpose based on a novel peptide welding technology (PWT). PWTs provide molecular scaffolds for the efficient synthesis of ultrapure peptide dendrimers, which allow the delivery of multiple ligands within a single macromolecular structure. Peptide vaccines incorporating T-cell epitopes derived from melanoma and B-cell epitopes derived from human immunodeficiency virus, synthesized using this approach, elicited primary immune responses in vitro and in vivo. Subcutaneous administration of the B-cell epitope-based vaccines also elicited more potent humoral responses than subcutaneous administration of the corresponding peptides alone. Highly immunogenic peptide epitope-based vaccines can therefore be generated quickly and easily using a novel PWT.
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BACKGROUND: The COVID-19 outbreak has heightened ongoing political debate about the international joint procurement of medicines and medical countermeasures. The European Union (EU) has developed what remains largely contractual and decentralized international procurement cooperation. The corona crisis has broadened and deepened public debate on such cooperation, in particular on the scope of cooperation, solidarity in the allocation of such cooperation, and delegation of cooperative decision-making. Crucial to political debate about these issues are public attitudes that constrain and undergird international cooperation. METHODS: Our survey includes a randomized survey experiment (conjoint analysis) on a representative sample in five European countries in March 2020, informed by legal and policy debate on medical cooperation. Respondents choose and rate policy packages containing randomized mixes of policy attributes with respect to the scope of medicines covered, the solidarity in conferring priority access and the level of delegation. RESULTS: In all country populations surveyed, the experiment reveals considerable popular support for European cooperation. Significant majorities preferred cooperation packages with greater rather than less scope of medicines regulated; with priority given to most in-need countries; and with delegation to EU-level rather than national expertise. CONCLUSION: Joint procurement raises delicate questions with regard to its scope, the inclusion of cross-border solidarity and the delegation of decision-making, that explain reluctance toward joint procurement among political decision-makers. This research shows that there is considerable public support across different countries in favor of centralization, i.e. a large scope and solidarity in the allocation and delegation of decision-making.
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Tratamento Farmacológico da COVID-19 , COVID-19 , Alocação de Recursos para a Atenção à Saúde , Cooperação Internacional , Preparações Farmacêuticas , Opinião Pública , COVID-19/epidemiologia , Europa (Continente)/epidemiologia , Alocação de Recursos para a Atenção à Saúde/organização & administração , Humanos , Inquéritos e QuestionáriosRESUMO
Toll-like receptor 9 (TLR9) agonists have gained traction in recent years as potential adjuvants for the induction of adaptive immune responses. It has nonetheless remained unclear to what extent such ligands can facilitate the priming events that generate antigen-specific effector and/or memory CD8+ T-cell populations. We used an established in vitro model to prime naive precursors from human peripheral blood mononuclear cells in the presence of various adjuvants, including CpG ODN 2006, a synthetic oligonucleotide TLR9 ligand (TLR9L). Unexpectedly, we found that TLR9L induced a suboptimal inflammatory milieu and promoted the antigen-driven expansion and functional maturation of naive CD8+ T cells ineffectively compared with either ssRNA40 or 2'3'-cGAMP, which activate other pattern recognition receptors (PRRs). TLR9L also inhibited the priming efficacy of 2'3'-cGAMP. Collectively, these results suggest that TLR9L is unlikely to be a good candidate for the optimal induction of de novo CD8+ T-cell responses, in contrast to adjuvants that operate via discrete PRRs.