Exploiting Host Genetics and Sex differences to predict immune response after anti-SARS-CoV-2 vaccination

COVID-19 folded the world in a very short time, contextually a prompt development of safe and effective vaccines has helped to contain the pandemic. A part sex and age, the first responsible for the extreme variability in symptoms and progression of the disease, researchers from all over the world also investigated the role that individual genetics might have played in the clinical phenotype manifestations by the establishment of international consortium as the Host Genetics Initiative (HGI). After that, also the response to vaccination raised concerns and extreme research interest mainly based on the observed wide range in the vaccine responses in terms of antibody levels and associated side effects among populations. To recognize possible genetic predispositions to the individual response to vaccine against SARS-CoV2 in terms of dynamic and duration of circulating antibodies, we obtained whole blood from 233 healthy adult subjects selected from 250 volunteers belonging to the staff of the University-Hospital of Ferrara who had received the second dose of mRNA-based vaccine, BNT162b2 (Pfizer-BioNTech, n=166) or Adenoviral vector (AdV)-based vaccine, ChAdOx1 (AstraZeneca, n=67) starting from 15 days to 199 days (about 6 months) after vaccination. Levels of anti-SARS-CoV-2 antibodies (IgG) and neutralizing antibodies (NAbs) were analysed by serological assays. Subsequent genetic analyses, involving genes mainly selected among those loci recognized by our group or by Genome Wide Association Study (GWAS) performed by researchers belonging to the HGI have been investigated in our cohort of subjects. It was also performed a phenotypic analysis of ABO blood group and Rh system. A strong positive correlation was found between IgG and NAbs levels during 199 days of follow-up (r2=0.809, p<0.0001), and was confirmed also when stratifying the whole cohort by vaccine formulation (r2=0. 769, p<0.0001 for mRNA-based vaccine and r2=0.880, p<0.0001 for AdV-based vaccine) and by sex (r2=0.779, p<0.0001 and r2=0.847, p<0.0001 for females and males, respectively). The gene variants showing genotype distributions significantly different when stratified by antibody levels and that could provide a potential prediction of vaccine induced antibody titre were: ABO, rs657152; TP53, rs1042522; APOE, rs7412/rs429358; ACE, rs1799752 and ACE2, rs2285666. More specifically, regression analyses and comparison of antibody mean levels yielded significant or appreciable differences after stratification by genotype/phenotype in the whole cohort and/or in the mRNA-based vaccine, with the following significances: ABO, rs657152 (PIgG=0.007; PNAbs=0.06); TP53, rs1042522 (PIgG=0.02; PNAbs=0.04); APOE, rs7412/rs429358 (PIgG=0.02; PNAbs<0.0001); ACE, rs1799752 (PIgG=0.12; PNAbs=0.05); ACE2, rs2285666 (PIgG=0.009; PNAbs=0.02); ABO blood group (PIgG=0.005; PNAbs=0.16) and Rh system (PIgG=0.02; PNAbs=0.03). To complete our statistic investigation, we performed a multivariate linear regression and a multivariate logistic regression. These analyses yielded significant results that could potentially predict antibody titre after vaccination for ABO, rs657152 (PIgG= 0.006); APOE, rs7412/rs429358 (PNAbs=0.012) and ABO blood group (PIgG< 0.001; PNAbs= 0.02). A focused genetic screening could identify those genetic favourable backgrounds for strong vaccination response and furthermore could direct those individuals with weak immune response into a focused and personalized vaccine type, dosage and booster dose timing. A genetic personalized approach to vaccination, taking into account the Interindividual differences, is one of the goal of the precision medicine to improve present and future vaccine campaigns.La pandemia da COVID-19 ha messo in ginocchio il mondo in tempi molto brevi, ma il rapido sviluppo dei vaccini ha contribuito a contenere la diffusione. Oltre a sesso ed età, considerati i primi responsabili dell’estrema variabilità dei sintomi e della progressione della malattia, i ricercatori di tutto il mondo hanno indagato anche il ruolo che la genetica individuale avrebbe avuto nelle manifestazioni del fenotipo clinico, istituendo il consorzio internazionale “Host Genetics Initiative” (HGI). In seguito, anche la risposta alla vaccinazione ha suscitato preoccupazioni ed estremo interesse da parte della comunità scientifica, soprattutto a causa dell’eterogeneità delle risposte al vaccino, osservate nella popolazione, in termini di livelli di anticorpi e di effetti collaterali. Per riconoscere eventuali predisposizioni genetiche che possano influenzare la dinamica e la durata degli anticorpi prodotti a seguito della vaccinazione anti-SARS-CoV-2, abbiamo arruolato 250 volontari adulti appartenenti allo staff dell'Azienda Ospedaliero-Universitaria di Ferrara. Dei 250 volontari, abbiamo selezionato e collezionato il sangue intero di 233 soggetti sani, che avevano ricevuto la seconda dose di vaccino a mRNA, BNT162b2 (Pfizer-BioNTech, n=166) o vaccino a vettore adenovirale (AdV), ChAdOx1 (AstraZeneca, n=67) a partire da 15 giorni fino a 199 giorni dopo la vaccinazione. I livelli di anticorpi anti-SARS-CoV-2 (IgG) e di anticorpi neutralizzanti (NAbs) sono stati analizzati mediante saggi sierologici. Successivamente, sono state condotte analisi genetiche di geni, selezionati dal nostro gruppo o riconosciuti dagli studi di associazione genome-wide (GWAS) eseguiti da ricercatori appartenenti all'HGI, come responsali della gravità di COVID-19. È stata, inoltre, eseguita un'analisi fenotipica del gruppo sanguigno ABO e del sistema Rh. Come primo risultato, abbiamo riscontrato una forte correlazione positiva tra i livelli di IgG e NAbs durante i 199 giorni di follow-up (r2=0.809, p<0.0001), confermata anche dopo la stratificazione per tipo di vaccino (mRNA: r2=0.769, p< 0.0001; AdV: r2=0.880, p<0.0001) e per sesso (Femmine: r2=0.779, p<0.0001; Maschi: r2=0.847, p<0.0001). Le varianti genetiche che hanno mostrato una significativa differenza nella distribuzione dei livelli di anticorpi e che potrebbero fornire una potenziale previsione del titolo anticorpale, sono state: ABO rs657152; TP53 rs1042522; APOE rs7412/rs429358; ACE rs1799752 e ACE2 rs2285666. In particolare, le analisi di regressione e il confronto dei livelli medi degli anticorpi hanno prodotto differenze significative o apprezzabili dopo la stratificazione per genotipo/fenotipo nell'intera coorte e/o per vaccino a base di mRNA, con le seguenti significatività: ABO rs657152 (PIgG=0.007; PNAbs=0.06); TP53 rs1042522 (PIgG=0.02; PNAbs=0.04); APOE rs7412/rs429358 (PIgG=0.02; PNAbs<0.0001); ACE rs1799752 (PIgG=0.12; PNAbs=0.05); ACE2 rs2285666 (PIgG=0.009; PNAbs=0.02); gruppo sanguigno ABO (PIgG=0.005; PNAbs=0.16) e sistema Rh (PIgG=0.02; PNAbs=0.03). Per completare la nostra indagine statistica, abbiamo eseguito una regressione lineare multivariata ed una regressione logistica multivariata. Queste analisi hanno prodotto risultati significativi potenzialmente predittivi del titolo anticorpale post-vaccinazione per: ABO rs657152 (PIgG=0.006); APOE rs7412/rs429358 (PNAbs=0.012) e gruppo sanguigno ABO (PIgG<0.001; PNAbs=0.02). L’attuazione di uno screening genetico mirato potrebbe essere utile non solo per identificare i background genetici responsabili di una forte risposta immunitaria, ma allo stesso tempo potrebbe indirizzare gli individui con una risposta più debole verso un tipo di vaccino, un dosaggio e una tempistica di richiamo mirati e personalizzati. Un approccio genetico personalizzato, che tenga conto delle diversità interindividuali, è uno degli obiettivi della medicina di precisione per migliorare le presenti e future campagne vaccinali

Effluent Charges: Water Polution Control

Various schemes to abate pollution have been proposed as the answer to the problem: expansion of existing treatment facilities; imposition of heavy penalties on individual polluters; granting tax incentives to reduce pollution; an absolute prohibition on dumping of certain or all pollutants; and the imposition of effluent charges. The particular remedy that is pursued should be selected on the basis of its ability to eliminate the root causes of pollution. Therefore, before an effective solution may be formulated, it is necessary to consider the reasons for the existence of the water pollution problem

Self Defense for Women Lawyers: Enforcement of Employment Rights

Employment and a concomitant opportunity to compete on the basis of individual merit for the rewards of achievement, whether they be money, power, prestige, personal satisfaction in a job well done, or the fulfillment of broad social aims, contribute to the assertion of legitimate human needs for independence and self-respect, and contribute to the expression and realization of individual potential. Women professionals and professional employers need to understand the applicable law regarding the proof of sex discrimination, what exceptions there are to prohibited sex discrimination, the procedures for enforcing that law and the benefits or detriments to be expected from enforcement proceedings. The purpose of this commentary is to analyze the employment rights of women, the obligations of their employers under the law to afford equal employment opportunity, and the important stages and available remedies in a fair employment practices proceeding should litigation become necessary

Case 4 : Returning to Our Roots: Building Capacity in Public Health for Action on the Social Determinants of Health

Canadians are healthier than ever before, and live longer. But improvements in health are not distributed evenly between population groups. In fact, studies show that only 25% of our health is determined by health care and 15% by our genetics. The remaining 60% is determined by factors outside the traditional health care system, such as our income and social status, education, employment and working conditions, social support networks, social and physical environments, and culture. These factors are called the social determinants of health (SDOH). When these conditions are distributed in ways that are unfair, unjust, or avoidable, they are termed health inequities. These determinants can also be protective when everyone is given fair opportunities to access them. Because the SDOH cut across the purview of many sectors, such as education, health, socio-economic and public policy, understanding roles and responsibilities for health equity action remains a challenge. Within the Canadian public sector, difficulty translating health equity rhetoric into action has been noted despite the critical role public health organizations play in reducing health inequities. This case explores the development of organizational capacity to address the social determinants of health in a public health unit

A ABORDAGEM TEXTUAL NO ENSINO DE LATIM

O estudo do latim está essencialmente voltado à aquisição de uma competência receptiva escrita. Por essa razão, o ensino dessa língua antiga deve ter como objetivo principal a formação de leitores. A eficaz compreensão de textos antigos depende de um processo de aprendizagem que passe por três níveis de competência: o nível linguístico, o nível textual e o nível intertextual. Como parte desse encaminhamento metodológico para o ensino de latim, que procura estreitar o distanciamento cultural existente entre o mundo antigo e o contemporâneo, evitando anacronismos na leitura e na interpretação de textos latinos, apresentam-se estratégias que permitem trabalhar com o estudo da gramática sem dissociá-la da leitura de textos autênticos

Ensino inicial de Latim: a cultura clássica através de textos

O entendimento do latim como língua materna impõe o texto legítimo como única fonte a partir da qual é possível extrair os dados daquele sistema linguístico. Dessa perspectiva, a aquisição da competência de leitura é o principal objetivo do estudo desse idioma. O presente artigo apresenta uma proposta didática que permite, desde as lições iniciais de Latim, trabalhar com a compreensão das estruturas oracionais simples e das oposições de caso, em função das noções de texto e contexto. O material é formulado a partir de fontes originais sem a necessidade de recorrer, por um lado, a adaptações ou facilitações em latim ou, por outro, ao uso de frases isoladas de seus contextos. Com isso, busca-se garantir não apenas o entendimento das estruturas linguísticas, mas também, e sobretudo, de importantes tópicos da cultura e literatura clássicas

Erythrocyte's aging in microgravity highlights how environmental stimuli shape metabolism and morphology

The determination of the function of cells in zero-gravity conditions is a subject of interest in many different research fields. Due to their metabolic unicity, the characterization of the behaviour of erythrocytes maintained in prolonged microgravity conditions is of particular importance. Here, we used a 3D-clinostat to assess the microgravity-induced modifications of the structure and function of these cells, by investigating how they translate these peculiar mechanical stimuli into modifications, with potential clinical interest, of the biochemical pathways and the aging processes. We compared the erythrocyte's structural parameters and selected metabolic indicators that are characteristic of the aging in microgravity and standard static incubation conditions. The results suggest that, at first, human erythrocytes react to external stimuli by adapting their metabolic patterns and the rate of consumption of the cell resources. On longer timeframes, the cells translate even small differences in the environment mechanical solicitations into structural and morphologic features, leading to distinctive morphological patterns of agin