B cell response after SARS-CoV-2 mRNA vaccination in people living with HIV

Background: Limited longitudinal data are available on immune response to mRNA SARS-CoV-2 vaccination in people living with HIV (PLWHIV); therefore, new evidence on induction and persistence of spike-specific antibodies and B cells is needed. Methods: In this pilot study we investigated the spike-specific humoral and B cell responses up to six months after vaccination with two doses of mRNA vaccines in 84 PLWHIV under antiretroviral therapy compared to 79 healthy controls (HCs). Results: Spike-specific IgG persisted six months in PLWHIV with no significant differences compared to HCs, even though a significantly lower IgG response was observed in patients with CD4+ T cells < 350/mmc. The frequency of subjects with antibodies capable of inhibiting ACE2/RBD binding was comparable between PLWHIV and HCs a month after the second vaccine dose, then a higher drop was observed in PLWHIV. A comparable percentage of spike-specific memory B cells was observed at month six in PLWHIV and HCs. However, PLWHIV showed a higher frequency of spike-specific IgD- CD27- double-negative memory B cells and a significantly lower rate of IgD- CD27+ Ig-switched memory B cells compared to HCs, suggesting a reduced functionality of the antigen-specific memory B population. Conclusions: The mRNA vaccination against SARS-CoV-2 elicits humoral and B cell responses quantitatively similar between PLWHIV and HCs, but there are important differences in terms of antibody functionality and phenotypes of memory B cells, reinforcing the notion that tailored vaccination policies should be considered for these patients

Carriers of ADAMTS13 Rare Variants Are at High Risk of Life-Threatening COVID-19

Thrombosis of small and large vessels is reported as a key player in COVID-19 severity. However, host genetic determinants of this susceptibility are still unclear. Congenital Thrombotic Thrombocytopenic Purpura is a severe autosomal recessive disorder characterized by uncleaved ultra-large vWF and thrombotic microangiopathy, frequently triggered by infections. Carriers are reported to be asymptomatic. Exome analysis of about 3000 SARS-CoV-2 infected subjects of different severities, belonging to the GEN-COVID cohort, revealed the specific role of vWF cleaving enzyme ADAMTS13 (A disintegrin-like and metalloprotease with thrombospondin type 1 motif, 13). We report here that ultra-rare variants in a heterozygous state lead to a rare form of COVID-19 characterized by hyper-inflammation signs, which segregates in families as an autosomal dominant disorder conditioned by SARS-CoV-2 infection, sex, and age. This has clinical relevance due to the availability of drugs such as Caplacizumab, which inhibits vWF-platelet interaction, and Crizanlizumab, which, by inhibiting P-selectin binding to its ligands, prevents leukocyte recruitment and platelet aggregation at the site of vascular damage

An explainable model of host genetic interactions linked to COVID-19 severity

We employed a multifaceted computational strategy to identify the genetic factors contributing to increased risk of severe COVID-19 infection from a Whole Exome Sequencing (WES) dataset of a cohort of 2000 Italian patients. We coupled a stratified k-fold screening, to rank variants more associated with severity, with the training of multiple supervised classifiers, to predict severity based on screened features. Feature importance analysis from tree-based models allowed us to identify 16 variants with the highest support which, together with age and gender covariates, were found to be most predictive of COVID-19 severity. When tested on a follow-up cohort, our ensemble of models predicted severity with high accuracy (ACC = 81.88%; AUCROC = 96%; MCC = 61.55%). Our model recapitulated a vast literature of emerging molecular mechanisms and genetic factors linked to COVID-19 response and extends previous landmark Genome-Wide Association Studies (GWAS). It revealed a network of interplaying genetic signatures converging on established immune system and inflammatory processes linked to viral infection response. It also identified additional processes cross-talking with immune pathways, such as GPCR signaling, which might offer additional opportunities for therapeutic intervention and patient stratification. Publicly available PheWAS datasets revealed that several variants were significantly associated with phenotypic traits such as "Respiratory or thoracic disease", supporting their link with COVID-19 severity outcome.A multifaceted computational strategy identifies 16 genetic variants contributing to increased risk of severe COVID-19 infection from a Whole Exome Sequencing dataset of a cohort of Italian patients

Gain- and Loss-of-Function CFTR Alleles Are Associated with COVID-19 Clinical Outcomes

Carriers of single pathogenic variants of the CFTR (cystic fibrosis transmembrane conductance regulator) gene have a higher risk of severe COVID-19 and 14-day death. The machine learning post-Mendelian model pinpointed CFTR as a bidirectional modulator of COVID-19 outcomes. Here, we demonstrate that the rare complex allele [G576V;R668C] is associated with a milder disease via a gain-of-function mechanism. Conversely, CFTR ultra-rare alleles with reduced function are associated with disease severity either alone (dominant disorder) or with another hypomorphic allele in the second chromosome (recessive disorder) with a global residual CFTR activity between 50 to 91%. Furthermore, we characterized novel CFTR complex alleles, including [A238V;F508del], [R74W;D1270N;V201M], [I1027T;F508del], [I506V;D1168G], and simple alleles, including R347C, F1052V, Y625N, I328V, K68E, A309D, A252T, G542*, V562I, R1066H, I506V, I807M, which lead to a reduced CFTR function and thus, to more severe COVID-19. In conclusion, CFTR genetic analysis is an important tool in identifying patients at risk of severe COVID-19

The polymorphism L412F in TLR3 inhibits autophagy and is a marker of severe COVID-19 in males

The polymorphism L412F in TLR3 has been associated with several infectious diseases. However, the mechanism underlying this association is still unexplored. Here, we show that the L412F polymorphism in TLR3 is a marker of severity in COVID-19. This association increases in the sub-cohort of males. Impaired macroautophagy/autophagy and reduced TNF/TNFα production was demonstrated in HEK293 cells transfected with TLR3L412F-encoding plasmid and stimulated with specific agonist poly(I:C). A statistically significant reduced survival at 28 days was shown in L412F COVID-19 patients treated with the autophagy-inhibitor hydroxychloroquine (p = 0.038). An increased frequency of autoimmune disorders such as co-morbidity was found in L412F COVID-19 males with specific class II HLA haplotypes prone to autoantigen presentation. Our analyses indicate that L412F polymorphism makes males at risk of severe COVID-19 and provides a rationale for reinterpreting clinical trials considering autophagy pathways. Abbreviations: AP: autophagosome; AUC: area under the curve; BafA1: bafilomycin A1; COVID-19: coronavirus disease-2019; HCQ: hydroxychloroquine; RAP: rapamycin; ROC: receiver operating characteristic; SARS-CoV-2: severe acute respiratory syndrome coronavirus 2; TLR: toll like receptor; TNF/TNF-α: tumor necrosis factor

SARS-CoV-2 susceptibility and COVID-19 disease severity are associated with genetic variants affecting gene expression in a variety of tissues

Variability in SARS-CoV-2 susceptibility and COVID-19 disease severity between individuals is partly due to genetic factors. Here, we identify 4 genomic loci with suggestive associations for SARS-CoV-2 susceptibility and 19 for COVID-19 disease severity. Four of these 23 loci likely have an ethnicity-specific component. Genome-wide association study (GWAS) signals in 11 loci colocalize with expression quantitative trait loci (eQTLs) associated with the expression of 20 genes in 62 tissues/cell types (range: 1:43 tissues/gene), including lung, brain, heart, muscle, and skin as well as the digestive system and immune system. We perform genetic fine mapping to compute 99% credible SNP sets, which identify 10 GWAS loci that have eight or fewer SNPs in the credible set, including three loci with one single likely causal SNP. Our study suggests that the diverse symptoms and disease severity of COVID-19 observed between individuals is associated with variants across the genome, affecting gene expression levels in a wide variety of tissue types

A first update on mapping the human genetic architecture of COVID-19

peer reviewe

Discrepancies between Vaccine Documentation and Serologic Status for Diphtheria, Tetanus, and Hepatitis B in Internationally Adopted Children

Internationally Adopted Children (IAC) often show suboptimal immunisation coverage, but available data are discordant. Data at the first evaluation of 2073 IAC (median age: 6 years) referred to the Meyer Children’s University Hospital (Florence, Italy) in 2009–2019 were analysed in order to evaluate their immunisation status against diphtheria, tetanus, and hepatitis B. Negative antibody titres were observed in 11.5% of the IAC for diphtheria, 18.6% for tetanus, and 39.0% for hepatitis B. At multivariate analysis, originating from Africa was an independent risk factor for seronegativity for the three diseases (p < 0.001), while age below four years was an independent factor associated with protective immunity, only considering hepatitis B (p < 0.001). Vaccine documentation was an additional factor independently associated with protective immunity. However, a discrepancy between documentation (indicating previous vaccinations) and serology (showing negative antibody titres) was evidenced in 3.8% of the children for diphtheria, 12.6% for tetanus, and 29.6% for hepatitis B. This finding suggests that although vaccine documentation may reflect the presence of protective antibody titres, it should not be accepted as absolute evidence of protective immunity, underlining the importance of a complete assessment of immunisation status in IAC, particularly in those originating from Africa and aged over four years

THE EFFECTS OF SWITCHING FROM DOLUTEGRAVIR/ABACAVIR/LAMIVUDINE TO BICTEGRAVIR/EMTRICITABINE/TENOFOVIR ALAFENAMIDE IN VIROLOGICALLY SUPPRESSED PEOPLE LIVING WITH HIV ON NEUROPSYCHIATRIC SYMPTOMS: PRELIMINARY FINDINGS FROM A RANDOMIZED STUDY

Background: Central nervous system adverse events (AE) occur with various antiretrovirals (ARVs) and have been a cause of discontinuation of dolutegravir-containing ART, especially when used in combination with abacavir. The main aim of the study was to evaluate whether the switch to bictegravir/emtricitabine/tenofovir alafenamide (B/F/TAF arm) is associated with a reduction in severity and incidence of neuropsychiatric symptoms compared to continued dolutegravir/abacavir/lamivudine (DTG/ABC/3TC arm). Quality of life, suicide risk, cognitive impairment and other selfreported symptoms (using validated questionnaires) were also evaluated. Materials and methods: DOBINeuro is an ongoing, 12-month, open label, randomised trial enrolling PLWHIV treated with DTG/ABC/3TC for >6 months and with HIV-1 RNA (VL) <50 copies/mL for >12 months. Exclusion criteria include previous AIDS events, active alcohol intake or substance abuse, major psychiatric disorders, history of virological failure on InSTI and HBsAg+. At baseline (BL) PLWHIV were randomised to continue DTG/ABC/3TC or switch to B/F/TAF. Here we describe preliminary findings at 3 months (3M) follow-up. Results: We included 34 PLWHIV (73% males, median age 51 years, median CD4 693 cells/mm3): 17 were randomised to continue DTG/ABC/3TC and 17 to switch to B/F/TAF (Table 1). At BL, clinical and laboratory characteristics were homogeneous in the two arms; overall, 14.7% of participants showed cognitive impairment at BL (def. global Z score ≤-1) with no difference between arms. At 3 months no significant differences were observed between and within arms regarding self-reported adherence, quality of life assessment and suicide risk. Being depressed (p = 0.029) and having muscle aches (p = 0.017) were less frequently reported with B/F/TAF at 3M than at BL. VL was confirmed <50 copies/mL for all participants in both arms. Only two non-serious AE were reported: one grade 3 triglycerides with DTG/ABC/3TC and one self-limited episode of abdominal pain with B/F/TAF, which was not treatment-related and did not lead to drug discontinuation. Conclusions: Switch from DTG/ABC/3TC to B/F/TAF in virologically suppressed PLWHIV was associated with improvement in two reported symptoms. Further data from the 12-month study followup are required to evaluate the potential impact on the incidence and severity of neuropsychiatric symptoms of treatment switch to B/F/TAF compared to continued DTG/ABC/3TC

Safety and Efficacy of Outpatient Treatments for COVID-19: Real-Life Data from a Regionwide Cohort of High-Risk Patients in Tuscany, Italy (the FEDERATE Cohort)

Early COVID-19 treatments can prevent progression to severe disease. However, real-life data are still limited, and studies are warranted to monitor the efficacy and tolerability of these drugs. We retrospectively enrolled outpatients receiving early treatment for COVID-19 in 11 infectious diseases units in the Tuscany region of Italy between 1 January and 31 March 2022, when Omicron sublineages BA.1 and BA.2 were circulating. Eligible COVID-19 patients were treated with sotrovimab (SOT), remdesivir (RMD), nirmatrelvir/ritonavir (NRM/r), or molnupiravir (MOL). We gathered demographic and clinical features, 28-day outcomes (hospitalization or death), and drugs tolerability. A total of 781 patients (median age 69.9, 66% boosted for SARS-CoV-2) met the inclusion criteria, of whom 314 were treated with SOT (40.2%), 205 with MOL (26.3%), 142 with RMD (18.2%), and 120 with NRM/r (15.4%). Overall, 28-day hospitalization and death occurred in 18/781 (2.3%) and 3/781 (0.3%), respectively. Multivariable Cox regression showed that patients receiving SOT had a reduced risk of meeting the composite outcome (28-day hospitalization and/or death) in comparison to the RMD cohort, while no significant differences were evidenced for the MOL and NRM/r groups in comparison to the RMD group. Other predictors of negative outcomes included cancer, chronic kidney disease, and a time between symptoms onset and treatment administration > 3 days. All treatments showed good safety and tolerability, with only eight patients (1%) whose treatment was interrupted due to intolerance. In the first Italian multicenter study presenting real-life data on COVID-19 early treatments, all regimens demonstrated good safety and efficacy. SOT showed a reduced risk of progression versus RMD. No significant differences of outcome were observed in preventing 28-day hospitalization and death among patients treated with RMD, MOL, and NRM/r