After a decade of successful cooperation through a series of Erasmus+ projects, we sought to evaluate the long-term impact of undergraduate medical students’ participation in the Infectious Disease International I3DC/IDEAL course organized in 4 different European Institutions: Catholic University, Rome-Italy; Paris-Descartes, currently Université de Paris Cité-France, University of Edinburgh-UK, and Antwerp University-Belgium. We invited 323 I3DC/IDEAL former students to complete an online questionnaire focused on how participation in these courses influenced: (a) study approach, (b) international experience, (c) European awareness, (d) choice of career path, (e) interest in Infectious Diseases. Former I3DC/IDEAL students reported a positive impact of course participation across all surveyed domains. Overall satisfaction was high, with 90

Even though HIV-TB co-infection is an emerging public health issue among migrants in European countries, the number of related articles has shown a decreasing trend. To better estimate the extent of this problem, we analyzed 34 articles reporting both prevalence and odds ratio for HIV-TB co-infection in migrants in European countries. Heterogeneity analysis was conducted to assess potential bias, and a random-effects model was used to calculate the effect size. The overall prevalence of HIV-TB co-infection was 9

Real-life data on cefiderocol for Gram-negative infections remain limited. We aimed to evaluate factors associated with mortality in patients treated with cefiderocol either as monotherapy or combination therapy. A retrospective multicenter study using the CEFI-BAC cohort was conducted across 17 Italian centers on adults treated with cefiderocol (January 2021–February 2023). Data included patient characteristics, infections, prescriptions, end-of-treatment (EOT) outcomes, and mortality (in-hospital/30-days). Statistical comparisons were performed using Chi-square/Fisher’s tests and the Mann-Whitney U test. Factors associated with 30-days mortality were analyzed using multivariate Cox regression. Among 243 patients, 65% were male (median age 68 years). Major infections included bloodstream infections (61%, 149/243) and nosocomial pneumonia (14%, 34/243) with Acinetobacter baumannii (64%, 157/243), Pseudomonas aeruginosa (17%, 42/243), and Klebsiella spp. (23%, 57/243) as most common pathogens. Median treatment lasted 10 days (IQR 7–15) with five adverse events reported. Clinical cure at EOT was 59% (143/243). EOT mortality for all patients was 22.5% (50/243), and in- hospital mortality was 40.3% (93/243). Cefiderocol was used in combination therapy in 56% of cases (137/243), mainly for severe infections, including polymicrobial infections (34%, 46/243) and septic shock (27%, 37/243) (Table 1). Monotherapy correlated with higher comorbidity burden. EOT mortality was 17% (18/106) for monotherapy and 23% (32/137) for combination therapy, with no significant differences in in-hospital mortality (36.5%, 35/243 versus 42.9%, 58/243; P = 0.320) or hospitalisation length (40 [IQR 24–72] versus 46 days [IQR 25–76]; P = 0.340). Kaplan-Meier analysis confirmed no significant differences in 30-day mortality (Figure 1). Multivariate Cox regression identified advanced age (aHR: 1.25/year, P = 0.038), prior antibiotics (aHR: 4.31–7.50, P < 0.05), concurrent SARS-CoV-2 infection (aHR: 4.40, P < 0.01), and New Delhi Metallo-beta-lactamase NDM-type infection mechanisms (aHR: 6.42, P = 0.001) as significant predictors of 30-days mortality. The study revealed no differences in efficacy between the use of cefiderocol as monotherapy or combination therapy, despite the former being preferred in patients with more comorbidities which may reflect a cautious approach to minimize drug interactions and toxicity. The lack of significant differences between the two strategies raises questions about the best strategy in severe infections, highlighting the need for a patient individualized approach. Figure 1.30-days in-hospital survival Kaplan-Meier according to therapy (monotherapy versus combination therapy).

OBJECTIVES:This study aimed to characterise the real-world use of cefiderocol in treating Gram-negative bacterial infections (GNBIs) across Italian hospitals. METHODS:We conducted a multicentre retrospective study enrolling patients with GNBI treated with cefiderocol from January 2021 to February 2023. Statistical analyses included Kaplan-Meier survival estimates and multivariable Cox regression. A propensity score analysis with inverse probability of treatment weighting (IPTW) was also performed to compare the treatment effect of combination therapy versus monotherapy adjusting for imbalances between treatment groups. RESULTS:A total of 239 patients were included. Bloodstream infections were the most common (49.8%), followed by ventilator-associated and hospital-acquired pneumonia. Acinetobacter baumannii was the most common isolate (64.8%), followed by Klebsiella spp. (23%), Pseudomonas aeruginosa (17.6%), and Stenotrophomonas maltophilia (8.8%). Overall 30-day survival was 71% (95% CI: 65-76), with no significant differences between monotherapy and combination therapy. Independent predictors of higher 30-day mortality were: having received 2 or 3 previous lines of antibiotic therapy (aHR: 4.26, 95% CI: 1.00-18.20; aHR: 7.33, 95% CI: 1.53-35.05), SARS-CoV-2 coinfection (aHR: 4.19, 95% CI: 2.04-8.59), and isolation of NDM-producing Klebsiella spp. (aHR: 6.22, 95% CI: 2.09-18.50). CONCLUSIONS:Real-world experience supports the role of cefiderocol as a valuable option for GNBIs, with no clinical advantage of combination therapy over monotherapy. Notably, NDM-producing infections and use of cefiderocol as salvage therapy are associated with poor outcomes, highlighting the need for optimised treatment strategies.

Recombination, a process of genetic exchange between distinct organisms, has played a critical role in the emergence of SARS-CoV-2 variants such as the XEC recombinant. This study provides a detailed genomic and structural characterization of XEC, derived from the recombination of lineages KP.3.3 (donor) and KS.1.1 (acceptor). Phylogenomic analyses reveal that XEC and its descendant XEC.1 form a monophyletic clade with close evolutionary ties to KP.3.3. The genomic breakpoint, spanning nucleotide positions 22,363–22,463, marks the shift from KS.1.1 to KP.3.3 within the spike protein gene. Mutational analysis highlights shared traits with its parental lineages, including mutations associated with immune evasion, receptor affinity, and fusogenicity. Notable changes, such as Q493E and L455S, may confer unique immunogenic properties, though XEC’s overall immune escape potential is limited by the absence of new mutations in conserved epitopes. Despite these mutations, XEC demonstrates restricted geographical spread, low genetic variability, and an evolutionary trajectory indicative of an evolutionary dead-end. Bayesian Skyline Plot analysis corroborates this, showing stable but declining population size. These findings underscore the need for ongoing genomic surveillance to monitor recombinant variants’ characteristics and public health impact. This study contributes to understanding viral evolution and highlights the importance of distinguishing variants of concern from those with minimal epidemiological significance.

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection, responsible for Coronavirus Disease 2019 (COVID-19), exhibits a spectrum of clinical manifestations, ranging from asymptomatic to severe pulmonary dysfunction or death. The variability in COVID-19 severity has largely been attributed to the host's genetic characteristics, suggesting a polygenic genetic architecture, without significant strong evidence of sex-related genetic differences. In this Italian retrospective case-control study, we investigated the association between COVID-19 severity (severe vs. asymptomatic/oligosymptomatic healed individuals) and HLA gene variants, analyzed by next-generation sequencing (NGS). We identified significant HLA alleles (according to the conventional nomenclature), SNPs and haplotypes in the HLA-B, -C, -F, -DQA1, -DRB1, and -DRB5 genes associated with COVID-19 severity. Interestingly, these variants showed biological sex-related effects. Also, we identified specific haplotypes associated with COVID-19 severity that are shared by different conventional HLA alleles, indicated here as "super-haplotypes". These haplotypes had a biological sex-specific impact on disease severity and markedly increased the risk of severe COVID-19 compared to the conventional HLA alleles (odds ratio of up to 15). Our data suggest that the revision of the current HLA nomenclature may help to identify variants with a stronger effect on disease susceptibility and that association studies could benefit from the stratification of patients by biological sex. If replicated in other disease models, these findings could help to define the functional diversity in immune response between sexes, also based on the HLA system. Finally, due to the global pandemic's mortality rate, we hypothesize here that SARS-CoV-2 may have acted as a natural selection trigger, leading to a drift in HLA allelic frequencies in the general population.

The ability of recombinant, SARS-CoV-2 Spike (S) protein to modulate the production of two COVID-19 relevant, pro-inflammatory cytokines (IL-6 and IFN-γ) in PBMC cultures of healthy, pre-COVID-19 subjects was investigated. We observed that cytokine production was largely and diversely modulated by the S protein depending on antigen or mitogen stimulation, as well as on the protein source, insect (S-in) or human (S-hu) cells. While both proteins co-stimulated cytokine production by polyclonally CD3-activated T cells, PBMC activation by the mitogenic lectin Concanavalin A (Con A) was up-modulated by S-hu protein and down-modulated by S-in protein. These modulatory effects were likely mediated by the S glycans, as demonstrated by direct Con A-S binding experiments and use of yeast mannan as Con A binder. While being ineffective in modulating memory antigenic T cell responses, the S proteins and mannan were able to induce IL-6 production in unstimulated PBMC cultures and upregulate the expression of the mannose receptor (CD206), a marker of anti-inflammatory M2 macrophage. Our data point to a relevant role of N-glycans, particularly N-mannosidic chains, decorating the S protein in the immunomodulatory effects here reported. These novel biological activities of the S glycan ectodomain may add to the comprehension of COVID-19 pathology and immunity to SARS-CoV-2.

Recombination is the main contributor to RNA virus evolution, and SARS-CoV-2 during the pandemic produced several recombinants. The most recent SARS-CoV-2 recombinant is the lineage labeled XBB, also known as Gryphon, which arose from BJ.1 and BM.1.1.1. Here we performed a genome-based survey aimed to compare the new recombinant with its parental lineages that never became dominant. Genetic analyses indicated that the recombinant XBB and its first descendant XBB.1 show an evolutionary condition typical of an evolutionary blind background with no further epidemiologically relevant descendant. Genetic variability and expansion capabilities are slightly higher than parental lineages. Bayesian Skyline Plot indicates that XBB reached its plateau around October 6, 2022 and after an initial rapid growth the viral population size did not further expand, and around November 10, 2022 its levels of genetic variability decreased. Simultaneously with the reduction of the XBB population size, an increase of the genetic variability of its first sub-lineage XBB.1 occurred, that in turn reached the plateau around November 9, 2022 showing a kind of vicariance with its direct progenitors. Structure analysis indicates that the affinity for ACE2 surface in XBB/XBB.1 RBDs is weaker than for BA.2 RBD. In conclusion, at present XBB and XBB.1 do not show evidence about a particular danger or high expansion capability. Genome-based monitoring must continue uninterrupted to individuate if further mutations can make XBB more dangerous or generate new subvariants with different expansion capability.

A 24-year-old male Bangladeshi asylum seeker presented to the emergency department of Policlinico A. Gemelli of Rome, Italy with multiple nodular, pruritic lesions on both lower limbs and both elbows. We present a skin disease typical for persons living in crowded conditions.

HIV MedicineVolume 24, Issue 6 p. 760-761 LETTER TO THE EDITOR Liver fibrosis may lower PSA levels: A further reason to be wary in prostate cancer screening in men with HIV? Maria Mazzitelli, Corresponding Author Maria Mazzitelli [email protected] orcid.org/0000-0003-0263-0703 Infectious and Tropical Disease Unit, Padua University Hospital, Padua, Italy University Hospital of Padua, Padua, Italy Correspondence Maria Mazzitelli, Infectious and Tropical Disease Unit, Padua University Hospital, Padua, Italy. Email: [email protected]Search for more papers by this authorEmanuele Foca', Emanuele Foca' orcid.org/0000-0003-4395-5379 Department of Clinical and Experimental Sciences, University of Brescia, Brescia, ItalySearch for more papers by this authorMattia Prosperi, Mattia Prosperi Department of Epidemiology, University of Florida, Gainesville, Florida, USASearch for more papers by this authorRoberto Cauda, Roberto Cauda Catholic University of the Sacred Heart, Rome, Italy Fondazione Policlinico Universitario “Agostino Gemelli” IRCCS, Rome, ItalySearch for more papers by this authorDamiano Farinacci, Damiano Farinacci Fondazione Policlinico Universitario “Agostino Gemelli” IRCCS, Rome, ItalySearch for more papers by this authorValentina Iannone, Valentina Iannone Fondazione Policlinico Universitario “Agostino Gemelli” IRCCS, Rome, ItalySearch for more papers by this authorFrancesco Castelli, Francesco Castelli Department of Clinical and Experimental Sciences, University of Brescia, Brescia, ItalySearch for more papers by this authorCanio Carriero, Canio Carriero Department of Clinical and Experimental Sciences, University of Brescia, Brescia, ItalySearch for more papers by this authorAngelo Pan, Angelo Pan Infectious and Tropical Diseases Unit of Cremona, Cremona, ItalySearch for more papers by this authorAnnalisa Saracino, Annalisa Saracino Clinic of Infectious Diseases, Policlinico Hospital of Bari, Bari, ItalySearch for more papers by this authorCarlo Torti, Carlo Torti Infectious and Tropical Diseases Unit, Magna Graecia University of Catanzaro, Catanzaro, ItalySearch for more papers by this authorEugenia Quiros-Roldan, Eugenia Quiros-Roldan Department of Clinical and Experimental Sciences, University of Brescia, Brescia, ItalySearch for more papers by this author Maria Mazzitelli, Corresponding Author Maria Mazzitelli [email protected] orcid.org/0000-0003-0263-0703 Infectious and Tropical Disease Unit, Padua University Hospital, Padua, Italy University Hospital of Padua, Padua, Italy Correspondence Maria Mazzitelli, Infectious and Tropical Disease Unit, Padua University Hospital, Padua, Italy. Email: [email protected]Search for more papers by this authorEmanuele Foca', Emanuele Foca' orcid.org/0000-0003-4395-5379 Department of Clinical and Experimental Sciences, University of Brescia, Brescia, ItalySearch for more papers by this authorMattia Prosperi, Mattia Prosperi Department of Epidemiology, University of Florida, Gainesville, Florida, USASearch for more papers by this authorRoberto Cauda, Roberto Cauda Catholic University of the Sacred Heart, Rome, Italy Fondazione Policlinico Universitario “Agostino Gemelli” IRCCS, Rome, ItalySearch for more papers by this authorDamiano Farinacci, Damiano Farinacci Fondazione Policlinico Universitario “Agostino Gemelli” IRCCS, Rome, ItalySearch for more papers by this authorValentina Iannone, Valentina Iannone Fondazione Policlinico Universitario “Agostino Gemelli” IRCCS, Rome, ItalySearch for more papers by this authorFrancesco Castelli, Francesco Castelli Department of Clinical and Experimental Sciences, University of Brescia, Brescia, ItalySearch for more papers by this authorCanio Carriero, Canio Carriero Department of Clinical and Experimental Sciences, University of Brescia, Brescia, ItalySearch for more papers by this authorAngelo Pan, Angelo Pan Infectious and Tropical Diseases Unit of Cremona, Cremona, ItalySearch for more papers by this authorAnnalisa Saracino, Annalisa Saracino Clinic of Infectious Diseases, Policlinico Hospital of Bari, Bari, ItalySearch for more papers by this authorCarlo Torti, Carlo Torti Infectious and Tropical Diseases Unit, Magna Graecia University of Catanzaro, Catanzaro, ItalySearch for more papers by this authorEugenia Quiros-Roldan, Eugenia Quiros-Roldan Department of Clinical and Experimental Sciences, University of Brescia, Brescia, ItalySearch for more papers by this author First published: 02 January 2023 https://doi.org/10.1111/hiv.13456 Maria Mazzitelli and Emanuele Foca' equally contributed to this work. Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onEmailFacebookTwitterLinkedInRedditWechat No abstract is available for this article. REFERENCES 1Wang A, Lazo M, Carte HB, Groopman JH, Nelson WG, Platz EA. Association between liver fibrosis and serum PSA among U.S. men: National Health and Nutrition Examination Survey (NHANES), 2001-2010. Cancer Epidemiol Biomarkers Prev. 2019; 28: 1331-1338. 2Torti C, Raffetti E, Donato F, et al. Cohort profile: standardized Management of Antiretroviral Therapy Cohort (MASTER cohort). Int J Epidemiol. 2017; 46:e12. 3Sterling RK, Lissen E, Clumeck N, et al. Development of a simple noninvasive index to predict significant fibrosis in patients with HIV/HCV coinfection. Hepatology. 2006; 43: 1317-1325. 4Sun D, Cao M, Li H, et al. Risk of prostate cancer in men with HIV/AIDS: a systematic review and meta-analysis. Prostate Cancer Prostatic Dis. 2021; 24: 24-34. 5Ryom L, Cotter A, De Miguel R, et al. 2019 update of the European AIDS Clinical Society Guidelines for treatment of people living with HIV version 10.0. HIV Med. 2020; 21: 617-624. Volume24, Issue6June 2023Pages 760-761 ReferencesRelatedInformation

An Ivorian woman presented to us with a 2-month history of fever, abdominal pain and nausea. Human immunodeficiency virus serology was positive. Abdominal ultrasound showed enlarged abdominal lymph nodes and wall thickening of the right colon. Colonic biopsy was suggestive of fungal infection and polymerase chain reaction for Histoplasma capsulatum on biopsy was positive.

Since the beginning of the pandemic, the generation of new variants periodically recurs. The XBB.1.5 SARS-CoV-2 variant is one of the most recent. This research was aimed at verifying the potential hazard of this new subvariant. To achieve this objective, we performed a genome-based integrative approach, integrating results from genetic variability/phylodynamics with structural and immunoinformatic analyses to obtain as comprehensive a viewpoint as possible. The Bayesian Skyline Plot (BSP) shows that the viral population size reached the plateau phase on 24 November 2022, and the number of lineages peaked at the same time. The evolutionary rate is relatively low, amounting to 6.9 × 10−4 subs/sites/years. The NTD domain is identical for XBB.1 and XBB.1.5 whereas their RBDs only differ for the mutations at position 486, where the Phe (in the original Wuhan) is replaced by a Ser in XBB and XBB.1, and by a Pro in XBB.1.5. The variant XBB.1.5 seems to spread more slowly than sub-variants that have caused concerns in 2022. The multidisciplinary molecular in-depth analyses on XBB.1.5 performed here does not provide evidence for a particularly high risk of viral expansion. Results indicate that XBB.1.5 does not possess features to become a new, global, public health threat. As of now, in its current molecular make-up, XBB.1.5 does not represent the most dangerous variant.

We read with interest the Letter to the Editor Evolution of SARS-CoV-2 Omicron subvariants BF.7 and XBB.1.5: Time to follow Africa and abort all COVID restrictions by Kelleni,1Kelleni M.T. Evolution of SARS-CoV-2 Omicron subvariants BF.7 and XBB.1.5: time to follow Africa and abort all COVID restrictions.J Infect. 2023; (in press)https://doi.org/10.1016/j.jinf.2023.01.027Abstract Full Text Full Text PDF Scopus (7) Google Scholar on the need, for the global health care authorities, to carefully consider the African COVID-19 safe and effective early treatment approach. In such a context, here we report on the global epidemic trajectory of SARS-CoV-2 XBB.1.5 lineage that we believe the above Authorities should consider in taking their decisions. The phylogenomic reconstruction, available at https://gisaid.org/phylodynamics/global/nextstrain/, depicts an evolutionary pattern of XBB.1.5 very similar to that of previous, recent variants such as BA.2.75,2Scarpa F. Sanna D. Azzena I. Giovanetti M. Benvenuto D. Angeletti S. et al.On the SARS-CoV-2 BA.2.75 variant: a genetic and structural point of view.J Med Virol. 2022; 95e28119https://doi.org/10.1002/jmv.28119Crossref PubMed Scopus (14) Google Scholar BA.2.12.1 and BQ.13Centers for Disease Control and Prevention (CDC) - COVID data tracker. 〈https://covid.cdc.gov/covid-data-tracker/#variant-proportions〉, last accessed on February 6, 2023.Google Scholar that appeared as an evolutionary blind background. Notably, this pattern has also been identified for the original recombinant XBB and its first descendant XBB.1,4Scarpa F. Sanna D. Azzena I. Casu M. Cossu P. Fiori P.L. et al.Genome-based comparison between the recombinant SARS-CoV-2 XBB and its parental lineages.J Med Virol. 2023; (in press)https://doi.org/10.1002/jmv.28625Crossref Scopus (17) Google Scholar which are now known not to exhibit characteristics of epidemiologically dangerous lineages. Actually, the XBB.1.5 lineage represents the first descendant of the recombinant XBB for which threats on public health impact originally arose. As of now, it has been detected in 54 countries and its speed of diffusion prompted the WHO to revise the confidence level of the risk assessment from low (January 11, 2023) to moderate (January 25, 2022).5World Health Organization. WHO XBB.1.5 Updated Rapid Risk Assessment, 25 January 2023. 〈https://www.who.int/docs/default-source/coronaviruse/25012023xbb.1.pdf?sfvrsn=c3956081_1/Weekly〉 epidemiological update on COVID-19 - 8 February 2023. https://www.who.int/publications/m/item/weekly-epidemiological-update-on-covid-19---8-february-2023, last accessed on February 13, 2023.Google Scholar However, the Bayesian Skyline Plot (BSP) in Fig. 1 (estimated on all high-quality genomes and coverage available on January 13, 2023 form the GSAID portal (https://gisaid.org/) by following Scarpa et al.2Scarpa F. Sanna D. Azzena I. Giovanetti M. Benvenuto D. Angeletti S. et al.On the SARS-CoV-2 BA.2.75 variant: a genetic and structural point of view.J Med Virol. 2022; 95e28119https://doi.org/10.1002/jmv.28119Crossref PubMed Scopus (14) Google Scholar, 4Scarpa F. Sanna D. Azzena I. Casu M. Cossu P. Fiori P.L. et al.Genome-based comparison between the recombinant SARS-CoV-2 XBB and its parental lineages.J Med Virol. 2023; (in press)https://doi.org/10.1002/jmv.28625Crossref Scopus (17) Google Scholar, 6Scarpa F. Sanna D. Benvenuto D. Borsetti A. Azzena I. Casu M. et al.Genetic and structural data on the SARS-CoV-2 Omicron BQ.1 variant reveal its low potential for epidemiological expansion.Int J Mol Sci. 2022; 23: 15264https://doi.org/10.3390/ijms232315264Crossref PubMed Scopus (12) Google Scholar), indicates quite a low level of genetic variability with very few fluctuation points over time. The viral genetic variability and the population size peaked reaching the plateau around November 24, 2022. This substantial lack of genetic variation during the time (also depicted by branches' length in the phylogenetic tree shown in Fig. S1) is not the trend of a lineage that is about to explode in terms of population size and, accordingly, in terms of contagiousness. Indeed, at the beginning of the pandemic, the genetic variability of SARS-CoV2 ancestral strain was shortly and quickly increasing with a very vertical curve.7Lai A. Bergna A. Acciarri C. Galli M. Zehender G. Early phylogenetic estimate of the effective reproduction number of SARS‐CoV‐2.J Med Virol. 2020; 92: 675-679https://doi.org/10.1002/jmv.25723Crossref PubMed Scopus (136) Google Scholar Conversely, XBB.1.5 seems to be quite typical of an evolutionary lineage that presents new features in comparison to its direct progenitor and to other recent variants, but unable to promote an abnormal expansion. The estimated evolutionary rate for XBB.1.5 (6.9×10−4 subs/site/year) further accounts for the low genetic variability and limited capacity for strong demographic expansion. The evolutionary rate of the variant BA.5, which remained dominant worldwide for several months in 2022, was slightly higher (7.4×10−4 subs/site/year),2Scarpa F. Sanna D. Azzena I. Giovanetti M. Benvenuto D. Angeletti S. et al.On the SARS-CoV-2 BA.2.75 variant: a genetic and structural point of view.J Med Virol. 2022; 95e28119https://doi.org/10.1002/jmv.28119Crossref PubMed Scopus (14) Google Scholar but BA.5 had been circulating for several months before peaking, and its plateau phase presented several fluctuations of the viral population size.2Scarpa F. Sanna D. Azzena I. Giovanetti M. Benvenuto D. Angeletti S. et al.On the SARS-CoV-2 BA.2.75 variant: a genetic and structural point of view.J Med Virol. 2022; 95e28119https://doi.org/10.1002/jmv.28119Crossref PubMed Scopus (14) Google Scholar A direct comparison of evolutionary rates of recent versus early SARS-CoV-2 strains should be taken cautiously because of the different population susceptibilities to infection among unvaccinated, vaccinated and preinfected subjects. Nonetheless, it remains noteworthy that the evolutionary rate of the pandemic starting, SARS-CoV-2 Wuhan-Hu-1 strain, was around 6.58 × 10−3 subs/site/year,8Benvenuto D. Giovanetti M. Salemi M. Prosperi M. De Flora C. Alcantara L.C.J. et al.The global spread of 2019-nCoV: a molecular evolutionary analysis.Pathog Glob Health. 2020; 114: 64-67https://doi.org/10.1080/20477724.2020.1725339Crossref PubMed Scopus (119) Google Scholar i.e., roughly 10 times faster than XBB.1.5. The lineage XBB.1.5 presents the same point mutations of interest in the spike protein sequence as its progenitor XBB (i.e., K417N, S477N, N501Y and P681H),4Scarpa F. Sanna D. Azzena I. Casu M. Cossu P. Fiori P.L. et al.Genome-based comparison between the recombinant SARS-CoV-2 XBB and its parental lineages.J Med Virol. 2023; (in press)https://doi.org/10.1002/jmv.28625Crossref Scopus (17) Google Scholar except for mutation at position 486.9Wang Q. Iketani S. Li Z. Liu L. Guo Y. Huang Y. et al.Alarming antibody evasion properties of rising SARS-CoV-2 BQ and XBB subvariants.Cell. 2023; 186: 279-286https://doi.org/10.1016/j.cell.2022.12.018Abstract Full Text Full Text PDF PubMed Scopus (232) Google Scholar Indeed, the NTD domain is identical for XBB.1 and XBB.1.5 whereas their RBDs only differ for the mutations at position 486, where the original Wuhan Phe (conserved in BA.2) is replaced by a Ser in XBB and XBB.1,4Scarpa F. Sanna D. Azzena I. Casu M. Cossu P. Fiori P.L. et al.Genome-based comparison between the recombinant SARS-CoV-2 XBB and its parental lineages.J Med Virol. 2023; (in press)https://doi.org/10.1002/jmv.28625Crossref Scopus (17) Google Scholar and a Pro in XBB.1.5. The predicted net electrostatic charges of the RBD and NTD domains, the changes of which have been reported to impact on virus transmissibility and infectivity, are reported in Table 1. While the three XBB descendants differ from BA.2 for their negative net charge on NTD, being in this similar to the first Omicron variant, the BA.1,10Pascarella S. Ciccozzi M. Benvenuto D. Borsetti A. Cauda R. Cassone A. Peculiar variations of the electrostatic potential of spike protein N-terminal domain associated with the emergence of successive SARS-CoV-2 Omicron lineages.J Infect. 2023; 86: 66-117https://doi.org/10.1016/j.jinf.2022.07.018Abstract Full Text Full Text PDF PubMed Scopus (6) Google Scholar no evident differences between lineages XBB/XBB.1 and XBB1.5 are present in the distribution of the electrostatic surface potential of NTD and RBD. The conserved F486 in BA.2 can establish Van der Waals contacts with residues in a hydrophobic pocket on the ACE2 receptor. The substituting Ser in XBB and XBB.1 tends to destabilize the RBD-ACE2 interface by disrupting hydrophobic interactions. Consistently, the interaction BA.2 RBD-ACE2 is inferred to be the most stable among the four tested variants.Table 1Net charge of NTD and RBD for BA.2, XBB, XBB.1, and XBB.1.5.BA.2XBBXBB.1XBB.1.5NTD0.95 ± 0.041.14 ± 0.041.18 ± 0.041.18 ± 0.04RBD5.19 ± 0.015.45 ± 0.025.45 ± 0.025.42 ± 0.01 Open table in a new tab It should also pointed out that XBB.1.5, as all these recent, BA.2 and BA.5-derived Omicron subvariants, have remained so far confined to selected regional areas of the USA, despite its high transmissibility and immune-evasion potential, as reported by "COVID data tracker" of the Centers for Disease Control and Prevention (CDC).3Centers for Disease Control and Prevention (CDC) - COVID data tracker. 〈https://covid.cdc.gov/covid-data-tracker/#variant-proportions〉, last accessed on February 6, 2023.Google Scholar Thus, the data reported here and our interpretation of a limited expansion potential of XBB.1.5 appear to be well in keeping with the current epidemiological, real-world observations. In conclusion, genetic and structural analyses here presented do not provide evidence for a particularly high risk of XBB.1.5 expansion to become a new, global public health threat. The Omicron variant of concern, and more specifically BA.5 and its descendant lineages, remain the dominant variants circulating globally.5World Health Organization. WHO XBB.1.5 Updated Rapid Risk Assessment, 25 January 2023. 〈https://www.who.int/docs/default-source/coronaviruse/25012023xbb.1.pdf?sfvrsn=c3956081_1/Weekly〉 epidemiological update on COVID-19 - 8 February 2023. https://www.who.int/publications/m/item/weekly-epidemiological-update-on-covid-19---8-february-2023, last accessed on February 13, 2023.Google Scholar The variant XBB.1.5 appears to spread even more slowly than the last subvariants that have caused concerns in 2022. However, it cannot be excluded that new mutations will occur and make XBB.1.5 more dangerous. In this context, extensive genome-based monitoring must continue uninterruptedly because it is the only way to identify and/or predict important changes in the genomic composition of SARS-CoV-2. This research was funded by FONDAZIONE DI SARDEGNA bando 2022–2023 for the Dipartimento di Scienze Biomediche - UNISS (to Fabio Scarpa and Daria Sanna). Marta Giovanetti is funded by PON "Ricerca e Innovazione" 2014–2020 and by the CRP—ICGEB RESEARCH GRANT 2020 Project CRP/BRA20-03, contract CRP/20/03, Oswaldo Cruz Foundation. Stefano Pascarella is in part supported by the Sapienza grant n. RP12117A7670A1E8.

Background:Among interleukin-6 inhibitors suggested for use in COVID-19, there are few robust evidences for the efficacy of sarilumab. Herein, we evaluated the efficacy and safety of sarilumab in severe COVID-19. Methods:In this phase 3, open-labeled, randomized clinical trial, conducted at 5 Italian hospitals, adults with severe COVID-19 pneumonia (excluding mechanically ventilated) were randomized 2:1 to receive intravenous sarilumab (400 mg, repeatable after 12 h) plus standard of care (SOC) (arm A) or to continue SOC (arm B). Randomization was web-based. As post-hoc analyses, the participants were stratified according to baseline inflammatory parameters. The primary endpoint was analysed on the modified Intention-To-Treat population, including all the randomized patients who received any study treatment (sarilumab or SOC). It was time to clinical improvement of 2 points on a 7-points ordinal scale, from baseline to day 30. We used Kaplan Meier method and log-rank test to compare the primary outcome between two arms, and Cox regression stratified by clinical center and adjusted for severity of illness, to estimate the hazard ratio (HR). The trial was registered with EudraCT (2020-001390-76). Findings:Between May 2020 and May 2021, 191 patients were assessed for eligibility, of whom, excluding nine dropouts, 176 were assigned to arm A (121) and B (55). At day 30, no significant differences in the primary endpoint were found (88% [95% CI 81-94] in arm A vs 85% [74-93], HR 1.07 [0.8-1.5] in arm B; log-rank p = 0.50). After stratifying for inflammatory parameters, arm A showed higher probability of improvement than B without statistical significance in the strata with C reactive protein (CRP) < 7 mg/dL (88% [77-96] vs 79% [63-91], HR 1.55 [0.9-2.6]; log-rank p = 0.049) and in the strata with lymphocytes <870/mmc (90% [79-96]) vs (73% [55-89], HR 1.53 [0.9-2.7]; log-rank p = 0.058). Overall, 39/121 (32%) AEs were reported in arm A and 14/55 (23%) in B (p = 0.195), while serious AEs were 22/121 (18%) and 7/55 (11%), respectively (p = 0.244). There were no treatment-related deaths. Interpretation:The efficacy of sarilumab in severe COVID-19 was not demonstrated both in the overall and in the stratified for severity analysis population. Exploratory analyses suggested that subsets of patients with lower CRP values or lower lymphocyte counts might have had benefit with sarilumab treatment, but this finding would require replication in other studies. The relatively low rate of concomitant corticosteroid use, could partially explain our results. Funding:This study was supported by INMI "Lazzaro Spallanzani" Ricerca Corrente Linea 1 on emerging and reemerging infections, funded by Italian Ministry of Health.

ABSTRACTWe retrospectively studied antibody immunity in 92 candidemia patients, using sera taken at candidemia diagnosis. All patients showed the presence of IgG antibodies against all tested Candida antigens, namely Als3, Mp65, Hyr1 and Eno1, at levels significantly higher than those of non-candidemia controls. Both correlation and multivariable logistic regression analyses showed that the antibodies against Als3 and-Mp65, two known immunodominant and virulence-related proteins, were significantly associated with lower 30-day patient mortality. In particular, high titers of anti-Als3 antibodies were associated with survival in all subgroups of frail, more critical patients (over-median aged, infected by C. albicans or with septic shock) while high anti-Mp65 IgG levels were associated with survival in younger patients and in those infected by non-albicans Candida species or showing no signs of septic shock. A multivariable logistic model including anti-Als3 or anti-MP65 antibody levels and other variables, such as the serum β-glucan level at candidemia diagnosis, septic shock occurrence, the presence of diabetes, and initial antifungal treatment with fluconazole, was highly predictive of candidemia outcome, with an area under the curve of 0.85–0.86. Overall, the data demonstrate the ability of candidemia patients to mount a sustained memory antibody response to Candida antigens and that some of these responses have a sizeable impact on patient survival. Our data invite consideration of a multicenter, prospective investigation of antibody immunity in candidemia.IMPORTANCECandidemia (bloodstream invasion by Candida species) is a major fungal disease in humans. Despite the recent progress in diagnosis and treatment, therapeutic options are limited and under threat of antimicrobial resistance. The disease mortality remains high (around 40%). In contrast with deep-seated invasive candidiasis, particularly that occurring in patients with hematologic malignancies and organ transplants, patients with candidemia are often not immunocompromised and therefore able to mount memory anticandidal immune responses, perhaps primed by Candida commensalism. We investigated antibody immunity in candidemia patients and report here on the ability of these patients to produce antibodies that react with Candida antigens. In particular, the patients with high titers of IgG reactive with two immunodominant, virulence-associated antigens (Als3 and MP65) had a higher 30-day survival. If confirmed by controlled, prospective clinical studies, our data could inform the development of antibody therapy to better treat a severe fungal infection such as candidiasis.

The ongoing severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic and heterologous immunization approaches implemented worldwide for booster doses call for diversified vaccine portfolios. GRAd-COV2 is a gorilla adenovirus-based COVID-19 vaccine candidate encoding prefusion-stabilized spike. The safety and immunogenicity of GRAd-COV2 is evaluated in a dose- and regimen-finding phase 2 trial (COVITAR study, ClinicalTrials.gov: NCT04791423) whereby 917 eligible participants are randomized to receive a single intramuscular GRAd-COV2 administration followed by placebo, or two vaccine injections, or two doses of placebo, spaced over 3 weeks. Here, we report that GRAd-COV2 is well tolerated and induces robust immune responses after a single immunization; a second administration increases binding and neutralizing antibody titers. Potent, variant of concern (VOC) cross-reactive spike-specific T cell response peaks after the first dose and is characterized by high frequencies of CD8s. T cells maintain immediate effector functions and high proliferative potential over time. Thus, GRAd vector is a valuable platform for genetic vaccine development, especially when robust CD8 response is needed.

Background. SARS-CoV-2 ongoing pandemic and heterologous immunization approaches implemented worldwide for booster doses call for diversified vaccines portfolio. We report safety and immunogenicity of GRAd-COV2, a novel gorilla adenovirus-based COVID-19 vaccine, in a phase 2 trial aimed at identifying the appropriate dose and schedule. Method. 917 eligible adults aged 18 years or older, including participants with co-morbidities, were randomised to receive, 21 days apart, a single vaccine administration at 2x1011 viral particles (vp) followed by placebo, or repeated vaccine administration at 1x1011 vp, or two doses of placebo. Primary endpoints were the incidence of local and systemic solicited AEs for 7 days post each dose and the post-treatment (35 days after the first dose), geometric mean titers (GMTs) and geometric mean fold rise (GMFRs) of ELISA antibody responses to Spike protein. Additional humoral and cellular immune response parameters were monitored for up to six months. Results. The safety profile of GRAd-COV2 was characterized by short-term, mild-to-moderate pain and tenderness at injection site, fatigue, headache, malaise, and myalgia. Neither related SAEs nor deaths were reported. Humoral (binding and neutralizing) Ab responses peaked at day 35 after a single administration, were boosted by a second vaccination, were sustained until day 57 to then decline at day 180. Potent, VOC cross-reactive T cell responses peaked already after first dose with high frequencies of long-lived CD8 T cells. Conclusion. GRAd-COV2 was safe, and induced robust immune responses after a single immunization; the second administration increased humoral but not cellular immune responses.

The BQ.1 SARS-CoV-2 variant, also known as Cerberus, is one of the most recent Omicron descendant lineages. Compared to its direct progenitor BA.5, BQ.1 has some additional spike mutations in some key antigenic sites, which confer further immune escape ability over other circulating lineages. In such a context, here, we perform a genome-based survey aimed at obtaining a complete-as-possible nuance of this rapidly evolving Omicron subvariant. Genetic data suggest that BQ.1 represents an evolutionary blind background, lacking the rapid diversification that is typical of a dangerous lineage. Indeed, the evolutionary rate of BQ.1 is very similar to that of BA.5 (7.6 × 10−4 and 7 × 10−4 subs/site/year, respectively), which has been circulating for several months. The Bayesian Skyline Plot reconstruction indicates a low level of genetic variability, suggesting that the peak was reached around 3 September 2022. Concerning the affinity for ACE2, structure analyses (also performed by comparing the properties of BQ.1 and BA.5 RBD) indicate that the impact of the BQ.1 mutations may be modest. Likewise, immunoinformatic analyses showed moderate differences between the BQ.1 and BA5 potential B-cell epitopes. In conclusion, genetic and structural analyses on SARS-CoV-2 BQ.1 suggest no evidence of a particularly dangerous or high expansion capability. Genome-based monitoring must continue uninterrupted for a better understanding of its descendants and all other lineages.