Bispecific IgG neutralizes SARS-CoV-2 variants and prevents escape in mice.

Neutralizing antibodies that target the receptor-binding domain (RBD) of the SARS-CoV-2 spike protein are among the most promising approaches against COVID-191,2. A bispecific IgG1-like molecule (CoV-X2) has been developed on the basis of C121 and C135, two antibodies derived from donors who had recovered from COVID-193. Here we show that CoV-X2 simultaneously binds two independent sites on the RBD and, unlike its parental antibodies, prevents detectable spike binding to the cellular receptor of the virus, angiotensin-converting enzyme 2 (ACE2). Furthermore, CoV-X2 neutralizes wild-type SARS-CoV-2 and its variants of concern, as well as escape mutants generated by the parental monoclonal antibodies. We also found that in a mouse model of SARS-CoV-2 infection with lung inflammation, CoV-X2 protects mice from disease and suppresses viral escape. Thus, the simultaneous targeting of non-overlapping RBD epitopes by IgG-like bispecific antibodies is feasible and effective, and combines the advantages of antibody cocktails with those of single-molecule approaches.

Molecular characterization of emerging Echovirus 11 (E11) shed light on the recombinant origin of a variant associated with severe hepatitis in neonates.

Echovirus 11 (E11) has gained attention owing to its association with severe neonatal infections. Due to the limited data available, the World Health Organization (WHO) considers public health risk to the general population to be low. The present study investigated the genetic variation and molecular evolution of E11 genomes collected from May to December 2023. Whole genome sequencing (WGS) was performed for 16 E11 strains. Phylogenetic analysis on WG showed how all Italian strains belonged to genogroup D5, similarly to other E11 strains recently reported in France and Germany all together aggregated into separate clusters. A cluster-specific recombination pattern was also identified using phylogenetic analysis of different genome regions. Echovirus 6 was identified as the major recombinant virus in 3Cpro and 3Dpol regions. The molecular clock analysis revealed that the recombination event probably occurred in June 2018 (95% HPD interval: Jan 2016-Jan 2020). Shannon entropy analyses, within P1 region, showed how 11 amino acids exhibited relatively high entropy. Five of them were exposed on the canyon region which is responsible for receptor binding with the neonatal Fc receptor. The present study showed the recombinant origin of a new lineage of E11 associated with severe neonatal infections.

Epidemiological impact of human adenovirus as causative agent of respiratory infections: An Italian multicentre retrospective study, 2022-2023.

Human adenoviruses are the causative agents of 5-7% of viral respiratory infections, mainly caused by species B and C. They can infect all age groups, but children are usually at high risk of infections. Adenovirus epidemiology is well documented in East-Asian countries but little is known about adenovirus circulation in Europe in recent years. This multicentre retrospective study aimed to investigate the circulation and molecular epidemiology of hAdVs. This surveillance collected a total of 54463 respiratory specimens between January 1, 2022 and June 20, 2023 were tested for the presence of respiratory viruses. Our results showed that adenovirus was detected in 6.6 % of all cases of acute respiratory infection included in the study and the median age of positive patients was 3 years, with male children in 1-2 years age group being the most affected. 43.5 % of adenovirus cases were co-infected with at least one other respiratory virus, and rhinovirus was co-detected in 54 % of cases. Genotyping of adenovirus allowed the identification of 6 different genotypes circulating in Italy, among which type B3 was the most frequently detected.

Enhanced laboratory surveillance of respiratory infection disclosed the rapid rise of enterovirus D68 cases, northern Italy, August to September 2024.

We report a considerable increase in enterovirus D68 (EV-D68) cases since July 2024, culminating in an ongoing outbreak of acute respiratory infections in northern Italy, accounting for nearly 90% of all enterovirus infections. The outbreak was identified by community- and hospital-based surveillance systems, detecting EV-D68 in individuals with mild-to-severe respiratory infections. These strains belonged to B3 and a divergent A2 lineage. An increase in adult cases was observed. Enhanced surveillance and molecular characterisation of EV-D68 across Europe are needed.

Fulminant echovirus 11 hepatitis in male non-identical twins in northern Italy, April 2023.

Echovirus 11 (E11) has recently been associated with a series of nine neonatal cases of severe hepatitis in France. Here, we present severe hepatitis caused by E11 in a pair of twins. In one of the neonates, the clinical picture evolved to fulminant hepatitis. The E11 genome showed 99% nucleotide identity with E11 strains reported in the cases in France. Rapid genome characterisation using next generation sequencing is essential to identify new and more pathogenetic variants.

The Effect of Different Types of Prostate Biopsy Techniques on Post-Biopsy Infectious Complications.

PURPOSE: The aim of our study was to compare infectious complication rates between different prostate biopsy techniques with various number of biopsy cores. MATERIALS AND METHODS: In this retrospective study, all patients from 2 hospitals who underwent prostate biopsy between 2012 and 2019 were identified. Cohorts with different types of prostate biopsies were compiled within these hospitals. Primary outcome measure was any registered infectious complication within 7 days post-biopsy. Secondary outcomes were infectious complications within 30 days, hospitalization and bacteremia. To compare the risk of infection following different prostate biopsy techniques, data was fitted into a logistic regression model adjusting for potential confounders. RESULTS: In total, 4,233 prostate biopsies in 3,707 patients were included. After systematic transrectal ultrasound-guided prostate biopsy (TRUSPB; 12±1.4 biopsy cores), 4.0% (2,607) of all patients had infectious complications within 7 days post-biopsy. Transperineal magnetic resonance imaging (MRI)-ultrasound fusion guided prostate biopsy (16±3.7 biopsy cores) was associated with significantly lower infection rates than systematic TRUSPB (adjusted OR: 0.29 [0.09-0.73] 95% confidence interval [CI]). Transrectal targeted MRI-ultrasound fusion guided prostate biopsy (3.1±0.8 biopsy cores) and transrectal targeted in-bore MRI guided prostate biopsy (2.8±0.8 biopsy cores) also showed fewer infectious complications than systematic TRUSPB (adjusted OR: 0.41 [0.12-1.12] 95% CI and 0.68 [0.37-1.20] 95% CI, respectively). CONCLUSIONS: Transperineal prostate biopsy, or transrectal prostate biopsy with reduced number of biopsy cores, could lower the risk of infectious complications.

SARS-CoV-2 infections in pediatric patients: A comparison of three pandemic waves.

The pediatric population seems to be at a lower risk of developing severe clinical symptoms of COVID-19. However, the clinical and epidemiological characteristics of COVID-19 in children are yet to be fully clarified. This retrospective observational study aimed to evaluate the frequency of pediatric laboratory-confirmed COVID-19 patients from February 2020 to April 2021. A total of 740 (5.1% of total) pediatric COVID-19 cases were observed during the study period. The peak of pediatric cases was observed in November 2020, with 239 cases. During the first wave of pandemics, the frequency of pediatric cases was 0.89% (49/5877 cases), ranging from 0.6% in February 2020 to 1.3% in April 2020. On the contrary, after the beginning of the second wave, the frequency of pediatric cases raised from 5.3% in September 2020 to 9.4%in February 2021, with an overall frequency of 8.2% (690/8416 cases). A different rate of SARS-CoV-2 circulation was observed among the pediatric population between the pandemic waves. During the second wave, two peaks of cases were observed. The last peak was associated with the spread of a more transmissive SARS-CoV-2 strain (VOC 202012/01).

Spread of multiple SARS-CoV-2 lineages April-August 2020 anticipated the second pandemic wave in Lombardy (Italy).

During the early phase of the pandemic (20 February-4 April 2020), we have investigated the temporal and geographical evolution of the virus in Lombardy showing the circulation of at least seven lineages distributed differently in the Region. In the present study, the molecular epidemiology of SARS-CoV-2 was monitored in a period between two pandemic waves in order to track the circulation of new variants (April-August 2020). A great majority of SARS-CoV-2 strains (70.8%) belonged to lineages B, B.1, B.1.1 and B.1.1.1, and five strains belonging to four lineages were already reported in Italy (B.1.1.148, B.1.1.162, B.1.1.71, and B.1.425). In addition, 21 SARS-CoV-2 strains belonged to six lineages not previously observed in Italy were detected. No variants of concern were observed. A total of 152/1274 (11.3%) amino acid changes were observed among spike gene sequences and only 26/152 (17.1%) occurred in the receptor-binding domain region of the spike protein. Results of this study are indicative of ongoing transmission throughout the lockdown period, rather than re-introduction of novel lineages past lockdown. The use of molecular epidemiology in Italy should be promoted in order to provide additional understanding of the transmission of the disease and to have major effect on controlling the spread of disease.

Multiple N-of-1 trials to investigate hypoxia therapy in Parkinson's disease: study rationale and protocol.

BACKGROUND: Parkinson's disease (PD) is a neurodegenerative disease, for which no disease-modifying therapies exist. Preclinical and clinical evidence suggest that hypoxia-based therapy might have short- and long-term benefits in PD. We present the contours of the first study to assess the safety, feasibility and physiological and symptomatic impact of hypoxia-based therapy in individuals with PD. METHODS/DESIGN: In 20 individuals with PD, we will investigate the safety, tolerability and short-term symptomatic efficacy of continuous and intermittent hypoxia using individual, double-blind, randomized placebo-controlled N-of-1 trials. This design allows for dose finding and for including more individualized outcomes, as each individual serves as its own control. A wide range of exploratory outcomes is deployed, including the Movement Disorders Society Unified Parkinson's Disease Rating scale (MDS-UPDRS) part III, Timed Up & Go Test, Mini Balance Evaluation Systems (MiniBES) test and wrist accelerometry. Also, self-reported impression of overall symptoms, motor and non-motor symptoms and urge to take dopaminergic medication will be assessed on a 10-point Likert scale. As part of a hypothesis-generating part of the study, we also deploy several exploratory outcomes to probe possible underlying mechanisms of action, including cortisol, erythropoietin and platelet-derived growth factor ß. Efficacy will be assessed primarily by a Bayesian analysis. DISCUSSION: This evaluation of hypoxia therapy could provide insight in novel pathways that may be pursued for PD treatment. This trial also serves as a proof of concept for deploying an N-of-1 design and for including individualized outcomes in PD research, as a basis for personalized treatment approaches. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT05214287 (registered January 28, 2022).

Impact of Key Assumptions About the Population Biology of Soil-Transmitted Helminths on the Sustainable Control of Morbidity.

The design and evaluation of control programs for soil-transmitted helminths (STHs) is based on surveillance data recording measurements of egg counts in the stool of infected individuals, which underpin estimates of the prevalence and average intensity of infection. There is considerable uncertainty around these measurements and their interpretation. The uncertainty is composed of several sources of measurement error and the limit of detection of fecal smear tests on the one hand, and key assumptions on STH biology on the other hand, including assumptions on the aggregation of worms within hosts and on the impact of density-dependent influences on worm reproduction. Using 2 independently developed models of STH transmission we show how different aspects of STH biology and human behavior impact on STH surveillance and control programs and how accounting for uncertainty can help to develop optimal and sustainable control strategies to meet the World Health Organization (WHO) morbidity target for STHs.

Predicted Impact of COVID-19 on Neglected Tropical Disease Programs and the Opportunity for Innovation.

Due to the COVID-19 pandemic, many key neglected tropical disease (NTD) activities have been postponed. This hindrance comes at a time when the NTDs are progressing towards their ambitious goals for 2030. Mathematical modelling on several NTDs, namely gambiense sleeping sickness, lymphatic filariasis, onchocerciasis, schistosomiasis, soil-transmitted helminthiases (STH), trachoma, and visceral leishmaniasis, shows that the impact of this disruption will vary across the diseases. Programs face a risk of resurgence, which will be fastest in high-transmission areas. Furthermore, of the mass drug administration diseases, schistosomiasis, STH, and trachoma are likely to encounter faster resurgence. The case-finding diseases (gambiense sleeping sickness and visceral leishmaniasis) are likely to have fewer cases being detected but may face an increasing underlying rate of new infections. However, once programs are able to resume, there are ways to mitigate the impact and accelerate progress towards the 2030 goals.

Mapping and characterising areas with high levels of HIV transmission in sub-Saharan Africa: A geospatial analysis of national survey data.

BACKGROUND: In the generalised epidemics of sub-Saharan Africa (SSA), human immunodeficiency virus (HIV) prevalence shows patterns of clustered micro-epidemics. We mapped and characterised these high-prevalence areas for young adults (15-29 years of age), as a proxy for areas with high levels of transmission, for 7 countries in Eastern and Southern Africa: Kenya, Malawi, Mozambique, Tanzania, Uganda, Zambia, and Zimbabwe. METHODS AND FINDINGS: We used geolocated survey data from the most recent United States Agency for International Development (USAID) demographic and health surveys (DHSs) and AIDS indicator surveys (AISs) (collected between 2008-2009 and 2015-2016), which included about 113,000 adults-of which there were about 53,000 young adults (27,000 women, 28,000 men)-from over 3,500 sample locations. First, ordinary kriging was applied to predict HIV prevalence at unmeasured locations. Second, we explored to what extent behavioural, socioeconomic, and environmental factors explain HIV prevalence at the individual- and sample-location level, by developing a series of multilevel multivariable logistic regression models and geospatially visualising unexplained model heterogeneity. National-level HIV prevalence for young adults ranged from 2.2% in Tanzania to 7.7% in Mozambique. However, at the subnational level, we found areas with prevalence among young adults as high as 11% or 15% alternating with areas with prevalence between 0% and 2%, suggesting the existence of areas with high levels of transmission Overall, 15.6% of heterogeneity could be explained by an interplay of known behavioural, socioeconomic, and environmental factors. Maps of the interpolated random effect estimates show that environmental variables, representing indicators of economic activity, were most powerful in explaining high-prevalence areas. Main study limitations were the inability to infer causality due to the cross-sectional nature of the surveys and the likely under-sampling of key populations in the surveys. CONCLUSIONS: We found that, among young adults, micro-epidemics of relatively high HIV prevalence alternate with areas of very low prevalence, clearly illustrating the existence of areas with high levels of transmission. These areas are partially characterised by high economic activity, relatively high socioeconomic status, and risky sexual behaviour. Localised HIV prevention interventions specifically tailored to the populations at risk will be essential to curb transmission. More fine-scale geospatial mapping of key populations,-such as sex workers and migrant populations-could help us further understand the drivers of these areas with high levels of transmission and help us determine how they fuel the generalised epidemics in SSA.

Rotavirus molecular epidemiology in hospitalized patients, Northern Italy, 2015-2018.

About 15,000 hospitalizations due to group A Rotavirus gastroenteritis (RVA) are recorded each year in Italy. In the present study, we report the seasonal distribution and molecular characterization of RVA in pediatric and adult hospitalized patients in the period September 2015-April 2018 in Pavia province, Lombardy Region. During the study period, stool samples of 1450 patients with acute gastroenteritis were analyzed and 122 were RVA positive, the majority belonging to pediatric patients (94.0%) while only a minority of patients (6.0%) were adults. G3P[8], G1P[8], G9P[8] and G2P[4] were the most detected RVA strains, with a prevalence of 82.4%. However, a variety of RVA strains circulated in Northern Italy in hospitalized patients over a period of three years, emphasizing distinct patterns of distribution in different age groups and between years.

Emergence of divergent enterovirus (EV) D68 sub-clade D1 strains, northern Italy, September to October 2018.

Between September and October 2018, an enterovirus D68 (EV-D68) outbreak occurred in patients hospitalised with severe acute respiratory infection in northern Italy; 21 laboratory-confirmed cases were reported. Phylogenetic analysis revealed that 16/20 of the EV-D68 sequences belonged to a divergent group within the sub-clade D1. Since its upsurge, EV-D68 has undergone rapid evolution with the emergence of new viral variants, emphasising the need for molecular surveillance that include outpatients with respiratory illness.

Molecular Characterization of Influenza Strains in Patients Admitted to Intensive Care Units during the 2017-2018 Season.

This study aimed at assessing the frequency and the distribution of influenza virus types/subtypes in 172 laboratory-confirmed influenza-positive patients admitted to intensive care units (ICUs) during the 2017-2018 season in the Lombardy region (Northern Italy), and to investigate the presence of molecular pathogenicity markers. A total of 102/172 (59.3%) patients had influenza A infections (83 A/H1N1pdm09, 2 H3N2 and 17 were untyped), while the remaining 70/172 (40.7%) patients had influenza B infections. The 222G/N mutation in the hemagglutinin gene was identified in 33.3% (3/9) of A/H1N1pdm09 strains detected in the lower respiratory tract (LRT) samples and was also associated with more severe infections, whereas no peculiar mutations were observed for influenza B strains. A single-point evolution was observed in site 222 of A/H1N1pdm09 viruses, which might advantage viral evolution by favouring virus binding and replication in the lungs. Data from 17 paired upper respiratory tract (URT) and LRT samples showed that viral load in LRT samples was mostly higher than that detected in URT samples. Of note, influenza viruses were undetectable in 35% of paired URT samples. In conclusion, LRT samples appear to provide more accurate clinical information than URT samples, thus ensuring correct diagnosis and appropriate treatment of patients with severe respiratory infections requiring ICU admission.

Inference of Transmission Network Structure from HIV Phylogenetic Trees.

Phylogenetic inference is an attractive means to reconstruct transmission histories and epidemics. However, there is not a perfect correspondence between transmission history and virus phylogeny. Both node height and topological differences may occur, depending on the interaction between within-host evolutionary dynamics and between-host transmission patterns. To investigate these interactions, we added a within-host evolutionary model in epidemiological simulations and examined if the resulting phylogeny could recover different types of contact networks. To further improve realism, we also introduced patient-specific differences in infectivity across disease stages, and on the epidemic level we considered incomplete sampling and the age of the epidemic. Second, we implemented an inference method based on approximate Bayesian computation (ABC) to discriminate among three well-studied network models and jointly estimate both network parameters and key epidemiological quantities such as the infection rate. Our ABC framework used both topological and distance-based tree statistics for comparison between simulated and observed trees. Overall, our simulations showed that a virus time-scaled phylogeny (genealogy) may be substantially different from the between-host transmission tree. This has important implications for the interpretation of what a phylogeny reveals about the underlying epidemic contact network. In particular, we found that while the within-host evolutionary process obscures the transmission tree, the diversification process and infectivity dynamics also add discriminatory power to differentiate between different types of contact networks. We also found that the possibility to differentiate contact networks depends on how far an epidemic has progressed, where distance-based tree statistics have more power early in an epidemic. Finally, we applied our ABC inference on two different outbreaks from the Swedish HIV-1 epidemic.

Revisiting the impact of Schistosoma mansoni regulating mechanisms on transmission dynamics using SchiSTOP, a novel modelling framework.

BACKGROUND: The transmission cycle of Schistosoma is remarkably complex, including sexual reproduction in human hosts and asexual reproduction in the intermediate host (freshwater snails). Patterns of rapid recrudescence after treatment and stable low transmission are often observed, hampering the achievement of control targets. Current mathematical models commonly assume regulation of transmission to occur at worm level through density-dependent egg production. However, conclusive evidence on this regulating mechanism is weak, especially for S. mansoni. In this study, we explore the interplay of different regulating mechanisms and their ability to explain observed patterns in S. mansoni epidemiology. METHODOLOGY/PRINCIPAL FINDINGS: We developed SchiSTOP: a hybrid stochastic agent-based and deterministic modelling framework for S. mansoni transmission in an age-structured human population. We implemented different models with regulating mechanisms at: i) worm-level (density-dependent egg production), ii) human-level (anti-reinfection immunity), and iii) snail-level (density-dependent snail dynamics). Additionally, we considered two functional choices for the age-specific relative exposure to infection. We assessed the ability of each model to reproduce observed epidemiological patterns pre- and post-control, and compared successful models in their predictions of the impact of school-based and community-wide treatment. Simulations confirmed that assuming at least one regulating mechanism is required to reproduce a stable endemic equilibrium. Snail-level regulation was necessary to explain stable low transmission, while models combining snail- and human-level regulation with an age-exposure function informed with water contact data were successful in reproducing a rapid rebound after treatment. However, the predicted probability of reaching the control targets varied largely across models. CONCLUSIONS/SIGNIFICANCE: The choice of regulating mechanisms in schistosomiasis modelling largely determines the expected impact of control interventions. Overall, this work suggests that reaching the control targets solely through mass drug administration may be more challenging than currently thought. We highlight the importance of regulating mechanisms to be included in transmission models used for policy.

A new case of Echovirus 11 neonatal fulminant hepatitis involving male twins in a Northern Italy Tertiary University Hospital: Insight on a possible immunological clue.

The European Center for Disease Prevention and Control has reported 19 cases of severe echovirus 11 infections in neonates since 2022, nine of which were fatal. We report a new fatal neonatal case that occurred in a male twin for which we evaluated the respiratory and intestinal mucosal innate immune response.