The decline of COVID-19 severity and lethality over two years of pandemic

Undernotification of SARS-CoV-2 infections has been a major obstacle to the tracking of critical quantities such as infection attack rates and the probability of severe and lethal outcomes. We use a model of SARS-CoV-2 transmission and vaccination informed by epidemiological and genomic surveillance data to estimate the number of daily infections occurred in Italy in the first two years of pandemic. We estimate that the attack rate of ancestral lineages, Alpha, and Delta were in a similar range (10-17%, range of 95% CI: 7-23%), while that of Omicron until February 20, 2022, was remarkably higher (51%, 95%CI: 33-70%). The combined effect of vaccination, immunity from natural infection, change in variant features, and improved patient management massively reduced the probabilities of hospitalization, admission to intensive care, and death given infection, with 20 to 40-fold reductions during the period of dominance of Omicron compared to the initial acute phase.

Effectiveness of vaccination against SARS-CoV-2 Omicron variant infection, symptomatic disease, and hospitalisation: a systematic review and meta-analysis.

BackgroundThe rapid rise of Sars-Cov2 B.1.1.529 variant (named Omicron) in the late November 2021 prompted the health authorities to estimate the potential impact on the existing countermeasures, including vaccines. This meta-analysis aims to assess the effectiveness of the current Sars-Cov2 vaccine regimens against laboratory-confirmed Omicron infection. A secondary endpoint aims to investigate the waning effectiveness of primary vaccination against symptomatic Omicron infection and related hospitalization. MethodsThe systematic review started on December 1, 2021 and was concluded on March 1, 2022. Random-effects (RE) frequentist meta-analyses are performed to estimate the primary vaccination course and the booster dose effectiveness against Omicron. Multiple meta-regressions are performed under mixed-effects model. This study is registered with PROSPERO, CRD42021240143. FindingsIn total, 15 out of 502 records are included in the quantitative synthesis. The meta-analysis on B.1.1.529 infection risk produces an OR=0{middle dot}69 (95%CI: 0{middle dot}57 to 0{middle dot}83; {tau}2=0{middle dot}225; I2=99{middle dot}49%) after primary vaccination and an OR=0{middle dot}30 (95%CI: 0{middle dot}23 to 0{middle dot}39; {tau}2=0{middle dot}469; I2=99{middle dot}33%) after one additional booster dose. According to the multiple meta-regression models, one booster dose significantly decreases by 69% the risk of symptomatic Omicron infection (OR=0{middle dot}31; 95%CI: 0{middle dot}23 to 0{middle dot}40) and by 88% the risk of hospitalization (OR=0{middle dot}12; 95%CI: 0{middle dot}08 to 0{middle dot}19) with respect to unvaccinated. Six months after primary vaccination, the average risk reduction declines to 22% (OR=0{middle dot}78; 95%CI: 0{middle dot}69 to 0{middle dot}88) against symptomatic infection and to 55% against hospitalization (OR=0{middle dot}45; 95%CI: 0{middle dot}30 to 0{middle dot}68). InterpretationDespite the high heterogeneity, this study confirms that primary vaccination does not provide sufficient protection against symptomatic Omicron infection. Although the effectiveness of the primary vaccination against hospitalization due to Omicron remains significantly above 50% after 3 months, it dramatically fades after 6 months. Therefore, the administration of one additional booster dose is recommended within 6 months and provides a 76% decrease in the odds of symptomatic Omicron after five months. FundingThere was no funding source for this study. ARTICLE HIGHLIGHTSO_LIthe primary vaccination decreases the risk of Omicron infection by 31%, while one additional booster dose decreases the risk by 70% C_LIO_LIthe primary vaccination course reduces the risk of symptomatic Omicron infection by 24% and the risk of hospitalization by 50% C_LIO_LIone additional booster dose decreases by 69% the risk of symptomatic Omicron infection and the risk of hospitalization by 88% C_LIO_LIthe effectiveness of the primary vaccination against hospitalization dramatically wanes after 3 months from vaccination, reaching a minimum of 45% in risk reduction after more than 6 months C_LI PANEL: research in contextO_ST_ABSEvidence before this studyC_ST_ABSOmicron variants higher transmissibility combined with an increased risk of infection among individuals vaccinated with primary vaccination have prompted health authorities to introduce a booster vaccination. The systematic review including "vaccine effectiveness", "Covid-19", "SARS-CoV-2", and "Omicron" search terms, is performed over three web engines and one early stage research platform (i.e., WHO COVID-19 DATABASE, PubMed, medRxiv + bioRxiv) Additionally, all relevant web sources reporting living data on vaccine effectiveness (i.e., https://view-hub.org/covid-19/ and https://covid-nma.com/), electronic databases and grey literature are considered. The last search update was on March 1, 2022. No country, language, study design restrictions are applied. Added value of this studyPrimary vaccination provides relatively low protection against the Omicron VOC, while one additional booster dose decreased substantially the risk of symptomatic Omicron infection and of hospitalization. Implications of all the available evidenceThe booster dose should be recommended after three months and no later than six months after the primary course vaccination, in order to avoid severe consequences, in particular among the elderly population.

Tracking the progressive spread of the SARS-CoV-2 Omicron variant in Italy, December 2021 - January 2022

The SARS-CoV-2 variant of concern Omicron was first detected in Italy in November 2021. Data from three genomic surveys conducted in Italy between December 2021 and January 2022 suggest that Omicron became dominant in less than one month (prevalence on January 3: 78.6%-83.8%) with a doubling time of 2.7-3.1 days. The mean net reproduction number rose from about 1.15 in absence of Omicron to a peak of 1.83 for symptomatic cases and 1.33 for hospitalized cases, while it remained stable for critical cases.

Inhibiting LSD1 suppresses coronavirus-induced inflammation but spares innate antiviral activity

Tissue-resident macrophages exert critical but conflicting effects on the progression of coronavirus infections by secreting both anti-viral type I Interferons and tissue-damaging inflammatory cytokines. Steroids, the only class of host-targeting drugs approved for Covid19, indiscriminately suppress both responses, possibly impairing viral clearance, and provide limited clinical benefit. Here we set up a mouse in vitro co-culture system that reproduces the macrophage response to SARS-CoV2 seen in patients and allows quantitation of inflammatory and antiviral activities. We show that the NFKB-dependent inflammatory response can be selectively inhibited by ablating the lysine-demethylase LSD1, which additionally unleashed interferon-independent ISG activation and blocked viral egress through the lysosomal pathway. These results provide a rationale for repurposing LSD1 inhibitors, a class of drugs extensively studied in oncology, for Covid-19 treatment. One-Sentence SummaryTargeting a chromatin-modifying enzyme in coronavirus infections curbs tissue-damage without affecting antiviral response

Differential plasmacytoid dendritic cell phenotype and type I Interferon response in asymptomatic and severe COVID-19 infection

SARS-CoV-2 fine-tunes the interferon (IFN)-induced antiviral responses, which play a key role in preventing coronavirus disease 2019 (COVID-19) progression. Indeed, critically ill patients show an impaired type I IFN response accompanied by elevated inflammatory cytokine and chemokine levels, responsible for cell and tissue damage and associated multi-organ failure. Here, the early interaction between SARS-CoV-2 and immune cells was investigated by interrogating an in vitro human peripheral blood mononuclear cell (PBMC)-based experimental model. We found that, even in absence of a productive viral replication, the virus mediates a vigorous TLR7/8-dependent production of both type I and III IFNs and inflammatory cytokines and chemokines, known to contribute to the cytokine storm observed in COVID-19. Interestingly, we observed how virus-induced type I IFN secreted by PBMC enhances anti-viral response in infected lung epithelial cells, thus, inhibiting viral replication. This type I IFN was released by plasmacytoid dendritic cells (pDC) via an ACE-2-indipendent mechanism. Viral sensing regulates pDC phenotype by inducing cell surface expression of PD-L1 marker, a feature of type I IFN producing cells. Coherently to what observed in vitro, asymptomatic SARS-CoV-2 infected subjects displayed a similar pDC phenotype associated to a very high serum type I IFN level and induction of anti-viral IFN-stimulated genes in PBMC. Conversely, hospitalized patients with severe COVID-19 display very low frequency of circulating pDC with an inflammatory phenotype and high levels of chemokines and pro-inflammatory cytokines in serum. This study further shed light on the early events resulting from the interaction between SARS-CoV-2 and immune cells occurring in vitro and confirmed ex vivo. These observations can improve our understanding on the contribution of pDC/type I IFN axis in the regulation of the anti-viral state in asymptomatic and severe COVID-19 patients. Author summarySARS-CoV-2 pandemic has resulted in millions of infections and deaths worldwide, yet the role of host innate immune responses in COVID-19 pathogenesis remains only partially characterized. Innate immunity represents the first line of host defense against viruses. Upon viral recognition, the secretion of type I and III interferons (IFN) establishes the cellular state of viral resistance, and contributes to induce the specific adaptive immune responses. Moving from in vitro evidences on the protective role played by plasmacytoid dendritic cells (pDC)-released type I IFN in the early phase of SARS-CoV-2 infection, here we characterized ex vivo the pDC phenotype and the balance between anti-viral and pro-inflammatory cytokines of COVID-19 patients stratified according to disease severity. Our study confirms in COVID-19 the crucial and protective role of pDC/type I IFN axis, whose deeper understanding may contribute to the development of novel pharmacological strategies and/or host-directed therapies aimed at boosting pDC response since the early phases of SARS-CoV-2 infection.

Co-circulation of SARS-CoV-2 variants B.1.1.7 and P.1

SARS-CoV-2 variants of concern (B.1.1.7, P.1 and B.1.351) have emerged in different continents of the world. To date, little information is available on their ecological interactions. Based on two genomic surveillance surveys conducted on February 18 and March 18, 2021 across the whole Italian territory and covering over 3,000 clinical samples, we found significant co-circulation of B.1.1.7 and P.1. We showed that B.1.1.7 was already dominant on February 18 in a majority of regions/autonomous provinces (national prevalence 54%) and almost completely replaced historical lineages by March 18 (dominant in all regions/autonomous provinces, national prevalence 86%). At the same time, we found a substantial proportion of cases of the P.1 lineage on February 18, almost exclusively in Central Italy (with an overall prevalence in the macro-area of 18%), which remained at similar values on March 18, suggesting the inability by this lineage to outcompete B.1.1.7. Only 9 cases from variant B.1.351 were identified in the two surveys. At the national level, we estimated a mean relative transmissibility of B.1.1.7 (compared to historical lineages) ranging between 1.55 and 1.57 (with confidence intervals between 1.45 and 1.66). The relative transmissibility of P.1 estimated at the national level varied according to the assumed degree of cross-protection granted by infection with other lineages and ranged from 1.12 (95%CI 1.03-1.23) in the case of complete immune evasion by P.1 to 1.39 (95%CI 1.26-1.56) in the case of complete cross-protection. These observations may have important consequences on the assessment of future pandemic scenarios.

Return to normal: COVID-19 vaccination under mitigation measures

Vaccination campaigns against COVID-19 are allowing the progressive release of physical distancing restrictions in many countries. However, the global spread of the highly transmissible Delta variant has likely suppressed the residual chances of SARS-CoV-2 elimination through herd immunity alone. Here we assess the impact of the vaccination program in Italy since its start on December 27, 2020 and evaluate possible prospects for reopening the society while at the same time keeping COVID-19 under control. To this aim, we propose a mathematical modeling framework where levels of social activity are adjusted to match the time-series of the net reproduction number as estimated from surveillance data. We compared the estimated level of social contacts, number of deaths, and transmission potential with those of a counterfactual scenario where the same epidemic trajectory is obtained in absence of vaccination. We then evaluate the prospective impact of different scenarios of vaccination coverage and different social activity levels on SARS-CoV-2 reproduction number. We estimate that by June 30, 2021, the COVID-19 vaccination program allowed the resumption of about half the social contacts that were recorded in pre-pandemic times; in absence of vaccination, only about one third could have been resumed to obtain the same number of cases, with the added cost of about 12,100 (95%CI: 6,600-21,000) extra deaths (+27%; 95%CI: 15-47%) between December 27, 2020 and June 30, 2021. We show that the negative effect of the Delta variant diffusion in July was entirely offset by vaccination in the month of July and August 2021. Finally, we estimate that a complete return to the pre-pandemic life could be safely attained only if >90%, including children from 5 years on, will be vaccinated using mRNA vaccines developed in 2020. In any case, increasing the vaccination coverage will allow further margins for societal reopening even in absence of a pediatric vaccine. These results may support the definition of vaccination targets for countries that have already achieved a broad population coverage.

Longevity of seropositivity and neutralizing titers among SARS-CoV-2 infected individuals after 4 months from baseline: a population-based study in the province of Trento

BackgroundThere are conflicting results about the duration of antibodies induced by SARS-CoV-2, but several studies show a rapid decay in a few months after infection. To evaluate antibody decline, we re-evaluated the presence of anti-SARS-CoV-2 antibodies among individuals found seropositive in a first population survey conducted 4 months before. MethodsAll individuals above ten years of age resident in 5 municipalities of the Autonomous Province of Trento, northern Italy, who resulted IgG positive for anti-SARS-CoV-2 nucleocapsid (NC) antibodies in a serosurvey conducted on May 2020 were retested after 4 months. Anti-SARS-CoV-2 antibodies were detected using the Abbott SARS-CoV-2 IgG assay (Abbott Diagnostics, USA) detecting anti-NC antibodies. Samples that gave a negative result were re-tested using the same test plus Liaison SARS-CoV-2 IgG assay (DiaSorin, Italy) to assess anti-spike (S) S1/S2 IgG antibodies. Seroprevalence was calculated as the proportion of positive people on the total number of tested. A neutralizing assay was performed on a subgroup of formerly positives sera using fifty-percent tissue culture infective dose (TCID50) as endpoint dilution to produce a cytopathic effect in 50% of inoculated Vero E6 cells culture. In all the analyses a p value < 0.05 were considered statistically significant. Statistical analysis was performed by STATA version 16.1 (STATA Corp., College Station, Texas, USA). FindingsOverall, 1159 out of 1402 initially anti-NC seropositive participants were enrolled in the study. Of them, 480 (41.1%) became seronegative for anti-NC IgG antibodies. When 479 negative sera were tested for anti-S IgG, 373 samples (77.9%) resulted positives. A functional neutralization assay was performed on 106 sera showing high concordance with anti-S antibodies positivity. InterpretationA decline of anti-NC IgG values was recorded 4 months after the first evaluation. Worth of note, a high proportion of anti-NC seronegative individuals were positive for anti-spike IgG antibodies, which appear to persist longer and to better correlate with neutralization activity.

Rapid inactivation of SARS-CoV-2 with LED irradiation of visible spectrum wavelenghts

The COVID-19 pandemic has caused a global health crisis. The difficulty to control the viral spread due to the absence of vaccines and prophylactics measures has raised concerns about prevention and control of SARS-CoV-2. Therefore, it becomes more and more crucial the reduction of environmental risk factors through viral inactivation of aerosols and fomites. Photodynamic inactivation of microorganisms by light energy emitted in the visible spectrum region (VIS), not harmful for mammalian cells and safe for humans, has recently been described. A LED-device emitting a special combination of frequencies in the visible light spectrum was tested on SARS-CoV-2 infected cell surnatant dilutions in order to evaluate the antiviral efficacy. This preliminary in vitro study showed for the first time the ability to inactivate SARS-CoV-2 through LED irradiation of visible spectrum wavelengths. If further and more extensive studies will confirm these data, the usage of this LED could potentially have a big impact on the sanitization of virtually all human environments.

Epidemiological characteristics of COVID-19 cases in Italy and estimates of the reproductive numbers one month into the epidemic

BackgroundIn February 2020, a locally-acquired COVID-19 case was detected in Lombardia, Italy. This was the first signal of ongoing transmission of SARS-CoV-2 in the country. The outbreak rapidly escalated to a national level epidemic, amid the WHO declaration of a pandemic. MethodsWe analysed data from the national case-based integrated surveillance system of all RT-PCR confirmed COVID-19 infections as of March 24th 2020, collected from all Italian regions and autonomous provinces. Here we provide a descriptive epidemiological summary on the first 62,843 COVID-19 cases in Italy as well as estimates of the basic and net reproductive numbers by region. FindingsOf the 62,843 cases of COVID-19 analysed, 71.6% were reported from three Regions (Lombardia, Veneto and Emilia-Romagna). All cases reported after February 20th were locally acquired. Estimates of R0 varied between 2.5 (95%CI: 2.18-2.83) in Toscana and 3 (95%CI: 2.68-3.33) in Lazio, with epidemic doubling time of 3.2 days (95%CI: 2.3-5.2) and 2.9 days (95%CI: 2.2-4.3), respectively. The net reproduction number showed a decreasing trend starting around February 20-25, 2020 in Northern regions. Notably, 5,760 cases were reported among health care workers. Of the 5,541 reported COVID-19 associated deaths, 49% occurred in people aged 80 years or above with an overall crude CFR of 8.8%. Male sex and age were independent risk factors for COVID-19 death. InterpretationThe COVID-19 infection in Italy emerged with a clustering onset similar to the one described in Wuhan, China and likewise showed worse outcomes in older males with comorbidities. Initial R0 at 2.96 in Lombardia, explains the high case-load and rapid geographical spread observed. Overall Rt in Italian regions is currently decreasing albeit with large diversities across the country, supporting the importance of combined non-pharmacological control measures. Fundingroutine institutional funding was used to perform this work.