Frequency of SARS-CoV2 infection in day care centers during reopening of the school activities (preprint)

Background: SARS-Cov2 already has over than 215 million people and more than 4.5 million fatalities. The beginning of the pandemic condition has led the health authorities in several countries to adopt no-pharmacological preventive measures, such as schools closures. The return took place at a time when the country had the highest rates of infection and mortality. In particular because of the circulation of the gamma variant (P.1) and the vaccination program were beginning in the country. Therefore, we aimed to investigate the prevalence of SARS-CoV2 in daycares after the return of educational activities. Methods The study involved seven childcare facilities. Swab samples from the nasopharynx and region were collected from each participant. This study was carried out between March 16 and September 3, 2021. Viral RNA was extracted using Invitrogen’s RNA purification kit. Viral diagnosis was obtained using RT-PCR, through the TaqMan system. Viral detection was performed with Seegene panel, Allplex TM 2019-nCoV Assay kit. Results and Conclusion: The study population included 201 participants among daycare workers and children. Only one sample (0,5%) was tested positive for the presence of SARS-CoV-2, which was an asymptomatic childcare worker, and no secondary cases were detected. Considering that the return to day care activities occurred in a period with high number of cases of deaths and lack of vaccines throughout the country, it is believed that the several preventive measures used by the day care center could be an indication of effectiveness in preventing transmission of SARS-CoV2.

Predicting SARS-CoV-2 variant spread in a completely seropositive population using semi-quantitative antibody measurements in blood donors (preprint)

Background SARS-CoV-2 serologic surveys estimate the proportion of the population with antibodies against historical variants which nears 100% in many settings. New analytic approaches are required to exploit the full information in serosurvey data. Method Using a SARS-CoV-2 anti-Spike (S) protein chemiluminescent microparticle assay, we attained a semi-quantitative measurement of population IgG titres in serial cross-sectional monthly samples of routine blood donations across seven Brazilian state capitals (March 2021-November 2021). In an ecological analysis (unit of analysis: age-city-calendar month) we assessed the relative contributions of prior attack rate and vaccination to antibody titre in blood donors. We compared blood donor anti-S titre across the seven cities during the growth phase of the Delta variant of concern (VOC) and use this to predict the resulting age-standardized incidence of severe COVID-19 cases. Results On average we tested 780 samples per month in each location. Seroprevalence rose to >95% across all seven capitals by November 2021. Driven proximally by vaccination, mean antibody titre increased 16-fold over the study. The extent of prior natural infection shaped this process, with the greatest increases in antibody titres occurring in cities with the highest prior attack rates. Mean anti-S IgG was a strong predictor (adjusted R2 =0.89) of the number of severe cases caused by the Delta VOC in the seven cities. Conclusions Semi-quantitative anti-S antibody titres are informative about prior exposure and vaccination coverage and can inform on the potential impact of future SARS-CoV-2 variants. Summary In the face of near 100% SARS-CoV-2 seroprevalence, we show that average semi-quantitative anti-S titre predicted the extent of the Delta variant’s spread in Brazil. This is a valuable metric for future seroprevalence studies.

Characterizing the SARS-CoV-2 Omicron variant shedding and duration of RT-PCR and rapid antigen test positivity on vaccinated individuals. (preprint)

The SARS-CoV-2 Omicron variant has demonstrated increased transmissibility and ability to escape natural and vaccine-induced immunity. We aimed to characterize the duration of Omicron’s shedding by comparing viral isolation to rapid antigen test (RAT) and real-time polymerase chain reaction (RT-PCR) positivity. Thus, we performed a cross-sectional study of 30 vaccinated individuals with mild COVID-19 to evaluate the ability to infect Vero cells at day 5, 7, 10 and 14 since symptoms onset. Viral growth was observed in 46% and 20% of respiratory samples at day 5 and 7, respectively, while all were negative from day 10. RAT showed 100% of sensitivity during the first 7 days of symptoms compared to viral isolation, being a better infectivity predictor than RT-PCR Ct values. In conclusion, immunocompetent vaccinated individuals with Omicron infection can still transmit the virus on the 7th day of symptoms. This data may impact decisions on end-isolation protocols for mild COVID-19.

SARS-CoV-2 antibody dynamics in blood donors and COVID-19 epidemiology in eight Brazilian state capitals (preprint)

There are large differences in the shape and size of regional SARS-CoV-2 epidemics in Brazil. Here we tested monthly blood donation samples for IgG antibodies from March 2020 to March 2021 in eight of Brazil’s most populous cities. There was large variation in the inferred attack rate adjusted for seroreversion across cities, and seroprevalence was consistently smaller in women and donors older than 55 years. The age-specific infection fatality rate differed between cities and consistently increased with age. The infection hospitalisation rate (IHR) increased significantly during the gamma-dominated second wave in Manaus, suggesting increased morbidity of the Gamma VOC compared to previous variants circulating in Manaus. The higher disease penetrance associated with the health system’s collapse increased the overall IFR by a minimum factor of 2.91 (95% CrI 2.43–3.53). These results demonstrate large heterogeneity in epidemic spread and highlight the utility of blood donor serosurveillance to monitor SARS-CoV-2 epidemics.

Report 46: Factors driving extensive spatial and temporal fluctuations in COVID-19 fatality rates in Brazilian hospitals (preprint)

The SARS-CoV-2 Gamma variant spread rapidly across Brazil, causing substantial infection and death waves. We use individual-level patient records following hospitalisation with suspected or confirmed COVID-19 to document the extensive shocks in hospital fatality rates that followed Gamma’s spread across 14 state capitals, and in which more than half of hospitalised patients died over sustained time periods. We show that extensive fluctuations in COVID-19 in-hospital fatality rates also existed prior to Gamma’s detection, and were largely transient after Gamma’s detection, subsiding with hospital demand. Using a Bayesian fatality rate model, we find that the geographic and temporal fluctuations in Brazil’s COVID-19 in-hospital fatality rates are primarily associated with geographic inequities and shortages in healthcare capacity. We project that approximately half of Brazil’s COVID-19 deaths in hospitals could have been avoided without pre-pandemic geographic inequities and without pandemic healthcare pressure. Our results suggest that investments in healthcare resources, healthcare optimization, and pandemic preparedness are critical to minimize population wide mortality and morbidity caused by highly transmissible and deadly pathogens such as SARS-CoV-2, especially in low- and middle-income countries. Note The following manuscript has appeared as ‘Report 46 - Factors driving extensive spatial and temporal fluctuations in COVID-19 fatality rates in Brazilian hospitals’ at https://spiral.imperial.ac.uk:8443/handle/10044/1/91875 . One sentence summary COVID-19 in-hospital fatality rates fluctuate dramatically in Brazil, and these fluctuations are primarily associated with geographic inequities and shortages in healthcare capacity.

Global disparities in SARS-CoV-2 genomic surveillance (preprint)

Genomic sequencing provides critical information to track the evolution and spread of SARS-CoV-2, optimize molecular tests, treatments and vaccines, and guide public health responses. To investigate the spatiotemporal heterogeneity in the global SARS-CoV-2 genomic surveillance, we estimated the impact of sequencing intensity and turnaround times (TAT) on variant detection in 167 countries. Most countries submit genomes >21 days after sample collection, and 77% of low and middle income countries sequenced <0.5% of their cases. We found that sequencing at least 0.5% of the cases, with a TAT <21 days, could be a benchmark for SARS-CoV-2 genomic surveillance efforts. Socioeconomic inequalities substantially impact our ability to quickly detect SARS-CoV-2 variants, and undermine the global pandemic preparedness. One-Sentence SummarySocioeconomic inequalities impacted the SARS-CoV-2 genomic surveillance, and undermined the global pandemic preparedness.

Dynamics of Inactivated SARS-CoV-2 Vaccine Antibody Response in SARS-CoV-2-Seropositive Autoimmune Rheumatic Disease Patients (preprint)

Background: Limited information is available on response to Covid-19 vaccines in autoimmune rheumatic disease patients(ARD) previously exposed to the SARS-CoV-2. We compared the dynamics of vaccine induced antibody production after immunization with CoronaVac in SARS-CoV-2 - seropositive ARD patients(ARD+) with two age/sex balanced groups: SARS-CoV-2 naïve ARD patients(NAÏVE-ARD) and SARS-CoV-2-seropositive control group(CTRL+).Methods: Participants of this phase 4 prospective controlled study were vaccinated with two doses of CoronaVac(28-days interval). Primary objective was immunogenicity dynamics evaluated by median neutralizing activity(NAb-activity)/anti-SARS-Cov-2 ln(IgG) titers[ln(IgG)] from D0-D28 and from D28-D69. Secondary objectives included safety and other immunogenicity parameters.Findings: Disease and therapy were similar in ARD+ and NAÏVE-ARD groups(p>0·05). A comparable dynamics was observed for ARD+ and CTRL+ with a plateau increase occurring from D0-D28[ARD+, NAb-activity:59·1% to 81·8%, mean difference -12·1%,p=0·002 and anti-S1/S2-GMT:52·3 to 128·9, ln(IgG) mean difference -0·9,p<0·001] and [CTRL+, NAb-activity:57·5 to 91·9%, mean difference -25·2%,p<0·001 and anti-S1/S2-GMT: 53·3 to 202·0, ln(IgG) mean difference -1·33,p<0·001]. Insignificant increments occurred from D28-D69 for ARD+ and CTRL+ regarding NAb-activity(p>0·999) and anti-S1/S2-GMT(p<0·999). In contrast, a distinct pattern was observed for NAÏVE-ARD with negligible increase from D0-D28 [NAÏVE-ARD: NAb-activity:15 vs. 15%, mean difference -8·3%,p<0·001 and anti-S1/S2-GMT:2·3 vs. 5·7, ln(IgG) mean difference -0·93,p<0·001] and a moderate increase from D28-D69[NAÏVE-ARD: NAb-activity:15·0 vs. 39·4%, mean difference -19·2%,p<0·001 and anti-S1/S2-GMT:5·7 vs. 29·6, ln(IgG) mean difference -1·65,p<0·001]. Supporting these findings, significant differences in NAb activity/ln(IgG) anti-S1/S2-GMT were observed between ARD+ vs. NAÏVE-ARD at D0:43·8%/3·14,p<0·001, D28:47·5%/3·12,p<0·001 and D69:29%/1·53,p<0·001, whereas no difference occurred between ARD+ vs. CTRL+ at D0:-0·5%/-0·02,p>0·999 and D69:-12·3%,p=0·167/0·32%,p=0·258 with minor difference at D28:-13·6%, p=0·067/-0·45,p=0·006.Interpretation: ARD+ patients mount a robust plateau response after a single dose of inactivated SARS-CoV-2 vaccine, independent of pre-existing ARD/therapy, whereas NAÏVE-ARD patients require the second dose to ensure a moderate antibody production. Our findings raise the possibility of a single dose regimen in ARD patients previously exposed to SARS-CoV-2.[clinicaltrials.gov#NCT04754698]Funding: FAPESP/CNPq/B3-Bolsa de Valores-Brasil.Declaration of Interest: The authors declare no competing interests.Ethical Approval: The protocol was approved by the National and Institutional Ethical Committee (CAAE: 42566621.0.0000.0068)

Understanding the Potential Impact of Different Drug Properties On SARS-CoV-2 Transmission and Disease Burden: A Modelling Analysis (preprint)

Background The unprecedented public health impact of the COVID-19 pandemic has motivated a rapid search for potential therapeutics, with some key successes. However, the potential impact of different treatments, and consequently research and procurement priorities, have not been clear. Methods and Findings We develop a mathematical model of SARS-CoV-2 transmission, COVID-19 disease and clinical care to explore the potential public-health impact of a range of different potential therapeutics, under a range of different scenarios varying: i) healthcare capacity, ii) epidemic trajectories; and iii) drug efficacy in the absence of supportive care. In each case, the outcome of interest was the number of COVID-19 deaths averted in scenarios with the therapeutic compared to scenarios without. We find the impact of drugs like dexamethasone (which are delivered to the most critically-ill in hospital and whose therapeutic benefit is expected to depend on the availability of supportive care such as oxygen and mechanical ventilation) is likely to be limited in settings where healthcare capacity is lowest or where uncontrolled epidemics result in hospitals being overwhelmed. As such, it may avert 22% of deaths in high-income countries but only 8% in low-income countries (assuming R=1.35). Therapeutics for different patient populations (those not in hospital, early in the course of infection) and types of benefit (reducing disease severity or infectiousness, preventing hospitalisation) could have much greater benefits, particularly in resource-poor settings facing large epidemics. Conclusions There is a global asymmetry in who is likely to benefit from advances in the treatment of COVID-19 to date, which have been focussed on hospitalised-patients and predicated on an assumption of adequate access to supportive care. Therapeutics that can feasibly be delivered to those earlier in the course of infection that reduce the need for healthcare or reduce infectiousness could have significant impact, and research into their efficacy and means of delivery should be a priority.

Immunogenicity and safety of an inactivated virus vaccine against SARS-CoV-2 in patients with autoimmune rheumatic diseases (preprint)

CoronaVac(SARS-CoV-2 inactivated vaccine) has been largely used as the main immunogen for COVID-19 in several countries. However, its immunogenicity in immunocompromised individuals has not been established. This was a prospective controlled study of 910 adult ARD patients and 182 age- and sex-matched control group(CG) who received two doses of CoronaVac in a 28-days interrval. Anti-SARS-Cov-2 IgG and neutralizing antibodies were assessed at each vaccine shot and 6 weeks after the 2nd dose. Vaccine adverse events(AE) were similar in both groups. We observed significant lower anti-SARS-Cov-2 IgG seroconversion(70.4% vs. 95.5%,p < 0.001) and titers[12.1(95%CI 11.0-13.2) vs. 29.7(95%CI 26.3–33.5),p < 0.001], frequency of neutralizing antibodies(56.3% vs. 79.3%),p < 0.001) and median (interquartile range) neutralization activity [58.7(43.1–77.2) vs. 64.5(48.4–81.4),p = 0.013] in ARD patients compared to CG. A significant decline in the number of COVID-19 cases (p < 0.0001) were observed 10 days after the second dose, with a predominant P1 variant. Safety analysis revealed no moderate/severe AEs. In conclusion, CoronaVac has an excellent safety profile and reasonable rates of quantitative serology(70.4%)/neutralization(56.3%) in ARD patients. The impact of this reduced immunogenicity in vaccine effectiveness warrants further evaluation.

Understanding the Potential Role of Therapeutics in Preventing Deaths Due to COVID-19: A Modelling Analysis (preprint)

Background: The unprecedented public health impact of the COVID-19 pandemic has motivated a rapid search for potential therapeutics, with some key successes. However, the potential impact of current and proposed treatments, and consequently research and procurement priorities, have not been clear. Methods: First, we used a model of SARS-CoV-2 transmission, COVID-19 disease and clinical care pathways to explore the potential impact of dexamethasone - the main treatment currently for hospitalised COVID-19 patients - under scenarios varying: i) healthcare capacity, ii) epidemic trajectories; and iii) the efficacy of dexamethasone in the absence of supportive care. We then fit the model to the observed epidemic trajectory to-date in 165 countries and analysed the potential future impact of dexamethasone in different countries, regions, and country-income strata. Finally, we constructed hypothetical profiles of novel therapeutics based on current trials, and compared the potential impact of each under different circumstances. In each case, the outcome of interest was the number of COVID-19 deaths averted in scenarios with the therapeutic compared to scenarios without. Findings: We find the potential benefit dexamethasone is severely limited in settings where healthcare capacity is lowest or where uncontrolled epidemics result in hospitals being overwhelmed. As such, it may avert 22% of deaths in high-income countries but only 8% in low-income countries (assuming R=1.35). However, therapeutics for different patient populations (in particular, those not in hospital and early in the course of infection) and types of benefit (in particular, reducing disease severity or infectiousness) could have much greater benefits. Such therapeutics would have particular value in resource-poor settings facing large epidemics, even if the efficacy or achievable coverage of such therapeutics is lower in comparison to other types. Interpretation: People in low-income countries will benefit the least from advances in the treatment of COVID-19 to date, which have focussed on hospitalised-patients with adequate access to supportive care. Therapeutics that can feasibly be delivered to those earlier in the course of infection that reduce the need for healthcare or reduce infectiousness could have much greater impact. Such therapeutics may be feasible and research into their efficacy and means of delivery should be a priority. Funding: None to declare. Declaration of Interest: None to declare.

Genomics and epidemiology of a novel SARS-CoV-2 lineage in Manaus, Brazil (preprint)

Cases of SARS-CoV-2 infection in Manaus, Brazil, resurged in late 2020, despite high levels of previous infection there. Through genome sequencing of viruses sampled in Manaus between November 2020 and January 2021, we identified the emergence and circulation of a novel SARS-CoV-2 variant of concern, lineage P.1, that acquired 17 mutations, including a trio in the spike protein (K417T, E484K and N501Y) associated with increased binding to the human ACE2 receptor. Molecular clock analysis shows that P.1 emergence occurred around early November 2020 and was preceded by a period of faster molecular evolution. Using a two-category dynamical model that integrates genomic and mortality data, we estimate that P.1 may be 1.4–2.2 times more transmissible and 25-61% more likely to evade protective immunity elicited by previous infection with non-P.1 lineages. Enhanced global genomic surveillance of variants of concern, which may exhibit increased transmissibility and/or immune evasion, is critical to accelerate pandemic responsiveness. One-Sentence Summary We report the evolution and emergence of a SARS-CoV-2 lineage of concern associated with rapid transmission in Manaus.

Levels of SARS-CoV-2 Lineage P.1 Neutralization by Antibodies Elicited after Natural Infection and Vaccination (preprint)

Background: A new SARS-CoV-2 lineage, named P.1 (20J/501Y.V3), has recently been detected in Brazil. Mutations accrued by the P.1 lineage include amino acid changes in the receptor-binding domain of the spike protein that also are reported in variants of concern in the United Kingdom (B.1.1.7) and South Africa (B.1.325).Methods: We isolated two P.1-containing specimens from nasopharyngeal and bronchoalveolar lavage samples of patients of Manaus, Brazil. We measured neutralization of the P.1 virus after incubation with the plasma of 19 COVID-19 convalescent blood donors and recipients of the chemically-inactivated CoronaVac vaccine and compared these results to neutralization of a SARS-CoV-2 B-lineage previously circulating in Brazil.Findings: The immune plasma of COVID-19 convalescent blood donors had 6-fold less neutralizing capacity against the P.1 than against the B-lineage. Moreover, five months after booster immunization with CoronaVac, plasma from vaccinated individuals failed to efficiently neutralize P.1 lineage isolates.Interpretation: These data indicate that the P.1 lineage may escape from neutralizing antibodies generated in response to polyclonal stimulation against previously circulating variants of SARS-CoV-2.Funding: São Paulo Research Foundation, MCTI/FINEP, Medical Research Council, National Council for Scientific and Technological Development, National Institutes of Health.Conflict of Interest: M.S.D. is a consultant for Inbios, Vir Biotechnology, NGMBiopharmaceuticals, and Carnival Corporation, and on the Scientific Advisory Boards of Moderna and Immunome. The Diamond laboratory has received funding support in sponsored research agreements from Moderna, Vir Biotechnology, and Emergent BioSolutions.Ethical Approval: All procedures followed the ethical standards of the responsible committee on humanexperimentation and approved by the ethics committees from the University of Campinas, Brazil (Approval number CONEP 4.021.484 for plasma collection of blood donors, CAEE32078620.4.0000.5404 and 30227920.9.0000.5404 for the sampling of vaccinated and viral genome sequencing, respectively). All patient data were anonymized before study inclusion.Informed consent was obtained from all subjects for being included in the study.

Exploratory analysis of COVID-19 patients usingprincipal component analysis, feature selection andpredictive algorithms (preprint)

The novel coronavirus disease (COVID-19) emerged in late 2019 has shown that research done with open data could bethe cornerstone for overcoming the need for collaborative, optimized and urgent analysis. Although several articles have beenpublished, identification of variables that can have correlation with positive PCR results is still a challenge. In this paper weshow a concrete example of open data analysis from 910 patients attended in the hospital undergoing SARS-CoV-2 RT-PCR inthree private institutions in S ̃ao Paulo, Brazil. We performed an exploratory analysis using principal component analysis, featureselection and predictive algorithms to test for associations between a number of laboratory test abnormalities and the SARS-CoV-2 RT-PCR result. More concretely, we found a set of 18 variables that showed some association with a positive PCR result.Among these variables elevated lactic dehydrogenase (LDH) and d-dimer were the most correlated with a positive RT-PCR. Wedeveloped a classifier that achieved 76% mean accuracy, 77% mean precision and 92% mean sensitivity to identify individualswith COVID-19

Are Mobile Phones part of the chain of transmission of SARS-CoV-2 in the hospital? (preprint)

SARS-CoV-2 cross-transmission has become an concern in hospitals. We investigate healthcare workers(HCWs) knowledge about SARS-CoV-2 cross-transmission and conceptions whether the virus can remain on HCWs mobile phones(MPs) and be part of the chain of transmission. A cross-sectional study was conducted at a COVID-19 Intensive Care Unit of a teaching-hospital. Fifty-one MPs were swabbed and a questionnaire about hand hygiene and MP use and disinfection was applied after an educational campaign. Although most of HCWs believed on the importance of cross-transmission and increased hand hygiene adhesion and MP disinfection during the pandemic, SARS-CoV-2 RNA was detected in two MPs(culture of the samples was negative). Implementation of official hospital policies to guide HCWs regarding disinfection and care of personal MP are needed.

CORRELATION BETWEEN SARS-COV-2 ANTIBODY SCREENING BY IMMUNOASSAY AND NEUTRALIZING ANTIBODY TESTING (preprint)

BackgroundPassive antibody therapy with convalescent plasma (CP) represents a promising alternative for the treatment of SARS-CoV-2 infection. The efficacy of CP therapy has been associated with high titers of neutralizing antibodies (nAbs) in the plasma of recovered patients, but the assays for quantifying nAbs are not widely available. Our goal was to develop a strategy to predict high titers of nAbs based on the results of anti-SARS-CoV-2 immunoassays and the clinical characteristics of the CP potential donors. MethodsTwo hundred and fourteen CP donors were enrolled and tested for the presence of anti-SARS-CoV-2 antibodies using two commercial immunoassays (IA): Anti-SARS-CoV-2 ELISA IgG EUROIMMUN and Anti-SARS-CoV-2 Chemiluminescence IgG Abbott. In parallel, quantification of neutralizing antibodies (nAbs) was performed using the Cytopathic effect-based virus neutralization test (CPE-VNT). Three criteria for identifying donors with high titers of nAbs ([≥]1:160) were tested: - Criterion1: Curve ROC Method; - Criterion 2: Conditional decision tree considering only the results from the IA and -Criterion 3: Conditional decision tree including both the IA results and the clinical variables. ResultsThe performance of Abbott and EUROIMMUN immunoassays was similar referring to both S/CO and predictive value for identifying nAbs titers [≥] 1:160. Regarding the three studied criteria for identifying CP donors with high nAbs titers ([≥] 1:160): 1) Criterion 1 showed 76.1% accuracy when the S/CO cut-off of 4.65 was used, 2) Criterion 2 presented 76.1% accuracy if the S/CO [≥] 4.57 was applied and 3) Criterion 3 had 71.6% accuracy if either S/CO [≥] 4.57 or S/CO between 2.68 and 4.57 and the last COVID-19-related symptoms occurred less than 19 days from donor recruiting were used. ConclusionThe results of SARS-CoV-2 immunoassays (S/CO) can be used to predict high nAbs titers of potential CP donors. This study has proposed three different criteria for identifying donors with [≥] 1:160 nAbs titer based on either solely S/CO results or S/CO together with clinical variables, all with high efficacy and accuracy.