Clinical outcomes and antibody transfer in a cohort of infants born to mothers with SARS-COV-2 infection during pregnancy (Coronascope Study) (preprint)

Purpose: We aimed to describe the outcomes, focusing on the hearing and neurological development, of children born to mothers with SARS-CoV-2 infection during pregnancy, and to evaluate the persistence of maternal antibodies in the first months of life. Methods:An observational, prospective study at a tertiary hospital in Madrid (Spain) on infants born to mothers infected with SARS CoV-2 during pregnancy between March and September 2020. A follow-up visit at 1-3 months of age with a physical and neurological examination, cranial ultrasound (cUS), SARS-CoV-2 RT-PCR on NPS and SARS-CoV-2 serology were performed. Hearing was evaluated at birth through the automated auditory brainstem response and at six months of age through the auditory steady-state response. A neurodevelopmental examination using the Bayley-III scale was performed at 12 months of age. Results:Of 95 infants studied, neurological examination was normal in all of them at the follow-up visit, as was the cUS in 81/85 (95%) infants, with only mild abnormalities in four of them. Serology was positive in 47/95 (50%) infants, which was not associated with symptoms or severity of maternal infection. No hearing loss was detected and neurodevelopment was normal in 96% of the children (median Z score: 0). Conclusions: In this cohort, the majority of infants born to mothers with SARS-CoV-2 infection during pregnancy were healthy children with a normal cUS, no hearing loss and normal neurodevelopment in the first year of life. Only half of the infants had a positive serological result during the follow-up.

Potency and Breadth of Neutralization after 3 doses of mRNA vaccines in COVID-19 Convalescent and Naive individuals (preprint)

Third doses of mRNA COVID-19 vaccines induced a significant increase in neutralizing potency and breadth in naive individuals comparable with convalescents who restored levels after the first two doses. These results suggest a limit to elicit neutralization in the number of stimuli by infection or vaccination with ancestral SARS-CoV-2 sequences

Potent Neutralizing Activity of Polyclonal Equine Antibodies against Omicron SARS-CoV-2 (preprint)

Using a polyclonal approach of equine anti-SARS-CoV-2 F(ab)2 antibodies we have achieved a high level of neutralizing potency against all SARS-CoV-2 variants tested. Neutralization titers were in the range of 105-106 IU/mL including Omicron: 111,403 UI/mL, which is 2-3 orders of magnitude what is normally achieved in response to SARS-CoV-2 infection and/or vaccination. The presence of high titers of a repertoire of antibodies targeting conserved epitopes in different regions of the spike protein could plausibly account for this remarkable breadth of neutralization. These results warrant the clinical investigation of anti-SARS-CoV-2 equine polyclonal F(ab)2 antibodies as a novel therapeutic strategy against COVID-19

Fever without source as the first manifestation of SARS-CoV-2 infection in infants less than 90 days old. (preprint)

Fever without source (FWS) in infants is a frequent cause of consultation at the emergency department and the emergence of SARS-CoV-2 could affect the approach to those infants. The aim of this study is to define the clinical characteristics and rates of bacterial coinfections of infants < 90 days with FWS as the first manifestation of SARS-CoV-2 infection. This is a cross-sectional study of infants under 90 days of age with FWS and positive SARS-CoV2 PCR in nasopharyngeal swab/aspirate, attended at the emergency departments of 49 Spanish hospitals (EPICO-AEP cohort) from March 1st to June 26th, 2020. Three hundred and thirty-three  children with COVID-19 were included in EPICO-AEP. A total of 67/336 (20%) were infants less than 90 days old, and 27/67(40%) presented with FWS. Blood cultures were performed in 24/27(89%) and were negative in all but one (4%) who presented a Streptococcus mitis bacteremia. Urine culture was performed in 26/27(97%) children and was negative in all, except in two (7%) patients. Lumbar puncture was performed in 6/27(22%) cases, with no growth of bacteria. Two children had bacterial coinfections: 1 had UTI and bacteremia, and 1 had UTI. C-reactive was protein over 20 mg/L in two children (one with bacterial coinfection), and procalcitonin was normal in all. One child was admitted to the Pediatric Intensive Care Unit because of apnea episodes. No patients died. Conclusion: FWS was frequent in infants under 90 days of age with SARS-CoV-2 infection. Standardized markers to rule out bacterial infections remain useful in this population, and the outcome is generally good.

DC/L-SIGN recognition of spike glycoprotein promotes SARS-CoV-2 trans-infection and can be inhibited by a glycomimetic antagonist (preprint)

The efficient spread of SARS-CoV-2 resulted in a pandemic that is unique in modern history. Despite early identification of ACE2 as the receptor for viral spike protein, much remains to be understood about the molecular events behind viral dissemination. We evaluated the contribution of C-type lectin receptors (CLRS) of antigen-presenting cells, widely present in air mucosa and lung tissue. DC-SIGN, L-SIGN, Langerin and MGL bind to diverse glycans of the spike using multiple interaction areas. Using pseudovirus and cells derived from monocytes or T-lymphocytes, we demonstrate that while virus capture by the CLRs examined does not allow direct cell infection, DC/L-SIGN, among these receptors, promote virus transfer to permissive ACE2+ cells. A glycomimetic compound designed against DC-SIGN, enable inhibition of this process. Thus, we described a mechanism potentiating viral capture and spreading of infection. Early involvement of APCs opens new avenues for understanding and treating the imbalanced innate immune response observed in COVID-19 pathogenesis

Persistent SARS-CoV-2 replication in severe COVID-19 (preprint)

Background: The diagnosis of SARS-CoV-2 infection is based on viral RNA detection by real-time RT-PCR (rRT-PCR) in respiratory samples. This detection can remain positive for weeks without implying virus viability. Methods: We have performed cell culture to assess viral replication in 106 respiratory samples rRT-PCR positive for SARS-CoV-2 from 105 patients with COVID-19. Fifty were samples from 50 patients with mild forms of COVID-19 who did not require hospital admission. Fifty-six samples were obtained from 55 hospitalized patients with severe pneumonia. Samples were obtained at different time points covering the time from clinical diagnosis to the follow up during hospital care. Results: In 49 samples (49/106, 46.2%) a cytopathic effect (CPE) was detected in cell culture. Our study demonstrates that while in patients with mild COVID-19, viral viability is maintained in fact up to 10 days in patients with severe COVID-19 the virus can remain viable for up to 32 days after the onset of symptoms. Patients with severe COVID-19 as compared with mild cases, presented infective virus in a significantly higher proportion in samples with moderate or low viral load (Ct value > 26): 22/46 (47.8%) versus 7/38 (18.4%), (p <0.01), respectively. Conclusions: Persistent SARS-CoV-2 replication could be demonstrated in severe COVID-19 cases for periods up to 32 days after the onset of symptoms and even at high Ct values. COVID-19 severity is a more determining factor for viral viability than the time elapsed since the onset of symptoms or the Ct value obtained in the RT-PCR assay.

SARS-CoV-2 infection in Health Care Workers in a large public hospital in Madrid, Spain, during March 2020 (preprint)

Background On January 31st the first case of COVID-19 was detected in Spain, an imported case from Germany in Canary Islands, and thereafter on February 25th the first case was detected in Madrid. The first case of COVID-19 was confirmed at the Hospital Universitario 12 de Octubre on March 1st, a large public hospital with 1200 beds, covering an area over 400000 inhabitants in southern Madrid. During March 2020 highly active circulation of SARS-CoV-2 was experienced in Madrid with 24090 cases officially reported by March 29th. Methods Since the beginning of the epidemics the Occupational Health and Safety Service (OHSS) organized the consulting and testing of the hospital personnel with confirmed exposure and also those presenting symptoms suggestive of viral respiratory infection. For molecular diagnosis of SARS-CoV-2 infection both nasopharyngeal and oropharyngeal swabs were obtained from suspected cases and processed at the Microbiology Laboratory by automatized specific PCR methods that was operative from February 25th as part of the preparedness. Results From a total of 6800 employees of the hospital, 2085 (30,6 %) were tested during the period 1-29 March 2020, some of them repeatedly (2286 total samples). The first HCW infected was confirmed on March 9th. A total of 791 HCW and personnel were confirmed to be infected by March 29th, representing 38% of those tested and 11,6 % of all the hospital workers. The proportion of infected individuals was estimated among the different groups of occupational exposure and the evolution of the cases during the expansive epidemic wave was compared between HCW and those patients attending at the Emergency Department (ER) during the same period and adjusted by the same age range. There were no statistically significant differences in the proportion of SARS-CoV-2 positive PCR detection between HCW from high risk areas involved in close contact with COVID-19 patients in comparison with clerical, administrative or laboratory personnel without direct contact with patients. The curves of evolution of accumulated cases between patients and HCW during March 2020 showed an almost parallel shape. Discussion The recommendation from our OHSS did not include testing of asymptomatic cases but was highly proactive in testing even patients with minor symptoms therefore, a high proportion of HCW and non-sanitary personnel was tested in March 2020 during the rapid period of expansion of the epidemics in Madrid, accounting for a total of 30,6 % of the hospital employees. Most of the COVID-19 cases among the hospital HCW and personnel were mild and managed at home under self-isolation measures, however 23 (3%) required hospitalization mostly due to severe bilateral interstitial pneumonia, two of those cases required mechanical ventilation at the ICU. No fatalities occurred during the study period. Although there were some cases of highly probable transmission from COVID-19 patients to HCWs, mainly at the first phase of the epidemics, there were no significant differences on the infection rates of HCW and hospital personnel that can be related to working in areas of high exposure risk. Furthermore, the evolution of cases during the same time period (March 2020) between patients attending the ER and hospital staff suggests that both groups were driven by the same dynamics. This experience is similar to the communicated from Wuhan verified by the WHO Joint Mission and also from recent experiences at hospital in the Netherlands, where most of the infections of HCW were related to household or community contacts. Significance Since the collective of hospital HCW are exhaustively screened in specific centers, their rate of infection for SARS-CoV-2 could be an indicator of the epidemic dynamics in the community. There appears to be a close connection between HCW infection and the driving forces of transmission in the community. Although we cannot exclude an additional risk factor of infection by SARS-CoV-2 due to the fact of the hospital environment, the similar proportions of positive cases among all the areas of the hospital and the evolutive wave of infection, as compared with the community, are clear arguments against a major factor of occupational risk. Exhaustive testing, such as the one carried out in our institution, covering over one third of all the workers, could be used as a reference of the population infected in the community. Since a significant proportion of COVID-19 cases can be asymptomatic and not all the hospital employees were actually tested, it is highly likely that this 11,6 % is a minimum estimation of the impact of SARS-CoV-2 circulation in Madrid during the first 4 weeks of the epidemics. This is in high and clear contrast with the official figures circulating at national and international levels. This has important implications to more precisely estimate the actual number of cases in the community and to develop public health policies for containment, treatment and recovery.