April 05, 2023

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Clinical Reports

Prevalence and Characteristics Associated With Post–COVID-19 Condition Among Nonhospitalized Adolescents and Young Adults
- This cohort study included 382 SARS-CoV-2–positive individuals and a control group of 85 SARS-CoV-2–negative individuals aged 12 to 25 years who were assessed at the early convalescent stage and at 6-month follow-up. When applying the World Health Organization case definition of PCC, prevalence at 6 months was 49%, but was also comparably high (47%) in the control group. PCC was not associated with biological markers specific to viral infection, but with initial symptom severity and psychosocial factors. These findings suggest that persistent symptoms in this age group are related to factors other than SARS-CoV-2 infection, and therefore question the usefulness of the WHO case definition of PCC
The Breadth of the Neutralizing Antibody Response to Original SARS-CoV-2 Infection is Linked to the Presence of Long COVID Symptoms
- The associations between longitudinal dynamics and the breadth of SARS-CoV-2 neutralizing antibody response with various Long COVID (LC) phenotypes prior to vaccination are not known. The capacity of antibodies to cross neutralize a variety of viral variants may be associated with ongoing pathology and persistent symptoms. Researchers measured longitudinal neutralizing and cross-neutralizing antibody responses to pre- and post-SARS-CoV-2 Omicron variants in participants infected during the early waves of the COVID-19 pandemic, prior to wide-spread rollout of SARS-CoV-2 vaccines. Cross sectional regression models adjusted for various clinical covariates and longitudinal mixed effects models were used to determine the impact of the breadth and rate of decay of neutralizing responses on the development of Long COVID symptoms in general, as well as LC phenotypes. Researchers identified several novel relationships between SARS-CoV-2 antibody neutralization and the presence of LC symptoms. Specifically, we show that, although neutralizing antibody responses to the original, infecting strain of SARS-CoV-2 were not associated with LC in cross-sectional analyses, cross-neutralization ID50 levels to the Omicron BA.5 variant approximately 4 months following acute infection was independently and significantly associated with greater odds of LC and with persistent gastrointestinal and neurological symptoms. Longitudinal modeling demonstrated significant associations in the overall levels and rates of decay of neutralization capacity with LC phenotypes. A higher proportion of participants had antibodies capable of neutralizing Omicron BA.5 compared with BA.1 or XBB.1.5 variants.These findings suggest that relationships between various immune responses and LC are likely complex but may involve the breadth of antibody neutralization responses. SARS-CoV-2-specific antibody neutralization of Omicron BA.5 variant approximately 4 months following acute infection with wild-type virus prior to vaccination was independently and significantly associated with greater odds of distinct Long COVID phenotypes.
Pathogenesis Underlying Neurological Manifestations of Long COVID Syndrome and Potential Therapeutics
- The development of long-term symptoms of coronavirus disease 2019 (COVID-19) more than four weeks after primary infection, termed “long COVID” or post-acute sequela of COVID-19 (PASC), can implicate persistent neurological complications in up to one third of patients and present as fatigue, “brain fog”, headaches, cognitive impairment, dysautonomia, neuropsychiatric symptoms, anosmia, hypogeusia, and peripheral neuropathy. Pathogenic mechanisms of these symptoms of long COVID remain largely unclear; however, several hypotheses implicate both nervous system and systemic pathogenic mechanisms such as SARS-CoV2 viral persistence and neuroinvasion, abnormal immunological response, autoimmunity, coagulopathies, and endotheliopathy. Outside of the CNS, SARS-CoV-2 can invade the support and stem cells of the olfactory epithelium leading to persistent alterations to olfactory function. SARS-CoV-2 infection may induce abnormalities in innate and adaptive immunity including monocyte expansion, T-cell exhaustion, and prolonged cytokine release, which may cause neuroinflammatory responses and microglia activation, white matter abnormalities, and microvascular changes. Additionally, microvascular clot formation can occlude capillaries and endotheliopathy, due to SARS-CoV-2 protease activity and complement activation, can contribute to hypoxic neuronal injury and blood–brain barrier dysfunction, respectively. Current therapeutics target pathological mechanisms by employing antivirals, decreasing inflammation, and promoting olfactory epithelium regeneration. Thus, from laboratory evidence and clinical trials in the literature, researchers sought to synthesize the pathophysiological pathways underlying neurological symptoms of long COVID and potential therapeutics.

Antiviral Therapeutics and Vaccines

Vaccine effectiveness against hospitalization among adolescent and pediatric SARS-CoV-2 cases between May 2021 and January 2022 in Ontario, Canada
- Vaccines against SARS-CoV-2 have been shown to reduce risk of infection as well as severe disease among those with breakthrough infection in adults. The latter effect is particularly important as immune evasion by Omicron variants appears to have made vaccines less effective at preventing infection. Therefore, researchers aimed to quantify the protection conferred by mRNA vaccination against hospitalization due to SARS-CoV-2 in adolescent and pediatric populations. Despite immune evasion by SARS-CoV-2 variants, vaccination continues to be associated with a lower likelihood of hospitalization among adolescent and pediatric Omicron (B.1.1.529) SARS-CoV-2 cases, even when the vaccines do not prevent infection. Continued efforts are needed to increase vaccine uptake among adolescent and pediatric populations.

Effectiveness of BNT162b2 after extending the primary series dosing interval in children and adolescents aged 5–17
- Extended intervals between the first and second doses of mRNA Covid-19 vaccines may reduce the risk of myocarditis in children and adolescents. However, vaccine effectiveness after this extension remains unclear. To examine this potential variable effectiveness, researchers conducted a population-based nested case-control study of children and adolescents aged 5–17 years who had received two doses of BNT162b2 in Hong Kong. From January 1 to August 15, 2022, 5396 Covid-19 cases and 202 Covid-19 related hospitalizations were identified and matched with 21,577 and 808 controls, respectively. For vaccine recipients with extended intervals there was a 29.2%-reduced risk of Covid-19 infection compared to those with regular intervals (21–27 days). If the threshold was set at eight weeks, the risk reduction was estimated at 43.5%. In conclusion, longer dosing intervals for children and adolescents should be considered.
Within-host genetic diversity of SARS-CoV-2 lineages in unvaccinated and vaccinated individuals
- Viral and host factors can shape SARS-CoV-2 evolution. However, little is known about lineage-specific and vaccination-specific mutations that occur within individuals. Here, researchers analysed deep sequencing data from 2,820 SARS-CoV-2 respiratory samples with different viral lineages to describe the patterns of within-host diversity under different conditions, including vaccine-breakthrough infections. In unvaccinated individuals, variant of Concern (VOC) Alpha, Delta, and Omicron respiratory samples were found to have higher within-host diversity and were under neutral to purifying selection at the full genome level compared to non-VOC SARS-CoV-2. Breakthrough infections in 2-dose or 3-dose Comirnaty and CoronaVac vaccinated individuals did not increase levels of non-synonymous mutations and did not change the direction of selection pressure. Vaccine-induced antibody or T cell responses did not appear to have significant impact on within-host SARS-CoV-2 sequence diversification. These findings suggest that vaccination does not increase exploration of SARS-CoV-2 protein sequence space and may not facilitate emergence of viral variants.
Live-attenuated vaccine sCPD9 elicits superior mucosal and systemic immunity to SARS-CoV-2 variants in hamsters
- Vaccines play a critical role in combating the COVID-19 pandemic. Future control of the pandemic requires improved vaccines with high efficacy against newly emerging SARS-CoV-2 variants and the ability to reduce virus transmission. Here researchers compare immune responses and preclinical efficacy of the mRNA vaccine BNT162b2, the adenovirus-vectored spike vaccine Ad2-spike and the live-attenuated virus vaccine candidate sCPD9 in Syrian hamsters, using both homogeneous and heterologous vaccination regimens. Comparative vaccine efficacy was assessed by employing readouts from virus titrations to single-cell RNA sequencing. These results show that sCPD9 vaccination elicited the most robust immunity, including rapid viral clearance, reduced tissue damage, fast differentiation of pre-plasmablasts, strong systemic and mucosal humoral responses, and rapid recall of memory T cells from lung tissue after challenge with heterologous SARS-CoV-2. Overall, these results demonstrate that live-attenuated vaccines offer advantages over currently available COVID-19 vaccines.
Fc-γR-dependent antibody effector functions are required for vaccine-mediated protection against antigen-shifted variants of SARS-CoV-2.
- Emerging severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants with antigenic changes in the spike protein are neutralized less efficiently by serum antibodies elicited by legacy vaccines against the ancestral Wuhan-1 virus. Nonetheless, these vaccines, including mRNA-1273 and BNT162b2, retained their ability to protect against severe disease and death, suggesting that other aspects of immunity control infection in the lung. Vaccine-elicited antibodies can bind Fc gamma receptors (FcγRs) and mediate effector functions against SARS-CoV-2 variants, and this property correlates with improved clinical coronavirus disease 2019 outcome. However, a causal relationship between Fc effector functions and vaccine-mediated protection against infection has not been established. Here, using passive and active immunization approaches in wild-type and FcγR-knockout mice, researchers determined the requirement for Fc effector functions to control SARS-CoV-2 infection. The antiviral activity of passively transferred immune serum was lost against multiple SARS-CoV-2 strains in mice lacking expression of activating FcγRs, especially murine FcγR III (CD16), or depleted of alveolar macrophages. After immunization with the pre-clinical mRNA-1273 vaccine, control of Omicron BA.5 infection in the respiratory tract also was lost in mice lacking FcγR III. These passive and active immunization studies in mice suggest that Fc–FcγR engagement and alveolar macrophages are required for vaccine-induced antibody-mediated protection against infection by antigenically changed SARS-CoV-2 variants, including Omicron strains.
COVID-19 convalescent plasma utilization in the United States: data from the National Inpatient Sample
- COVID-19 convalescent plasma (CCP) use between October-December 2020 was characterized using the National Inpatient Sample database. CCP was administered in 18.0% of COVID-19-associated hospitalizations, and was strongly associated with older age and increased disease severity. There were disparities in the receipt of CCP by race and ethnicity, geography, and insurance.
FDA authorizes Gohibic (vilobelimab) injection for the treatment of COVID-19
- FDA has issued an emergency use authorization (EUA) for the use of Gohibic (vilobelimab) injection for the treatment of COVID-19 in hospitalized adults when initiated within 48 hours of receiving invasive mechanical ventilation or extracorporeal membrane oxygenation (artificial life support).
Anti-C5a antibody IFX-1 (vilobelimab) treatment versus best supportive care for patients with severe COVID-19 (PANAMO): an exploratory, open-label, phase 2 randomised controlled trial
- Severe COVID-19 is characterised by inflammation and coagulation in the presence of complement system activation. Researchers aimed to explore the potential benefit and safety of selectively blocking the anaphylatoxin and complement protein C5a with the monoclonal antibody IFX-1 (vilobelimab), in patients with severe COVID-19. In this small exploratory phase 2 part of the PANAMO trial, C5a inhibition with IFX-1 appears to be safe in patients with severe COVID-19. The secondary outcome results in favour of IFX-1 are preliminary because the study was not powered on these endpoints, but they support the investigation of C5a inhibition with IFX-1 in a phase 3 trial using 28-day mortality as the primary endpoint.

Anti-C5a antibody (vilobelimab) therapy for critically ill, invasively mechanically ventilated patients with COVID-19 (PANAMO): a multicentre, double-blind, randomised, placebo-controlled, phase 3 trial
- Vilobelimab, an anti-C5a monoclonal antibody, was shown to be safe in a phase 2 trial of invasively mechanically ventilated patients with COVID-19. Here, we aimed to determine whether vilobelimab in addition to standard of care improves survival outcomes in this patient population. In addition to standard of care, vilobelimab improves survival of invasive mechanically ventilated patients with COVID-19 and leads to a significant decrease in mortality. Vilobelimab could be considered as an additional therapy for patients in this setting and further research is needed on the role of vilobelimab and C5a in other acute respiratory distress syndrome-causing viral infections.
Triple combination therapy with two antivirals and monoclonal antibodies for persistent or relapsed SARS-CoV-2 infection in immunocompromised patients
- Severely immunocompromised patients are at risk for prolonged or relapsed COVID-19 leading to increased morbidity and mortality. We aimed to evaluate efficacy and safety of combination treatment in immunocompromised COVID-19 patients. Researchers included all immunocompromised patients with prolonged/relapsed COVID-19 treated with combination therapy with two antivirals (remdesivir plus nirmatrelvir/ritonavir, or molnupiravir in case of renal failure) plus, if available, anti-spike monoclonal antibodies (Mabs), between February and October 2022. The main outcomes were virological response at day 14 (negative SARS-CoV-2 swab) and virological and clinical response (alive, asymptomatic, with negative SARS-CoV-2 swab) at day 30 and the last follow-up. Overall, 22 patients (Omicron variant in 17/18) were included: 18 received full combination of two antivirals and Mabs and 4 received two antivirals only; in 20/22 (91%) two antivirals were nirmatrelvir/ritonavir plus remdesivir. Nineteen (86%) patients had hematological malignancy, 15 (68%) had received anti-CD20 therapy. All were symptomatic; 8 (36%) required oxygen. Four patients received second course of combination treatment. Response rate at day 14, 30 and last follow-up was, respectively, 75% (15/20 evaluable), 73% (16/22) and 82% (18/22). Day 14 and 30 response rates were significantly higher when combination therapy included Mabs. Higher number of vaccine doses was associated with better final outcome. Two patients (9%) developed severe side effects: bradycardia leading to remdesivir discontinuation and myocardial infarction. Combination therapy including two antivirals (mainly remdesivir and nirmatrelvir/ritonavir) and Mabs was associated with high rate of virological and clinical response in immunocompromised patients with prolonged/relapsed COVID-19.

Epidemiology

Adeno-associated virus type 2 in US children with acute severe hepatitis
- As of August 2022, clusters of acute severe hepatitis of unknown etiology in children have been reported from 35 countries, including the United States. Previous studies have found human adenoviruses (HAdVs) in the blood from cases in Europe and the United States, although it is unclear whether this virus is causative. Here researchers used PCR testing, viral enrichment based sequencing, and agnostic metagenomic sequencing to analyze samples from 16 HAdV-positive cases from October 1, 2021 to May 22, 2022, in parallel with 113 controls. In blood from 14 cases, adeno-associated virus 2 (AAV2) sequences were detected in 93%, compared to 3.5% of 113 controls and to 0 of 30 patients with hepatitis of defined etiology. In controls, HAdV-41 was detected in blood from 39.1% of the 23 patients with acute gastroenteritis (without hepatitis), including 8 of 9 patients with positive stool HAdV testing, but co-infection with AAV2 was observed in only 13.0% of these 23 patients versus 93% of cases. Co-infections by Epstein-Barr virus (EBV), human herpesvirus 6 (HHV-6), and/or enterovirus A71 (EV-A71) were also detected in 85.7% of 14 cases, with higher herpesvirus detection in cases versus controls. These findings suggest that the severity of the disease is related to co-infections involving AAV2 and one or more helper viruses.
Genomic investigations of unexplained acute hepatitis in children
- Since its first identification in Scotland, over 1000 cases of unexplained pediatric hepatitis in children have been reported worldwide, including 278 cases in the UK. Here researchers report investigation of 38 cases, 66 age-matched immunocompetent controls and 21 immunocompromised comparator subjects, using a combination of genomic, transcriptomic, proteomic and immunohistochemical methods. Researchers detected high levels of adeno-associated virus 2 (AAV2) DNA in liver, blood, plasma or stool from 27/28 cases. Researchers found low levels of Adenovirus (HAdV) and Human Herpesvirus 6B (HHV-6B), in 23/31 and 16/23 respectively of the cases tested. In contrast, AAV2 was infrequently detected at low titre in blood or liver from control children with HAdV, even when profoundly immunosuppressed. AAV2, HAdV and HHV-6 phylogeny excluded emergence of novel strains in cases. Histological analyses of explanted livers showed enrichment for T-cells and B-lineage cells. Proteomic comparison of liver tissue from cases and healthy controls, identified increased expression of HLA class 2, immunoglobulin variable regions and complement proteins. HAdV and AAV2 proteins were not detected in the livers. Instead, researchers identified AAV2 DNA complexes reflecting both HAdV and HHV-6B-mediated replication. We hypothesize that high levels of abnormal AAV2 replication products aided by HAdV and in severe cases HHV-6B, may have triggered immune-mediated hepatic disease in genetically and immunologically predisposed children.
Surveillance of SARS-CoV-2 at the Huanan Seafood Market
- Emerging in December 2019, coronavirus disease 2019 (COVID-19) eventually became a pandemic and posed a tremendous threat to global public health. However, the origins of SARS-CoV-2, the causative agent of COVID-19, remain to be determined. It has been reported that a certain number of the early case clusters had a contact history with the Huanan Seafood Market. Therefore, surveillance of SARS-CoV-2 within the market is of vital importance. Herein, researchers presented the SARS-CoV-2 detection results of 1380 samples collected from the environment since 1st Jan and animals since 18th Jan within the market in early 2020. By SARS-CoV-2-specific RT-qPCR, 73 environmental samples tested positive for SARS-CoV-2 and three live viruses were successfully isolated. The viruses from the market shared nucleotide identity of 99.99% to 100% with the human isolate HCoV-19/Wuhan/IVDC-HB-01/2019. The A lineage (8782T and 28144C), as the likely ancestral SARS-CoV-2 lineage, was found in an environmental sample. No virus was detected in the animal swabs covering 18 species of animals in the market. The RNA-seq analysis of SARS-CoV-2 positive/negative environmental samples showed the abundance of different vertebrata genera. In summary, this study provided convincing evidence of the prevalence of SARS-CoV-2 in the Huanan Seafood Market during the early stage of COVID-19 outbreak.