Virological characteristics of SARS-CoV-2 BA.2 variant (preprint)

Soon after the emergence and global spread of a new severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron lineage, BA.1 (ref1, 2), another Omicron lineage, BA.2, has initiated outcompeting BA.1. Statistical analysis shows that the effective reproduction number of BA.2 is 1.4-fold higher than that of BA.1. Neutralisation experiments show that the vaccine-induced humoral immunity fails to function against BA.2 like BA.1, and notably, the antigenicity of BA.2 is different from BA.1. Cell culture experiments show that BA.2 is more replicative in human nasal epithelial cells and more fusogenic than BA.1. Furthermore, infection experiments using hamsters show that BA.2 is more pathogenic than BA.1. Our multiscale investigations suggest that the risk of BA.2 for global health is potentially higher than that of BA.1.

Ineffective neutralization of the SARS-CoV-2 Mu variant by convalescent and vaccine sera (preprint)

On August 30, 2021, the WHO classified the SARS-CoV-2 Mu variant (B.1.621 lineage) as a new variant of interest. The WHO defines "comparative assessment of virus characteristics and public health risks" as primary action in response to the emergence of new SARS-CoV-2 variants. Here, we demonstrate that the Mu variant is highly resistant to sera from COVID-19 convalescents and BNT162b2-vaccinated individuals. Direct comparison of different SARS-CoV-2 spike proteins revealed that Mu spike is more resistant to serum-mediated neutralization than all other currently recognized variants of interest (VOI) and concern (VOC). This includes the Beta variant (B.1.351) that has been suggested to represent the most resistant variant to convalescent and vaccinated sera to date (e.g., Collier et al, Nature, 2021; Wang et al, Nature, 2021). Since breakthrough infection by newly emerging variants is a major concern during the current COVID-19 pandemic (Bergwerk et al., NEJM, 2021), we believe that our findings are of significant public health interest. Our results will help to better assess the risk posed by the Mu variant for vaccinated, previously infected and naive populations.

Antibody responses to BNT162b2 mRNA COVID-19 vaccine in 2,015 healthcare workers in a single tertiary referral hospital in Japan (preprint)

We measured antibody responses in 2,015 healthcare workers who were receiving 2 doses of BNT162b2 mRNA vaccine against SARS-CoV-2. The vast majority (99.9%) had either seroconversion or a substantial increase in antibody titer. A multivariate linear regression model identified predictive factors for antibody responses which may have clinical implications.

Japan COVID-19 Task Force: a nation-wide consortium to elucidate host genetics of COVID-19 pandemic in Japan (preprint)

To elucidate the host genetic loci affecting severity of SARS-CoV-2 infection, or Coronavirus disease 2019 (COVID-19), is an emerging issue in the face of the current devastating pandemic. Here, we report a genome-wide association study (GWAS) of COVID-19 in a Japanese population led by the Japan COVID-19 Task Force, as one of the initial discovery GWAS studies performed on a non-European population. Enrolling a total of 2,393 cases and 3,289 controls, we not only replicated previously reported COVID-19 risk variants (e.g., LZTFL1, FOXP4, ABO, and IFNAR2), but also found a variant on 5p35 (rs60200309-A at DOCK2) that was significantly associated with severe COVID-19 in younger (<65 years of age) patients with a genome-wide significant p-value of 1.2 x 10-8 (odds ratio = 2.01, 95% confidence interval = 1.58-2.55). This risk allele was prevalent in East Asians, including Japanese (minor allele frequency [MAF] = 0.097), but rarely found in Europeans. Cross-population Mendelian randomization analysis made a causal inference of a number of complex human traits on COVID-19. In particular, obesity had a significant impact on severe COVID-19. The presence of the population-specific risk allele underscores the need of non-European studies of COVID-19 host genetics.

Elevated oxygen demand in a case of COVID-19 with severe ARDS: a point for optimal oxygenation therapy including ECMO management (preprint)

Background: Coronavirus disease 2019 (COVID-19) caused by SARS-CoV-2 has become a global pandemic, and those developing critically ill conditions have been reported to have mortality in the range of 39% to 61%. Due to the lack of definitive treatments, mechanical ventilation and supportive oxygenation therapy are key management strategies for the survival of patients with acute respiratory distress syndrome (ARDS). Optimizing oxygenation therapy is mandatory to treat patients with severe respiratory failure, to sufficiently compensate for the oxygen (O2) demand. We experienced a case of severe ARDS due to COVID-19 successfully treated with extracorporeal membrane oxygenation (ECMO) after increasing oxygen delivery according to O2 consumption measurement by indirect calorimetryCase Presentation: A 29-year-old obese but otherwise healthy man was hospitalized for treatment of COVID-19 pneumonia presenting with a 4-day history of persisting cough, high fever, and dyspnea. Mechanical ventilation, nitric oxide inhalation, and prone positioning were initiated in the ICU against severe respiratory dysfunction. Indirect calorimetry on the 3rd and 6th ICU days revealed persistent elevation of oxygen consumption (VO2) of 380 mL/min. Veno-venous ECMO was initiated on the 7th ICU day after further deterioration of respiratory failure. Periodic events of SpO2 decline due to effortful breathing was not resolved by neuromuscular blockade in attempt to reduce O2 consumption. Increasing the ECMO flow induced hemolysis and hyperkalemia despite the use of large bore cannulas and ECMO circuit free of clots and defects. The hemoglobin management level was elevated from 10 g/dL to 13 g/dL to increase blood oxygen capacity, enabling the reduction of ECMO flow while attenuating respiratory effort and maintaining SpO2. Lung protective ventilation strategy and prone positioning were continued for successful weaning from ECMO on the 16th ICU day, and the ventilator on the 18th ICU day.Conclusion: The present case of severe ARDS due to COVID-19 was successfully treated with ECMO. Enhancing oxygen delivery was crucial to compensate for the elevated O2 demand. Measuring O2 consumption by indirect calorimetry can elucidate the oxygen demand for optimizing the oxygenation therapy for successful management and survival of critically ill COVID-19 patients.