Omicron subvariant BA.5 is highly contagious but containable: Successful experience from Macau.

Introduction: Due to its high transmissibility and immune escape, Omicron subvariant BA.5 has become the dominant strain of the SARS-CoV-2 virus and led to escalating COVID-19 cases, how to cope with it becomes an urgent issue. A BA.5 infection surge burst out on 18 June 2022 and brought an unprecedented challenge to Macau, the most densely populated region worldwide. This study aimed to analyze the characteristics of this outbreak and summarize the useful anti-epidemic measures and experiences during this outbreak. Methods: All data were obtained from the Government Portal of Macao SAR (https://www.gov.mo), and the Special Webpage Against Epidemics, the Macao Health Bureau (www.ssm.gov.mo). An epidemiologic study was performed to analyze epidemic outcomes, including the infection rate, the proportion of symptomatic cases, the case fatality ratio (CFR), etc. Data were analyzed using SPSS Version 20. A p-value <0.05 was considered statistically significant. The anti-epidemic measures and experience were reviewed and summarized. Results: The BA.5 outbreak resulted in 1,821 new cases, which was significantly more than the cumulative cases of the previous variants of COVID-19 in Macau. The symptomatic cases accounted for 38.71% of the total cases, which was higher than that of the previous variants. After 6-week concerted efforts, Macau effectively controlled the outbreak, with an infection rate of 0.27%, which was much lower than many BA.5-attacked regions. The CFR was approximately 0.86%, which was not statistically different from that of previous variants. Six victims were chronically ill senior elders and their vaccination rate was much lower than the average level. Macau took a comprehensive anti-epidemic strategy to win a quick victory against BA.5, especially the "relatively static" strategy that was first formulated and applied by Macau for the management of the COVID-19 pandemic. Successful experience showed that although BA.5 was highly contagious, it could be contained by comprehensive anti-epidemic measures, including adequate anti-epidemic preparation, herd immunity through vaccination, repeated mass nucleic acid tests and rapid antigen tests, KN-95 mask mandate, the "relatively static" strategy, precise prevention and control, epidemiological investigation and tracing, and traditional Chinese medicine treatment, etc. Discussion: In Macau, compared with the previous subvariants, BA.5 is associated with increased transmissibility and a higher proportion of symptomatic cases, however, the risk of death remains similar, and the infection rate is much lower than that in many other BA.5-attacked regions. BA.5 is highly contagious but still containable, Macau's experience may offer hints for the regions experiencing the BA.5 waves to choose or adjust a more rational anti-epidemic strategy.

Delivery of mRNA for regulating functions of immune cells.

Abnormal immune cell functions are commonly related to various diseases, including cancer, autoimmune diseases, and infectious diseases. Messenger RNA (mRNA)-based therapy can regulate the functions of immune cells or assign new functions to immune cells, thereby generating therapeutic immune responses to treat these diseases. However, mRNA is unstable in physiological environments and can hardly enter the cytoplasm of target cells; thus, effective mRNA delivery systems are critical for developing mRNA therapy. The two mRNA vaccines of Pfizer-BioNTech and Moderna have demonstrated that lipid nanoparticles (LNPs) can deliver mRNA into dendritic cells (DCs) to induce immunization against severe acute respiratory syndrome coronavirus 2, which opened the floodgates to the development of mRNA therapy. Apart from DCs, other immune cells are promising targets for mRNA therapy. This review summarized the barriers to mRNA delivery and advances in mRNA delivery for regulating the functions of different immune cells.

Omicron subvariant BA.5 is highly contagious but containable: Successful experience from Macau

Introduction Due to its high transmissibility and immune escape, Omicron subvariant BA.5 has become the dominant strain of the SARS-CoV-2 virus and led to escalating COVID-19 cases, how to cope with it becomes an urgent issue. A BA.5 infection surge burst out on 18 June 2022 and brought an unprecedented challenge to Macau, the most densely populated region worldwide. This study aimed to analyze the characteristics of this outbreak and summarize the useful anti-epidemic measures and experiences during this outbreak. Methods All data were obtained from the Government Portal of Macao SAR (https://www.gov.mo), and the Special Webpage Against Epidemics, the Macao Health Bureau (www.ssm.gov.mo). An epidemiologic study was performed to analyze epidemic outcomes, including the infection rate, the proportion of symptomatic cases, the case fatality ratio (CFR), etc. Data were analyzed using SPSS Version 20. A p-value <0.05 was considered statistically significant. The anti-epidemic measures and experience were reviewed and summarized. Results The BA.5 outbreak resulted in 1,821 new cases, which was significantly more than the cumulative cases of the previous variants of COVID-19 in Macau. The symptomatic cases accounted for 38.71% of the total cases, which was higher than that of the previous variants. After 6-week concerted efforts, Macau effectively controlled the outbreak, with an infection rate of 0.27%, which was much lower than many BA.5-attacked regions. The CFR was approximately 0.86%, which was not statistically different from that of previous variants. Six victims were chronically ill senior elders and their vaccination rate was much lower than the average level. Macau took a comprehensive anti-epidemic strategy to win a quick victory against BA.5, especially the "relatively static” strategy that was first formulated and applied by Macau for the management of the COVID-19 pandemic. Successful experience showed that although BA.5 was highly contagious, it could be contained by comprehensive anti-epidemic measures, including adequate anti-epidemic preparation, herd immunity through vaccination, repeated mass nucleic acid tests and rapid antigen tests, KN-95 mask mandate, the "relatively static” strategy, precise prevention and control, epidemiological investigation and tracing, and traditional Chinese medicine treatment, etc. Discussion In Macau, compared with the previous subvariants, BA.5 is associated with increased transmissibility and a higher proportion of symptomatic cases, however, the risk of death remains similar, and the infection rate is much lower than that in many other BA.5-attacked regions. BA.5 is highly contagious but still containable, Macau's experience may offer hints for the regions experiencing the BA.5 waves to choose or adjust a more rational anti-epidemic strategy.

Preclinical Toxicity and Immunogenicity of a COVID-19 Vaccine (ZF2001) in Cynomolgus Monkeys.

Although the new coronavirus disease 2019 (COVID-19) outbreak occurred in late 2019, it is still endemic worldwide, and has become a global public health problem. Vaccination against SARS-CoV-2 is considered to be the most effective intervention to prevent the spread of COVID-19. ZF2001 is a recombinant protein vaccine based on SARS-CoV-2 receptor-binding domain (RBD) subunit which contains aluminum adjuvant. In order to advance our research on ZF2001 into clinical trial, we investigated the general toxicity and immunogenicity of ZF2001 in cynomolgus monkeys and assessed the possible target organs for vaccine-induced toxicity. In the present research, we observed no significant systemic toxicities and abnormal cardiovascular and respiratory events following four times injections of intramuscular ZF2001 in cynomolgus monkeys. Histological examination revealed recoverable inflammatory changes in quadricep muscle and adjacent lymph node at the vaccine injection site. As expected, the vaccine can produce a strongly specific binding antibody and neutralizing antibodies in cynomolgus monkeys after inoculation. Taken together, our regulatory toxicology research proves the safety and immunogenicity of the ZF2001 vaccine, supporting its entry into large scale clinical trials.

The Association between Allergic Rhinitis and COVID-19: A Systematic Review and Meta-Analysis.

Objective: Previous studies have yielded conflicting results regarding the association of coronavirus disease 2019 (COVID-19) with allergic rhinitis (AR). Data on AR prevalence in COVID-19 patients are limited. Consequently, whether AR is a harmful or protective factor for COVID-19 patients remains controversial. Therefore, we analyzed the relationship between COVID-19 and AR. Methods: We systematically searched PubMed, Embase, Cochrane, and Web of Science databases for studies published between January 1, 2020 and January 11, 2022. We included studies reporting the epidemiological and clinical characteristics of COVID-19 and its incidence in patients with AR. We excluded letters, case reports, literature review articles, non-English language article, and non-full-text articles. The raw data from these studies were pooled into a meta-analysis. Results: We analyzed the results of nine studies. The prevalence of AR in patients with COVID-19 was 0.13 (95% confidence interval [CI] 0.04-0.25), with an overall I 2 of 99.77%, P=0.24. COVID-19 patients with AR are less prone to severe disease (odds ratio [OR] = 0.79, 95% CI, 0.52-1.18, P=0.25) and hospitalization (OR = 0.23, 95%CI, 0.02-2.67, P ≤ 0.0001) than patients without AR. Conclusion: Our data suggest that allergic rhinitis is a protective factor in patients with COVID-19.

The impact of invisible-spreaders on COVID-19 transmission and work resumption.

The global impact of coronavirus disease 2019 (COVID-19) is unprecedented, and many control and prevention measures have been implemented to test for and trace COVID-19. However, invisible-spreaders, who are associated with nucleic acid detection and asymptomatic infections, have received insufficient attention in the current COVID-19 control efforts. In this paper, we analyze the time series infection data for Italy, Germany, Brazil, India and Sweden since the first wave outbreak to address the following issues through a series of experiments. We conclude that: 1) As of June 1, 2020, the proportion of invisible-spreaders is close to 0.4% in Sweden, 0.8% in early Italy and Germany, and 0.4% in the middle and late stages. However, in Brazil and India, the proportion still shows a gradual upward trend; 2) During the spread of this pandemic, even a slight increase in the proportion of invisible-spreaders could have large implications for the health of the community; and 3) On resuming work, the pandemic intervention measures will be relaxed, and invisible-spreaders will cause a new round of outbreaks.

The prevalence of mental ill-health in women during pregnancy and after childbirth during the Covid-19 pandemic: a Systematic Review and Meta- analysis (preprint)

Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV) is a respiratory disease which causes coronavirus and has given rise to the Middle East Respiratory Syndrome (MERS), SARS-CoV in Hong Kong and SARS-CoV-2 (COVID-19). COVID-19, to date, has had the highest morbidity and mortality rates globally, thus reaching the pandemic status. Whilst research has explored the impact of pandemic on general wellbeing, there appears to be a paucity on its association with women’s mental health, with many pregnant women reporting the pandemic negatively impacted their mental health. This study aims to explore the prevalence of the impact of the COVID-19, MERS and SARS pandemics on the mental health of pregnant women. A study protocol was developed and published in PROSPERO (CRD42021235356) to explore several key objectives. A literature search was carried out and identified 316 studies. A meta-analysis was conducted to report the findings. There were no studies reporting the mental health impact due to MERS and SARS. Results showed that women who were pregnant or had just given birth displayed various symptoms of poor mental health including those relating to depression (24.9%), anxiety (32.8%), stress (29.44%), Post Traumatic Stress Disorder (PTSD) (27.93%), and sleep disorders (24.38%) during the COVID-19 pandemic. The importance of managing mental health during pregnancy and after-delivery improves the quality of life and wellbeing of mothers hence developing an evidence-based approached as part of pandemic preparedness would improve mental health during challenging times.  

The prevalence of mental ill-health in women during pregnancy and after childbirth during the Covid-19 pandemic: a Systematic review and Meta-analysis (preprint)

Background Severe Acute Respiratory Syndrome Coronavirus (SARSCoV) is a respiratory disease causing coronavirus. SARSCoV has caused the Middle East Respiratory Syndrome (MERS), SARSCoV in Hong King and SARSCoV2 (COVID19). COVID19, to date, have had the highest mortality and morbidity globally, thus reaching the pandemic status. In comparison to research conducted to explore the impact of pandemics on the general wellbeing, there appears to be a paucity on its association with womens mental health. Many pregnant women have reported that the pandemic negatively impacted their mental health. Aim This study aimed is to explore the prevalence of the impact of the COVID19, MERS and SARS pandemics on the mental health of pregnant women. Method A study protocol was developed and published in PROSPERO (CRD42021235356) to explore a number of key objectives. For the purpose of this study PubMed, Science direct, Ovid PsycINFO and EMBASE databases were searched from December 2000 to July 2021. The search results were screened, first by title, and then by abstract. A metaanalysis was conducted to report the findings. Results There were no studies reporting the mental health impact due to MERS and SARS. We systematically identified 316 studies that reported on the mental health of women that were pregnant and soon after birth. The metaanalysis indicated 24.9% (21.37% to 29.02%) of pregnant women reported symptoms of depression, 32.8% (29.05% to 37.21%) anxiety, 29.44% (18.21% to 47.61%) stress, 27.93% (9.05%to 86.15 %) PTSD, and 24.38% (11.89% to 49.96%) sleep disorders during the COVID19 pandemic. Furthermore, the I2 test showed a high heterogeneity value. Conclusion The importance of managing the mental health during pregnancy and after delivery improves the quality of life and wellbeing of mothers. Developing an evidence based mental health framework as part of pandemic preparedness to help pregnant women would improve the quality of care received during challenging times. Keywords: Covid19, Mental ill health, Depression, Anxiety, Stress, Pregnancy, Antenatal care, Postnatal care, Wellbeing

Molecular basis of receptor binding and antibody neutralization of Omicron.

The SARS-CoV-2 Omicron variant exhibits striking immune evasion and is spreading rapidly worldwide. Understanding the structural basis of the high transmissibility and enhanced immune evasion of Omicron is of high importance. Here, using cryo-electron microscopy, we present both the closed and the open states of the Omicron spike (S) protein, which appear more compact than the counterparts of the G614 strain1, potentially related to enhanced inter-protomer and S1-S2 interactions induced by Omicron residue substitution. The closed state showing dominant population may indicate a conformational masking mechanism for the immune evasion of Omicron. Moreover, we captured three states for the Omicron S-ACE2 complex, revealing that the substitutions on the Omicron RBM result in new salt bridges and hydrogen bonds, more favourable electrostatic surface properties, and an overall strengthened S-ACE2 interaction, in line with the observed higher ACE2 affinity of Omicron S than of G614. Furthermore, we determined the structures of Omicron S in complex with the Fab of S3H3, an antibody that is able to cross-neutralize major variants of concern including Omicron, elucidating the structural basis for S3H3-mediated broad-spectrum neutralization. Our findings shed light on the receptor engagement and antibody neutralization or evasion of Omicron and may also inform the design of broadly effective vaccines against SARS-CoV-2.

Conformational dynamics of the Beta and Kappa SARS-CoV-2 spike proteins and their complexes with ACE2 receptor revealed by cryo-EM.

The emergence of SARS-CoV-2 Kappa and Beta variants with enhanced transmissibility and resistance to neutralizing antibodies has created new challenges for the control of the ongoing COVID-19 pandemic. Understanding the structural nature of Kappa and Beta spike (S) proteins and their association with ACE2 is of significant importance. Here we present two cryo-EM structures for each of the Kappa and Beta spikes in the open and open-prone transition states. Compared with wild-type (WT) or G614 spikes, the two variant spikes appear more untwisted/open especially for Beta, and display a considerable population shift towards the open state as well as more pronounced conformational dynamics. Moreover, we capture four conformational states of the S-trimer/ACE2 complex for each of the two variants, revealing an enlarged conformational landscape for the Kappa and Beta S-ACE2 complexes and pronounced population shift towards the three RBDs up conformation. These results implicate that the mutations in Kappa and Beta may modify the kinetics of receptor binding and viral fusion to improve virus fitness. Combined with biochemical analysis, our structural study shows that the two variants are enabled to efficiently interact with ACE2 receptor despite their sensitive ACE2 binding surface is modified to escape recognition by some potent neutralizing MAbs. Our findings shed new light on the pathogenicity and immune evasion mechanism of the Beta and Kappa variants.

Conformational dynamics of SARS-CoV-2 trimeric spike glycoprotein in complex with receptor ACE2 revealed by cryo-EM.

The recent outbreaks of SARS-CoV-2 pose a global health emergency. The SARS-CoV-2 trimeric spike (S) glycoprotein interacts with the human ACE2 receptor to mediate viral entry into host cells. We report the cryo-EM structures of a tightly closed SARS-CoV-2 S trimer with packed fusion peptide and an ACE2-bound S trimer at 2.7- and 3.8-Å resolution, respectively. Accompanying ACE2 binding to the up receptor-binding domain (RBD), the associated ACE2-RBD exhibits continuous swing motions. Notably, the SARS-CoV-2 S trimer appears much more sensitive to the ACE2 receptor than the SARS-CoV S trimer regarding receptor-triggered transformation from the closed prefusion state to the fusion-prone open state, potentially contributing to the superior infectivity of SARS-CoV-2. We defined the RBD T470-T478 loop and Y505 as viral determinants for specific recognition of SARS-CoV-2 RBD by ACE2. Our findings depict the mechanism of ACE2-induced S trimer conformational transitions from the ground prefusion state toward the postfusion state, facilitating development of anti-SARS-CoV-2 vaccines and therapeutics.

Studies on the level of neutralizing antibodies produced by inactivated COVID-19 vaccines in the real world (preprint)

BackgroundAlthough effective vaccines have been developed against COVID-19, the level of neutralizing antibodies (Nabs) induced after vaccination in the real world is still unknown. To evaluate the level and persistence of NAbs induced by two inactivated COVID-19 vaccines in China. Methods and findingsSerum samples were collected from 1,335 people aged 18 and over who were vaccinated with COVID-19 inactivated vaccine in Peking University Peoples Hospital from January 19 to June 23, 2021, for detection of COVID-19 antibodies. The WHO standard of SARS-CoV-2 NAbs was detected. The coefficients of variation between the detection results and the true values of the NAbs detected by the WHO standard were all lower than the WHO international standard 3% after the dilution of the original and the dilution of the theoretical concentrations of 500 IU/mL, 250 IU/mL, 125 IU/mL, 72.5 IU/mL, 36.25 IU/mL and 18.125 IU/mL. On day 11-70, the positive rate of NAbs against COVID-19 was 82% to 100%; From day 71 to 332, the positive rate of NAbs decreased to 27%. The level of NAbs was significantly higher at 3-8 Weeks than at 0-3 Weeks. There was a high linear correlation between NAbs and IgG antibodies in 1335 vaccinated patients. NAbs levels were decreased in 31 of 38 people (81.6%) at two time points after the second dose of vaccine. There was no significant difference in age between the group with increased and decreased neutralizing antibody levels ({chi}2 =-0.034, P>0.05). The positive rate of NAbs in the two-dose vaccine group (77.3%) was significantly higher than that in the one-dose group (18.1%), with statistical difference ({chi}2=312.590, P<0.001). A total of 206 people who were 11-70 days after receiving the second dose were tested and divided into three groups: 18-40 years old, 41-60 years old and >60 years old. The positive rates of NAbs in three groups (18-40 years old, 41-60 years old and >60 years old) were 95.14%, 78.43% and 81.8%, respectively. The positive rate of NAbs was significantly higher in 18-40 years old than in 41-60 years old ({chi}2=12.547, P <0.01). The titer of NAbs in 18-40 years old group was significantly higher than that in 41-60 years old group (t=-0.222, P <0.01). The positive rate of NAbs in male group (89.32%) was lower than in female (91.26%), but there was no significant difference ({chi}2=0.222, P >0.05). ConclusionsThe positive rate of NAbs was the highest from 10 to 70 days after the second dose of vaccine, and the positive rate gradually decreased as time went by. There was a high linear correlation between COVID-19 NAbs and IgM/IgG antibodies in vaccinators, suggesting that in cases where NAbs cannot be detected, IgM/IgG antibodies can be detected instead. The level of NAbs produced after vaccination was affected by age, but not by gender. The highest levels of NAbs were produced between shots 21 to 56 days apart, suggesting that 21 to 56 days between shots is suitable for vaccination. Author summaryO_ST_ABSWhy was this study done?C_ST_ABSO_LIAt present, the inactivated vaccines that have been approved to market in China have passed clinical trials to prove their effectiveness and safety. But the level of neutralizing antibodies induced by vaccination in the real world remains unclear. C_LIO_LISerological testing for neutralizing antibodies against COVID-19 is important for assessing vaccine and treatment responses and comparing multiple drug candidates. We assessed the levels of neutralizing antibodies produced in populations receiving inactivated vaccines and assessed the persistence of these vaccines in producing COVID-19 neutralizing antibodies in healthy adults. C_LI What did the researchers do and find?O_LIWe collected serum samples from 1,335 people aged 18 and above who had received COVID-19 vaccine in Peking University Peoples Hospital, and divided them into two groups according to one dose of inactivated vaccine and two doses of inactivated vaccine. C_LIO_LIOur study found that the positive rate of NAbs was 66.2% in adults who received one or two doses of inactivated vaccine and 77.3% in adults who received two doses of inactivated vaccine in the real world. C_LIO_LIFrom 11 to 70 days after the second dose of vaccine, the positive rate of neutralizing antibodies against COVID-19 was 82-100%; On days 71-332, the positive rate of neutralizing antibodies decreased to 27%. C_LIO_LIThe titer and the positive rate of NAbs in 18-40 years old group were significantly higher than that in 41-60 years old group. C_LI What do these findings mean?O_LIWhat is novel is we observed that in the real world, the positive rate of neutralization antibody was the highest at 10 to 70 days after the second vaccination, and with the extension of the vaccination time, the positive rate of antibody gradually decreased. Therefore, we recommend that the third dose of vaccine be administered at day 61 to day 70 for COVID-19 neutralizing antibodies levels. C_LIO_LIWe observed that there was a high linear correlation between COVID-19 neutralization antibodies and COVID-19 IgM/IgG antibodies in vaccinators, suggesting that in cases where NAbs cannot be detected, COVID-19 IgM/IgG antibodies can be detected instead. C_LIO_LIIn our manuscript, we found that the titer and positive rate of neutralizing antibodies in 18-40 years old group were higher than those in 41-60 years old group. The level of neutralizing antibodies produced after vaccination was affected by age, but not by gender. C_LIO_LIWe also observed that the highest levels of NAbs were produced between shots 21 to 35 days apart, suggesting that 21 to 35 days between shots is suitable for vaccination. C_LI

Development and structural basis of a two-MAb cocktail for treating SARS-CoV-2 infections.

The ongoing pandemic of coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Neutralizing antibodies against SARS-CoV-2 are an option for drug development for treating COVID-19. Here, we report the identification and characterization of two groups of mouse neutralizing monoclonal antibodies (MAbs) targeting the receptor-binding domain (RBD) on the SARS-CoV-2 spike (S) protein. MAbs 2H2 and 3C1, representing the two antibody groups, respectively, bind distinct epitopes and are compatible in formulating a noncompeting antibody cocktail. A humanized version of the 2H2/3C1 cocktail is found to potently neutralize authentic SARS-CoV-2 infection in vitro with half inhibitory concentration (IC50) of 12 ng/mL and effectively treat SARS-CoV-2-infected mice even when administered at as late as 24 h post-infection. We determine an ensemble of cryo-EM structures of 2H2 or 3C1 Fab in complex with the S trimer up to 3.8 Å resolution, revealing the conformational space of the antigen-antibody complexes and MAb-triggered stepwise allosteric rearrangements of the S trimer, delineating a previously uncharacterized dynamic process of coordinated binding of neutralizing antibodies to the trimeric S protein. Our findings provide important information for the development of MAb-based drugs for preventing and treating SARS-CoV-2 infections.