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2.
Nature ; 607(7917): 119-127, 2022 07.
Article in English | MEDLINE | ID: covidwho-1915276

ABSTRACT

The recent emergence of SARS-CoV-2 Omicron (B.1.1.529 lineage) variants possessing numerous mutations has raised concerns of decreased effectiveness of current vaccines, therapeutic monoclonal antibodies and antiviral drugs for COVID-19 against these variants1,2. The original Omicron lineage, BA.1, prevailed in many countries, but more recently, BA.2 has become dominant in at least 68 countries3. Here we evaluated the replicative ability and pathogenicity of authentic infectious BA.2 isolates in immunocompetent and human ACE2-expressing mice and hamsters. In contrast to recent data with chimeric, recombinant SARS-CoV-2 strains expressing the spike proteins of BA.1 and BA.2 on an ancestral WK-521 backbone4, we observed similar infectivity and pathogenicity in mice and hamsters for BA.2 and BA.1, and less pathogenicity compared with early SARS-CoV-2 strains. We also observed a marked and significant reduction in the neutralizing activity of plasma from individuals who had recovered from COVID-19 and vaccine recipients against BA.2 compared to ancestral and Delta variant strains. In addition, we found that some therapeutic monoclonal antibodies (REGN10987 plus REGN10933, COV2-2196 plus COV2-2130, and S309) and antiviral drugs (molnupiravir, nirmatrelvir and S-217622) can restrict viral infection in the respiratory organs of BA.2-infected hamsters. These findings suggest that the replication and pathogenicity of BA.2 is similar to that of BA.1 in rodents and that several therapeutic monoclonal antibodies and antiviral compounds are effective against Omicron BA.2 variants.


Subject(s)
Antiviral Agents , COVID-19/drug therapy , SARS-CoV-2 , Animals , Antibodies, Monoclonal/pharmacology , Antibodies, Monoclonal/therapeutic use , Antibodies, Monoclonal, Humanized , Antibodies, Neutralizing/pharmacology , Antibodies, Neutralizing/therapeutic use , Antibodies, Viral/pharmacology , Antibodies, Viral/therapeutic use , Antiviral Agents/pharmacology , Antiviral Agents/therapeutic use , COVID-19/genetics , COVID-19/immunology , COVID-19/virology , Cricetinae , Cytidine/analogs & derivatives , Drug Combinations , Hydroxylamines , Indazoles , Lactams , Leucine , Mice , Nitriles , Proline , SARS-CoV-2/drug effects , SARS-CoV-2/genetics , SARS-CoV-2/pathogenicity , Spike Glycoprotein, Coronavirus/genetics , Triazines , Triazoles
3.
Antiviral Res ; 205: 105372, 2022 Sep.
Article in English | MEDLINE | ID: covidwho-1914151

ABSTRACT

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron subvariant BA.2 has spread in many countries, replacing the earlier Omicron subvariant BA.1 and other variants. Here, using a cell culture infection assay, we quantified the intrinsic sensitivity of BA.2 and BA.1 compared with other variants of concern, Alpha, Gamma, and Delta, to five approved-neutralizing antibodies and antiviral drugs. Our assay revealed the diverse sensitivities of these variants to antibodies, including the loss of response of both BA.1 and BA.2 to casirivimab and of BA.1 to imdevimab. In contrast, EIDD-1931 and nirmatrelvir showed a more conserved activities to these variants. The viral response profile combined with mathematical analysis estimated differences in antiviral effects among variants in the clinical concentrations. These analyses provide essential evidence that gives insight into variant emergence's impact on choosing optimal drug treatment.


Subject(s)
COVID-19 , SARS-CoV-2 , Antibodies, Monoclonal, Humanized , Antibodies, Neutralizing , Antibodies, Viral , Antiviral Agents/pharmacology , COVID-19/drug therapy , Humans
4.
Nat Microbiol ; 7(8): 1252-1258, 2022 Aug.
Article in English | MEDLINE | ID: covidwho-1890192

ABSTRACT

The spike protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the major antigen stimulating the host's protective immune response. Here we assessed the efficacy of therapeutic monoclonal antibodies (mAbs) against Omicron variant (B.1.1.529) sublineage BA.1 variants in Syrian hamsters. Of the FDA-approved therapeutic mAbs tested (that is, REGN10987/REGN10933, COV2-2196/COV2-2130 and S309), only COV2-2196/COV2-2130 efficiently inhibited BA.1 replication in the lungs of hamsters, and this effect was diminished against a BA.1.1 variant possessing the S-R346K substitution. In addition, treatment of BA.1-infected hamsters with molnupiravir (a SARS-CoV-2 RNA-dependent RNA polymerase inhibitor) or S-217622 (a SARS-CoV-2 protease inhibitor) strongly reduced virus replication in the lungs. These findings suggest that the use of therapeutic mAbs in Omicron-infected patients should be carefully considered due to mutations that affect efficacy, and demonstrate that the antiviral compounds molnupiravir and S-217622 are effective against Omicron BA.1 variants.


Subject(s)
COVID-19 , SARS-CoV-2 , Animals , Antibodies, Monoclonal/therapeutic use , Antibodies, Neutralizing , Antiviral Agents/pharmacology , Antiviral Agents/therapeutic use , COVID-19/drug therapy , Cricetinae , Humans , Mesocricetus , RNA, Viral
5.
Vaccine ; 40(31): 4231-4241, 2022 Jul 29.
Article in English | MEDLINE | ID: covidwho-1882604

ABSTRACT

The vaccine S-268019-b is a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike (S)-protein vaccine consisting of full-length recombinant SARS-CoV-2 S-protein (S-910823) as antigen, mixed with the squalene-based adjuvant A-910823. The current study evaluated the immunogenicity of S-268019-b using various doses of S-910823 and its vaccine efficacy against SARS-CoV-2 challenge in cynomolgus monkeys. The different doses of S-910823 combined with A-910823 were intramuscularly administered twice at a 3-week interval. Two weeks after the second dosing, dose-dependent humoral immune responses were observed with neutralizing antibody titers being comparable to that of human convalescent plasma. Pseudoviruses harboring S proteins from Beta and Gamma SARS-CoV-2 variants displayed approximately 3- to 4-fold reduced sensitivity to neutralizing antibodies induced after two vaccine doses compared with that against ancestral viruses, whereas neutralizing antibody titers were reduced >14-fold against the Omicron variant. Cellular immunity was also induced with a relative Th1 polarized response. No adverse clinical signs or weight loss associated with the vaccine were observed, suggesting safety of the vaccine in cynomolgus monkeys. Immunization with 10 µg of S-910823 with A-910823 demonstrated protective efficacy against SARS-CoV-2 challenge according to genomic and subgenomic viral RNA transcript levels in nasopharyngeal, throat, and rectal swab specimens. Pathological analysis revealed no detectable vaccine-dependent enhancement of disease in the lungs of challenged vaccinated monkeys. The current findings provide fundamental information regarding vaccine doses for human trials and support the development of S-268019-b as a safe and effective vaccine for controlling the current pandemic, as well as general protection against SARS-CoV-2 moving forward.


Subject(s)
COVID-19 , Viral Vaccines , Animals , Antibodies, Neutralizing , Antibodies, Viral , COVID-19/prevention & control , COVID-19/therapy , Immunization, Passive , Immunogenicity, Vaccine , Macaca fascicularis , SARS-CoV-2 , Spike Glycoprotein, Coronavirus
6.
Med (N Y) ; 3(4): 249-261.e4, 2022 04 08.
Article in English | MEDLINE | ID: covidwho-1783638

ABSTRACT

Background: The immune profile against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has dramatically diversified due to a complex combination of exposure to vaccines and infection by various lineages/variants, likely generating a heterogeneity in protective immunity in a given population. To further complicate this, the Omicron variant, with numerous spike mutations, has emerged. These circumstances have created the need to assess the potential of immune evasion by Omicron in individuals with various immune histories. Methods: The neutralization susceptibility of the variants, including Omicron and their ancestors, was comparably assessed using a panel of plasma/serum derived from individuals with divergent immune histories. Blood samples were collected from either mRNA vaccinees or from those who suffered from breakthrough infections of Alpha/Delta with multiple time intervals following vaccination. Findings: Omicron was highly resistant to neutralization in fully vaccinated individuals without a history of breakthrough infections. In contrast, robust cross-neutralization against Omicron was induced in vaccinees that experienced breakthrough infections. The time interval between vaccination and infection, rather than the variant types of infection, was significantly correlated with the magnitude and potency of Omicron-neutralizing antibodies. Conclusions: Immune histories with breakthrough infections can overcome the resistance to infection by Omicron, with the vaccination-infection interval being the key determinant of the magnitude and breadth of neutralization. The diverse exposure history in each individual warrants a tailored and cautious approach to understanding population immunity against Omicron and future variants. Funding: This study was supported by grants from the Japan Agency for Medical Research and Development (AMED).


Subject(s)
COVID-19 , SARS-CoV-2 , Antibodies, Viral , COVID-19 Vaccines , Humans , Postoperative Complications , Vaccination
8.
EuropePMC; 2022.
Preprint in English | EuropePMC | ID: ppcovidwho-329162

ABSTRACT

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron subvariant BA.2 has spread in many countries, replacing the earlier Omicron subvariant BA.1 and other variants. Here, using a cell culture infection assay, we quantified the intrinsic sensitivity of BA.2 and BA.1 compared with other variants of concern, Alpha, Gamma, and Delta, to five approved-neutralizing antibodies and antiviral drugs. Our assay revealed the diverse sensitivities of these variants to antibodies, including the loss of response of both BA.1 and BA.2 to casirivimab and of BA.1 to imdevimab. In contrast, EIDD-1931 and nirmatrelvir showed a more conserved activities to these variants. The viral response profile combined with mathematical analysis estimated differences in antiviral effects among variants in the clinical concentrations. These analyses provide essential evidence that gives insight into the impact of variant emergence on choosing optimal drug treatment.

9.
Viruses ; 14(2)2022 01 27.
Article in English | MEDLINE | ID: covidwho-1662708

ABSTRACT

We aimed to analyze the situation of the first two epidemic waves in Myanmar using the publicly available daily situation of COVID-19 and whole-genome sequencing data of SARS-CoV-2. From March 23 to December 31, 2020, there were 33,917 confirmed cases and 741 deaths in Myanmar (case fatality rate of 2.18%). The first wave in Myanmar from March to July was linked to overseas travel, and then a second wave started from Rakhine State, a western border state, leading to the second wave spreading countrywide in Myanmar from August to December 2020. The estimated effective reproductive number (Rt) nationwide reached 6-8 at the beginning of each wave and gradually decreased as the epidemic spread to the community. The whole-genome analysis of 10 Myanmar SARS-CoV-2 strains together with 31 previously registered strains showed that the first wave was caused by GISAID clade O or PANGOLIN lineage B.6 and the second wave was changed to clade GH or lineage B.1.36.16 with a close genetic relationship with other South Asian strains. Constant monitoring of epidemiological situations combined with SARS-CoV-2 genome analysis is important for adjusting public health measures to mitigate the community transmissions of COVID-19.


Subject(s)
COVID-19/epidemiology , Community-Acquired Infections/epidemiology , Community-Acquired Infections/virology , Epidemics/statistics & numerical data , Public Health/statistics & numerical data , SARS-CoV-2/genetics , Adult , Aged , COVID-19/transmission , Child , Community-Acquired Infections/transmission , Female , Genome, Viral , Humans , Male , Middle Aged , Mutation , Myanmar/epidemiology , Phylogeny , SARS-CoV-2/classification , Whole Genome Sequencing , Young Adult
11.
Influenza Other Respir Viruses ; 15(4): 488-494, 2021 07.
Article in English | MEDLINE | ID: covidwho-1132956

ABSTRACT

BACKGROUND: Coronavirus disease (COVID-19), which is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), was first detected in Japan in January 2020 and has spread throughout the country. Previous studies have reported that viral interference among influenza virus, rhinovirus, and other respiratory viruses can affect viral infections at the host and population level. METHODS: To investigate the impact of COVID-19 on influenza and other respiratory virus infections, we analyzed clinical specimens collected from 2244 patients in Japan with respiratory diseases between January 2018 and September 2020. RESULTS: The frequency of influenza and other respiratory viruses (coxsackievirus A and B; echovirus; enterovirus; human coronavirus 229E, HKU1, NL63, and OC43; human metapneumovirus; human parainfluenza virus 1, 2, 3, and 4; human parechovirus; human respiratory syncytial virus; human adenovirus; human bocavirus; human parvovirus B19; herpes simplex virus type 1; and varicella-zoster virus) was appreciably reduced among all patients during the COVID-19 pandemic except for that of rhinovirus in children younger than 10 years, which was appreciably increased. COVID-19 has not spread among this age group, suggesting an increased risk of rhinovirus infection in children. CONCLUSIONS: Rhinovirus infections should be continuously monitored to understand their increased risk during the COVID-19 pandemic and viral interference with SARS-CoV-2.


Subject(s)
COVID-19/epidemiology , Picornaviridae Infections/epidemiology , Rhinovirus/isolation & purification , Adult , Child , Child, Preschool , Coinfection/diagnosis , Coinfection/epidemiology , Coinfection/virology , Female , Humans , Infant , Infant, Newborn , Japan/epidemiology , Male , Picornaviridae Infections/diagnosis , Picornaviridae Infections/virology , Respiratory Tract Infections/diagnosis , Respiratory Tract Infections/epidemiology , Respiratory Tract Infections/virology , Risk , SARS-CoV-2 , Virus Diseases/diagnosis , Virus Diseases/epidemiology , Virus Diseases/virology , Viruses/isolation & purification
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