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1.
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
2.
Jpn J Infect Dis ; 2022 Jun 30.
Article in English | MEDLINE | ID: covidwho-1912148

ABSTRACT

Immunocompromised patients are more likely to develop severe COVID-19 and their mortality is high, while it is hypothesized that chronic infection in these patients can be a risk of developing new variants. We describe a patient with prolonged active infection of COVID-19 who became infected during treatment with anti-CD20 antibody (obinutuzumab) for follicular lymphoma. This patient had persistent RT-PCR positivity and live virus isolation for nine months despite treatment with remdesivir and other potential antiviral therapies. The computed tomography image of the chest showed that the viral pneumonia repeatedly appeared and disappeared in different lobes, as if new infection had occurred continuously. His antibody titer of SARS-CoV-2 was negative throughout the illness, even after two doses of BNT162b2 mRNA vaccine given in the seventh month. Combination of monoclonal antibody therapy against COVID-19 (casirivimab and imdevimab) and antivirals resulted in negative RT-PCR and the virus was no longer isolated. The patient was clinically cured. During the 9-month active infection, no fixed mutations in the S protein were detected and the in vitro susceptibility to remdesivir was retained. Therapeutic administration of anti-SARS-CoV-2 monoclonal antibodies is essential for immunocompromised patients. Measures to prevent resistance against these key drugs are in dire need.

3.
Viruses ; 14(5)2022 05 01.
Article in English | MEDLINE | ID: covidwho-1862910

ABSTRACT

Viral infections are influenced by various microorganisms in the environment surrounding the target tissue, and the correlation between the type and balance of commensal microbiota is the key to establishment of the infection and pathogenicity. Some commensal microorganisms are known to resist or promote viral infection, while others are involved in pathogenicity. It is also becoming evident that the profile of the commensal microbiota under normal conditions influences the progression of viral diseases. Thus, to understand the pathogenesis underlying viral infections, it is important to elucidate the interactions among viruses, target tissues, and the surrounding environment, including the commensal microbiota, which should have different relationships with each virus. In this review, we outline the role of microorganisms in viral infections. Particularly, we focus on gaining an in-depth understanding of the correlations among viral infections, target tissues, and the surrounding environment, including the commensal microbiota and the gut virome, and discussing the impact of changes in the microbiota (dysbiosis) on the pathological progression of viral infections.


Subject(s)
Gastrointestinal Microbiome , Microbiota , Virus Diseases , Viruses , Dysbiosis , Humans
4.
Sci Transl Med ; 14(657): eabm4908, 2022 Aug 10.
Article in English | MEDLINE | ID: covidwho-1846321

ABSTRACT

The SARS-CoV-2 B.1.621 (Mu) variant emerged in January 2021 and was categorized as a variant of interest by the World Health Organization in August 2021. This designation prompted us to study the sensitivity of this variant to antibody neutralization. In a live virus neutralization assay with serum samples from individuals vaccinated with the Pfizer/BioNTech or Moderna mRNA vaccines, we measured neutralization antibody titers against B.1.621, an early isolate (spike 614D), and a variant of concern (B.1.351, Beta variant). We observed reduced neutralizing antibody titers against the B.1.621 variant (3.4- to 7-fold reduction, depending on the serum sample and time after the second vaccination) compared to the early isolate and a similar reduction when compared to B.1.351. Likewise, convalescent serum from hamsters previously infected with an early isolate neutralized B.1.621 to a lower degree. Despite this antibody titer reduction, hamsters could not be efficiently rechallenged with the B.1.621 variant, suggesting that the immune response to the first infection is adequate to provide protection against a subsequent infection with the B.1.621 variant.


Subject(s)
COVID-19 , Viral Envelope Proteins , Antibodies, Neutralizing , Antibodies, Viral , COVID-19/therapy , Humans , Immunization, Passive , Membrane Glycoproteins/genetics , Neutralization Tests , SARS-CoV-2 , Spike Glycoprotein, Coronavirus/genetics , Vaccination , Viral Envelope Proteins/genetics
5.
EuropePMC; 2022.
Preprint in English | EuropePMC | ID: ppcovidwho-335196

ABSTRACT

Summary The detailed mechanisms of COVID-19 infection pathology remain poorly understood. To improve our understanding of SARS-CoV-2 pathology, we performed a multi-omics analysis of an immunologically naïve SARS-CoV-2 clinical cohort from the plasma of uninfected controls, mild, and severe infections. A comparison of healthy controls and patient samples showed activation of neutrophil degranulation pathways and formation of neutrophil extracellular trap (NET) complexes that were activated in a subset of the mild infections and more prevalent in severe infections (containing multiple NET proteins in individual patient samples). As a potential mechanism to suppress NET formation, multiple redox enzymes were elevated in the mild and severe symptom population. Analysis of metabolites from the same cohort showed a 24- and 60-fold elevation in plasma L-cystine, the oxidized form of cysteine, which is a substrate of the powerful antioxidant glutathione, in mild and severe patients, respectively. Unique to patients with mild infections, the carnosine dipeptidase modifying enzyme (CNDP1) was up-regulated. The strong protein and metabolite oxidation signatures suggest multiple compensatory pathways working to suppress oxidation and NET formation in SARS-CoV-2 infections.

6.
J Infect Chemother ; 28(7): 1015-1017, 2022 Jul.
Article in English | MEDLINE | ID: covidwho-1768315

ABSTRACT

By December 2021, about 80% of people over the age of 12 had been vaccinated in Japan, and almost all people were vaccinated with the mRNA vaccine. We investigated here the anti-spike protein antibody titer at the time of breakthrough infection of SARS-CoV-2 omicron. A total of 32 SARS-CoV2 omicron breakthrough infection was included in the study. The median antibody titer at breakthrough infection was 776 AU/mL overall, of which the median antibody titer of BNT162b2 vaccinated was 633 AU/mL and that of mRNA-1273 vaccinated was 9416 AU/mL. This result suggests that low levels of antibody titers 6 months after vaccination do not provide sufficient antibodies to prevent the omicron variant breakthrough infection, which may occur with a higher anti-spike antibody titer after vaccination with mRNA-1273. However, antibody titers in some patients were comparable to those immediately after the second vaccination with either mRNA vaccine.


Subject(s)
COVID-19 , SARS-CoV-2 , Antibodies, Viral , BNT162 Vaccine , COVID-19 Vaccines , Humans , RNA, Viral , Vaccines, Synthetic , mRNA Vaccines
7.
Microbiol Spectr ; 10(2): e0168921, 2022 04 27.
Article in English | MEDLINE | ID: covidwho-1731262

ABSTRACT

The role of the intestinal microbiota in coronavirus disease 2019 (COVID-19) is being elucidated. Here, we analyzed the temporal changes in microbiota composition and the correlation between inflammation biomarkers/cytokines and microbiota in hospitalized COVID-19 patients. We obtained stool specimens, blood samples, and patient records from 22 hospitalized COVID-19 patients and performed 16S rRNA metagenomic analysis of stool samples over the course of disease onset compared to 40 healthy individual stool samples. We analyzed the correlation between the changes in the gut microbiota and plasma proinflammatory cytokine levels. Immediately after admission, differences in the gut microbiota were observed between COVID-19 patients and healthy subjects, mainly including enrichment of the classes Bacilli and Coriobacteriia and decrease in abundance of the class Clostridia. The bacterial profile continued to change throughout the hospitalization, with a decrease in short-chain fatty acid-producing bacteria including Faecalibacterium and an increase in the facultatively anaerobic bacteria Escherichia-Shigella. A consistent increase in Eggerthella belonging to the class Coriobacteriia was observed. The abundance of the class Clostridia was inversely correlated with interferon-γ level and that of the phylum Actinobacteria, which was enriched in COVID-19, and was positively correlated with gp130/sIL-6Rb levels. Dysbiosis was continued even after 21 days from onset. The intestines tended to be an aerobic environment in hospitalized COVID-19 patients. Because the composition of the gut microbiota correlates with the levels of proinflammatory cytokines, this finding emphasizes the need to understand how pathology is related to the temporal changes in the specific gut microbiota observed in COVID-19 patients. IMPORTANCE There is growing evidence that the commensal microbiota of the gastrointestinal and respiratory tracts regulates local and systemic inflammation (gut-lung axis). COVID-19 is primarily a respiratory disease, but the involvement of microbiota changes in the pathogenesis of this disease remains unclear. The composition of the gut microbiota of patients with COVID-19 changed over time during hospitalization, and the intestines tended to be an aerobic environment in hospitalized COVID-19 patients. These changes in gut microbiota may induce increased intestinal permeability, called leaky gut, allowing bacteria and toxins to enter the circulatory system and further aggravate the systemic inflammatory response. Since gut microbiota composition correlates with levels of proinflammatory cytokines, this finding highlights the need to understand how pathology relates to the gut environment, including the temporal changes in specific gut microbiota observed in COVID-19 patients.


Subject(s)
COVID-19 , Gastrointestinal Microbiome , Bacteria/genetics , Cytokines , Dysbiosis/microbiology , Feces/microbiology , Gastrointestinal Microbiome/physiology , Hospitalization , Humans , Inflammation , RNA, Ribosomal, 16S/genetics
9.
JPRN; 26/12/2021; TrialID: JPRN-jRCT1031210517
Clinical Trial Register | ICTRP | ID: ictrp-JPRN-jRCT1031210517

ABSTRACT

Condition:

COVID-19
COVID-19

Primary outcome:

We will investigate various antibody reactions and cell-mediated immune responses as an exploratory study of immunogenicity, mainly surrogate markers and biomarkers.

Criteria:

Inclusion criteria: Subjects who meet all the inclusion criteria and do not meet any of the exclusion criteria are targeted.

Group who are 20 to under 65 years and finished two intramuscular injections of Pfizer Comirnaty
1. Subjects who are 20 years old or older and under 65 years old at the time of obtaining consent
2. Subjects who have been vaccinated twice with Pfizer Comirnaty intramuscular injection before receiving this investigational drug and 6-12 months have passed since the first vaccine.
3. Subjects with no apparent history of SARS-CoV-2 infection prior to inoculation of this investigational drug
4. Subjects who can obtain written consent

Group who are 65 years or older and finished two intramuscular injections of Pfizer Comirnaty
1. Subjects aged 65 and over at the time of obtaining consent
2. Subjects who have been vaccinated twice with Pfizer Comirnaty intramuscular injection before receiving this investigational drug and 6-12 months have passed since the first vaccine.
3. Subjects with no apparent history of SARS-CoV-2 infection prior to inoculation of this investigational drug
4. Subjects who can obtain written consent

Group who are 20 to under 65 years and finished two intramuscular injections of Takeda/Moderna vaccine
1. Subjects who are 20 years old or older and under 65 years old at the time of obtaining consent
2. Subjects who have been vaccinated twice with Takeda/Moderna vaccine intramuscular injection before receiving this investigational drug and 6-12 months have passed since the first vaccine.
3. Subjects with no apparent history of SARS-CoV-2 infection prior to inoculation of this investigational drug
4. Subjects who can obtain written consent


Group who are 65 years or older and finished two intramuscular injections of Takeda/Moderna vaccine
1. Subjects aged 65 and over at the time of obtaining consent
2. Subjects who have been vaccinated twice with Takeda/Moderna vaccine intramuscular injection before receiving this investigational drug and 6-12 months have passed since the first vaccine.
3. Subjects with no apparent history of SARS-CoV-2 infection prior to inoculation of this investigational drug
4. Subjects who can obtain written consent

Group who have been vaccinated with Pfizer Comirnaty intramuscular injection only once
1. Subjects who are 20 years old or older at the time of obtaining consent
2. Subjects who have been vaccinated once with Pfizer Comirnaty intramuscular injection before receiving this investigational drug and 6-12 months have passed since the vaccine.
3. Subjects with no apparent history of SARS-CoV-2 infection prior to inoculation of this investigational drug
4. Subjects who can obtain written consent


Group who have been vaccinated with Takeda/Moderna vaccine intramuscular injection only once
1. Subjects who are 20 years old or older at the time of obtaining consent
2. Subjects who have been vaccinated once with Takeda/Moderna vaccine intramuscular injection before receiving this investigational drug and 6-12 months have passed since the vaccine.
3. Subjects with no apparent history of SARS-CoV-2 infection prior to inoculation of this investigational drug
4. Subjects who can obtain written consent

Group who have been vaccinated with Pfizer Comirnaty intramuscular injection twice with a history of SARS-CoV-2 infection
1. Those who are 20 years of age or older at the time of obtaining consent
2. Subjects who ha

Exclusion criteria: 1.Subjects who tested positive for SARS-CoV-2 by a PCR test at screening,
2.Subjects with COVID-19,
3.Close contact with COVID-19 patients at the time of the inoculation
4.Subjects with a history of administration of anti-SARS-CoV-2 monoclonal antibody within three months before the inoculation of the investigational drug
5.Subjects who have developed anaphylaxis due to a component of the investigational drug (thimerosal)
6.Pregnant women, women who may be pregnant, women who wish to become pregnant by four weeks after the inoculation of the investigational drug, women who are breastfeeding
7.Subjects with progressive ossifying fibrodysplasia
8.Subjects with underlying diseases such as severe cardiovascular disease, kidney disease, liver disease, blood disease, growth disorder, respiratory disease and diabetes etc
9.Subjects who have had the fever (excluding the feeling of heat at the inoculation site) within two days after the vaccination except for the COVID-19 preventive vaccine, and those who have had symptoms suspected of allergies such as a systemic rash (cause) Not applicable if it is confirmed that the ingredient is not contained in the investigational drug)
10.Subjects who have a history of convulsions in the past
11.Subjects having been diagnosed with immunodeficiency or having a close relative with congenital immunodeficiency,
12.Subjects who have experienced documented anaphylaxis caused by an ingredient of the investigational product (thimerosal),
13.Subjects who participated in other clinical trials or clinical trials within 120 days from the date of inoculation of the study drug, or subjects who plan to participate by the end of the follow-up period of this study.
14.Subjects who have received transfusion or a gamma globulin preparation within three months (90 days), or a bolus therapy (>=200 mg/kg) with a gamma globulin preparation within six months (180 days), prior to the date of the first dose of study product,
15.Subject who have received any treatments that may affect the immune function within six months (180 days) prior to the date of the first dose of study product, including radiotherapy, immunosuppressants (except for external use), immunosuppressive therapy, antirheumatics, adrenocorticotropic hormones, or corticosteroids (treatment at prednisolone equivalent doses >=2 mg/kg/day for >=14 days, except for external use.),
16.Subjects who are judged by the principal investigator or the sub-investigator as ineligible for the study as a result of the screening test,
17.Subject being otherwise ineligible for this study in the principal investigator's or sub-investigator's opinion.

10.
JPRN; 21/12/2021; TrialID: JPRN-jRCT2031210503
Clinical Trial Register | ICTRP | ID: ictrp-JPRN-jRCT2031210503

ABSTRACT

Condition:

Prevention of COVID-19

Intervention:

Inoculate KD-414 (0.5 mL / dose) once into the muscle

Primary outcome:

[Safety and tolerance]
Percentage of subjects who reported any adverse event even once
Frequency of each adverse event item after coding
Percentage of subjects who reported the relevant adverse event even once by grade
Summary statistics for safety-related inspection items

[Immunogenicity] Geometric mean of neutralizing antibody titers of each group against SARS-CoV-2 at four weeks after the investigational drug, and geometric mean fold rise of neutralizing antibody titers of each group against SARS-CoV-2 after the investigational drug compared to the titer before the first vaccination

Criteria:

Inclusion criteria: Group who are 20 to under 65 years and finished two intramuscular injections of Pfizer Comirnaty
1. Subjects who are 20 years old or older and under 65 years old at the time of obtaining consent
2. Subjects who have been vaccinated twice with Pfizer Comirnaty intramuscular injection before receiving this investigational drug and 6-12 months have passed since the first vaccine.
3. Subjects with no apparent history of SARS-CoV-2 infection prior to inoculation of this investigational drug
4. Subjects who can obtain written consent

Group who are 65 years or older and finished two intramuscular injections of Pfizer Comirnaty
1. Subjects aged 65 and over at the time of obtaining consent
2. Subjects who have been vaccinated twice with Pfizer Comirnaty intramuscular injection before receiving this investigational drug and 6-12 months have passed since the first vaccine.
3. Subjects with no apparent history of SARS-CoV-2 infection prior to inoculation of this investigational drug
4. Subjects who can obtain written consent

Group who are 20 to under 65 years and finished two intramuscular injections of Takeda/Moderna vaccine
1. Subjects who are 20 years old or older and under 65 years old at the time of obtaining consent
2. Subjects who have been vaccinated twice with Takeda/Moderna vaccine intramuscular injection before receiving this investigational drug and 6-12 months have passed since the first vaccine.
3. Subjects with no apparent history of SARS-CoV-2 infection prior to inoculation of this investigational drug
4. Subjects who can obtain written consent

Group who are 65 years or older and finished two intramuscular injections of Takeda/Moderna vaccine
1. Subjects aged 65 and over at the time of obtaining consent
2. Subjects who have been vaccinated twice with Takeda/Moderna vaccine intramuscular injection before receiving this investigational drug and 6-12 months have passed since the first vaccine.
3. Subjects with no apparent history of SARS-CoV-2 infection prior to inoculation of this investigational drug
4. Subjects who can obtain written consent

Group who have been vaccinated with Pfizer Comirnaty intramuscular injection only once
1. Subjects who are 20 years old or older at the time of obtaining consent
2. Subjects who have been vaccinated once with Pfizer Comirnaty intramuscular injection before receiving this investigational drug and 6-12 months have passed since the vaccine.
3. Subjects with no apparent history of SARS-CoV-2 infection prior to inoculation of this investigational drug
4. Subjects who can obtain written consent

Group who have been vaccinated with Takeda/Moderna vaccine intramuscular injection only once
1. Subjects who are 20 years old or older at the time of obtaining consent
2. Subjects who have been vaccinated once with Takeda/Moderna vaccine intramuscular injection before receiving this investigational drug and 6-12 months have passed since the vaccine.
3. Subjects with no apparent history of SARS-CoV-2 infection prior to inoculation of this investigational drug
4. Subjects who can obtain written consent

Group who have been vaccinated with Pfizer Comirnaty intramuscular injection twice with a history of SARS-CoV-2 infection
1. Those who are 20 years of age or older at the time of obtaining consent
2. Subjects who have been vaccinated twice with Pfizer Comirnaty intramuscular injection have been vaccinated for 6 to 12 mon

Exclusion criteria: 1.Subjects who tested positive for SARS-CoV-2 by a PCR test at screening,
2.Subjects with COVID-19,
3.Close contact with COVID-19 patients at the time of the inoculation
4.Subjects with a history of administration of anti-SARS-CoV-2 monoclonal antibody within three months before the inoculation of the investigational drug
5.Subjects who have developed anaphylaxis due to a component of the investigational drug (thimerosal)
6.Pregnant women, women who may be pregnant, women who wish to become pregnant by four weeks after the inoculation of the investigational drug, women who are breastfeeding
7.Subjects with progressive ossifying fibrodysplasia
8.Subjects with underlying diseases such as severe cardiovascular disease, kidney disease, liver disease, blood disease, growth disorder, respiratory disease and diabetes etc
9.Subjects who have had the fever (excluding the feeling of heat at the inoculation site) within two days after the vaccination except for the COVID-19 preventive vaccine, and those who have had symptoms suspected of allergies such as a systemic rash (cause) Not applicable if it is confirmed that the ingredient is not contained in the investigational drug)
10.Subjects who have a history of convulsions in the past
11.Subjects having been diagnosed with immunodeficiency or having a close relative with congenital immunodeficiency,
12.Subjects who have experienced documented anaphylaxis caused by an ingredient of the investigational product (thimerosal),
13.Subjects who participated in other clinical trials or clinical trials within 120 days from the date of inoculation of the study drug, or subjects who plan to participate by the end of the follow-up period of this study.
14.Subjects who have received transfusion or a gamma globulin preparation within three months (90 days), or a bolus therapy (>=200 mg/kg) with a gamma globulin preparation within six months (180 days), prior to the date of the first dose of study product,
15.Subject who have received any treatments that may affect the immune function within six months (180 days) prior to the date of the first dose of study product, including radiotherapy, immunosuppressants (except for external use), immunosuppressive therapy, antirheumatics, adrenocorticotropic hormones, or corticosteroids (treatment at prednisolone equivalent doses >=2 mg/kg/day for >=14 days, except for external use.),
16.Subjects who are judged by the principal investigator or the sub-investigator as ineligible for the study as a result of the screening test,
17.Subject being otherwise ineligible for this study in the principal investigator's or sub-investigator's opinion.

11.
EClinicalMedicine ; 32: 100734, 2021 Feb.
Article in English | MEDLINE | ID: covidwho-1385450

ABSTRACT

BACKGROUND: To develop an effective vaccine against a novel viral pathogen, it is important to understand the longitudinal antibody responses against its first infection. Here we performed a longitudinal study of antibody responses against SARS-CoV-2 in symptomatic patients. METHODS: Sequential blood samples were collected from 39 individuals at various timepoints between 0 and 154 days after onset. IgG or IgM titers to the receptor binding domain (RBD) of the S protein, the ectodomain of the S protein, and the N protein were determined by using an ELISA. Neutralizing antibody titers were measured by using a plaque reduction assay. FINDINGS: The IgG titers to the RBD of the S protein, the ectodomain of the S protein, and the N protein peaked at about 20 days after onset, gradually decreased thereafter, and were maintained for several months after onset. Extrapolation modeling analysis suggested that the IgG antibodies were maintained for this amount of time because the rate of reduction slowed after 30 days post-onset. IgM titers to the RBD decreased rapidly and disappeared in some individuals after 90 days post-onset. All patients, except one, possessed neutralizing antibodies against authentic SARS-CoV-2, which they retained at 90 days after onset. The highest antibody titers in patients with severe infections were higher than those in patients with mild or moderate infections, but the decrease in antibody titer in the severe infection cohort was more remarkable than that in the mild or moderate infection cohort. INTERPRETATION: Although the number of patients is limited, our results show that the antibody response against the first SARS-CoV-2 infection in symptomatic patients is typical of that observed in an acute viral infection. FUNDING: The Japan Agency for Medical Research and Development and the National Institutes of Allergy and Infectious Diseases.

12.
Proc Natl Acad Sci U S A ; 118(27)2021 07 06.
Article in English | MEDLINE | ID: covidwho-1276013

ABSTRACT

The spike (S) protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) plays a key role in viral infectivity. It is also the major antigen stimulating the host's protective immune response, specifically, the production of neutralizing antibodies. Recently, a new variant of SARS-CoV-2 possessing multiple mutations in the S protein, designated P.1, emerged in Brazil. Here, we characterized a P.1 variant isolated in Japan by using Syrian hamsters, a well-established small animal model for the study of SARS-CoV-2 disease (COVID-19). In hamsters, the variant showed replicative abilities and pathogenicity similar to those of early and contemporary strains (i.e., SARS-CoV-2 bearing aspartic acid [D] or glycine [G] at position 614 of the S protein). Sera and/or plasma from convalescent patients and BNT162b2 messenger RNA vaccinees showed comparable neutralization titers across the P.1 variant, S-614D, and S-614G strains. In contrast, the S-614D and S-614G strains were less well recognized than the P.1 variant by serum from a P.1-infected patient. Prior infection with S-614D or S-614G strains efficiently prevented the replication of the P.1 variant in the lower respiratory tract of hamsters upon reinfection. In addition, passive transfer of neutralizing antibodies to hamsters infected with the P.1 variant or the S-614G strain led to reduced virus replication in the lower respiratory tract. However, the effect was less pronounced against the P.1 variant than the S-614G strain. These findings suggest that the P.1 variant may be somewhat antigenically different from the early and contemporary strains of SARS-CoV-2.


Subject(s)
COVID-19/virology , SARS-CoV-2/physiology , SARS-CoV-2/pathogenicity , Virus Replication , Animals , Antibodies, Neutralizing , COVID-19/diagnostic imaging , COVID-19/pathology , Cricetinae , Humans , Immunogenicity, Vaccine , Lung/pathology , Mesocricetus , Mice , Spike Glycoprotein, Coronavirus/genetics , X-Ray Microtomography
13.
HLA ; 98(1): 37-42, 2021 07.
Article in English | MEDLINE | ID: covidwho-1199730

ABSTRACT

HLA-A, -C, -B, and -DRB1 genotypes were analyzed in 178 Japanese COVID-19 patients to investigate the association of HLA with severe COVID-19. Analysis of 32 common HLA alleles at four loci revealed a significant association between HLA-DRB1*09:01 and severe COVID-19 (odds ratio [OR], 3.62; 95% CI, 1.57-8.35; p = 0.00251 [permutation p value = 0.0418]) when age, sex, and other common HLA alleles at the DRB1 locus were adjusted. The DRB1*09:01 allele was more significantly associated with risk for severe COVID-19 compared to preexisting medical conditions such as hypertension, diabetes, and cardiovascular diseases. These results indicate a potential role for HLA in predisposition to severe COVID-19.


Subject(s)
COVID-19 , HLA-DRB1 Chains , Alleles , COVID-19/diagnosis , COVID-19/genetics , Gene Frequency , Genetic Predisposition to Disease , Genotype , HLA-DRB1 Chains/genetics , Humans
14.
Sci Adv ; 7(10)2021 03.
Article in English | MEDLINE | ID: covidwho-1119272

ABSTRACT

Limited knowledge exists on immune markers associated with disease severity or recovery in patients with coronavirus disease 2019 (COVID-19). Here, we elucidated longitudinal evolution of SARS-CoV-2 antibody repertoire in patients with acute COVID-19. Differential kinetics was observed for immunoglobulin M (IgM)/IgG/IgA epitope diversity, antibody binding, and affinity maturation in "severe" versus "mild" COVID-19 patients. IgG profile demonstrated immunodominant antigenic sequences encompassing fusion peptide and receptor binding domain (RBD) in patients with mild COVID-19 who recovered early compared with "fatal" COVID-19 patients. In patients with severe COVID-19, high-titer IgA were observed, primarily against RBD, especially in patients who succumbed to SARS-CoV-2 infection. The patients with mild COVID-19 showed marked increase in antibody affinity maturation to prefusion SARS-CoV-2 spike that associated with faster recovery from COVID-19. This study revealed antibody markers associated with disease severity and resolution of clinical disease that could inform development and evaluation of effective immune-based countermeasures against COVID-19.


Subject(s)
Antibodies, Viral/blood , Antibodies, Viral/immunology , Antigens, Viral/immunology , Biomarkers/blood , COVID-19/immunology , COVID-19/pathology , SARS-CoV-2/physiology , Severity of Illness Index , Antibody Affinity/immunology , Antibody Formation/immunology , COVID-19/blood , COVID-19/virology , Cytokines/blood , HEK293 Cells , Hospitalization , Humans , Immunoglobulin Class Switching , Kinetics , Neutralization Tests , Protein Binding , Protein Domains , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/immunology , Viral Load
15.
Viruses ; 12(12)2020 12 10.
Article in English | MEDLINE | ID: covidwho-970091

ABSTRACT

Reverse transcription-quantitative PCR (RT-qPCR)-based tests are widely used to diagnose coronavirus disease 2019 (COVID-19). As a result that these tests cannot be done in local clinics where RT-qPCR testing capability is lacking, rapid antigen tests (RATs) for COVID-19 based on lateral flow immunoassays are used for rapid diagnosis. However, their sensitivity compared with each other and with RT-qPCR and infectious virus isolation has not been examined. Here, we compared the sensitivity among four RATs by using severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) isolates and several types of COVID-19 patient specimens and compared their sensitivity with that of RT-qPCR and infectious virus isolation. Although the RATs read the samples containing large amounts of virus as positive, even the most sensitive RAT read the samples containing small amounts of virus as negative. Moreover, all RATs tested failed to detect viral antigens in several specimens from which the virus was isolated. The current RATs will likely miss some COVID-19 patients who are shedding infectious SARS-CoV-2.


Subject(s)
Antigens, Viral/analysis , COVID-19 Serological Testing/methods , COVID-19/diagnosis , Point-of-Care Systems , SARS-CoV-2/isolation & purification , False Negative Reactions , Humans , Immunoassay , Real-Time Polymerase Chain Reaction , SARS-CoV-2/immunology , Sensitivity and Specificity , Specimen Handling
16.
Hepatol Res ; 51(2): 227-232, 2021 Feb.
Article in English | MEDLINE | ID: covidwho-852324

ABSTRACT

AIM: Liver dysfunction is sometimes observed in patients with coronavirus disease 2019 (COVID-19), but most studies are from China, and the frequency in other countries is unclear. In addition, previous studies suggested several mechanisms of liver damage, but precise or additional mechanisms are not clearly elucidated. Therefore, we examined COVID-19 patients to explore the proportion of patients with liver dysfunction and also the factors associated with liver dysfunction. METHODS: We retrospectively examined 60 COVID-19 patients hospitalized at the Hospital affiliated with The Institute of Medical Science, The University of Tokyo (Tokyo, Japan). Patients who presented ≥40 U/L alanine aminotransferase (ALT) levels at least once during their hospitalization were defined as high-ALT patients, and the others as normal-ALT patients. The worst values of physical and laboratory findings during hospitalization for each patient were extracted for the analyses. Univariable and multivariable logistic regression models with bootstrap (for 1000 times) were carried out. RESULTS: Among 60 patients, there were 31 (52%) high-ALT patients. The high-ALT patients were obese, and had significantly higher levels of D-dimer and fibrin/fibrinogen degradation products, as well as white blood cell count, and levels of C-reactive protein, ferritin, and fibrinogen. Multivariable analysis showed D-dimer and white blood cells as independent factors. CONCLUSIONS: Considering that higher D-dimer level and white blood cell count were independently associated with ALT elevation, liver dysfunction in COVID-19 patients might be induced by microvascular thrombosis in addition to systemic inflammation.

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