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1.
Microorganisms ; 10(2)2022 Feb 10.
Article in English | MEDLINE | ID: covidwho-1706054

ABSTRACT

As the COVID-19 pandemic moves into its third year, there remains a need for additional animal models better recapitulating severe COVID to study SARS-CoV-2 pathogenesis and develop countermeasures, especially treatment options. Pigs are known intermediate hosts for many viruses with zoonotic potential and are susceptible to infection with alpha, beta and delta genera of coronaviruses. Herein, we infected young (3 weeks of age) pigs with SARS-CoV-2 using a combination of respiratory and parenteral inoculation routes. Pigs did not develop clinical disease, nor macroscopic or microscopic pathologic lesions upon SARS-CoV-2 infection. Despite occasional low levels of SARS-CoV-2 genomic RNA in the respiratory tract, subgenomic RNA and infectious virus were never found, and SARS-CoV-2-specific adaptive immune responses were not detectable over the 13-day study period. We concluded that pigs are not susceptible to productive SARS-CoV-2 infection and do not serve as a SARS-CoV-2 reservoir for zoonotic transmission.

2.
Antiviral Res ; 198: 105246, 2022 02.
Article in English | MEDLINE | ID: covidwho-1639070

ABSTRACT

The utility of remdesivir treatment in COVID-19 patients is currently limited by the necessity to administer this antiviral intravenously, which has generally limited its use to hospitalized patients. Here, we tested a novel, subcutaneous formulation of remdesivir in the rhesus macaque model of SARS-CoV-2 infection that was previously used to establish the efficacy of remdesivir against this virus in vivo. Compared to vehicle-treated animals, macaques treated with subcutaneous remdesivir from 12 h through 6 days post inoculation showed reduced signs of respiratory disease, a reduction of virus replication in the lower respiratory tract, and an absence of interstitial pneumonia. Thus, early subcutaneous administration of remdesivir can protect from lower respiratory tract disease caused by SARS-CoV-2.


Subject(s)
Adenosine Monophosphate/analogs & derivatives , Alanine/analogs & derivatives , Antiviral Agents/therapeutic use , COVID-19/drug therapy , Lung Diseases, Interstitial/prevention & control , SARS-CoV-2/drug effects , Adenosine Monophosphate/administration & dosage , Adenosine Monophosphate/pharmacokinetics , Adenosine Monophosphate/therapeutic use , Administration, Cutaneous , Alanine/administration & dosage , Alanine/pharmacokinetics , Alanine/therapeutic use , Animals , Antiviral Agents/administration & dosage , Antiviral Agents/pharmacokinetics , Disease Models, Animal , Female , Lung/pathology , Lung/virology , Macaca mulatta , Male , Viral Load/drug effects , Virus Replication/drug effects
3.
Life Sci Alliance ; 5(4)2022 04.
Article in English | MEDLINE | ID: covidwho-1637974

ABSTRACT

Advanced age is a key predictor of severe COVID-19. To gain insight into this relationship, we used the rhesus macaque model of SARS-CoV-2 infection. Eight older and eight younger macaques were inoculated with SARS-CoV-2. Animals were evaluated using viral RNA quantification, clinical observations, thoracic radiographs, single-cell transcriptomics, multiparameter flow cytometry, multiplex immunohistochemistry, cytokine detection, and lipidomics analysis at predefined time points in various tissues. Differences in clinical signs, pulmonary infiltrates, and virus replication were limited. Transcriptional signatures of inflammation-associated genes in bronchoalveolar lavage fluid at 3 dpi revealed efficient mounting of innate immune defenses in both cohorts. However, age-specific divergence of immune responses emerged during the post-acute phase. Older animals exhibited sustained local inflammatory innate responses, whereas local effector T-cell responses were induced earlier in the younger animals. Circulating lipid mediator and cytokine levels highlighted increased repair-associated signals in the younger animals, and persistent pro-inflammatory responses in the older animals. In summary, despite similar disease outcomes, multi-omics profiling suggests that age may delay or impair antiviral cellular immune responses and delay efficient return to immune homeostasis.


Subject(s)
Aging/immunology , COVID-19/immunology , COVID-19/veterinary , SARS-CoV-2/immunology , Acute Disease , Animals , Antibody Formation/immunology , Bronchoalveolar Lavage Fluid , COVID-19/complications , COVID-19/genetics , Cytokines/blood , Gene Expression Regulation , Gene Regulatory Networks , Genomics , Immunity, Cellular/genetics , Immunomodulation , Inflammation/complications , Inflammation/pathology , Lung/immunology , Lung/pathology , Lung/virology , Lymphoid Tissue/pathology , Macaca mulatta/immunology , Macaca mulatta/virology , Models, Biological , Single-Cell Analysis , T-Lymphocytes/immunology , Transcription, Genetic
4.
Emerg Microbes Infect ; 10(1): 2173-2182, 2021 Dec.
Article in English | MEDLINE | ID: covidwho-1493581

ABSTRACT

The continuing emergence of SARS-CoV-2 variants calls for regular assessment to identify differences in viral replication, shedding and associated disease. In this study, we compared African green monkeys infected intranasally with either the UK B.1.1.7 (Alpha) variant or its contemporary D614G progenitor. Both variants caused mild respiratory disease with no significant differences in clinical presentation. Significantly higher levels of viral RNA and infectious virus were found in upper and lower respiratory tract samples and tissues from B.1.1.7 infected animals. Interestingly, D614G infected animals showed significantly higher levels of viral RNA and infectious virus in rectal swabs and gastrointestinal tissues. Our results indicate that B.1.1.7 infection in African green monkeys is associated with increased respiratory replication and shedding but no disease enhancement similar to human B.1.1.7 cases.


Subject(s)
COVID-19/virology , Chlorocebus aethiops/virology , Respiratory System/virology , Virus Replication , Virus Shedding , Administration, Intranasal , Animals , COVID-19/epidemiology , Gastrointestinal Tract/virology , Host Specificity , Polymorphism, Single Nucleotide , RNA, Viral/isolation & purification , Random Allocation , Rectum/virology , United Kingdom/epidemiology , Vero Cells , Viral Load
5.
Sci Adv ; 7(43): eabj3627, 2021 Oct 22.
Article in English | MEDLINE | ID: covidwho-1483968

ABSTRACT

The emergence of several SARS-CoV-2 variants has caused global concerns about increased transmissibility, increased pathogenicity, and decreased efficacy of medical countermeasures. Animal models can be used to assess phenotypical changes in the absence of confounding factors. Here, we compared variants of concern (VOC) B.1.1.7 and B.1.351 to a recent B.1 SARS-CoV-2 isolate containing the D614G spike substitution in the rhesus macaque model. B.1.1.7 behaved similarly to D614G with respect to clinical disease and replication in the respiratory tract. Inoculation with B.1.351 resulted in lower clinical scores, lower lung virus titers, and less severe lung lesions. In bronchoalveolar lavages, cytokines and chemokines were up-regulated on day 4 in animals inoculated with D614G and B.1.1.7 but not with B.1.351. In nasal samples, cytokines and chemokines were up-regulated only in the B.1.1.7-inoculated animals. Together, our study suggests that circulation under diverse evolutionary pressures favors transmissibility and immune evasion rather than increased pathogenicity.

6.
Viruses ; 13(8)2021 08 19.
Article in English | MEDLINE | ID: covidwho-1367918

ABSTRACT

Many different vaccine candidates against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the etiological agent of COVID-19, are currently approved and under development. Vaccine platforms vary from mRNA vaccines to viral-vectored vaccines, and several candidates have been shown to produce humoral and cellular responses in small animal models, non-human primates, and human volunteers. In this study, six non-human primates received a prime-boost intramuscular vaccination with 4 µg of mRNA vaccine candidate CV07050101, which encodes a pre-fusion stabilized spike (S) protein of SARS-CoV-2. Boost vaccination was performed 28 days post prime vaccination. As a control, six animals were similarly injected with PBS. Humoral and cellular immune responses were investigated at time of vaccination, and two weeks afterwards. No antibodies could be detected at two and four weeks after prime vaccination. Two weeks after boost vaccination, binding but no neutralizing antibodies were detected in four out of six non-human primates. SARS-CoV-2 S protein-specific T cell responses were detected in these four animals. In conclusion, prime-boost vaccination with 4 µg of vaccine candidate CV07050101 resulted in limited immune responses in four out of six non-human primates.


Subject(s)
Antibodies, Viral/blood , COVID-19 Vaccines/immunology , Immunization, Secondary , Immunogenicity, Vaccine , SARS-CoV-2/immunology , Vaccines, Synthetic/immunology , Animals , Antibodies, Neutralizing/blood , COVID-19 Vaccines/administration & dosage , Immunity, Cellular , Immunization Schedule , Macaca mulatta , Male , Spike Glycoprotein, Coronavirus/immunology , T-Lymphocytes/immunology , Vaccines, Synthetic/administration & dosage
7.
Sci Transl Med ; 13(607)2021 08 18.
Article in English | MEDLINE | ID: covidwho-1329033

ABSTRACT

ChAdOx1 nCoV-19/AZD1222 is an approved adenovirus-based vaccine for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) currently being deployed globally. Previous studies in rhesus macaques revealed that intramuscular vaccination with ChAdOx1 nCoV-19/AZD1222 provided protection against pneumonia but did not reduce shedding of SARS-CoV-2 from the upper respiratory tract. Here, we investigated whether intranasally administered ChAdOx1 nCoV-19 reduces detection of virus in nasal swabs after challenging vaccinated macaques and hamsters with SARS-CoV-2 carrying a D614G mutation in the spike protein. Viral loads in swabs obtained from intranasally vaccinated hamsters were decreased compared to control hamsters, and no viral RNA or infectious virus was found in lung tissue after a direct challenge or after direct contact with infected hamsters. Intranasal vaccination of rhesus macaques resulted in reduced virus concentrations in nasal swabs and a reduction in viral loads in bronchoalveolar lavage and lower respiratory tract tissue. Intranasal vaccination with ChAdOx1 nCoV-19/AZD1222 reduced virus concentrations in nasal swabs in two different SARS-CoV-2 animal models, warranting further investigation as a potential vaccination route for COVID-19 vaccines.


Subject(s)
COVID-19 , SARS-CoV-2 , Animals , COVID-19 Vaccines , Cricetinae , Macaca mulatta , Vaccination , Virus Shedding
8.
mBio ; 12(4): e0150321, 2021 08 31.
Article in English | MEDLINE | ID: covidwho-1327616

ABSTRACT

Severe coronavirus disease 2019 (COVID-19) has been associated with T cell lymphopenia, but no causal effect of T cell deficiency on disease severity has been established. To investigate the specific role of T cells in recovery from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections, we studied rhesus macaques that were depleted of either CD4+, CD8+, or both T cell subsets prior to infection. Peak virus loads were similar in all groups, but the resolution of virus in the T cell-depleted animals was slightly delayed compared to that in controls. The T cell-depleted groups developed virus-neutralizing antibody responses and class switched to IgG. When reinfected 6 weeks later, the T cell-depleted animals showed anamnestic immune responses characterized by rapid induction of high-titer virus-neutralizing antibodies, faster control of virus loads, and reduced clinical signs. These results indicate that while T cells play a role in the recovery of rhesus macaques from acute SARS-CoV-2 infections, their depletion does not induce severe disease, and T cells do not account for the natural resistance of rhesus macaques to severe COVID-19. Neither primed CD4+ nor CD8+ T cells appeared critical for immunoglobulin class switching, the development of immunological memory, or protection from a second infection. IMPORTANCE Patients with severe COVID-19 often have decreased numbers of T cells, a cell type important in fighting most viral infections. However, it is not known whether the loss of T cells contributes to severe COVID-19 or is a consequence of it. We studied rhesus macaques, which develop only mild COVID-19, similar to most humans. Experimental depletion of T cells slightly prolonged their clearance of virus, but there was no increase in disease severity. Furthermore, they were able to develop protection from a second infection and produced antibodies capable of neutralizing the virus. They also developed immunological memory, which allows a much stronger and more rapid response upon a second infection. These results suggest that T cells are not critical for recovery from acute SARS-CoV-2 infections in this model and point toward B cell responses and antibodies as the essential mediators of protection from re-exposure.


Subject(s)
Antibodies, Neutralizing/immunology , Antibodies, Viral/immunology , COVID-19/pathology , Immunologic Memory/immunology , Lymphopenia/immunology , SARS-CoV-2/immunology , Animals , CD4-Positive T-Lymphocytes/cytology , CD4-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/cytology , CD8-Positive T-Lymphocytes/immunology , COVID-19/immunology , Female , Lymphocyte Depletion/methods , Macaca mulatta/immunology , Male
9.
JCI Insight ; 6(10)2021 05 24.
Article in English | MEDLINE | ID: covidwho-1197299

ABSTRACT

Emerging coronaviruses from zoonotic reservoirs, including severe acute respiratory syndrome coronavirus (SARS-CoV), Middle East respiratory syndrome coronavirus (MERS-CoV), and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), have been associated with human-to-human transmission and significant morbidity and mortality. Here, we study both intradermal and intramuscular 2-dose delivery regimens of an advanced synthetic DNA vaccine candidate encoding a full-length MERS-CoV spike (S) protein, which induced potent binding and neutralizing antibodies as well as cellular immune responses in rhesus macaques. In a MERS-CoV challenge, all immunized rhesus macaques exhibited reduced clinical symptoms, lowered viral lung load, and decreased severity of pathological signs of disease compared with controls. Intradermal vaccination was dose sparing and more effective in this model at protecting animals from disease. The data support the further study of this vaccine for preventing MERS-CoV infection and transmission, including investigation of such vaccines and simplified delivery routes against emerging coronaviruses.


Subject(s)
Coronavirus Infections/veterinary , Macaca mulatta/immunology , Middle East Respiratory Syndrome Coronavirus/immunology , Vaccines, DNA/therapeutic use , Viral Vaccines/therapeutic use , Animals , Coronavirus Infections/immunology , Coronavirus Infections/prevention & control , Immunogenicity, Vaccine , Injections, Intradermal , Middle East Respiratory Syndrome Coronavirus/genetics , Spike Glycoprotein, Coronavirus/genetics , Spike Glycoprotein, Coronavirus/immunology , Vaccines, DNA/administration & dosage , Vaccines, DNA/genetics , Viral Vaccines/administration & dosage , Viral Vaccines/genetics
10.
Cell Rep Med ; 2(4): 100230, 2021 04 20.
Article in English | MEDLINE | ID: covidwho-1147272

ABSTRACT

The deployment of a vaccine that limits transmission and disease likely will be required to end the coronavirus disease 2019 (COVID-19) pandemic. We recently described the protective activity of an intranasally administered chimpanzee adenovirus-vectored vaccine encoding a pre-fusion stabilized spike (S) protein (ChAd-SARS-CoV-2-S [chimpanzee adenovirus-severe acute respiratory syndrome-coronavirus-2-S]) in the upper and lower respiratory tracts of mice expressing the human angiotensin-converting enzyme 2 (ACE2) receptor. Here, we show the immunogenicity and protective efficacy of this vaccine in non-human primates. Rhesus macaques were immunized with ChAd-Control or ChAd-SARS-CoV-2-S and challenged 1 month later by combined intranasal and intrabronchial routes with SARS-CoV-2. A single intranasal dose of ChAd-SARS-CoV-2-S induces neutralizing antibodies and T cell responses and limits or prevents infection in the upper and lower respiratory tracts after SARS-CoV-2 challenge. As ChAd-SARS-CoV-2-S confers protection in non-human primates, it is a promising candidate for limiting SARS-CoV-2 infection and transmission in humans.

12.
Sci Transl Med ; 13(578)2021 01 27.
Article in English | MEDLINE | ID: covidwho-1024212

ABSTRACT

Detailed knowledge about the dynamics of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is important for uncovering the viral and host factors that contribute to coronavirus disease 2019 (COVID-19) pathogenesis. Old-World nonhuman primates recapitulate mild to moderate cases of COVID-19, thereby serving as important pathogenesis models. We compared African green monkeys inoculated with infectious SARS-CoV-2 or irradiated, inactivated virus to study the dynamics of virus replication throughout the respiratory tract. Genomic RNA from the animals inoculated with the irradiated virus was found to be highly stable, whereas subgenomic RNA, an indicator of viral replication, was found to degrade quickly. We combined this information with single-cell RNA sequencing of cells isolated from the lung and lung-draining mediastinal lymph nodes and developed new analysis methods for unbiased targeting of important cells in the host response to SARS-CoV-2 infection. Through detection of reads to the viral genome, we were able to determine that replication of the virus in the lungs appeared to occur mainly in pneumocytes, whereas macrophages drove the inflammatory response. Monocyte-derived macrophages recruited to the lungs, rather than tissue-resident alveolar macrophages, were most likely to be responsible for phagocytosis of infected cells and cellular debris early in infection, with their roles switching during clearance of infection. Together, our dataset provides a detailed view of the dynamics of virus replication and host responses over the course of mild COVID-19 and serves as a valuable resource to identify therapeutic targets.


Subject(s)
COVID-19/epidemiology , COVID-19/virology , Lung/virology , SARS-CoV-2/physiology , Sequence Analysis, RNA , Single-Cell Analysis , Alveolar Epithelial Cells/pathology , Alveolar Epithelial Cells/virology , Animals , Bronchoalveolar Lavage Fluid/virology , COVID-19/genetics , Chlorocebus aethiops , DNA, Viral/genetics , Female , Genome, Viral/genetics , Inflammation/pathology , Lung/pathology , Lymph Nodes/pathology , Macrophages/pathology , Macrophages/virology , Male , Mediastinum/pathology , Transcription, Genetic , Viral Load , Virus Replication
13.
JCI Insight ; 5(23)2020 12 03.
Article in English | MEDLINE | ID: covidwho-890008

ABSTRACT

We remain largely without effective prophylactic/therapeutic interventions for COVID-19. Although many human COVID-19 clinical trials are ongoing, there remains a deficiency of supportive preclinical drug efficacy studies to help guide decisions. Here we assessed the prophylactic/therapeutic efficacy of hydroxychloroquine (HCQ), a drug of interest for COVID-19 management, in 2 animal disease models. The standard human malaria HCQ prophylaxis (6.5 mg/kg given weekly) and treatment (6.5 mg/kg given daily) did not significantly benefit clinical outcome, nor did it reduce SARS-CoV-2 replication/shedding in the upper and lower respiratory tract in the rhesus macaque disease model. Similarly, when used for prophylaxis or treatment, neither the standard human malaria dose (6.5 mg/kg) nor a high dose (50 mg/kg) of HCQ had any beneficial effect on clinical disease or SARS-CoV-2 kinetics (replication/shedding) in the Syrian hamster disease model. Results from these 2 preclinical animal models may prove helpful in guiding clinical use of HCQ for prophylaxis/treatment of COVID-19.


Subject(s)
Antiviral Agents/therapeutic use , COVID-19/therapy , Hydroxychloroquine/therapeutic use , SARS-CoV-2/drug effects , Animals , COVID-19/drug therapy , COVID-19/pathology , COVID-19/prevention & control , Chlorocebus aethiops , Cricetinae , Cytokines/metabolism , Disease Models, Animal , Drug Evaluation, Preclinical , Humans , Lung/pathology , Lung/virology , Macaca mulatta , Male , Treatment Outcome , Vero Cells , Viral Load/drug effects , Virus Replication/drug effects , Virus Shedding/drug effects
14.
Nature ; 586(7830): 578-582, 2020 10.
Article in English | MEDLINE | ID: covidwho-691215

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged in December 20191,2 and is responsible for the coronavirus disease 2019 (COVID-19) pandemic3. Vaccines are an essential countermeasure and are urgently needed to control the pandemic4. Here we show that the adenovirus-vector-based vaccine ChAdOx1 nCoV-19, which encodes the spike protein of SARS-CoV-2, is immunogenic in mice and elicites a robust humoral and cell-mediated response. This response was predominantly mediated by type-1 T helper cells, as demonstrated by the profiling of the IgG subclass and the expression of cytokines. Vaccination with ChAdOx1 nCoV-19 (using either a prime-only or a prime-boost regimen) induced a balanced humoral and cellular immune response of type-1 and type-2 T helper cells in rhesus macaques. We observed a significantly reduced viral load in the bronchoalveolar lavage fluid and lower respiratory tract tissue of vaccinated rhesus macaques that were challenged with SARS-CoV-2 compared with control animals, and no pneumonia was observed in vaccinated SARS-CoV-2-infected animals. However, there was no difference in nasal shedding between vaccinated and control SARS-CoV-2-infected macaques. Notably, we found no evidence of immune-enhanced disease after viral challenge in vaccinated SARS-CoV-2-infected animals. The safety, immunogenicity and efficacy profiles of ChAdOx1 nCoV-19 against symptomatic PCR-positive COVID-19 disease will now be assessed in randomized controlled clinical trials in humans.


Subject(s)
Betacoronavirus/immunology , Coronavirus Infections/immunology , Coronavirus Infections/prevention & control , Disease Models, Animal , Macaca mulatta , Pandemics/prevention & control , Pneumonia, Viral/prevention & control , Viral Vaccines/immunology , Adenoviridae/genetics , Animals , Bronchoalveolar Lavage Fluid , COVID-19 , COVID-19 Vaccines , Coronavirus Infections/genetics , Coronavirus Infections/virology , Cytokines/immunology , Female , Immunity, Cellular , Immunity, Humoral , Immunoglobulin G/immunology , Lung/immunology , Lung/pathology , Lung/virology , Macaca mulatta/immunology , Macaca mulatta/virology , Male , Mice , Pneumonia, Viral/immunology , Pneumonia, Viral/virology , SARS-CoV-2 , Spike Glycoprotein, Coronavirus/genetics , Spike Glycoprotein, Coronavirus/immunology , Th1 Cells/immunology , Vaccination , Viral Load , Viral Vaccines/administration & dosage , Viral Vaccines/genetics
15.
Nature ; 585(7824): 273-276, 2020 09.
Article in English | MEDLINE | ID: covidwho-592386

ABSTRACT

Effective therapies to treat coronavirus disease 2019 (COVID-19) are urgently needed. While many investigational, approved, and repurposed drugs have been suggested as potential treatments, preclinical data from animal models can guide the search for effective treatments by ruling out those that lack efficacy in vivo. Remdesivir (GS-5734) is a nucleotide analogue prodrug with broad antiviral activity1,2 that is currently being investigated in COVID-19 clinical trials and recently received Emergency Use Authorization from the US Food and Drug Administration3,4. In animal models, remdesivir was effective against infection with Middle East respiratory syndrome coronavirus (MERS-CoV) and severe acute respiratory syndrome coronavirus (SARS-CoV)2,5,6. In vitro, remdesivir inhibited replication of SARS-CoV-27,8. Here we investigate the efficacy of remdesivir in a rhesus macaque model of SARS-CoV-2 infection9. Unlike vehicle-treated animals, macaques treated with remdesivir did not show signs of respiratory disease; they also showed reduced pulmonary infiltrates on radiographs and reduced virus titres in bronchoalveolar lavages twelve hours after the first dose. Virus shedding from the upper respiratory tract was not reduced by remdesivir treatment. At necropsy, remdesivir-treated animals had lower lung viral loads and reduced lung damage. Thus, treatment with remdesivir initiated early during infection had a clinical benefit in rhesus macaques infected with SARS-CoV-2. Although the rhesus macaque model does not represent the severe disease observed in some patients with COVID-19, our data support the early initiation of remdesivir treatment in patients with COVID-19 to prevent progression to pneumonia.


Subject(s)
Adenosine Monophosphate/analogs & derivatives , Alanine/analogs & derivatives , Betacoronavirus/drug effects , Coronavirus Infections/drug therapy , Coronavirus Infections/virology , Disease Models, Animal , Macaca mulatta/virology , Pneumonia, Viral/prevention & control , Adenosine Monophosphate/pharmacokinetics , Adenosine Monophosphate/pharmacology , Adenosine Monophosphate/therapeutic use , Alanine/pharmacokinetics , Alanine/pharmacology , Alanine/therapeutic use , Animals , Betacoronavirus/genetics , Betacoronavirus/pathogenicity , Bronchoalveolar Lavage Fluid/virology , COVID-19 , Coronavirus Infections/pathology , Coronavirus Infections/physiopathology , DNA Mutational Analysis , Disease Progression , Drug Resistance, Viral , Female , Lung/drug effects , Lung/pathology , Lung/physiopathology , Lung/virology , Male , Pandemics , Pneumonia, Viral/drug therapy , Pneumonia, Viral/pathology , Pneumonia, Viral/physiopathology , Pneumonia, Viral/virology , SARS-CoV-2 , Secondary Prevention , Time Factors , Viral Load/drug effects , Virus Replication/drug effects , Virus Shedding/drug effects
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