Recent:

Bioluminescence Imaging Reveals Enhanced SARS-CoV-2 Clearance in Mice with Combinatorial Regimens

Ullah et al., iScience, doi:10.1016/j.isci.2024.109049

Jan 2024

Source PDF

Mouse study showing that monotherapy with approved antiviral drugs favipiravir, molnupiravir or nirmatrelvir reduced but did not clear SARS-CoV-2 Delta and Omicron variants in K18-hACE2 mice. Combination therapy with molnupiravir and nirmatrelvir demonstrated additive efficacy and led to near complete virus clearance. Authors found combining molnupiravir with inflammasome inhibitor mitigated inflammation and lung pathology. Additionally, combining molnupiravir with convalescent plasma exhibited synergistic effects, rapidly clearing infection and improving survival. Overall, the results highlight the potential of antiviral drug combinations, with or without immunotherapy, to combat evolving SARS-CoV-2 variants.

Important missing comments or errors? Let us know.

Ullah et al., 31 Jan 2024, peer-reviewed, 14 authors. Contact: priti.kumar@yale.edu, echatelain@dndi.org, pradeep.uchil@yale.edu.

This Paper Miscellaneous All

Bioluminescence Imaging Reveals Enhanced SARS-CoV-2 Clearance in Mice with Combinatorial Regimens

Irfan Ullah, Fanny Escudie, Ivan Scandale, Zoela Gilani, Gabrielle Gendron-Lepage, Fleur Gaudette, Charles Mowbray, Laurent Fraisse, Renée Bazin, Andrés Finzi, Walther Mothes, Priti Kumar, Eric Chatelain, Pradeep D Uchil

iScience, doi:10.1016/j.isci.2024.109049

Direct acting antivirals (DAAs) represent critical tools for combating SARS-CoV-2 variants of concern (VOCs) that have escaped vaccine-elicited spike-based immunity and future coronaviruses with pandemic potential. Here, we used bioluminescence imaging to evaluate therapeutic efficacy of DAAs that target SARS-CoV-2 RNA-dependent RNA polymerase (favipiravir, molnupiravir) or Main protease (nirmatrelvir) against Delta or Omicron VOCs in K18-hACE2 mice. Nirmatrelvir displayed the best efficacy followed by molnupiravir and favipiravir in suppressing viral loads in the lung. Unlike neutralizing antibody treatment, DAA monotherapy regimens did not eradicate SARS-CoV-2 in mice but combining molnupiravir with nirmatrelvir exhibited superior additive efficacy and led to virus clearance. Furthermore, combining molnupiravir with Caspase-1/4 inhibitor mitigated inflammation and lung pathology whereas combining molnupiravir with COVID-19 convalescent plasma demonstrated synergy, rapid virus clearance and 100% survival. Thus, our study provides insights into in vivo treatment efficacies of DAAs and other effective combinations to bolster COVID-19 therapeutic arsenal.

Competing interest The authors declare no competing interests. J o u r n a l P r e -p r o o f Brain and lung samples were collected from mice at the time of necropsy. Approximately, 20 mg of tissue was suspended in 500 µL of RLT lysis buffer, and RNA was extracted using RNeasy plus Mini kit (Qiagen Cat # 74136), reverse transcribed with iScript advanced cDNA kit (Bio-Rad Cat #1725036). To determine mRNA copy numbers of signature inflammatory cytokines, multiplex qPCR was conducted using iQ Multiplex Powermix (Bio Rad Cat # 1725848) and PrimePCR Probe Assay mouse primers FAM-GAPDH, HEX-IL6, TEX615-CCL2, Cy5-CXCL10, Cy5.5-IFNgamma and HEX-IL1B. The reaction plate was analyzed using CFX96 touch real time PCR detection system. Scan mode was set to all channels. The PCR conditions were 95 °C 2 min, 40 cycles of 95 °C for 10 s and 60 °C for 45 s, followed by a melting curve analysis to ensure that each primer pair resulted in amplification of a single PCR product. mRNA copy numbers of Il6, Ccl2, Cxcl10, Ifng and Il1b in the cDNA samples of infected mice were normalized to Gapdh mRNA with the formula ΔC t (target gene)=C t (target gene)-C t (Gapdh). The fold increase was determined using 2 -ΔΔCt method comparing treated mice to uninfected controls. Cryo-immunohistology of lung tissue Lung tissues were isolated after necropsy and fixed in 1X PBS containing freshly prepared 4% PFA for 12 h at RT or 4 C. They were then washed with PBS, cryoprotected with 10, 20 and 30% ascending..

References

Abdalhamid, Bilder, Mccutchen, Hinrichs, Koepsell et al., Assessment of Specimen Pooling to Conserve SARS CoV-2 Testing Resources, Am J Clin Pathol, doi:10.1093/ajcp/aqaa064

Abdelnabi, Foo, Jochmans, Vangeel, De Jonghe et al., The oral protease inhibitor (PF-07321332) protects Syrian hamsters against infection with SARS-CoV-2 variants of concern, Nat Commun, doi:10.1038/s41467-022-28354-0

Abdelnabi, Foo, Kaptein, Zhang, Do et al., The combined treatment of Molnupiravir and Favipiravir results in a potentiation of antiviral efficacy in a SARS-CoV-2 hamster infection model, EBioMedicine, doi:10.1016/j.ebiom.2021.103595

Agency, COVID-19 vaccine surveillance report Week 19

Agrawal, Goel, Gupta, Emerging prophylaxis strategies against COVID-19, Monaldi Arch Chest Dis, doi:10.4081/monaldi.2020.1289

Alter, Yu, Liu, Chandrashekar, Borducchi et al., Immunogenicity of Ad26.COV2.S vaccine against SARS-CoV-2 variants in humans, Nature, doi:10.1038/s41586-021-03681-2

Amarilla, Sng, Parry, Deerain, Potter et al., A versatile reverse genetics platform for SARS-CoV-2 and other positive-strand RNA viruses, Nat Commun, doi:10.1038/s41467-021-23779-5

Arostegui, Castro, Schwarz, Vaidy, Rabinowitz et al., Persistent SARS-CoV-2 nucleocapsid protein presence in the intestinal epithelium of a pediatric patient 3 months after acute infection, Jpgn Reports

Bobrowski, Chen, Eastman, Itkin, Shinn et al., Synergistic and Antagonistic Drug Combinations against SARS-CoV-2, Mol Ther, doi:10.1016/j.ymthe.2020.12.016

Boretti, Favipiravir use for SARS CoV-2 infection, Pharmacological Reports

Callaway, COVID drug drives viral mutations -and now some want to halt its use, Nature

Chen, Prevost, Ullah, Romero, Lisi et al., Molecular basis for antiviral activity of two pediatric neutralizing antibodies targeting SARS-CoV-2 Spike RBD, iScience, doi:.10.1016/j.isci.2022.105783

Choi, Park, Tsagkogeorga, Yanagita, Koo et al., Inflammatory Signals Induce AT2 Cell-Derived Damage-Associated Transient Progenitors that Mediate Alveolar Regeneration, Cell Stem Cell, doi:10.1016/j.stem.2020.06.020

Cohen, Jaudon, Schurman, Kava, Vogel et al., Impact of extended-course oral nirmatrelvir/ritonavir (Paxlovid) in established Long COVID: Case series and research considerations, Res Sq, doi:10.21203/rs.3.rs-3359429/v1

Crunfli, Carregari, Veras, Silva, Nogueira et al., Morphological, cellular, and molecular basis of brain infection in COVID-19 patients, Proc Natl Acad Sci U S A, doi:10.1073/pnas.2200960119

Da Silva Santos, Gamon, De Azevedo, Telezynski, De Souza et al., Virulence Profiles of Wild-Type, P. 1 and Delta SARS-CoV-2 Variants in K18-hACE2 Transgenic Mice, Viruses

De Rivero Vaccari, Dietrich, Keane, De Rivero, Vaccari, The inflammasome in times of COVID-19, Frontiers in immunology

Doitsh, Galloway, Geng, Yang, Monroe et al., Cell death by J o u r n a l P r e -p r o o f pyroptosis drives CD4 T-cell depletion in HIV-1 infection, Nature, doi:10.1038/nature12940

Douaud, Lee, Alfaro-Almagro, Arthofer, Wang et al., SARS-CoV-2 is associated with changes in brain structure in UK Biobank, Nature, doi:10.1038/s41586-022-04569-5

Dye, The benefits of large scale covid-19 vaccination, BMJ, doi:10.1136/bmj.o867

Eltobgy, Zani, Kenney, Estfanous, Kim et al., Caspase-4/11 exacerbates disease severity in SARS-CoV-2 infection by promoting inflammation and immunothrombosis, Proc Natl Acad Sci U S A, doi:10.1073/pnas.2202012119

Etter, Martins, Kulsvehagen, Possnecker, Duchemin et al., Severe Neuro-COVID is associated with peripheral immune signatures, autoimmunity and neurodegeneration: a prospective cross-sectional study, Nat Commun, doi:10.1038/s41467-022-34068-0

Fan, Lou, Fan, Li, Tong, The emergence of powerful oral anti-COVID-19 drugs in the post-vaccine era, The Lancet Microbe

Focosi, Mcconnell, Shoham, Casadevall, Maggi et al., Nirmatrelvir and COVID-19: development, pharmacokinetics, clinical efficacy, resistance, relapse, and pharmacoeconomics, Int J Antimicrob Agents, doi:10.1016/j.ijantimicag.2022.106708

Furuta, Gowen, Takahashi, Shiraki, Smee et al., Favipiravir (T-705), a novel viral RNA polymerase inhibitor, Antiviral Res, doi:10.1016/j.antiviral.2013.09.015

Gandhi, Klein, Robertson, Pena-Hernandez, Lin et al., De novo emergence of a remdesivir resistance mutation during treatment of persistent SARS-CoV-2 infection in an immunocompromised patient: a case report, Nat Commun, doi:10.1038/s41467-022-29104-y

Group, Dexamethasone in hospitalized patients with Covid-19, New England Journal of Medicine

Grunst, Uchil, Fc effector cross-reactivity: A hidden arsenal against SARS-CoV-2's evasive maneuvering, Cell Rep Med

Halfmann, Iida, Iwatsuki-Horimoto, Maemura, Kiso et al., SARS-CoV-2 Omicron virus causes attenuated disease in mice and hamsters, Nature, doi:10.1038/s41586-022-04441-6

Hammond, Leister-Tebbe, Gardner, Abreu, Bao et al., Oral Nirmatrelvir for High-Risk, Nonhospitalized Adults with Covid-19, N Engl J Med, doi:10.1056/NEJMoa2118542

Hashemian, Sheida, Taghizadieh, Memar, Hamblin et al., Paxlovid (Nirmatrelvir/Ritonavir): A new approach to Covid-19 therapy?, Biomed Pharmacother, doi:10.1016/j.biopha.2023.114367

Honko, Bean, Henao, Vasquez, Downs et al., Rapid Quantification and Neutralization Assays for Novel Coronavirus SARS-CoV-2 Using Avicel RC-591 Semi-Solid Overlay

Ianevski, Giri, Aittokallio, SynergyFinder 2.0: visual analytics of multi-drug combination synergies, Nucleic Acids Res, doi:10.1093/nar/gkaa216

Illingworth, Guerra-Assuncao, Gregg, Charles, Pang et al., Genetic consequences of effective and suboptimal dosing with mutagenic drugs in a hamster model of SARS-CoV-2 infection, bioRxiv

Islam, Hasan, Rahman, Islam, Comparative evaluation of authorized drugs for treating Covid-19 patients, Health Science Reports

Jeong, Chokkakula, Min, Kim, Choi et al., Combination therapy with nirmatrelvir and molnupiravir improves the survival of SARS-CoV-2 infected mice, Antiviral Res, doi:10.1016/j.antiviral.2022.105430

Jeong, Chokkakula, Min, Kim, Choi et al., Combination therapy with nirmatrelvir and molnupiravir improves the survival of SARS-CoV-2 infected mice, Antiviral Research

Joyce, Hu, Wang, The history, mechanism, and perspectives of nirmatrelvir (PF-07321332): an orally bioavailable main protease inhibitor used in combination with ritonavir to reduce COVID-19-related hospitalizations, Med Chem Res, doi:10.1007/s00044-022-02951-6

Junqueira, Crespo, Ranjbar, De Lacerda, Lewandrowski et al., FcgammaR-mediated SARS-CoV-2 infection of monocytes activates inflammation, Nature, doi:10.1038/s41586-022-04702-4

Kato, Takayama-Ito, Satoh, Kawahara, Kitaura et al., Favipiravir treatment prolongs the survival in a lethal mouse model intracerebrally inoculated with Jamestown Canyon virus, PLoS Negl Trop Dis, doi:10.1371/journal.pntd.0009553

Larkin, Global COVID-19 Death Toll May Be Triple the Reported Deaths, JAMA, doi:1438.10.1001/jama.2022.4767

Lehmann, Allers, Heldt, Meinhardt, Schmidt et al., Human small intestinal infection by SARS-CoV-2 is characterized by a mucosal infiltration with activated CD8+ T cells, Mucosal Immunology

Lenharo, WHO declares end to COVID-19's emergency phase, Nature

Mao, Jin, Wang, Hu, Chen et al., Neurologic Manifestations of Hospitalized Patients With Coronavirus Disease 2019 in Wuhan, China, JAMA Neurol, doi:10.1001/jamaneurol.2020.1127

Marcelin, Pettifor, Janes, Brown, Kublin et al., COVID-19 Vaccines and SARS-CoV-2 Transmission in the Era of New Variants: A Review and Perspective, Open Forum Infect Dis, doi:ofac124.10.1093/ofid/ofac124

Nair, Jacob, A simple practice guide for dose conversion between animals and human, J Basic Clin Pharm, doi:10.4103/0976-0105.177703

Owen, Allerton, Anderson, Aschenbrenner, Avery et al., An oral SARS-CoV-2 M(pro) inhibitor clinical candidate for the treatment of COVID-19, Science, doi:10.1126/science.abl4784

Perreault, Tremblay, Fournier, Drouin, Beaudoin-Bussieres et al., Waning of SARS-CoV-2 RBD antibodies in longitudinal convalescent plasma samples within 4 months after symptom onset, Blood, doi:10.1182/blood.2020008367

Richardson, Manamela, Motsoeneng, Kaldine, Ayres et al., SARS-CoV-2 Beta and Delta variants trigger Fc effector function with increased cross-reactivity, Cell Rep Med, doi:10.1016/j.xcrm.2022.100510

Rodrigues, De Sá, Ishimoto, Becerra, Oliveira et al., Inflammasomes are activated in response to SARS-CoV-2 infection and are associated with COVID-19 severity in patients, Journal of Experimental Medicine

Rosenke, Lewis, Feldmann, Bohrnsen, Schwarz et al., Combined molnupiravir and nirmatrelvir treatment improves the inhibitory effect on SARS-CoV-2 in Rhesus Macaques, bioRxiv

Rosenke, Lewis, Feldmann, Bohrnsen, Schwarz et al., Combined molnupiravir-nirmatrelvir treatment improves the inhibitory effect on SARS-CoV-2 in macaques, JCI Insight, doi:10.1172/jci.insight.166485

Rosenke, Okumura, Lewis, Feldmann, Meade-White et al., Molnupiravir inhibits SARS-CoV-2 variants including Omicron in the hamster model, JCI insight

Sanderson, Hisner, Donovan-Banfield, Hartman, Lochen et al., A molnupiravir-associated mutational signature in global SARS-CoV-2 genomes, Nature

Sefik, Qu, Junqueira, Kaffe, Mirza et al., Inflammasome activation in infected macrophages drives COVID-19 pathology, doi:bioRxiv.10.1101/2021.09.27.461948

Stein, Ramelli, Grazioli, Chung, Singh et al., SARS-CoV-2 infection and persistence in the human body and brain at autopsy, Nature, doi:10.1038/s41586-022-05542-y

Strunz, Simon, Ansari, Kathiriya, Angelidis et al., Alveolar regeneration through a Krt8+ transitional stem cell state that persists in human lung fibrosis, Nat Commun, doi:10.1038/s41467-020-17358-3

Suthar, Wang, Seffren, Wiegand, Griffing et al., Public health impact of covid-19 vaccines in the US: observational study, BMJ, doi:10.1136/bmj-2021-069317

Syed, Molnupiravir: First Approval, Drugs, doi:10.1007/s40265-022-01684-5

Tarrés-Freixas, Trinité, Pons-Grífols, Romero-Durana, Riveira-Muñoz et al., Heterogeneous infectivity and pathogenesis of SARS-CoV-2 variants beta, delta and omicron in transgenic K18-hACE2 and wildtype mice, Frontiers in Microbiology

Tartof, Slezak, Puzniak, Hong, Xie et al., Durability of BNT162b2 vaccine against hospital and emergency department admissions due to the omicron and delta variants in a large health system in the USA: a test-negative case-control study, Lancet Respir Med, doi:10.1016/S2213-2600(22)00101-1

Tian, Yang, Song, Zhou, Wen et al., Efficacy and safety of paxlovid (nirmatrelvir/ritonavir) in the treatment of COVID-19: An updated meta-analysis and trial sequential analysis, Rev Med Virol, doi:10.1002/rmv.2473

Ullah, Beaudoin-Bussieres, Symmes, Cloutier, Ducas et al., The Fc-effector function of COVID-19 convalescent plasma contributes to SARS-CoV-2 treatment efficacy in mice, Cell Rep Med, doi:10.1016/j.xcrm.2022.100893

Ullah, Prevost, Ladinsky, Stone, Lu et al., Live imaging of SARS-CoV-2 infection in mice reveals that neutralizing antibodies require Fc function for optimal efficacy, Immunity, doi:10.1016/j.immuni.2021.08.015

Vangeel, Chiu, De Jonghe, Maes, Slechten et al., Remdesivir, Molnupiravir and Nirmatrelvir remain active against SARS-CoV-2 Omicron and other variants of concern, Antiviral research

Vora, Lieberman, Wu, Inflammasome activation at the crux of severe COVID-19, Nature Reviews Immunology

Wagoner, Herring, Hsiang, Ianevski, Biering et al., Combinations of Host-and Virus-Targeting Antiviral Drugs Confer Synergistic Suppression of SARS-CoV-2, Microbiol Spectr, doi:10.1128/spectrum.03331-22

Xiao, Tong, Zhang, Profile of RT-PCR for SARS-CoV-2: a preliminary study from 56 COVID-19 patients, Clin Infect Dis, doi:10.1093/cid/ciaa460

Xu, Shrestha, Preat, Beloqui, An overview of in vitro, ex vivo and in vivo models for studying the transport of drugs across intestinal barriers, Adv Drug Deliv Rev, doi:10.1016/j.addr.2021.05.005

Yamin, Jones, Hoffmann, Schafer, Kao et al., Fc-engineered antibody therapeutics with improved anti-SARS-CoV-2 efficacy, Nature, doi:10.1038/s41586-021-04017-w

{ 'DOI': '10.1016/j.isci.2024.109049', 'ISSN': ['2589-0042'], 'URL': 'http://dx.doi.org/10.1016/j.isci.2024.109049', 'alternative-id': ['S2589004224002700'], 'article-number': '109049', 'assertion': [ {'label': 'This article is maintained by', 'name': 'publisher', 'value': 'Elsevier'}, { 'label': 'Article Title', 'name': 'articletitle', 'value': 'Bioluminescence Imaging Reveals Enhanced SARS-CoV-2 Clearance in Mice with ' 'Combinatorial Regimens'}, {'label': 'Journal Title', 'name': 'journaltitle', 'value': 'iScience'}, { 'label': 'CrossRef DOI link to publisher maintained version', 'name': 'articlelink', 'value': 'https://doi.org/10.1016/j.isci.2024.109049'}, {'label': 'Content Type', 'name': 'content_type', 'value': 'article'}, {'label': 'Copyright', 'name': 'copyright', 'value': '© 2024 The Author(s).'}], 'author': [ {'affiliation': [], 'family': 'Ullah', 'given': 'Irfan', 'sequence': 'first'}, {'affiliation': [], 'family': 'Escudie', 'given': 'Fanny', 'sequence': 'additional'}, {'affiliation': [], 'family': 'Scandale', 'given': 'Ivan', 'sequence': 'additional'}, {'affiliation': [], 'family': 'Gilani', 'given': 'Zoela', 'sequence': 'additional'}, {'affiliation': [], 'family': 'Gendron-Lepage', 'given': 'Gabrielle', 'sequence': 'additional'}, {'affiliation': [], 'family': 'Gaudette', 'given': 'Fleur', 'sequence': 'additional'}, {'affiliation': [], 'family': 'Mowbray', 'given': 'Charles', 'sequence': 'additional'}, {'affiliation': [], 'family': 'Fraisse', 'given': 'Laurent', 'sequence': 'additional'}, {'affiliation': [], 'family': 'Bazin', 'given': 'Renée', 'sequence': 'additional'}, {'affiliation': [], 'family': 'Finzi', 'given': 'Andrés', 'sequence': 'additional'}, {'affiliation': [], 'family': 'Mothes', 'given': 'Walther', 'sequence': 'additional'}, {'affiliation': [], 'family': 'Kumar', 'given': 'Priti', 'sequence': 'additional'}, {'affiliation': [], 'family': 'Chatelain', 'given': 'Eric', 'sequence': 'additional'}, { 'ORCID': 'http://orcid.org/0000-0002-7236-858X', 'affiliation': [], 'authenticated-orcid': False, 'family': 'Uchil', 'given': 'Pradeep D.', 'sequence': 'additional'}], 'container-title': 'iScience', 'container-title-short': 'iScience', 'content-domain': { 'crossmark-restriction': True, 'domain': ['cell.com', 'elsevier.com', 'sciencedirect.com']}, 'created': {'date-parts': [[2024, 1, 30]], 'date-time': '2024-01-30T17:59:50Z', 'timestamp': 1706637590000}, 'deposited': { 'date-parts': [[2024, 1, 30]], 'date-time': '2024-01-30T17:59:51Z', 'timestamp': 1706637591000}, 'funder': [ {'DOI': '10.13039/100000002', 'doi-asserted-by': 'publisher', 'name': 'NIH'}, {'DOI': '10.13039/100000060', 'doi-asserted-by': 'publisher', 'name': 'NIAID'}, {'DOI': '10.13039/100010269', 'doi-asserted-by': 'publisher', 'name': 'Wellcome Trust'}, {'DOI': '10.13039/501100000024', 'doi-asserted-by': 'publisher', 'name': 'CIHR'}], 'indexed': {'date-parts': [[2024, 1, 31]], 'date-time': '2024-01-31T00:44:35Z', 'timestamp': 1706661875625}, 'is-referenced-by-count': 0, 'issued': {'date-parts': [[2024, 1]]}, 'language': 'en', 'license': [ { 'URL': 'https://www.elsevier.com/tdm/userlicense/1.0/', 'content-version': 'tdm', 'delay-in-days': 0, 'start': { 'date-parts': [[2024, 1, 1]], 'date-time': '2024-01-01T00:00:00Z', 'timestamp': 1704067200000}}, { 'URL': 'http://creativecommons.org/licenses/by-nc-nd/4.0/', 'content-version': 'vor', 'delay-in-days': 23, 'start': { 'date-parts': [[2024, 1, 24]], 'date-time': '2024-01-24T00:00:00Z', 'timestamp': 1706054400000}}], 'link': [ { 'URL': 'https://api.elsevier.com/content/article/PII:S2589004224002700?httpAccept=text/xml', 'content-type': 'text/xml', 'content-version': 'vor', 'intended-application': 'text-mining'}, { 'URL': 'https://api.elsevier.com/content/article/PII:S2589004224002700?httpAccept=text/plain', 'content-type': 'text/plain', 'content-version': 'vor', 'intended-application': 'text-mining'}], 'member': '78', 'original-title': [], 'page': '109049', 'prefix': '10.1016', 'published': {'date-parts': [[2024, 1]]}, 'published-print': {'date-parts': [[2024, 1]]}, 'publisher': 'Elsevier BV', 'reference-count': 0, 'references-count': 0, 'relation': {}, 'resource': {'primary': {'URL': 'https://linkinghub.elsevier.com/retrieve/pii/S2589004224002700'}}, 'score': 1, 'short-title': [], 'source': 'Crossref', 'subject': ['Multidisciplinary'], 'subtitle': [], 'title': 'Bioluminescence Imaging Reveals Enhanced SARS-CoV-2 Clearance in Mice with Combinatorial ' 'Regimens', 'type': 'journal-article', 'update-policy': 'http://dx.doi.org/10.1016/elsevier_cm_policy'}

Please send us corrections, updates, or comments. c19early involves the extraction of 100,000+ datapoints from thousands of papers. Community updates help ensure high accuracy. Treatments and other interventions are complementary. All practical, effective, and safe means should be used based on risk/benefit analysis. No treatment or intervention is 100% available and effective for all current and future variants. We do not provide medical advice. Before taking any medication, consult a qualified physician who can provide personalized advice and details of risks and benefits based on your medical history and situation. FLCCC and WCH provide treatment protocols.

Submit

Post

@CovidAnalysis

FAQ

Public domain CC0 1.0