COVID-19 Update: Where We Are One Year Later Dr

Fifth CME Update on COVID19 (SARS-CoV-2) March 17th; April 2nd, May 10th, July 5th & December 14th 2020 COVID-19 Update: Where we are one year later Dr. José Mª Miró Infectious Diseases Service Hospital Clinic - IDIBAPS University of Barcelona Barcelona (Spain)

E-mail address: [email protected] Transparency Declaration

Dr. José M Miró has received honoraria for speaking or participating in Advisory Boards and/or research grants from the following Pharmaceutical Companies:

Abbvie Merck Angelini-Allergan Medtronic Bristol-Myers Squibb Novartis Contrafect Pfizer Genentech Roche Gilead Sciencies Theravance Jansen ViiV Healthcare 82,620 peer-reviewed publications in 9 months !

December 13th 2020 COVID-19 Update: Where we are one year later

Normile D. Science. Jan. 3, 2020 , 10:35 AM SARS-CoV-2 Global Cases (December 13, 2020)

Overall mortality 2.24%

https://www.arcgis.com/apps/opsdashboard/index.html#/bda7594740fd40299423467b48e9ecf6; accessed on December 13th 2020 at 19:30 h COVID-19 Update: Where we are one year later

>72 million cases globally >1.6 million deaths

Africa: 3% all cases, 4% deaths Americas: 43% all cases, 49% deaths Asia: 24% all cases, 18% deaths Europe: 29% all cases, 29% deaths

Source: ECDC, https://www.ecdc.europa.eu/en/cases-2019-ncov-eueea Global COVID-19: More than 10,000 daily deaths!

Europe ≈ 45% Infection Fatality Ratio (IFR)* - Low-income countries (95%CI): 0.23% (0.14-0.42) - High income countries (95%CI): 1.15% (0.78-1.79)

https://www.ft.com/content/a2901ce8-5eb7-4633-b89c-cbdf5b386938?shareType=nongift – December 13th 2020 * https://www.imperial.ac.uk/mrc-global-infectious-disease-analysis/covid-19/report-34-IFR/ European COVID-19: More deaths in 2nd Wave!

https://www.nytimes.com/interactive/2020/12/04/world/europe/europe-covid-deaths.html?campaign_id=154&emc=edit_cb_20201204&instance_id=24741&nl=coronavirus- briefing®i_id=130981634&segment_id=46144&te=1&user_id=590f9ed22b54db842d283471a79f6fca EU: Where the 2nd Wave was Deadlier than the First

Daily deaths per 100,000 people

Exceeded spring peak (N=19, 63%)

Below spring peak (N=9, 30%)

Far below spring peak (N=2, 7%)

https://www.nytimes.com/interactive/2020/12/04/world/europe/europe‐covid‐deaths.html?campaign_id=154&emc=edit_cb_20201204&instance_id=24741&nl=coronavirus‐briefing®i_id=130981634&segment_id=46144&te=1&user_id=590f9ed22b54db842d283471a79f6fca Distribution of COVID-19 Cases in Europe (December 13 2020)

Second Wave

>14 million cases in the EU/EEA and the UK >350 000 deaths ~60% in France, Italy, UK, Spain, Germany

First Wave ?

Source: ECDC, https://www.ecdc.europa.eu/en/cases-2019-ncov-eueea Mutations in SARS-CoV-2 Spike: from D614 to G614 form

A SARS-CoV-2 variant with Spike G614 has replaced D614 as the dominant pandemic form

Exchange of an aspartic acid (D) for a glycine (G) in position 614

Korber B et al. Cell. 2020 Aug 20; 182:812-827.e19. doi: 10.1016/j.cell.2020.06.043. Mutations in SARS-CoV-2 Spike: from D614 to G614 form

Korber B et al. Cell. 2020 Aug 20; 182:812-827.e19. doi: 10.1016/j.cell.2020.06.043; Wesley-Long S et al. medRxiv September 29, 2020; doi: https://doi.org/10.1101/2020.09.22.20199125 . Mutations in SARS-CoV-2 Spike: G614 Increases Infectivity of the Virus but not the Severity of COVID-19 Disease

G614 is Associated with Higher Viral Korber B et al. Cell. 2020 Aug 20; 182:812-827.e19. doi: 10.1016/j.cell.2020.06.043; Load and Younger Age of Patients Volz E et al. Cell. 2020 Nov 19;S0092-8674(20)31537-3. doi: 10.1016/j.cell.2020.11.020. Wesley-Long S et al. medRxiv September 29, 2020; doi: https://doi.org/10.1101/2020.09.22.20199125 Efficacy of the Facial Mask & Superspreading Events

8% of people transmit the infection to 60% of persons

Avoid the 3Cs: Aerosols: • Crowded places • Ventilate • Closed places closed spaces • Close Contacts

Lemieux JE et al. Science. Dec 10 2020 ;eabe3261. doi: 10.1126/science.abe3261. Jones BMJ 2020. https://www.nytimes.com/2020/12/04/upshot/epidemiologists-virus-survey-.html?auth=login-email&campaign_id=154&emc=edit_cb_20201204&instance_ id=24741&login=email&nl=coronavirus-briefing®i_id=130981634&segment_id=46144&te=1&user_id=590f9ed22b54db842d283471a79f6fca COVID-19 Update: Where we are one year later

→ Acute extrapulmonary clinical manifestations (including CNS) are common !!! ACE2

Chen L et al. Cardiovascular Research. 2020; 116, 1097–1100 * Li D et al. JAMA Network Open. May 7th 2020;3(5):e208292 ACE2 mRNA Expression in the Brain & SARS-CoV-2 Infection

ACE2 mRNA Expression in the Brain

ACE2

Detection of SARS-CoV-2 in oro- and nasopharyngeal as well as CNS regions (pathological study)

Olfactory transmucosal SARS-CoV-2 CNS invasion Zubair AS et al. JAMA Neurol. 2020 May 29. doi: 10.1001/jamaneurol.2020.2065. https://app.biorender.com Meinhardt J et al. Nat Neurosci. Nov 30 2020. doi: 10.1038/s41593-020-00758-5. Acute Extrapulmonary Manifestations of COVID-19

Gupta A, et al. Nature Med. 2020; 26: 1017–1032 Acute Extrapulmonary Manifestations of COVID-19 • Cardiovascular Myocarditis and myocardial injury Myocardial Infarction Heart Failure Arrhythmias Thromboembolic Disease • Neurological Anosmia, dysgeusia Stroke Guillain–Barré Syndrome • Dermatological Several types of skin lesions • Others Gastrointestinal, Hepatic, Renal, Endocrine

Madjid M et al. JAMA Cardiol, March 27, 2020; Mao L et al. JAMA Neurol. April 10, 2020; Toscano G et al. NEJM, April 17, 2020; Fan Z et al. Clin Gastroenterol Hepatol. April 3 2020; Cheng Y et al. Kidney Intern. March 20 2020; Lala A et al. medRxiv preprint doi: https://doi.org/10.1101/2020.04.20.20072702; Galvan-Casas C et al. Br J Dermatol. Apr 29 2020. Acute COVID-19 Cardiovascular Manifestations

Hendren NS, et al. Circulation. 2020 Jun 9;141(23):1903-1914; Montone RA et al. Eur Cardiol. 2020 Jun 23;15:e52. doi: 10.15420/ecr.2020.22; Frangogiannis NG. Eur Heart J. Oct 14 2020;41(39):3836-3838. doi: 10.1093/eurheartj/ehaa727. Myocardial Injury in Hospitalized Patients with COVID-19 Infection

N=2,736 on mortality first 24 h

40% <0.03 ng/mL

HR: 1.77 0.03-0.09 ng/mL 95% CI 1.39-2.26

HR 3.23 >0.09 ng/mL 95% CI 2.59-4.02

Lala A et al. J Am Coll Cardiol. Aug 4 2020;76(5):533-546. doi: 10.1016/j.jacc.2020.06.007. Cardiovascular Complications in Hospitalized COVID-19 Patients

Sabatino J et al. PLoS One. 2020 Aug 14;15(8):e0237131. Incidence of Thrombotic Events in Hospitalized Patients With COVID-19

16%

DVT, deep vein thrombosis; ICU, intensive care unit; IQR, interquartile range; MI,myocardial infarction; PE, pulmonary embolism. Predictors: Age, Gender, Race, CAD and D-dimer levels at admission >500 ng/mL Bilaloglu S. et al. JAMA 2020 Jul 20;e2013372. doi: 10.1001/jama.2020.13372. Acute COVID-19 Associated Neurological Disease: Timeline for Positive Diagnostic Tests, Clinical Presentation, and Pathogenesis.

Acute disseminated encephalomyelitis

Ellul MA, et al. Lancet Neurol. 2020 Jul 2:S1474-4422(20)30221-0. doi: 10.1016/S1474-4422(20)30221-0. Smell/taste alterations are very common (64%) and are associated with a good prognosis

Spinato G, et al. JAMA. 2020; 323:2089-90; Zubair AS et al. JAMA Neurol. 2020 May 29. doi: 10.1001/jamaneurol.2020.2065. https://app.biorender.com; Rubio-Rivas M et al. J Clin Med. Oct 29 2020; 9:3488. doi: 10.3390/jcm9113488. Spectrum of COVID-19 Disease: from Acute to Late Sequelae 8-24 weeks

Deblina Datta S et al.JAMA. 2020 Dec 8; 324:2251-2252; Nath A. Neurology. 2020 Sep 29 2020; 95:559-560. Persistent Symptoms of COVID-19 in One-Third of Cases

• To describe COVID-19 symptom evolution and persistence in an outpatient setting (N=669) in Geneva, Switzerland, from day 1 through day 30 to 45 after diagnosis (COVICARE cohort).

32% Fatigue, dyspnea, and loss of taste or smell were the main persistent symptoms at 30-45 days after diagnosis

Nehme M et al. Ann Intern Med. 2020 Dec 8. doi: 10.7326/M20-5926. Online ahead of print. Persistent Symptoms of COVID-19 are Common at 2 months

• 143 Italian patients were assessed a mean of 60 days after onset of the first COVID-19 symptom. • At the time of the evaluation, 87% only 18 (13%) were completely had at least one free of any COVID-19–related symptom 60 symptom, while 32% had 1/2 symptoms and 55% had 3 or days after more. COVID-19! • Worsened quality of life (QoL) was observed among 44% of patients.

Carfi A et al. JAMA. 2020; 324:603-605. Mid/Long-term Sequelae of COVID-19 • Lung Abnormal pulmonary function tests Organizing pneumonia Pulmonary fibrosis

• Cardiovascular Myocardial injury (MRI) Post-discharge thromboembolic disease (D-dimer)

• Neurological Persistent anosmia and dysgeusia Cognitive and psychological disorders • Others Chronic kidney injury, new onset diabetes

• “Post-COVID-19” syndrome Fatigue, exhaustion, muscle or joint pain and a tight feeling or pain in the chest during several weeks

Herridge MS et al. N Engl J Med. 2011; 364:1293-304; Kamdar BB et al. Thorax. 2018; 73:125-133; Huang Y et al. Respir Res. Jun 29 2020; 21(1):163. doi: 10.1186/s12931-020-01429-6; Mitrani RD et al. Heart Rhythm. 2020 Jun 26:S1547-5271(20)30625-1. doi: 10.1016/j.hrthm.2020.06.026; Manto M et al. Front Neurol. 2020 May 22;11:516. doi: 10.3389/fneur.2020.00516; Halasz G et al. G Ital Cardiol (Rome). 2020 Jul;21(7):523-525. doi: 10.1714/3386.33638; Ahmed H et al. J Rehabil Med. 2020 May 31;52(5):jrm00063. doi: 10.2340/16501977-2694; Candan SA et al. Physiother Theory Pract. 2020 Jun;36(6):663-668. doi: 10.1080/09593985.2020.1766181; Boscolo- Rizzo P et al. JAMA Otolaryngol Head Neck Surg. 2020 Jul 2. doi: 10.1001/jamaoto.2020.1379; https://www.nytimes.com/2020/07/01/health/coronavirus-recovery-survivors.html?ca Myocardial Injury detected in 78% of Patients Recovered From COVID-19 by CMR Imaging at 2-3 months

• To evaluate the presence of myocardial injury in 100 unselected patients recently recovered from COVID-19 illness. • The median (IQR) time interval between COVID-19 diagnosis and CMR was 71 (64- 92) days. • High-sensitivity troponin was significantly correlated with CMR findings. • Cardiovascular magnetic resonance (CMR) revealed cardiac involvement in 78% of patients and ongoing myocardial inflammation in 60% of patients

Puntmann VO et al. JAMA Cardiol. 2020 Jul 27;e203557. doi: 10.1001/jamacardio.2020.3557. COVID-19 Update: Where we are one year later

. This story started in Wuhan in December 2019! . What we know of the second wave of SARS-CoV-2 . COVID-19: beyond acute respiratory disease . HCQ for PrEP, PEP or COVID-19 does not work . Remdesivir, yes or not, that’s the question . Dexamethasone and … something else? . Vaccines are here! … the beginning of the end? . Take-home messages December 14th 2020 Objectives COVID-19 Treatment: Treat Early & Hard

2.- Antivirals 3.- Anti-inflammatory drugs

Procoagulant phase

1.‐ Prophylactic‐dose low‐molecular‐weight heparin (LMWH)

Siddiqu HK, Mehra MR. J Heart Lung Transplant. 2020 doi: 10.1016/j.healun.2020.03.012; Pericas JM, Hernandez-Meneses M et al. Eur Heart J. June 8th 2020. SARS-CoV-2 life cycle: Potential targets for antivirals

Convalescent Plasma/Monoclonal Antibodies Entry inhibitors hrACE2 – APN01 Ribavirin ACE2 Interferon-beta* Chloroquine Hydroxychloroquine Ivermectin Nitazoxanide

Lopinavir/rtv Potential for combining several antiviral drugs

* Interferon induces hundreds of genes which can act on various parts of the lifecycle from Remdesivir? potentially degrading viral RNA (OAS, RNASL) to inhibiting virus egress (BST-2) De Wit Nature Rev Microbiol, 2016; Sanders JM, et al. JAMA. 2020 Apr 13. doi: 10.1001/jama.2020.6019. Coronavirus Drug and Treatment Tracker (Dec 13th 2020)

Remdesivir drug (FDA, EMA) Convalescent plasma (FDA EUA) Monoclonal antibodies (FDA EUA) Dexamethasone and other corticosteroids (NIH, IDSA)

https://www.nytimes.com/interactive/2020/science/coronavirus-drugs-treatments.html Hydroxychloroquine = Does not Work

. SARS-CoV-2 prophylaxis - Pre-exposure prophylaxis (PrEP) - Post-exposure prophylaxis (PEP)

. COVID-19 treatment - Mild/Moderate COVID-19 - Severe/Critical COVID-19

December 14th 2020 PrEP: Hydroxychloroquine did not Prevent COVID-19

• To evaluate the efficacy of hydroxychloroquine (HCQ) to prevent transmission of SARS-CoV-2 in hospital-based health-care workers (HCW) with exposure to patients with COVID-19 using a pre-exposure prophylaxis strategy (PrEP). • Randomized, double-blind, placebo-controlled trial in two tertiary US urban hospitals. • Hydroxychloroquine, 600mg, daily, or size-matched placebo taken orally for 8 weeks. • Primary end-point: incidence of SARS-CoV-2 infection as determined by a nasopharyngeal swab during the 8 weeks of treatment. • The trial was terminated early for futility before reaching a planned enrollment of 200 participants

HCQ Placebo P-value Number of HCW 64 61 - SARS-CoV-2 infection 6.3% 6.6% 0.99 - Adverse events, any 45% 26% 0.03

Abella BS et al. JAMA Intern Med. Sep 30, 2020 doi:10.1001/jamainternmed.2020.6319 PEP: Hydroxychloroquine (HCQ) did not Prevent COVID-19

HCQ PBO/SoC P-value

Boulware et al.* (N=821; 1:1) - Confirmed (or probable) COVID-19 2.7% (11.6%) 2.2% (13.5%) 0.35 - Adverse events (any) 40.1% 16.8% <0.001

Mitja O et al.** (N=2,314; 1:1) - Confirmed (or probable) COVID-19 5.7% (18.7%) 6.2% (17.8%) 0.65 - Adverse events (any) 56.1% 5.9% <0.001

* Randomized, double-blind, placebo-controlled trial in United States and Canada. HCQ (800 mg once, followed by 600 mg in 6 to 8 hours, then 600 mg daily for 4 days) vs. Placebo. ** RCT done in Spain assigning clusters of contacts to the HCQ arm (800 mg once, followed by 400 mg daily for 6 days) or to no specific therapy (SoC, Standard of Care). Household members or HCW exposed to confirmed COVID-19. Primary end-point for both trials: laboratory-confirmed Covid-19 or symptomatic Covid-19 within 14 days.

Boulware D et al, NEJM June 3 2020. Mitja O et al. NEJM November 24 2020 Hydroxychloroquine (HCQ): No benefit in COVID-19 RCTs

HCQ PBO/SoC P-value

Non-hospitalized (mild-moderate) Hospitalization - Skipper et al (Annals, 2020)* 2% 3% 0.29 - Mitja et al. (CID, 2020)** 6% 7% 0.38

Hospitalized (severe-critical) Mortality, 28 d - Recovery (NEJM, 2020) 26% 23.5% 0.10 - Solidarity (NEJM, 2020) 10% 9% 0.23

* More side effects with HCQ than placebo; **Open label RCT. The respiratory tract viral RNA loads over time did not differ between the HCQ recipients and those receiving standard care; FDA rescinded the emergency use authorization (EUA) of HCQ to treat COVID- 19 patients on June 15; NIH halts clinical trial of HCQ on June 20. Study showed treatment does no harm, but provides no benefit. Lopinavir/Ritonavir (Kaletra): No benefit in COVID-19 RCTs

LPV/rtv SoC P-value Mortality, 28 d Hospitalized (severe-critical) - Cao et al. (NEJM, 2020)* 19% 25% NS - Recovery (Lancet, 2020)** 23% 22% 0.60 - Solidarity (NEJM, 2020) 10% 10% 0.97

*The respiratory tract viral RNA loads over time did not differ between the lopinavir–ritonavir recipients and those receiving standard care **No evidence of beneficial effects on the risk of progression to mechanical ventilation or length of hospital stay. The number of patients on invasive mechanical ventilation was low because of difficulty administering the drug to patients on ventilators. DDIs, adverse events and particularly gastrointestinal adverse events were more common in the lopinavir–ritonavir group in the three RCT. COVID-19 Update: Where we are one year later

Sheahan TP et al. Sci Transl Med, 2017; De Wit ET al. Proc Natl Acad Sci U S A, 2020; Sheahan TP et al. Nat Commun; 2020; Williamson BN et al. bioRxiv preprint doi: https://doi.org/10.1101/2020.04.15.043166. Remdesevir (GS-5734)

. GS-441524: New drug on development . Preclinical studies on going . Oral and IV formulations . Easier to synthesize and to manufacture

Biotransformation of Remdesivir (inactive prodrug) into GS-441524 and then GS-443902 (active metabolite, triphosphate analogue).

Le MP et al. Antimicrob Agents Chemother. 2020 Oct 20;64(11):e01521-20. Remdesivir - Adaptive COVID-19 Treatment Trial (ACTT)

• Double-blind, randomized, placebo-controlled trial involving 1,063 hospitalized patients with advanced COVID-19 disease • A total of 68 sites ultimately joined the study— 47 in the United States and 21 in countries in Europe and Asia. • Primary endpoint: time to recovery was defined as being well enough for hospital discharge or returning to normal activity level. • NIH showed preliminary data of interim analysis on April 29th 2020.

Remdesivir Placebo P-value NIAID trial - Median time to recovery, days* 11 15 <0.001 - Mortality 8% 11.6% 0.059

*Patients who received remdesivir had a 31% faster time to recovery than those who received placebo.

Beigel JH et al. N Engl J Med. 2020. Remdesivir - Adaptive COVID-19 Treatment Trial (ACTT)

Remdesivir Placebo P-value NIAID trialFDA Approval, May 1 2020 - Median time to recovery, days* 11 15 <0.001 - MortalityEMA Approval, June8% 2511.6% 20200.059

*Patients who received remdesivir had a 31% faster time to recovery than those who received placebo.

Beigel JH et al. N Engl J Med. 2020 May 22. doi: 10.1056/NEJMoa2007764. Remdesivir – ACTT (NIH) vs. Solidarity (WHO) ACTT (NIH) Solidarity (WHO)

SAEs: 21% REM vs. 27% PBO Beigel JH et al. N Engl J Med. Nov 5 2020; Solidarity, NEJM Dec 2020

Remdesivir or not Remdesivir that is the question

Hamlet, Act III, Scene I. Sir William Shakespeare, 1564 - 1616. Remdesivir – ACTT (NIH): Only Good Results in Stage 5

(Stage 5)

Positive results in patients: - ≤ 10 days symptoms duration - Stage 5: receiving oxygen

Beigel JH et al. N Engl J Med. Nov 5 2020 Remdesivir in Solidarity RCT: It does not analyze stages 5 and 6 separately

(Stage 5 & 6)

(Stage 5) (Stage 6)

→ Remdesivir is effective against moderate and severe COVID-19 (stages 4-5), although it does not reduce mortality.

Beigel JH et al. N Engl J Med. Nov 5 2020; Solidarity, medRxiv Oct 28 2020 Remdesivir – No antiviral effect in the respiratory tract

Viral load by quantitative PCR on the respiratory tract specimens

Upper respiratory tract Lower respiratory tract

Beigel JH et al. N Engl J Med. Nov 5 2020 Remdesivir did not reduce the SARS-CoV-2 viral load in the upper respiratory tract in Rhesus Macaques

Williamson BN et al. Nature. Sep 2020; 585: 273-276. doi: 10.1038/s41586-020-2423-5. Epub 2020 Jun 9. Remdesivir Reduced the SARS-CoV-2 VL in BAL from Rhesus Macaques SARS-CoV-2 VL and virus titers in BAL fluid and lung lobes collected from six Rhesus Macaques Infectious virus titers in VL in BAL (N=6) VL in tissues at necropsy (N=36) BAL (N=6)

• 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. VL = Viral load; BAL = Bronchoalveolar lavage Williamson BN et al. Nature. Sep 2020; 585: 273-276. doi: 10.1038/s41586-020-2423-5. Epub 2020 Jun 9. Remdesivir – Phase 3 SIMPLE Trial in Moderate COVID-19

• Open-label, phase 3 SIMPLE RCT 1:1:1 evaluating 5-day vs. 10-day dosing durations of the Remdesivir vs. Standard of Care (SoC) in hospitalized patients with moderate COVID-19 disease (NIH stages 4 & 5). • Gilead announced results on June 1st 2020: 5-d = 10-d of Remdesivir treatment and better SoC.

5-d vs. SoC p=0.026

No safety concerns

Spinner CD, et al. JAMA. Aug 21 2020. Interferon-β1a: Parenteral (Solidarity trial) vs. Inhalation (UK trial) Parenteral* (SC or IV, 6 d) Inhalation (6 MIU/d, 14 d)

*44 µg/d SC three doses; 10 µg IV daily. Solidarity, medRxiv Oct 28 2020; Monk PD et al. Lancet Respir Med Nov 12 2020 Convalescent Plasma Transfusions . Open-label, EAP for the treatment of 35,322 COVID-19 patients with human convalescent plasma (Mayo Clinic). Convalescent plasma reduced 7-day (9% vs. 12%) and 30-day (22% vs. 27%) mortality rates. Antibody levels are key! . FDA Issues Emergency Use Authorization (EUA) for Convalescent Plasma on August 23 2020

Joyner MJ et al. medRxiv preprint doi: https://doi.org/10.1101/2020.08.12.20169359. August 12, 2020 Convalescent Plasma Transfusions . RCT performed in Argentina. 228 patients were assigned to receive convalescent plasma and 105 to receive placebo. . Median time of symptoms was 8 days (IQR, 5 to 10). Hypoxemia was the most frequent severity criterion for enrollment. . The infused convalescent plasma had a median titer of 1:3200 of total SARS-CoV-2 antibodies (IQR, 1:800 to1:3200).

Time to Death or to Improvement after Treatment with Convalescent Plasma or Placebo Simonovich VA et al. NEJM Nov 24 2020 DOI: 10.1056/NEJMoa2031304 Monoclonal Antibodies against the SARS-CoV-2 spike protein: Effective treatment in patients with mild Covid-19 with high risk of progression

mAb Placebo P-value Hospitalization rates at 28 days Bamlanivimab (iv single dose) - Chen P et al (N=552; 3:1)* 1,6% 6.3% 0.017

Casirivimab plus Imvedimab (iv single dose) - Regeneron mAb (N=799; 2:1)** 3% 9% <0.001

* 452 patients were assigned to receive a single IV infusion of neutralizing antibody LY-CoV555 in one of three doses (700 mg, 2800 mg, or 7000 mg) or placebo ** 266 patients received a single IV infusion of 2,400 milligrams casirivimab and imdevimab (1,200 mg of each), 267 received 8,000 mg casirivimab and imdevimab (4,000 mg of each), and 266 received a placebo, within three days of obtaining a positive SARS-CoV-2 viral test

Chen P et al on behalf BLAZE-1 Investigators. NEJM Oct 28 2020; REGENERON Press Release Nov 21 2020 COVID-19 Update: Where we are one year later

ACE2

Cytokine Acute Respiratory Distress Sydrome (ARDS) pathology Acute diffuse alveolar damage, with pulmonary edema and Storm formation of a hyaline membrane in a SARS-CoV patient The airspaces are indicated by asterisks and some of the hyaline membranes lining the alveolar → ARDS spaces are highlighted by arrows (hematoxylin and eosin stain; original magnification,x100).

Ware LB et al. NEJM, 2000. Tse GMK et al. J Clin Pathol 2004; Shi Y et al. Cell Death & Differentiation. 2020. SARS-CoV-2 (COVID19): Anti-inflammatory Treatment • Corticosteroids • IL-6 inhibitors - Tocilizumab - Sarilumab no activity. - Siltuximab ACE2 • IL-1 inhibitors - Anakinra • JAK inhibitors - Baricitinib (also entry inhibitor) Cytokine • Bruton tyrosin-kinase inhibitors Storm - Acalabrutinib → ARDS • GM-CSF blockers (Mavrilimumab) • Colchicine (also entry inhibitor) Adapted from Ware LB et al. NEJM, 2000 RECOVERY Trial: Low-dose Dexamethasone Reduced Death • RECOVERY was established as a randomized clinical trial to test a range of potential drugs for COVID-19, including dexamethasone. • The trial has proceeded at unprecedented speed, enrolling over 11,000 patients from 175 NHS hospitals in the UK. • The Independent Data Monitoring Committee (IDMC) has reviewed the emerging data about every two weeks to determine if there is evidence that would be strong enough to affect national and global treatment of COVID-19. • Dexamethasone: 6 mg once per day (either by mouth or by intravenous injection) for 10 days vs. Standard of Care (SoC). • On June 8 IDMC concluded that dexamethasone reduced deaths in hospitalized patients with severe COVID-19. Dexamethasone SoC RR (95%CI) Recovery trial Number of patients 2104 4321 28-day mortality 21.6% 24.6% 0.83 (0.74;0.92) - Mechanical ventilation* 29% 41% 0.65 (0.51;0.82) - Oxygen supply* 21% 25% 0.80 (0.70;0.92) - No respiratory intervention* 17% 13% 1.22 (0.86;1.75)

RECOVERY Trial press release, June 16 2020; Horby PW et al. medRxiv. June 22, 2020; The *Rate Ratio (95% confidence interval) RECOVERY Collaborative Group. NEJM July 17 2020. DOI: 10.1056/NEJMoa2021436. RECOVERY Trial: Low-dose Dexamethasone Reduced Death • RECOVERY was established as a randomized clinical trial to test a range of potential drugs for COVID-19, including dexamethasone. • The trial has proceeded at unprecedented speed, enrolling over 11,000 patients from 175 NHS hospitals in the UK. • The Independent Data Monitoring Committee (IDMC) has reviewed the emerging data about every two weeks to determine if there is evidence that would be strong enough to affect national and global treatment of COVID-19. • Dexamethasone: 6 mg once per day (either by mouth or by intravenous injection) for 10 days vs. Standard of Care (SoC). • On June 8 IDMC concluded that dexamethasone reduced deaths in hospitalized patients with severe COVID-19.

0.66 (0.53-0.82) 0.70 (0.48-1.01)

WHO. JAMA. doi:10.1001/jama.2020.17023. Published online September 2, 2020. Tocilizumab (IL-6 inhibitor) was an Effective Treatment of 21 patients with Severe COVID-19 in China • N=21, 17 severe, 4 critical. • Mean age 57 yr. 85% males. All 21 patients received SoC treatment for a week before deteriorating with sustained fever, hypoxemia, and chest CT image worsening. • Mean IL-6 level before tocilizumab was 132.38 pg/mL (normal < 7 pg/mL). • Efficacy: fever returned to normal, all other symptoms improved remarkably • 15/20 patients (75.0%) had lowered their oxygen intake, 1 needed no oxygen therapy • CT scans showed significant remission of opacities in both lungs in 19/20 patients (90.5%) after treatment. • No adverse drug reactions and no subsequent pulmonary infections were reported • All but one patients discharged. • No deaths Xiaoling Xu et al, Proc Natl Acad Sci U S A. 2020 May 19;117(20):10970-10975. Tocilizumab: Did not Reduce Mortality at 28 days

Tocilizumab PBO/SoC P-value Severe COVID-19 - RCT-TCZ (JAMA IM, 2020) 3.3% 1.6% 0.87 - CORIMUNO (JAMA IM, 2020) 11.1% 11.9% 0.88 - BACC (NEJM, 2020)* 5.6% 4.9% 0.81 - EMPACTA (medRxiv, 2020)* 10.4% 8.6% 0.57 Severe & Critical COVID-19 - COVACTA (medRxiv, 2020)* 19.7% 19.4% 0.94

Tocilizumab = 8 mg/kg with possible second dose; SoC = Standard of Care; * Usual care plus placebo Tociluzumab Phase III EMPACTA RCT trial

• Multicenter and multinational (USA, South Africa, Kenya, Brazil, Mexico, Peru), randomized, double-blind, placebo-controlled phase III trial investigating tocilizumab in severe COVID-19 pneumonia. • Included 389 patients with SpO2<94% who did not require noninvasive or invasive mechanical ventilation.

Outcomes at 28 days Tocilizumab PBO P-value

- Mechanical ventilation/Death* 12% 19% 0.04 - Time to hospital discharge 6 days 7.5 days 0.25 - Time to clinical improvement 6 days 7 days 0.26 - Mortality 10.4% 8.6% 0.51 - Infection rates 10.0% 12.6% 0.44

*Primary end-point: 44% lesser risk to progress to mechanical ventilation or death (HR [95%CI]: 0.56 [0.32;0.97]). The most common AEs were: constipation (6%), anxiety (5%) and headache (3%).

Roche Press Release. Basel, September 18th 2020; Salama C et al. medRxiv Oct 23 2020. Baricitinib has antiviral and anti-inflammatory properties

• There is a high expression of TYK2 gene in COVID- 19 patients with poor outcome. JAK 1/2 inhibitors (baricitinib) could be useful to prevent inflammation.

• Baricitinib is indicated for the treatment of moderate to severe active rheumatoid arthritis in adult patients with an inadequate response or intolerance to one or more disease-modifying antirheumatic drugs. The recommended dose is 4 mg QD orally.

• The first pilot retrospective multicenter study showed that baricitinib 4 mg/day used for 2 weeks (together with LPV/rtv) was not associated with SAEs, reduced SARS-CoV-2 viral burden in nasopharyngeal swabs and ICU admissions of patients with COVID-19 pneumonia* AAK1 = AP2-associated protein kinase 1; GAK = cyclin G- Richardson P et al. Lancet, February 3, 2020; Stebbing J et al. Lancet, Feb 27 associated kinase; JAK1/2 = janus kinase 1/2 inhibitors 2020; *Cantini F et al. J infect. Jun 242020 . doi: 10.1016/j.jinf.2020.06.052; Pairo- Castineira E. et al. Nature. 2020 Dec 11. doi: 10.1038/s41586-020-03065-y. Remdesivir plus Baricitinib – ACTT-2 (NIH): Stage 6

Baseline Ordinal Scale 6 (Stage 6)

Positive results in patients: - Severe disease - Stage 6: high-flow oxygen & NIMV

NIMV = Non-invasive mechanical ventilation Kalil AC et al. N Engl J Med. Dec. 11 2020. DOI: 10.1056/NEJMoa2031994 Community Hospital - Ward Hospital - ICU Disease Asymptomatic/Mild Moderate/Severe Critical (MV, ECMO) stages Stages 1-2 Stages 3-5 Stages 6-7 Isolation, at least 10-14 days

Treatment Symptomatic treatment - Early antiviral therapy Close monitoring for early - Proper timing detection of progression. anti-inflammatory drugs Potential use of IV monoclonal antibody therapy in high risk persons Remdesivir, IV, 5-10 d. Stages 4 (no oxygen) & 5 (low-flow oxygen supply) Stage 6 plus baricitinib, oral, 14 days Dexamethasone, IV/oral, 10 d. Stages 5-7, low/high-flow oxygen supply, MV and ECMO Low molecular weight heparin, SC Dr. JM Miro, personal opinion. December 2020. During the entire hospitalization period COVID-19 Update: Where we are one year later

. This story started in Wuhan in December 2019! . What we know of the second wave of SARS-CoV-2 . COVID-19: beyond an acute respiratory disease . HCQ for PrEP, PEP or COVID-19 does not work . Remdesivir, yes or not, that’s the question . Dexamethasone and … something else? . Vaccines are here! … the beginning of the end? . Take-home messages December 14th 2020 What level of SARS-CoV-2 herd immunity must we reach for the pandemic end? 60% !!! • Natural immunity = SARS-CoV-2 infection -World ≈ 7,700 million people → ≈ 4,620 millions (60%) - 2020 estimated # infections: 130-700 millions (3-15%) → Vaccination, vaccination, vaccination! ENE-COVID STUDY 19. Preliminary report. June 3, 2020 https://www.arcgis.com/apps/opsdashboard/index.html#/bda7594740fd40299423467b48e9ecf6; accessed on December 11th 2020 https://www.imperial.ac.uk/mrc-global-infectious-disease-analysis/covid-19/report-34-IFR/ Herd Immunity Thresholds (1-1/R0); SARS-CoV-2 = 60%

60%

R =2.5 0 Omer SB, et al. JAMA. 2020 Nov 24;324(20):2095-2096. Immune response to SARS-CoV-2 infection

Humoral (antibody) responses Cellular (T-cell) responses Callaway E. Nature. April 2020; 580:576-577. doi: 10.1038/d41586-020-01221-y. Duration of humoral & cellular responses: at least 6 months

(Post-symptom onset)

Antiviral antibodies against SARS-CoV-2 in Iceland (N= 1797) Relationships between immune memory compartments in did not decline within 4 months after diagnosis. COVID-19 subjects over time (up to 6 months)

Gudbjartsson DF et al. N Engl J Med. 2020 Oct 29; 383:1724-1734. Dan JM et al. bioRxiv Nov 16 2020 doi: https://doi.org/10.1101/2020.11.15.383323. COVID-19 Reinfections Occur, but Remain Rare

• How common is reinfection? Reinfections are rare. Only 28 confirmed cases have been reported. • Are reinfections more or less severe than the first? Clinical picture is similar. Mortality rates range: 1.2%-3.6%. • What implications do reinfections have for vaccine development? It is an important topic that is currently being studied.

https://bnonews.com/index.php/2020/08/covid-19-reinfection-tracker/; ECDC; Ledford H. Nature. Sep 2020; 585:168-169. doi:10.1038/d41586-020-02506-y A vaccine from Australia’s University of Queensland is abandoned False positive HIV test results

https://www.nytimes.com/interactive/2020/science/coronavirus-vaccine-tracker.html Traditional and accelerated vaccine-development pipelines Traditional: 15 years or longer

SARS-CoV-2: 10-18 months

Krammer F. Nature. 2020 Oct;586(7830):516-527. doi: 10.1038/s41586-020-2798-3. Mucosal and systemic immune responses to natural infection with respiratory viruses and to vaccination

• Avoid transmission • Disease severity

Krammer F. Nature. 2020 Oct;586(7830):516-527. doi: 10.1038/s41586-020-2798-3.

Vaccine Candidates: Inactivated SARS-CoV-2 virus

SARS-CoV-2 virus Compound Current Type of Vaccine Sponsor Trial Phase

Inactivated BBIBP-CorV 3 SARS-CoV-2 Sinopharm, Beijing, China Inactivated COVID-19 3 SARS-CoV-2 WIBP and Sinopharm, Wuham, China Inactivated Coronavac 3 SARS-CoV-2 Sinovac, China

Callaway Ewen. Nature 2020; 580, 576-577. doi: https://doi.org/10.1038/d41586-020-01221-y; IDSA COVID-19 Vaccines, Updated December 4 2020 Vaccine Candidates: Viral-vector Vaccines

Adenovirus vector Name Current Type of Vaccine Sponsor Trial Phase

Adenovirus Ad5-nCoV 3 type 5 vector CanSino Biologics China

rAdenovirus Gam-COVID-Vac 2/3 types 26 & 5 Sputnik V vector Gamaleya RIEM, Russia

Weakened AZT1222 2/3 Adenovirus Oxford - Astra Zeneca, UK

Callaway Ewen. Nature 2020; 580, 576-577. doi: https://doi.org/10.1038/d41586-020-01221-y; IDSA COVID-19 Vaccines, Updated December 4 2020 Vaccine Candidates: Viral-vector Vaccines

Adenovirus Name Current Type of Vaccine Sponsor Trial Phase

Adenovirus Ad26.COV2.S 3 type 26 Janssen, Johnson recombinant & Johnson vector Belgium, USA

Callaway Ewen. Nature 2020; 580, 576-577. doi: https://doi.org/10.1038/d41586-020-01221-y; IDSA COVID-19 Vaccines, Updated December 4 2020 Efficacy of Adenovirus-vector Vaccines AZD1222 Sputnik V Oxford-Astra Zeneca Gamaleya RIEM 59-90% 92%

AstraZeneca joins forces with Russia’s Gamaleya Institute.

Voysey M et al. Lancet Dec 8 2020; S0140-6736(20)32661-1. doi: 10.1016/S0140-6736(20)32661-1 Sputnik V phase 3 RCT data not published yet. Callaway E et al. Nature. Nov 11 2020. doi: 10.1038/d41586-020-03209-0 https://www.nytimes.com/live/2020/12/11/world/covid-19-coronavirus?#british-and-russian-vaccine-makers-are-set-to-begin-clinical-trials-combining-two-vaccines Efficacy of the ChAdOx1 nCoV-19 vaccine (AZD1222)

• A randomized, double-blind study done across the UK, Brazil, and South Africa (N=23,848, N=11,636 interim analysis). • Participants aged 18 years and older were randomly assigned (1:1) to ChAdOx1 nCoV-19 vaccine or control (meningococcal group A, C, W, and Y conjugate vaccine or saline). • Participants in the ChAdOx1 nCoV-19 group received two doses containing 5x10¹⁰ viral particles (standard dose; SD/SD cohort); a subset in the UK trial received a half dose as their first dose (low dose) and a standard dose as their second dose (LD/SD cohort). • The primary efficacy analysis included symptomatic COVID-1 with a nucleic acid amplification test-positive swab ≥14 days after a second dose of vaccine. Vaccine efficacy (95% CI) 70% • LD/SD 90% (67;97) • SD/SD 59% (25;78)

Voysey M et al. Lancet Dec 8 2020; S0140-6736(20)32661-1. doi: 10.1016/S0140-6736(20)32661-1 034577 Efficacy & Safety of the ChAdOx1 nCoV-19 vaccine (AZD1222) Vaccine Control (N=12,021) (N=11,724) COVID-19 (PCR+), n. - Symptomatic infection 51 141 - Hospitalization 0 10 - Severe COVID-19 0 2

Adverse events, n. - SAEs 79 89 - Transverse myelitis (one-related) 2 1 - Hemolytic anaemia (related) 0 1 - Deaths (all unrelated)* 1 3

*Traffic accident, blunt force trauma, homicide, and fungal pneumonia Voysey M et al. Lancet Dec 8 2020; S0140-6736(20)32661-1. doi: 10.1016/S0140-6736(20)32661-1 034577 Durability of Responses after ChAdOx1 nCoV-19 vaccination (AZD1222)

• ChAdOx1nCoV-19 had similar immunogenicity B- and T-cell responses across all age groups after a boost dose. By 14 days after the boost dose, 208 (>99%) of 209 boosted participants had neutralizing antibody and peaked T-cell responses. • SARS-CoV-2 IgG response to the receptor binding domain (A) and the spike protein (B) in the standard-dose groups by age.

• Antibody titers maintained for 2 months • Good immune response across all ages

Ramasamy MN et al. Lancet. 2020 Nov 18;S0140-6736(20)32466-1. Vaccine Candidates: mRNA vaccines

mRNA → Spike Name Current Type of Vaccine Sponsor Trial Phase

mRNA BNT162 3 Nanoparticles Pfizer-BioNTech USA-Germany

mRNA mRNA-1273 3 Nanoparticles Moderna USA

Callaway Ewen. Nature 2020; 580, 576-577. doi: https://doi.org/10.1038/d41586-020-01221-y; IDSA COVID-19 Vaccines, Updated December 4 2020 Efficacy of mRNA Vaccines Pfizer- Moderna BioNTech USA USA-Germany 95% 94%

Polack FP et al. NEJM Dec.10 2020; DOI: 10.1056/NEJMoa2034577 Callaway E. Nature. Nov. 16 2020; 587:337-338. doi: 10.1038/d41586-020-03248-7 Jackson LA et al. N Engl J Med. 2020 Nov 12;383(20):1920-1931. doi: 10.1056/NEJMoa2022483 EMA Dec 29, 2020 Safety and Efficacy of the BNT162b2 mRNA Covid-19 Vaccine

• A randomized, double-blind study of an mRNA vaccine encoding the SARS-CoV-2 spike protein. • 43,548 participants ≥16 years old were assigned to receive the vaccine or placebo by intramuscular injection on days 0 and 21. • Participants were followed for safety and for the development of symptomatic Covid-19 for a median of 2 months.

Early protection, 12 days after the 1st dose

95%

• Safety: Vaccine recipients had local reactions and systemic reactions (e.g., fever, headache, myalgias) at higher rates than placebo recipients. More reactions following the second dose. Most were mild to moderate and resolved rapidly. → Some severe hypersensitivity reactions and Bell's palsy reported. Polack FP et al. NEJM December 10 2020; DOI: 10.1056/NEJMoa2034577 Safety and Efficacy of the BNT162b2 mRNA Covid-19 Vaccine

(1 death)

• Two doses of an mRNA-based vaccine were effective (95% protection) and safe • Avoid in most cases severe COVID-19 disease. • Age: same results in those over or under 55 years old • Median protection of at least two months Polack FP et al. NEJM December 10 2020; DOI: 10.1056/NEJMoa2034577 Efficacy of the SARS-CoV-2 mRNA-1273 Vaccination (Moderna)

• A randomized, double-blind study of an mRNA vaccine encoding the SARS-CoV-2 spike protein. • 30,000 participants were assigned to receive dos doses of the vaccine or placebo by intramuscular injection on days 0 and 28.

Vaccine Control COVID-19 (PCR+), n. - SARS-CoV-2 infection 11 185 - Severe COVID-19 disease 0 30 94%

Adverse events, n. - Deaths 0 1

• Two doses of an mRNA-based vaccine were effective (94% protection) and safe • Efficacy was consistent across age, race and ethnicity and gender demographics. Moderna Press Release, Nov 20 2020 Durability of Responses after SARS-CoV-2 mRNA-1273 Vaccination (Moderna)

• Immunogenicity data 90 days after the second vaccination in 34 healthy adult participants who received two injections of vaccine (100 μg)

• Antibody titers maintained for 3 months • Good immune response across all ages

Time Course of SARS-CoV-2 Antibody Binding and Neutralization Responses after mRNA-1273 Vaccination. Widge AT et al. N Engl J Med. Dec 3 2020 DOI: 10.1056/NEJMc2032195 Vaccine Candidates: Protein vaccines

SARS-CoV-2 Name Current Type of Vaccine Spike Protein Sponsor Trial Phase

rSARS-CoV-2 NVX-CoV2373 1/2b/3 nanoparticle Novavax, vaccine* USA

*Trimeric full-length SARS-CoV-2 spike glycoproteins and Matrix-M1 adjuvant Callaway Ewen. Nature 2020; 580, 576-577. doi: https://doi.org/10.1038/ Keech C et al. N Engl J Med 2020; 383: 2320-32. DOI: 10.1056/NEJMoa2026920 Cost of two doses 7 €

54 €

33 € Vaccine Limitations and Remaining Questions

 To what extent does the vaccine prevent the most severe cases  Does the vaccine prevent asymptomatic disease and limit transmission?  How well the vaccine works in different groups (e.g., very older, children, pregnant women, and immunocompromised persons)  How long the vaccine’s effectiveness will last (2-4 months)  How to deal with those who miss the second vaccine dose  Should people who have had a SARS-CoV-2 infection get vaccinated?  Will unexpected safety issues arise when the number grows to millions and possibly billions of people? Will side effects emerge with longer follow- up?  Vaccine trial ethics (placebo-controlled trials) once we have efficacious vaccines

Rubin EJ & Longo DL, M.D. NEJM December 10, 2020. DOI: 10.1056/NEJMe2034717; Wendler D et al. Science. Dec 11 2020; 370:1277-1279. SARS-CoV-2 Vaccine Prioritization Strategies P1-P3 Refer to Phases of Vaccine Introduction Lottery allocation when numbers outweigh resources for equal risk Royal Society in UK National Academy of WHO ACIP Medicine US Health-Care Workers (HCW) P1 P1a P1 P1 First Responders P1 P1a P1 P1 Elderly persons P1 P1b P1 P1 Elderly 65+ living in Lottery Elderly congregate settings allocation P2 P2 Other elderly 65+ >65 years old Patients with comorbidities P1 P1b P1 P2 - High risk P2 Lottery allocation - Moderate risk Specific Essential Occupations P2 P2 P2 Teachers and occupations at Teachers K-12 & staff, Essential high risk of exposure critical industry workers workers

Underprivileged Groups P2 Homeless, institutionalized & Staff Participants in Trials P2 or P3 GCMSC proposal for COVID-19 vaccination

SMALL  Health-care workers (HCW) in contact with patients including nursing QUANTITY homes and first responders  Elderly above age 80+, 65+  People with morbid conditions like diabetes mellitus type 2, ischemic heart disease, CODP, morbid obesity, chronic kidney disease, cancer patients, immunosuppression.  Institutionalized people and at risk of social exclusion (prisons, migrants, refugee centers)  Essential workers (transportation, education, food)

 Over 55 years old People with evidence of previous SARS-COV-2 infection should 45+M  Vaccines for all not be considered a priority when accessing vaccines

GCMSC = Grupo Colaborativo Multidisciplinar para el Seguimiento Científico de la COVID-19 (Scientific Advisory Group on COVID-19) – ISGlobal, COMB, ACER. https://www.isglobal.org/en/-/-a-quien-vacunar-primero-un-grupo-multidisciplinar-de-personas-expertas-propone-una-estrategia-de-vacunacion-contra-la-covid-19 COVID-19 Vaccination - Numbers in Spain

Potential Priority Groups Phase 1-2 Population • Health workers if in contact with patients 513,777 • First responders and essential workers 1.7/7.5 M • Older than 64 (19%) 9 M • Older than 64 and diabetes (21%) 2 M • Diabetes 6.5 M • Incarcerated 59,589

TOTAL POPULATION 47.3M Numbers are approximate based on routine statistics and reports https://www.isglobal.org/en/-/-a-quien-vacunar-primero-un-grupo-multidisciplinar-de-personas-expertas-propone-una-estrategia-de-vacunacion-contra-la-covid-19 What plan do we have for 2021: facial masks, hand washing, social distance and ... vaccines!

Facial Masks* - ↓ Transmission rates - ↓ Severity of disease

Rail commuters wearing white protective masks, one with the additional message “wear a mask or go to jail,” during the 1918 influenza pandemic in California. Vintage Space/Alamy https://www.nytimes.com/2020/08/03/us/mask-protests-1918.html; *Gandhi M et al. NEJM Oct 29 2020 https://www.nejm.org/doi/full/10.1056/NEJMp2026913 What plan do we have for 2021. The Swiss Cheese Respiratory Virus model of pandemic defense: Multiple layers of protection improve success!

Dr. Ian M. Mackay was creator of the “Swiss Cheese Respiratory Pandemic Defense.” Credit: Faye Sakura for The New York Times https://www.nytimes.com/2020/12/05/health/coronavirus-swiss-cheese-infection-mackay.html COVID-19 Update: Where we are one year later

. This story started in Wuhan in December 2019! . What we know of the second wave of SARS-CoV-2 . COVID-19: beyond an acute respiratory disease . HCQ for PrEP, PEP or COVID-19 does not work . Remdesivir, yes or not, that’s the question . Dexamethasone and … something else? . Vaccines are here! … the beginning of the end? . Take-home messages December 14th 2020 Take-home messages . The second wave of the SARS-CoV-2 pandemic has been due to a mutation of the virus spike (G614) that has made the virus much more transmissible and that has affected much younger people. . The extrapulmonary manifestations of COVID-19 are frequent as well as the long-term manifestations, whose pathophysiology is not well characterized yet. . Remdesivir alone or plus baricitinib is effective against moderate and severe COVID-19 (stages 4-6), although it does not reduce mortality. . Dexamethasone reduced mortality in severe and critical COVID-19. . The rapid development of the SARS-CoV-2 vaccine has been an extraordinary achievement. mRNA vaccines are 95% effective and safe in the short term. Acknowledgements O. Coll M. Peck G. Mora J.M. Pericàs A. Moreno C. Pontes A. Pharris T.P. Sheahan R. Paredes A. Vallano To all front-line health-care workers To our patients and their families