COVID-19 Second Year: SARS-Cov-2 Variants, Long COVID & Vaccines Dr

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6th CME Update on COVID19 (SARS-CoV-2) March 17th; April 2nd, May 10th, July 5th, December 14th 2020 & May 25th 2021 COVID-19 Second Year: SARS-CoV-2 Variants, Long COVID & Vaccines Dr. José Mª Miró Infectious Diseases Service Hospital Clinic - IDIBAPS University of Barcelona Barcelona (Spain)

E-mail address: [email protected] COVID-19 Second Year: SARS-CoV-2 Variants, Long COVID-19 & Vaccines . Current epidemiological and mortality data . New SARS-CoV-2 variants update . Long COVID-19: where we are one year later . Remdesivir, dexamethasone, heparin and … something else? . Reinfections: state of the art . Vaccines efficacy and impact of new SARS-CoV-2 variants . Vaccines safety: TTS* . Take-home messages *Thrombosis with Thrombocytopenia Syndrome (TTS) May 25th 2021 COVID-19 Global Cases (May 25th 2021)

Overall mortality 2.07%

https://www.arcgis.com/apps/opsdashboard/index.html#/bda7594740fd40299423467b48e9ecf6; accessed on May 25th 2021 Distribution of COVID-19 cases Worldwide: Almost 5 million weekly cases

Cases in Africa under reported!

https://www.ecdc.europa.eu/en/geographical-distribution-2019-ncov-casesgift – May 24th 2021 Global COVID-19: More than 12,000 daily deaths!

Europe ≈ 16%

LatAm ≈ 31%

India ≈ 33%

https://www.ft.com/content/a2901ce8-5eb7-4633-b89c-cbdf5b386938?shareType=nongift – May 25th 2021 Reduction of COVID-19 In-Hospital Mortality in the United States During the COVID-19 Pandemic

↓ 34-42% >50 yr. in comparison 1st wave

Roth GA et al. JAMA Netw Open. May 3 2021; 4(5):e218828. doi: 10.1001/jamanetworkopen.2021.8828. Global Coronavirus Death Toll Could Be 60% Higher Than Reported

https://www.ft.com/content/a2901ce8-5eb7-4633-b89c-cbdf5b386938?shareType=nongift – April 26th 2021 Mortality: 7-10 millions

https://www.nytimes.com/live/2021/05/21/world/covid-vaccine-coronavirus-mask#who-covid-deaths-excess COVID-19 Second Year: SARS-CoV-2 Variants, Long COVID-19 & Vaccines . Current epidemiological and mortality data . New SARS-CoV-2 variants update . Long COVID-19: where we are one year later . Remdesivir, dexamethasone, heparin and … something else? . Reinfections: state of the art . Vaccines efficacy and impact of new SARS-CoV-2 variants . Vaccines safety: TTS* . Take-home messages *Thrombosis with Thrombocytopenia Syndrome (TTS) May 25th 2021 Binding of the spike to an ACE2 receptor allows the virus to enter human cells

RBD RBD RBD

RBD Spike

RBD RBD ACE2 receptor

RBD=Receptor binding domain.

Lorenzo Casalino, Amaro Lab, U.C. San Diego. https://www.nytimes.com/interactive/2020/health/coronavirus-unveiled.html?campaign_id=154&emc=edit_cb_20201009&instance_id=23018&nl%E2%80%A6 Mutations in SARS-CoV-2 Spike: First transition D614 to G614

RBD RBD

A spike protein, at left, and a protective coating of sugars, at right RBD=Receptor binding domain. 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 https://www.nytimes.com/interactive/2020/health/coronavirus-unveiled.html?campaign_id=154&emc=edit_cb_20201009&instance_id=23018&nl%E2%80%A6 Mutations in SARS-CoV-2 Spike: First transition D614 to G614

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. Baric RS. NEJM; 2020; 383,2684-2686. Mutations in SARS-CoV-2 Spike: Global Transition D614 to G614

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

Load and Younger Age of Patients Korber B et al. Cell. 2020 Aug 20; 182:812-827.e19. doi: 10.1016/j.cell.2020.06.043; 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; Diez-Fuertes et al. J Virol. 2021 doi: 10.1128/JVI.01583-20 Mechanisms for Generating SARS-CoV-2 Variability

SARS CoV-2 virus • Low polymerase error rate (Nsp14, error correction exoribonuclease activity) • High-level replication • The population is the incubator → Global vaccination!

Quasispecies dynamics: Evolutionary advantages • Improves replicative capacity → Entry, infectivity, transmission • Improves ability to interact with cellular factors • Escape to class I interferon innate response • Escape to acquired response → Antibodies, CTLs • It may increase disease severity • Genetic "drift", founder effect Alcami J, personal communication. Selected SARS-CoV-2 Lineages

Variant of Interest (VOI) → Multiple mutations, rapid increase in incidence, spread in areas of high immunity. e.g. California, New York, India

Variant of Concern (VOC) → Increased transmission, virulence, UK immune escape. e.g. UK, Brazil, South Africa

D614G → Increased transmission. N501Y → Increased transmission.

India K417 → Increased ACE2r affinity. B.1.617 B.1.618 E484K → Associated with “antibody resistance”. New SARS-CoV-2 VOC: B.1.1.7 (United Kingdom); B.1.351 (South Africa); P.1 (Brazil).

Galloway SE et al. MMWR Morb Mortal Wkly Rep. Jan 15 2021 New SARS-CoV-2 VOC: B.1.1.7 (United Kingdom) The variant was first detected in the United Kingdom in September 2020, and a look back at previous samples found it as early as September 20th 2020. It has now been detected in over 110 countries.

https://www.nytimes.com/interactive/2021/health/coronavirus-variant-tracker.html, May 24th 2021 New SARS-CoV-2 VOC: B.1.351 (South Africa) The variant spread from South Africa into neighboring countries in October 2020. It has since spread to at least 68 countries.

https://www.nytimes.com/interactive/2021/health/coronavirus-variant-tracker.html, May 24th 2021 New SARS-CoV-2 VOC: P.1 (Brazil) P.1 was discovered in December 2020 and reached the United States in January, but it may have been circulating as early as October 2020 in Manaus, Brazil. It has now spread to at least 37 countries.

https://www.nytimes.com/interactive/2021/health/coronavirus-variant-tracker.html, May 24th 2021 New SARS-CoV-2 VOI: B.1.617.2 (India) In just a few weeks, the B.1.617 variant has become the dominant strain across India and has spread to about 40 nations, including the United Kingdom, Fiji and Singapore.

Almost 400,000 new Same growing rate as infections on May 9 2021! B.1.1.7 (UK variant)

Vaidyanathan G. Nature. 2021; 593: 321-322; https://www.ft.com/content/a2901ce8-5eb7-4633-b89c-cbdf5b386938 New SARS-CoV-2 VOI: B.1.617.2 (India) In just a few weeks, the B.1.617 variant has become the dominant strain across India and has spread to about 40 nations, including the United Kingdom, Fiji and Singapore.

RBD

RBD=Receptor binding domain. Tada T et al. bioRxiv May 16th 2021 preprint doi: https://doi.org/10.1101/2021.05.14.444076; https://www.nature.com/articles/d41586-021-01274-7 B.1.617.2 (India): Increased Infectivity In just a few weeks, the B.1.617 variant has become the dominant strain across India and has spread to about 40 nations, including the United Kingdom, Fiji and Singapore. Infectivity in pseudotyped viruses

RLU=Luciferase activity was measured two days post-infection.

Tada T et al. bioRxiv May 16th 2021 preprint doi: https://doi.org/10.1101/2021.05.14.444076 B.1.617.2 (India): Lower Neutralization by Sera & Vaccines In just a few weeks, the B.1.617 variant has become the dominant strain across India and has spread to about 40 nations, including the United Kingdom, Fiji and Singapore. Neutralization of spike protein variants by convalescent sera and antibodies elicited by BNT162b2 and mRNA1273 vaccines

UK variant = B.1.1.7; South Africa variant = B.1.1351 Tada T et al. bioRxiv May 16th 2021 preprint doi: https://doi.org/10.1101/2021.05.14.444076 B.1.617.2 (India): Lower Neutralization by monoclonal nAbs In just a few weeks, the B.1.617 variant has become the dominant strain across India and has spread to about 40 nations, including the United Kingdom, Fiji and Singapore. Neutralization of B.1.617 and B.1.618 spike protein variants by neutralizing monoclonal REGN10933 and REGN10987 antibodies

(UK) (South Africa)

Tada T et al. bioRxiv May 16th 2021 preprint doi: https://doi.org/10.1101/2021.05.14.444076 Remember these new variants of SARS-COV-2

Potential clinicalUK implications: B1.1.7 (D614G, N501Y) - Loss of efficacy of monoclonal antibodies/convalescent plasma - LossSouth of efficacy Africa of vaccines B.1.351(D614G, N501Y, K417N, E484R) → N501Y (UK variant) → Vaccines and antibodies OK → E484KBrazil(South Africa, Brazil, India variants)P.1 →(D614G, Viral scape N501Y, toK417T, vaccines E484R) and antibodies - Reinfections (variants w/E484K): Overcome natural & vaccine immunity India B.1.617.2 (D614G, L452R, P681R, E484R) COVID-19 Second Year: SARS-CoV-2 Variants, Long COVID-19 & Vaccines . Current epidemiological and mortality data . New SARS-CoV-2 variants update . Long COVID-19: where we are one year later . Remdesivir, dexamethasone, heparin and … something else? . Reinfections: state of the art . Vaccines efficacy and impact of new SARS-CoV-2 variants . Vaccines safety: TTS* . Take-home messages *Thrombosis with Thrombocytopenia Syndrome (TTS) May 25th 2021 WHO post-acute COVID-19 = 10% at 12 weeks

Spain 3,650,000 cases 10% = 365,000 cases long COVID

https://www.euro.who.int/en/about-us/partners/observatory-old/news/news/2021/02/new-policy-brief-calls-on-decision-makers-to-support-patients-as-1-in-10-report-symptoms-of-long-covid Timeline of post-acute COVID-19

Nalbandian A et al. Post-acute COVID-19 syndrome. Nat Med. 2021 Apr;27(4):601-615. Case Definition Post-Acute Covid-19 (≥4 weeks) • Long Covid Persistent symptoms beyond 4 weeks that may be present or not in acute-COVID or appear later in asymptomatic subjects and are not the result of an apparent irreversible organ damage Clinical phenotypes • Permanent • Relapsing/remitting • Progressive and slow improvement

• Sequelae Irreversible tissue damage after 12 weeks that could represent different degrees of permanent dysfunction and symptoms Clinical scenarios • Post-intensive care syndrome. • Post-thrombotic or hemorrhagic complications • Immunomediated phenomena in the acute phase. • MIS-C and MIS-A.

Lledo G on behalf the Multidisciplinary Collaborative Group for the Scientific Monitoring of COVID-19 (GCMSC); https://www.isglobal.org/documents Long-COVID Pathogenesis

• Direct viral toxicity • “Cytokine storm”  Hyperinflammatory state • Immune system dysregulation complex interplay INN – ADAPT immune response • Microvascular injury: Thrombo-inflammation + Endothelitis • Neuro-psychiatric: – Neuroinflammation/degeneration (neurofilament) – Dysfunctional lymphatic drainage (glymphatic system & CFS. Wostyn et el) – Astrogliosis • Gastrointestinal/Hepatobiliar: lung-gut axis • MIS-C/MIS-A. Aberrant acquired immune response: Immune complexes, complement activation, antibody through viral host mimicry.

Lledo G on behalf the Multidisciplinary Collaborative Group for the Scientific Monitoring of COVID-19 (GCMSC); https://www.isglobal.org/documents; Nalbandian A et al. Nat Med. 2021 Apr;27(4):601-615; Wostyn P. Med Hypotheses. 2021 Jan;146:110469 Clinical Manifestations

• Cognitive impairment • Sicca syndrome MIS-C/A • Anxiety, depression, PTSD • Aphtas . Children: 7-21 Y (2: 100.000 • Sleep disorders • Odynophagia . Adults: young (30 reported cases) • Red eyes . >21 days after COVID diagnosis • Visual disturbances . Inflammatory markers: CPR, • Anosmia & Dysgeusia ESR,Ferritin 45 % • Ischemic or hemorrhagic stroke • Encephalitis- myelitis . Multi-organ dysfunction: 10-27 % 62% • Guillain Barre syndrome • Tinnitus Fever • Critical Illness myopathy or neuropathy • Long COVID • Dizziness 25 % 40% • Headache (migraine-like) • Hearing loss • Dysautonomia • Sequelae 10% • “Brain fog”

• Chest pain • Dyspnea 30 % 33 % • Skin lesions • Cough • Pruritus FATIGUE • Fibrotic changes- DLCO impairment • Hair loss (“telogen effluvium”) 52%

30-42 %

• Arrhytmia, palpitations • Myocarditis • Abdominal pain 10-17 % • Pericarditis • Diarrhea • Vomiting • Hyporexia 1 % • Hepatitis 7.2 % • CKD 28-30 % **COVAN **Post-AKI COVID 20 % • Cytopenias • Arthralgias • Thrombosis • DM • Menstrual cycle disorders Autoimmune Disorders • Arthritis • Thyroiditis • Bone demineralization • Myalgia Lledo G on behalf GCMSC. https://www.isglobal.org/documents Follow up Symptoms and Sequelae

% 100 90 80 75% 70

10 15%

0 1st week 4 weeks 8 weeks 12 weeks 16 weeks 20 weeks 24 weeks Townsend Carfi D´Cruz Garrigues Halpin Carvalho‐Schneider Goërtz Huang Davis Dennis Petersen Xiong Mandal Rauch Logue Arnold Moreno‐Perez ONS Sudre Sykes Nehme Chopra SEMG

Lledo G on behalf GCMSC. https://www.isglobal.org/documents Treatment

• No treatment data … but nowadays there are treatment for specific symptoms

• Rule out other causes • Individualize Not the same treatment for everyone • Physical Rehabilitation • Psychological support • Multidisciplinary Team • Best treatment… early diagnosis (screening) • … Vaccines? Multidisciplinary Approach

Phillips M. British Society of Rehabilitation Medicine, 2020; Greenhalgh T et al. BMJ. 2020 Aug 11;370:m3026. doi: 10.1136/bmj.m3026; Lledo G on behalf GCMSC. https://www.isglobal.org/documents Vaccines were safe and improved some symptoms in patients with long COVID in UK

Decrease in worsening symptoms (6% vaccinated vs 14% unvaccinated) and increase in symptom resolution (23% vaccinated vs 15% unvaccinated) (p=0.035).

Arnold DT et al. medRxiv March 14, 2021. https://doi.org/10.1101/2021.03.11.21253225; Lledo G on behalf GCMSC. https://www.isglobal.org/documents COVID-19 Second Year: SARS-CoV-2 Variants, Long COVID-19 & Vaccines . Current epidemiological and mortality data . New SARS-CoV-2 variants update . Long COVID-19: where we are one year later . Remdesivir, dexamethasone, heparin and … something else? . Reinfections: state of the art . Vaccines efficacy and impact of new SARS-CoV-2 variants . Vaccines safety: TTS* . Take-home messages *Thrombosis with Thrombocytopenia Syndrome (TTS) May 25th 2021 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. Coronavirus Drug and Treatment Tracker (May 25th 2021)

Remdesivir drug (FDA, EMA but not WHO) Convalescent plasma (FDA EUA) Monoclonal antibodies (FDA EUA) Dexamethasone and other corticosteroids (NIH, IDSA) IL-6 inhibitors: Tocilizumab

https://www.nytimes.com/interactive/2020/science/coronavirus-drugs-treatments.html Remdesevir (GS-5734) . RNA-dependent RNA polymerase inhibitor. . Effective in vitro and in animal models against zoonotic and epidemic SARS- CoV, MERS-CoV and SARS-CoV-2 as both prophylactic and therapeutic agent. . PK: Renal excretion. Not recommended eGFR ≤30 ml/min. Few DDI. . Dosage: 200 mg IV, then 100 mg/24 h during 5-10 days. . Safety: few side effects (hypotension during infusion).

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. 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, medRxiv Oct 28 2020 Remdesivir in Solidarity RCT: It does not analyze stages 5 and 6 separately

(Stage 5 & 6)

(Stage 5) (Stage 6)

Beigel JH et al. N Engl J Med. Nov 5 2020; Solidarity, medRxiv Oct 28 2020 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. Ivermectin in Adults with Mild COVID-19

• Double-blind RCT conducted at a single site in Cali, Colombia. A total of 476 adults with mild disease and symptoms for 7 days or fewer (at home or hospitalized) were enrolled between July and November 2020, and followed up through December 2020. • Patients were randomized to receive ivermectin, 300 μg/kg of body weight per day for 5 days (n = 200) or placebo (n = 200). • Primary outcome was time to resolution of symptoms within a 21-day follow-up.

Time to Resolution of Symptoms in the Primary Analysis Population.

• Symptoms resolution: 82% in the ivermectin group and 79% in the placebo group by day 21.

• The trial do not support the use of ivermectin for treatment of mild COVID-19. Lopez-Medina E et al. JAMA. doi:10.1001/jama.2021.3071. Published online March 4, 2021. Molnupiravir – An Oral Drug for COVID-19 Treatment

• Molnupiravir has potent in vitro activity against a broad range of coronaviruses, including SARS-COV-2 (including remdesivir-resistant mutants). • Demonstrated activity in ferret and mouse models of SARS-CoV-2 disease, including prophylaxis, treatment, and prevention of transmission • It is rapidly absorbed and distributed after oral administration and subsequently converted intracellularly to active form. • Inhibits SARS-COV-2 replication by inducing viral error catastrophe. It is not mutagenic or genotoxic in mammals.

• CROI 2021: Phase 2a RCT. 182 participants randomized 1:1 (200 mg) or 3:1 (400 mg, 800 mg) sequentially to receive molnupiravir or placebo twice-daily for 5 days. • 78 cases (42.9%) had positive baseline cultures • Overall, there was a significant reduction in positive viral culture at day 5 in molnupiravir-treated participants. Best activity reached with 800 mg BID. No infectious virus was recovered in any molnupiravir-treated participants. • The drug was safe and well tolerated. Four cases experienced a serious AE (0 drug-related) and 7 discontinued study drug (3 due to an AE). Painter W, et al. CROI 2021 Poster #777. Molnupiravir – An Oral Drug for COVID-19 Treatment

Update on Progress of Clinical Development Program for Molnupiravir, an Investigational Oral Therapeutic for the Treatment of Mild-to-Moderate COVID-19 → Phase 2/3 MOVe-IN Study in Hospitalized Patients Stopped. • Phase 2/3, randomized, placebo-controlled, double-blind, multi-site trial evaluating the efficacy, safety, and pharmacokinetics of orally administered molnupiravir in hospitalized participants at least 18 years of age with laboratory confirmed. 304 participants randomized 1:1:1:1 to who received molnupiravir 200 mg, 400 mg, 800 mg or placebo twice daily for 5 days. The primary efficacy endpoint was to evaluate the rate of sustained recovery from randomization through Day 29. → Phase 3 MOVe-OUT Study in Outpatients is ongoing. • Phase 2/3, randomized, placebo-controlled, double-blind, multisite study evaluating the efficacy, safety and pharmacokinetics of orally administered molnupiravir in non-hospitalized participants with COVID-19 confirmed using PCR. The primary efficacy objective is assessed by the percentage of patients who are hospitalized and/or die from the time of randomization through Day 29. Part 1 of MOVe-OUT enrolled a total of 302 participants, with symptom onset within seven days prior to randomization, who were assigned to receive molnupiravir 200 mg (75), 400 mg (77), or 800 mg (76), or placebo (74). • Final data is estimated to be available in September/ October 2021 → Molnupiravir for PEP in the second half of 2021

Merck and Ridgeback Biotherapeutics press release. April 14th 2021. Convalescent plasma transfusions do no work . 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 Convalescent plasma transfusions do not work

Treatment with convalescent plasma compared with placebo or standard of care was not significantly associated with a decrease in all-cause mortality or with any benefit for other clinical outcomes ((length of hospital stay or mechanical ventilation use) Janiaud P et al. JAMA. February 26, 2021. doi:10.1001/jama.2021.2747 Early convalescent plasma transfusion works . Randomized, double-blind, placebo-controlled trial of convalescent plasma with high IgG titers against SARS-CoV-2 in older adult patients (≥75 years or between 65-74 years with ≥1 comorbidity) ≤72 hours after the onset of mild Covid-19 symptoms. . Primary end point was severe respiratory disease, defined as a respiratory rate of 30 breaths per minute or more, an oxygen saturation of less than 93% while the patient was breathing ambient air, or both. Time to the Development of Primary End Point according to Donor SARS-CoV-2 S IgG Titer. Severe Respiratory Disease (ITT)

-73% -31%

The trial was stopped early at 76% of its projected sample size because cases of Covid-19 in the trial region decreased considerably and enrollment of trial patients became impossible. Libster R et al. INFANT–COVID-19 Group. NEJM. Jan 6th 2021 Monoclonal Antibodies against the SARS-CoV-2 Spike Protein: Early Treatment (<10 d.) in Patients at High Risk of Progression

mAb PBO 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 Imdevimab (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. The combination of casirivimab plus imdevimab is particularly effective in reducing VL in patients who are antibody-negative and those with high baseline VL.

Chen P et al on behalf BLAZE-1 Investigators. NEJM Oct 28 2020; REGN-COV-2. REGENERON Press Release Nov 21 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 • Fluvoxamina 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. Tocilizumab plus Dexamethasone – RECOVERY Trial • Randomized, controlled, open-label, platform trial, including 4,116 patients. • Inclusion criteria: patients with hypoxia (oxygen saturation <92% on air or requiring oxygen therapy) and evidence of systemic inflammation (C-reactive protein [CRP] ≥75 mg/L) • RCT: Standard of care alone (dexamethasone) vs. usual standard of care plus tocilizumab at a dose of 400 mg to 800 mg (depending on weight) given intravenously. A second dose could be given 12-24 h. • The primary outcome was 28-day mortality, assessed in the intention-to-treat population. 28-day Mortality 28-day Discharge from hospital days

RECOVERY Collaborative Group (Horby PW). Lancet 2021; 397: 1637–45. Tocilizumab plus Dexamethasone – RECOVERY Trial • Randomized, controlled, open-label, platform trial, including 4,116 patients. • Inclusion criteria: patients with hypoxia (oxygen saturation <92% on air or requiring oxygen therapy) and evidence of systemic inflammation (C-reactive protein [CRP] ≥75 mg/L) • RCT: Standard of care alone (dexamethasone) vs. usual standard of care plus tocilizumab at a dose of 400 mg to 800 mg (depending on weight) given intravenously. A second dose could be given 12-24 h. • The primary outcome was 28-day mortality, assessed in the intention-to-treat population.

*Rate Ratio (95% confidence interval) RECOVERY Collaborative Group (Horby PW). Lancet 2021; 397: 1637–45. Tocilizumab: Meta-analysis of mortality in RCTs in hospitalized patients with COVID-19

*Rate Ratio (95% confidence interval) RECOVERY Collaborative Group (Horby PW). Lancet 2021; 397: 1637–45. 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. March 4, 2021. DOI: 10.1056/NEJMoa2031994 Baricitinib – Phase 3 RCT COV-BARRIER

• COV-BARRIER is a Phase 3 study evaluating baricitinib 4 mg once daily plus standard of care (SoC) vs. placebo plus SoC for 14 days. • The trial did not meet statistical significance on the primary endpoint, which was defined as a difference in the proportion of participants progressing to the first occurrence of non-invasive ventilation including high flow oxygen or invasive mechanical ventilation (MV) including extracorporeal membrane oxygenation (ECMO) or death by Day 28. • Baricitinib-treated patients were 2.7 percent less likely than those receiving standard of care to progress to ventilation (non-invasive or mechanical) or death, a difference that was not statistically significant (OR: 0.85; 95% CI 0.67, 1.08; p=0.1800). Baricitinib Placebo P-value End-points by day 28 - Number of patients 764 761 - Combined (MV, ECMO, death) NA NA 0.180 - 28-day mortality (secondary) 8.1% 13.1% <0.001

• A reduction in mortality was also seen for the subgroups of patients being treated with or without corticosteroids at baseline. • Serious infections and venous thromboembolism (VTE) occurred in 8.5 percent and 2.7 percent of patients treated with baricitinib, respectively, versus 9.8 percent and 2.5 percent of patients treated with placebo. • NA = Not available Lilly and Incyte press release, April 8, 2021 Colchicine has antiviral and anti-inflammatory properties: the GRECCO Trial • Open-label, randomized clinical trial in Greece. 105 patients hospitalized with mild-moderate COVID-19 were included. • Colchicine (1.5-mg loading dose followed by 0.5mg after 60 min and maintenance doses of 0.5 mg BID) with SoC for 3 weeks • Primary end-point: increase hscTroponin/CRP or clinical deterioration by 2 points on a 7-grade clinical status scale.

D-Dimer: Colchicine, 0.76 vs. Control, 0.92 ug/mL AEs: Colchicine, 45% (GI) vs. Control,18%

Deftereos SG et al, JAMA Network Open. 2020;3(6):e2013136. doi:10.1001/jamanetworkopen.2020.13136 Colchicine in Non-Hospitalized Patients with COVID-19 (COLCORONA RCT)

• Double-blind RCT performed in Canada involving non-hospitalized patients with COVID-19 diagnosed by PCR testing or clinical criteria. • The patients were randomly assigned to receive colchicine (0.5 mg twice daily for 3 days and once daily thereafter) or placebo for 30 days. • The primary efficacy endpoint was the composite endpoint of death or hospitalization for COVID-19. Colchicine Placebo P-value

ITT analysis - All patients (N=4,488) 4.7% 5.8% 0.08 - Only PCR positive (N=4,159) 4.6% 6.0% 0.04

• There were no differences in total SAE. However, patients who took colchicine had more gastrointestinal side effects (diarrhea): 23.9% vs. 14.9% p = <0.001.

Tardif JC et al. medRxiv preprint January 27, 2021; doi: https://doi.org/10.1101/2021.01.26.21250494. Colchicine in Hospitalized Patients with COVID-19 (RECOVERY RCT)

• The RECOVERY trial was established as a RCT to test a range of potential treatments for COVID-19. Since November 2020, the RECOVERY trial has included a randomized comparison of colchicine vs. usual care alone. • The preliminary analysis is based on 2178 reported deaths among 11,162 randomized patients, 94% of whom were being treated with a corticosteroid such as dexamethasone. There is no significant difference in the primary endpoint of 28-day mortality (20% colchicine vs. 19% usual care alone; risk ratio 1.02 [95% confidence interval 0.94-1.11]; p=0.63). • DSMB closed recruitment on March 4th 2021.

Colchicine SoC P-value Mortality at 28 days - All patients (N=11,162) 20% 19% 0.63

Statement from the RECOVERY trial chief investigators, 5 March 2021 https://www.recoverytrial.net/news/recovery-trial-closes-recruitment-to-colchicine-treatment-for-patients-hospitalised-with-covid-19. Virchow’s Triad and COVID-19 Associated Coagulopathy

COVID-19, coronavirus disease-2019; DIC, disseminated intravascular coagulopathy; FDP, fibrin degradation products; GM-CSF, granulocyte-macrophage colony-stimulating factor; IL, interleukin; LV, left ventricular; PAI, plasminogen activator inhibitor; RNA, ribonucleic acid; SIC, sepsis-induced coagulopathy; TF, tissue factor; TNF, tumor necrosis factor; tPA, tissue type plasminogen activators; uPA, urokinase plasminogen activators; vWF, von Willebrand factor. Talasaz AH, et al. J Am Coll Cardiol. 2021 Apr 20;77(15):1903-1921. Effect of Intermediate-Dose vs. Standard-Dose Prophylactic Anticoagulation in ICU Patients with COVID-19: The INSPIRATION RCT

• Multicenter randomized trial with a 2 × 2 factorial design performed in 10 academic centers in Iran among 562 adult patients admitted to the ICU with COVID-19. • Intermediate-dose (enoxaparin, 1mg/kg daily) (n = 276) vs. standard prophylactic anticoagulation (enoxaparin, 40mg daily) (n = 286), with modification according to body weight and creatinine clearance. • The primary outcome was a composite of adjudicated acute arterial thrombosis, venous thromboembolism, extracorporeal membrane oxygenation (ECMO), or all- cause mortality during 30 days from enrollment.

→ This RCT does not support the routine empirical use of intermediate-dose prophylactic anticoagulation in unselected patients admitted to the ICU with COVID-19. INSPIRATION investigators. JAMA. March 18, 2021. doi:10.1001/jama.2021.4152. Ongoing Antithrombotic Therapy Trials in COVID-19 (N=83)

Talasaz AH, et al. J Am Coll Cardiol. 2021 Apr 20;77(15):1903-1921. 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 plasma & IV monoclonal antibodies Remdesivir, IV, 5-10 d. therapy in high risk persons 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 + Tocilizumab, single IV dose Low molecular weight heparin, SC Dr. JM Miro, personal opinion. May 2021. During the entire hospitalization period PEP trials with Monoclonal Antibodies (mABs)

- Randomized, double-blind, placebo-controlled trials for prevention of SARS-COV-2 infection in residents and staff of skilled nursing and assisted living facilities where at least 1 case of SARS-CoV-2 infection had been confirmed in the previous 7 days or in asymptomatic household contacts of people with COVID-19 documented within the previous 4 days and returning home. - mABs can offer immediate protection for exposed or unvaccinated individuals in high risk settings (in contrast to vaccines that take 7- 14 days to offer protection. mAB PBO P-value

BLAZE-2 57% (80%*) reduction <0.001 - Bamlanivimab (4,200 mg IV) symptomatic COVID-19

R10933-10987-COV-2069A** 81% reduction - Casirivimab/imdevimab (1,200 mg SC) symptomatic COVID-19 <0.001

*Nursing home residents; **Reduction of SARS-CoV-2 infection, shortened time of viral shedding and shortened time of high viral load (>104 copies/mL) shedding suggesting a benefit for reduced transmission.

Lilly press release, January 27, 2021; REGENERON press release, April 12, 2021 COVID-19 Second Year: SARS-CoV-2 Variants, Long COVID-19 & Vaccines . Current epidemiological and mortality data . New SARS-CoV-2 variants update . Long COVID-19: where we are one year later . Remdesivir, dexamethasone, heparin and … something else? . Reinfections: state of the art . Vaccines efficacy and impact of new SARS-CoV-2 variants . Vaccines safety: TTS* . Take-home messages *Thrombosis with Thrombocytopenia Syndrome (TTS) May 25th 2021 COVID-19 Reinfections Occur, but Remain Rare

• How common is reinfection? Reinfections are rare. Only 72 confirmed cases have been reported. • Are reinfections more or less severe than the first? Clinical picture is similar (88%). Mortality rates range: 0.1%-4.1%. • 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 Re-infection with SARS-CoV-2 in Patients Undergoing Serial Laboratory Testing = 0.7% (95%CI 0.5-0.9%) • Analysis of 9,119 patients with SARS-CoV-2 infection who received serial tests in total of 62 healthcare facilities in United States between December 1, 2019 to November 13, 2020. • Re-infection was defined by two positive tests separated by interval of greater than 90 days after resolution of first infection was confirmed by two or more consecutive negative tests. • Re-infection (N=63) was identified in 0.7% (95% CI 0.5%-0.9%). • There was a significantly lower rate of pneumonia, heart failure, and acute kidney injury observed with re-infection compared with primary infection. There were two deaths (3.2%) associated with re-infection.

• A logistic regression analysis identified that asthma (odds ratio [OR] 1.9, 95% CI 1.1-3.2) and nicotine dependence/tobacco use (OR 2.7, 95% CI 1.6-4.5) were associated with re-infection

→ Authors identified a low rate of re-infection confirmed by laboratory tests in a large cohort of patients with SARS-CoV-2 infection. Although re-infection appeared to be milder than primary infection, there was associated mortality. Qureshi AI et al. Clin Infect Dis. Apr 25 2021; ciab345. doi: 10.1093/cid/ciab345. The Resurgence of COVID-19 in Manaus, Brazil, despite high SARS-CoV-2 seroprevalence was linked to a new P1 variant → Cases of SARS-CoV-2 infection in Manaus, Brazil, resurged in late 2020, despite previously high levels of infection. Genome sequencing of viruses sampled in Manaus between November 2020 and January 2021 revealed the emergence and circulation of a novel SARS-CoV-2 variant of concern: P1 P.1 variant • P.1 variant, acquired 17 mutations, including a trio in the spike protein (K417T, E484K and N501Y) associated with increased binding to the human ACE2 receptor.

• Molecular clock analysis shows that P.1 emergence occurred around mid-November 2020 and was preceded by a period of faster molecular evolution.

• P.1 may be 1.7-2.4-fold more transmissible, and that previous SARS-CoV-2 non-P.1 infection only provided 54-79% of the protection against infection with new P.1 variant.

Sabino EC et al. Lancet. 2021 Feb 6;397(10273):452-455. doi: 10.1016/S0140-6736(21)00183-5. Faria NR et al. Science. 2021 Apr 14;eabh2644. doi: 10.1126/science.abh2644. Protection against reinfection of natural immunity generated by past SARS-CoV-2 infection Same Virus New P1 Variant >99% 50-80%

→ Implications for vaccine efficacy (immune escape)

P.1 variant acquired 17 mutations, including a trio in the spike protein (K417T, E484K and N501Y) COVID-19 Second Year: SARS-CoV-2 Variants, Long COVID-19 & Vaccines . Current epidemiological and mortality data . New SARS-CoV-2 variants update . Long COVID-19: where we are one year later . Remdesivir, dexamethasone, heparin and … something else? . Reinfections: state of the art . Vaccines efficacy and impact of new SARS-CoV-2 variants . Vaccines safety: TTS* . Take-home messages *Thrombosis with Thrombocytopenia Syndrome (TTS) May 25th 2021 https://www.nytimes.com/interactive/2020/science/coronavirus-vaccine-tracker.html Tracking Coronavirus Vaccinations Around the World By Josh Holder - Updated May 25th 2021

22 doses for every 100 people

https://www.nytimes.com/interactive/2021/world/covid-vaccinations-tracker.html May 25th , 2021 Doses administered per 100 people in the World

https://www.nytimes.com/interactive/2021/world/covid-vaccinations-tracker.html May 25th , 2021 Vaccination rates by continent Doses administered per 100 people

WHO Director-General Calls Out “Scandalous Inequity” In Distribution Of COVID-19 Vaccines And Sets New Targets For Vaccinating People In World’s Poorest Countries; May 24th 2021

https://www.nytimes.com/interactive/2021/world/covid-vaccinations-tracker.html May 25th , 2021 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 79% Inactivated COVID-19 3 SARS-CoV-2 WIBP and Sinopharm, Wuham, China Inactivated Coronavac 3 SARS-CoV-2 Sinovac, 51% Brazil China 91% Turkey Callaway Ewen. Nature 2020; 580, 576-577. IDSA COVID-19 Vaccines; https://www.nytimes.com/2020/12/25/health/turkey-brazil-sinovac-coronavirus- vaccine.html; https://www.nytimes.com/2020/12/30/business/china-vaccine.html; Abdool Karim SS et al. N Engl J Med; March 24 2021. 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, Last updated: January 15, 2021 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, Last updated: January 15, 2021 Efficacy of Adenovirus-vector Vaccines

AZD1222 Sputnik V Ad26.COV2.S Oxford-Astra Zeneca Gamaleya Janssen* 70% 92% 66%

*Single dose. Including patients with South Africa variant; Sadoff J et al. NEJM. April 21, 2021.. 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 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, Last updated: January 15, 2021 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 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 89% UK

*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 Where each vaccine is being used (I) The Oxford‐AstraZeneca vaccine is known as Covishield in India. Only countries that report doses administered are shown. Other countries may have approved vaccines but have not administered them yet

https://www.nytimes.com/interactive/2021/world/covid-vaccinations-tracker.html May 8, 2021 Where each vaccine is being used (II) The Oxford‐AstraZeneca vaccine is known as Covishield in India. Only countries that report doses administered are shown. Other countries may have approved vaccines but have not administered them yet

https://www.nytimes.com/interactive/2021/world/covid-vaccinations-tracker.html May 8, 2021 Protection starts 12 days after 1st Vaccine Dose (Pfizer)!

Polack FP et al. NEJM December 10 2020; DOI: 10.1056/NEJMoa2034577 Mucosal and systemic immune responses to natural infection with respiratory viruses and to vaccination

Pfizer (BNT162b2) vaccine reduced viral load in breakthrough infections occurring 12–37 days after the first dose of vaccine and thereby further suppress onward transmission.

• Avoid transmission • Disease severity Decreased SARS-CoV-2 viral load after 12 d post-vaccination Krammer F. Nature. 2020 Oct;586(7830):516-527. Levine-Tiefenbrun M et al. Nat Med. May 2021; 27:790-792. Vaccination in persons with a history of SARS-CoV-2 infection

1 or 2 doses?

Krammer F et al. N Engl J Med. April 8 2021; 384:1372-1374. Anichiniet G. al. N Engl J Med. April 14 2021; doi: 10.1056/NEJMc2103825; Bradley T, et al. N Engl J Med. 2021 May 20; 384:1959-1961. Vaccination in persons with a history of SARS-CoV-2 infection: 1 dose is enough! Immunogenicity of SARS-CoV-2 RNA Vaccines

A single dose of mRNA vaccine in seropositive participants ≥ seronegative participants who received two vaccinations. Krammer F et al. N Engl J Med. April 8 2021; 384:1372-1374. Vaccination in persons with a history of SARS-CoV-2 infection: 1 dose is enough! Reactogenicity (Side Effects) of SARS-CoV-2 RNA Vaccines

Vaccine recipients with preexisting immunity had more systemic side effects than those without preexisting immunity (fatigue, headache, chills, muscle pain, fever, and joint pain, in order of decreasing frequency). Krammer F et al. N Engl J Med. April 8 2021; 384:1372-1374. Vaccine efficacy against new SARS-CoV-2 variants UK B1.1.7 South Africa B.1.351 Brazil P.1 India B.1.617.2 Vaccine efficacy against UK (B.1.1.7) & South Africa (B.1.351) variants Efficacy against symptomatic disease Mild/Moderate Severe Pfizer-BioNTech (Qatar) - UK (B.1.1.7) 89.5% 100% - South Africa (B.1.351) 75% 100% Pfizer (BNT162b2 mRNA) also did a trial in 800 individuals in South Africa, with no cases of Covid-19 in the vaccine group and nine cases in the placebo group. Of the nine cases, six strains were confirmed to be of the B.1.351 lineage

Abu-Raddad LJ et al. N Engl J Med. May 5 2021; Pfizer and BioNTech press release, April 1 2021. https://www .pfizer .com/ news/ press -release/ press -release -detail/ pfizer -and -biontech -confirm -high -efficacy -and -no -serious. Vaccine efficacy against South African variant (B.1.351) Efficacy against symptomatic disease Mild/Moderate Severe AstraZeneca - ChAdOx1 nCoV-19 (x2) 10% No cases Janssen - Ad26.COV2.S (x1) 64% 82% Novavax - NVX-CoV2373 (x2) 51% No cases

Madhi SA et al. N Engl J Med 2021;384:1885-98; Shinde V et al. N Engl J Med 2021;384:1899-909; Sadoff J et al. N Engl J Med. April 21 2021. doi: 10.1056/NEJMoa2101544. Vaccine efficacy against UK (B.1.1.7) & India (B.1.617.2) variants Efficacy against symptomatic disease

Single dose (at 3 wk.) Two doses (at 2 wk.) AstraZeneca - UK (B.1.1.7) 50% 66% - India (B.1.617.2) 33% 60% Pfizer-BioNTech - UK (B.1.1.7) 50% 93% - India (B.1.617.2) 33% 88%

https://www.gov.uk/government/news/vaccines-highly-effective-against-b-1-617-2-variant-after-2-doses press release, May 22 202; Emary KRW et al. Lancet. Apr 10 2021; 397:1351-1362. Sumary of vaccine efficacy against new SARS- CoV-2 variants

• Good efficacy against UK (B.1.1.7) and India (B.1.617.2) variants. • Poor efficacy against South Africa (B.1.351) variant. The good news are current vaccines protected individuals from severe disease. • Few data against P.1 variant (Sinovac, 51%) COVID-19 Second Year: SARS-CoV-2 Variants, Long COVID-19 & Vaccines . Current epidemiological and mortality data . New SARS-CoV-2 variants update . Long COVID-19: where we are one year later . Remdesivir, dexamethasone, heparin and … something else? . Reinfections: state of the art . Vaccines efficacy and impact of new SARS-CoV-2 variants . Vaccines safety: TTS* . Take-home messages *Thrombosis with Thrombocytopenia Syndrome (TTS) May 25th 2021 Safety of COVID-19 Vaccines: 627,383 individuals in UK • Local side-effects after BNT162b2 (Pfizer) and ChAdOx1 nCoV-19 (Astra-Zeneca) vaccination occur at frequencies lower than reported in phase 3 trials.

Pfizer 1st dose Pfizer 2nd dose Astra-Zeneca 1st dose 72% 68% 59%

Menni C et al. Lancet Infect Dis April 27, 2021 Safety of COVID-19 Vaccines: 627,383 individuals in UK • Local adverse effects self-reported to the COVID Symptom Study app after COVID-19 vaccination, stratified by sex, age, BMI, health status, and previous SARS-CoV-2 test status

Pfizer 2nd dose Astra-Zeneca 1st dose

Female gender, younger people, BMI<30 kg/m2, no comorbidities and previous SARS-CoV-2 test status were associated with local adverse effects Menni C et al. Lancet Infect Dis April 27, 2021 Safety of COVID-19 Vaccines: 627,383 individuals in UK • Systemic side-effects after BNT162b2 (Pfizer) and ChAdOx1 nCoV-19 (Astra- Zeneca) vaccination occur at frequencies lower than reported in phase 3 trials.

Pfizer 1st dose Pfizer 2nd dose Astra-Zeneca 1st dose 13% 22% 34%

Menni C et al. Lancet Infect Dis April 27, 2021 Safety of COVID-19 Vaccines: 627,383 individuals in UK • Systemic adverse effects self-reported to the COVID Symptom Study app after COVID-19 vaccination, stratified by sex, age, BMI, health status, and previous SARS-CoV-2 test status

Pfizer 2nd dose Astra_Zeneca 1st dose

Female gender, younger people, BMI<30 kg/m2, comorbidities and previous SARS-CoV-2 test status were associated with systemic adverse effects Menni C et al. Lancet Infect Dis April 27, 2021 Delayed Large Local Reactions to mRNA-1273 (Moderna) Vaccine

• Injection-site reactions are common and observed in 84% of the participants after the first dose of mRNA-1273 vaccines. • Delayed injection-site reactions are rare events that occurred in 244 of the 30,420 participants (0.8%) after the first dose and in 68 participants (0.2%) after the second dose. • Delayed-type or T-cell–mediated hypersensitivity was supported by skin-biopsy specimens.

Baden LR, et al. N Engl J Med 2021; 384:403-16; Blumenthal KG et al. N Engl J Med. April 1 2021. Thrombosis with Thrombocytopenia Syndrome (TTS)* • Incidence is extremely rare but can be life-threatening - Described in a very few hundred people (women <50 years), mainly vaccinated with recombinant adenovirus-vector vaccines.

• Diagnosis (must meet all four criteria) - Recombinant adenovirus-vector COVID-19 vaccine 4 to 30 days previously (median 8 days, peak 6-14 days) - Venous or arterial thrombosis (often cerebral [sinus venous] or abdominal [splanchnic]) - Mild to severe thrombocytopenia (<150,000/µL)** - Positive PF4 “HIT” (heparin-induced thrombocytopenia) antibodies by ELISA • Prognosis - Mortality rates ranging 20-50%. • Treatment - IgG Immunoglobulin (IGIG) 1g/kg daily for 2 days or 0.4 gr/Kg/day for 5 days (or plasmapheresis). Eculizumab***. - Avoid platelet transfusions and aspirin. No consensus on corticosteroids. - Non-heparin anticoagulation (argatroban/bivalirudin, fondaparinux, danaparoid, rivaroxaban/apixaban).

*Also defined as VIPIT (vaccine-induced prothrombotic immune thrombocytopenia) or VITT (Vaccine-Induced Thrombotic Thrombocytopenia). ** Most patients have elevated D-dimer levels and low fibrinogen levels, suggesting DIC. ***Complement inhibition with eculizumab has been used in progressing patients https://www.hematology.org/covid-19/vaccine-induced-immune-thrombotic-thrombocytopenia#:~:text=This%20syndrome%20has%20been%20termed,by%20the%20CDC%20and%20FDA. Updated April 29th 2021. Second Dose Astra-Zeneca Vaccine

Yes or Not

Blanco J on behalf the Multidisciplinary Collaborative Group for the Scientific Monitoring of COVID-19 (GCMSC); https://www.isglobal.org/documents Alternatives for individuals under 60 years of age having received the first dose of Astra-Zeneca vaccine • Administer a 2nd dose of the same Astra-Zeneca vaccine: an option with the potential risk of TTS.

Blanco J on behalf the Multidisciplinary Collaborative Group for the Scientific Monitoring of COVID-19 (GCMSC); https://www.isglobal.org/documents Thrombosis with Thrombocytopenia Syndrome (TTS) Rates

Adenovirus-vector vaccines • Oxford-Astra Zeneca - After 1st dose: 10 cases per million → After 2nd dose: 1 case per million • Jansen: 2-4 cases per million • Sputnik V: no information mRNA vaccines • Pfizer-BioNTech, 0.2 cases per million • Moderna, 0.4 cases per million

Blanco J on behalf the Multidisciplinary Collaborative Group for the Scientific Monitoring of COVID-19 (GCMSC); https://www.isglobal.org/documents ICU admissions prevented with COVID-19 Vaccination and risk of TTS per age group

Blanco J on behalf the Multidisciplinary Collaborative Group for the Scientific Monitoring of COVID-19 (GCMSC); https://www.isglobal.org/documents Administer a 2nd dose of a different Vaccine: mRNA Pfizer or Moderna vaccine • Preclinical evidence in animal models. • Two studies in UK and one in Spain (ISCIII, Madrid) are on going. Not powered to provide safety data. • Com-COV* provided initial reactogenicity data after 2nd dose Prime/Boost Fever reported Paracematol use x AEs - AZ followed by AZ 10% 36% - AZ followed by Pfizer 34% 57% - Pfizer followed by Pfizer 21% 41% - Pfizer followed by AZ 41% 60%

Blanco J on behalf the Multidisciplinary Collaborative Group for the Scientific Monitoring of COVID-19 (GCMSC); https://www.isglobal.org/documents *Shaw RH et al. Lancet. May 12, 2021 Alternatives for individuals under 60 years of age having received the first dose of Astra-Zeneca vaccine • Administer a 2nd dose of the same Astra-Zeneca vaccine: an option with the potential risk of TTS. • Administer a 2nd dose of a different vaccine (mRNA Pfizer or Moderna): an option that lacks data. • Wait until evidence for one of the previous options is generated. This option relies on a still unknown parameter: the durability of immune response after a single dose.

Blanco J on behalf the Multidisciplinary Collaborative Group for the Scientific Monitoring of COVID-19 (GCMSC); https://www.isglobal.org/documents Wait until evidence for previous options is generated: There is an important risk of leaving people with a single dose beyond 3 months!

• There are no data (nor clinical trials) with Astra-Zeneca on how long the protection lasts beyond 3 months after the first dose. • Antibody levels are not optimal after one dose of Astra Zeneca, and seem to be lower compared to Pfizer and Moderna’s vaccines. • People could be more susceptible to infections by new SARS-CoV-2 variants, as suggested by several studies showing that people receiving one vaccine dose without prior infection showed reduced immunity against B1.1.7 (British), B1.351 (South African) and B.1.617 (India) variants.

Blanco J on behalf the Multidisciplinary Collaborative Group for the Scientific Monitoring of COVID-19 (GCMSC); https://www.isglobal.org/documents; https://www.gov.uk/government/news/vaccines-highly-effective-against-b-1-617-2-variant-after-2-doses press release, May 22 2021; Emary KRW et al. Lancet. Apr 10 2021; 397:1351-1362. Recommendations of the Multidisciplinary Collaborative Group for the Scientific Monitoring of COVID-19 (GCMSC)

• The safety/efficacy evidence for the administration of a second dose of mRNA vaccines to Astra-Zeneca vaccinated individuals is currently being studied. • Meanwhile, a second dose of Astra-Zeneca should be offered no later than 3 months after 1st dose to individuals under age 60 given the strong evidence for efficacy and the very low risk of TTS.

Blanco J on behalf the Multidisciplinary Collaborative Group for the Scientific Monitoring of COVID-19 (GCMSC); https://www.isglobal.org/documents Pharmacovigilance!

• When millions of vaccines are administered, serious unexpected serious adverse reactions (SUSARs) can be detected. • CDC investigating reports some young COVID-19 vaccine recipients have experienced myocarditis*

*https://www.nytimes.com/2021/05/22/health/cdc-heart-teens-vaccination.html; May 22 2021 What plan do we have for 2021? Vaccination but still facial masks, hand washing, social distance!!!

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 COVID-19 Second Year: SARS-CoV-2 Variants, Long COVID-19 & Vaccines . Current epidemiological and mortality data . New SARS-CoV-2 variants update . Long COVID-19: where we are one year later . Remdesivir, dexamethasone, heparin and … something else? . Reinfections: state of the art . Vaccines efficacy and impact of new SARS-CoV-2 variants . Vaccines safety: TTS* . Take-home messages *Thrombosis with Thrombocytopenia Syndrome (TTS) May 25th 2021 Take-home messages . The SARS-COV-2 virus is continually evolving with new variants appearing (UK, South Africa, Brazil, India) that give it greater transmissibility and in some cases resistance to the antibodies generated by natural immunity or vaccines. . It is very important to distinguish the symptoms of long COVID from the sequelae of the infection. The prevalence is high and can persist for weeks or months. There is no specific treatment. . Remdesivir is effective against moderate and severe COVID-19 (stages 4-6), although it does not reduce mortality. Dexamethasone plus tocilizumab reduced mortality in severe and critical COVID-19. . Although there are already many millions of people vaccinated against COVID-19, implementation is uneven around the world. Some newer variants may escape vaccines, although the good news is vaccines still protect individuals against severe disease. Acknowledgements J. Blanco A. Moreno C. Brotons R. Paredes B. Clotet C. Pontes S. de San José M. Sans O. Coll A. Sarukhan G.M. Lledó J. Sellares G. Mora A. Vallano To all front-line health-care workers

To our patients and their families May 25th 2021 Acknowledgements J. Blanco A. Moreno C. Brotons R. Paredes B. Clotet C. Pontes ThanksS. de San to José the 1,500,000M. Sans people O. Coll A. Sarukhan who haveG.M. Lledó seen theseJ. SellaresCME videos! G. Mora A. Vallano To all front-line health-care workers

To our patients and their families May 25th 2021 ACTUALIZACIONES CONTENIDO COVID-19

Gracias al patrocinio de #YoMeCorono

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