Friday General Session

COVID and COVID Vaccine Update

Jason Bowling, MD Associate Professor of Infectious Disease, Medical Director of Infection Control and Hospital Epidemiologist Company UT Health San Antonio San Antonio, Texas

Educational Objectives By completing this educational activity, the participant should be better able to: 1. Evaluate the diagnostic challenges surrounding COVID. 2. Assess the risk factors for mild versus severe disease in patients infected with COVID. 3. Assess the rapidly changing treatment landscape for COVID patients with mild to moderate disease. Discuss the mechanism of action, side effects, and adverse events of COVID vaccines and review recommendations regarding COVID vaccination.

Speaker Disclosure Dr. Bowling has disclosed that neither he nor members of his immediate family have a relevant financial relationship with an ineligible company. 6

COVID-19 and COVID-19 Vaccine Update Disclosures Jason Bowling, MD, FIDSA Associate Professor of Medicine Medical Director Infection Prevention UH & UTHSA Hospital Epidemiologist, University Hospital • I have no financial disclosures or conflicts of interest to report. • I will discuss medications being used in the context of a clinical trial.

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Objectives

• Analyze the clinical impact of the virology and epidemiology of COVID-19. • Evaluate the diagnostic challenges surrounding COVID-19. • Assess the rapidly changing treatment landscape for COVID-19 patients: outpatients and inpatients. • Discuss the mechanism of action, side effects, and adverse effects of COVID-19 vaccines and review recommendations regarding COVID-19 vaccination.

https://coronavirus.jhu.edu/map.html - Accessed 5-19-21 34

San Antonio Metro Health: 5-19-21

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1 Hospitalized COVID-19 Patients IHME COVID-19 PROJECTIONS: TEXAS University Hospital

5-19-21 COVID-19 (healthdata.org) – Updated 5/19/21 78

Brief SARS-CoV-2 Virology SARS-CoV-2 Pathogenesis

• Spike protein binds ACE-2 receptor in human host • ACE-2 receptors . Respiratory tract epithelium - Oropharynx, upper airway . Blood vessel endothelium . GI tract, kidneys • Some proofreading during replication = less mutation than other RNA viruses

BMJ 2020;371:m3862 BMJ 2020;371:m3862 910

Clinical Presentations of Influenza Question #1 and Other Respiratory Illnesses (continued)

Influenza1 COVID‐19a2,3 Colds1 Allergiesb4 Signs/ Clinical diagnosis can readily distinguish COVID-19 from Symptoms

Gradual onset, influenza infection. Abrupt onset, fever, Fever, dry cough, Rhinitis, sneezing, sneezing, sore aches, chills, fatigue, dyspnea, myalgia, sinus congestion, Common throat, stuffy nose, weakness, cough, fatigue, new loss of mild cough, mild to moderate headache taste or smell sore throat cough 1. True Pharyngitis, Less Sore throat, stuffy headache, GI upset, Fatigue, headache — common nose, GI upset 2. False productive cough Fever, dyspnea, Fever, dyspnea, Rare Dyspnea, sneezing — GI upset myalgia, GI upset

aInformation evolving rapidly and subject to change bSeasonal GI, gastrointestinal 1. CDC. 12/30/19. www.cdc.gov/flu/symptoms/coldflu.htm. Accessed 8/17/20. 2. CDC. 8/4/20. www.cdc.gov/flu/symptoms/flu‐vs‐covid19.htm. Accessed 8/17/20. 3. Auwaerter PG. 5/23/20. www.hopkinsguides.com/hopkins/view/Johns_Hopkins_ ABX_Guide/540747/all/Coronavirus_ COVID_19__SARS_CoV_2_. Accessed 8/17/20. 4. National Institute of Allergy and Infectious Diseases. www.niaid.nih.gov/ diseases‐conditions. Accessed 8/17/20. 13 11 13

2 Clinical Course of Influenza vs. COVID‐19 Natural History of COVID-19 Infection Influenza Clinical Course1,2 Fever, chills, fatigue, myalgia, Cough may persist >2 wk (eg, dry cough, sore Symptoms elderly, chronic lung disease) throat, headache, peak rhinitis

1 3 4 7 14+ Day Infectivity: 1 d before to 3‐4 d after symptom onset3 COVID‐19 Clinical Course2,4 Fever, cough, sore throat, new loss of taste/smell, Symptoms peak: ≈2‐4 wk headache, myalgias Recovery stage: ≈2‐8 wk

1 71410 21+ Day Remdesivir,Re Dexamethasone, Convalescent plasma, Monoclonal antibodies Infectivity (still under investigation): 2 d before to ≥10 d after symptom onset3

1. CDC. 3/8/19. www.cdc.gov/flu/professionals/acip/clinical.htm. Accessed 8/3/20. 2. Solomon DA et al. JAMA. 2020 Aug 14. [Epub ahead of print] 3. CDC. 7/27/20. www.cdc.gov/flu/symptoms/flu‐vs‐covid19.htm#anchor_1595599599www.cdc.gov/flu/about/disease/spread.htm. Accessed 8/3/20. 4. Subbarao K et al. Immunity 2020;52(6):905‐909. 14 14 15

Risk Factors for Severe COVID-19 Question #2

• Older age Mr. Jones is a 54 y/o male patient of yours who has had 2 days of acute • Chronic obstructive pulmonary disease fever, fatigue, loss of taste and smell, and a dry cough. His son returned home from college a week ago, was not feeling well, and tested positive for • Cardiovascular disease (e.g., heart failure, coronary artery disease, COVID-19. Mr. Jones went to an urgent care clinic near his house yesterday or cardiomyopathy) and had a rapid SARS-CoV-2 antigen test that was negative. He is now • Type 2 diabetes mellitus calling you for evaluation of his persistent symptoms. The best approach to • Obesity (BMI >= 30) establish his diagnosis would be to: • Sickle cell disease 1. Repeat the SARS-CoV-2 antigen test Chronic kidney disease • 2. Obtain a rapid test for influenza • Immunocompromised state from solid organ transplant 3. Perform a PCR test for SARS-CoV-2 • Cancer 4. Obtain an antibody test for SARS-CoV-2 5. Start doxycycline and see if he gets better N Engl J Med 2020;383:1757-66. 16 17

Direct Viral Tests for SARS-CoV-2

Nucleic acid amplification tests Antigen tests COVID-19 Diagnostic Tests (NAAT) • Various assays, PCR is most • Target nucleocapsid protein common • Less sensitive than PCR test • Many target 2 or more genes: . Can cause false negative . nucleocapsid, envelope, spike • Works best earlier in illness when • Highly sensitive and specific viral loads are higher • Require specialized lab • Faster turnaround time (15-30 min) • Turnaround in lab • Point-of-care • More expensive • Cheaper

Image credit: www.nejm.org 19 20

3 SARS-CoV-2 Antigen vs PCR testing CDC Algorithm

• CDC analysis of 2 community COVID testing sites • Compared Antigen vs PCR testing and viral culture • Sensitivity . Asymptomatic: 35.8% . Symptomatic: 64.2% • Specificity . 99.8-100% in both groups • Can be useful but BEWARE risk of false negative

MMWR Jan 2021;70(3):100-150 21 22

Suggested Approach with Antigen Important Caveats

• Use in symptomatic patients • Direct viral tests good for time of test – like Polaroid • Best if used within first few days of symptom onset • PCR tests can remain persistently positive for weeks • Negative test in high risk should have PCR test • Negative antigen tests should have f/u PCR test • Positive test in consistent clinical presentation is likely a • Neither category is affected by variants thus far true positive • Neither category detects variants • COVID-19 vaccination does not influence results of direct viral tests

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Antibody Tests Question #3

• Detect both neutralizing and non-neutralizing antibodies Your patient Mr. Jones had a positive PCR test for COVID-19. His O2 saturation is 98% on room air and he doesn’t require hospitalization. You • Early in pandemic, EUA was voluntary are concerned about his risk of progression to more severe COVID-19 disease because he has a BMI of 42, DM2, and 3 vessel CAD. What • Some tests cross-react with common coronavirus would be the best treatment recommendation for him? • Not recommended for use in first 14 days after symptom onset (IDSA guidelines) 1. Monoclonal antibody therapy • Not indicated to determine response to vaccine 2. Hydroxychloroquine 3. Azithromycin 4. High dose dexamethasone 5. Hydroxychloroquine, azithromycin, and dexamethasone www.idsociety.org/COVID19guidelines/serology 25 26

4 COVID-19 Treatment

• Majority of rigorous trial data for treatment has focused on hospitalized patients COVID-19 Treatment • Currently no oral FDA-approved or authorized therapies for COVID-19 Outpatient Management Strategies • NIH and IDSA guidelines do not recommend non-FDA approved therapies outside of a clinical trial

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COVID-19 Treatment Outpatient Strategies

• Majority of rigorous trial data for • General Recommendations • Isolation – Persons treatment has focused on • Nutrition/hydration diagnosed with COVID-19 hospitalized patients • Adequate sleep should isolate at home. • Currently no oral FDA-approved • Continue isolation for: or authorized therapies for • Stop/limit smoking and vaping . 10 days from symptom-onset COVID-19 AND • NIH and IDSA guidelines do not • Limit alcohol use . At least 24 hours afebrile recommend non-FDA approved • Acetaminophen or ibuprofen • Asymptomatic – 10 days therapies outside of a clinical trial for fever from first positive test

Document available at www.strac.org (Southwest Texas Regional Advisory Council) 30 31

Outpatient Strategies Monoclonal Antibodies

Equipment for home Warning Signs – SEEK CARE • FDA authorization under EUA: • Thermometer • Oxygen saturation <94% at rest . Bamlanivimab and etesevimab • Pulse oximeter • Significant desaturation into . Casirivimab and imdevimab • Home blood pressure cuff 85% range upon walking • Only available via IV infusion over 1 hour with post-monitoring • Persistent shortness of breath Possible side effects: infusion-related reactions such as fever, • Persistent fever • chills, flushing, hives, itching, anaphylaxis • Decrease in mental status • Significant decrease in blood pressure

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5 Monoclonal Antibodies – Who? Not Recommended

. Have had a positive direct viral test for SARS-CoV-2 . Corticosteroids – not in outpatients . Have had < 5 days of symptoms (up to 10 days) - RECOVERY trial showed benefit for those requiring . 12 years of age and older supplemental oxygen. . Weigh at least 40 kilograms (about 88 pounds) - Pts who did not require oxygen had worse clinical outcomes . AND at high risk for progressing to severe COVID-19 and/or . Hydroxychloroquine hospitalization - Multiple well-conducted studies show negative results . Especially at risk: > 65 yo or BMI > 35 - Side effects – GI and prolonged QT interval

www.covid19treatmentguidelines.nih.gov The Recovery Collaborative Group. Dexamethasone in Hospitalized Patients with Covid-19. New Eng J Med NEJM oa2021436, 2020 Saag MS. Misguided use of hydroxychloroquine for COVID-19. Jour Amer Med Assoc Published online November 9, 2020 34 35

Not Recommended Need More Data

. Azithromycin and doxycycline • Aspirin - Studies largely done with hydroxychloroquine . Preliminary observational study showed less complications in - Well-conducted trials have been negative hospitalized patients who had received ASA within 24 hours of - Side effects – prolonged QT interval, GI, C. difficile colitis admission or 7 days prior to admission . Vitamin C . Risk of bleeding - Studied in sepsis with variable outcomes . Avoid in children due to Reye’s Syndrome - Few safety concerns

www.covid19treatmentguidelines.nih.gov The Recovery Collaborative Group. Dexamethasone in Hospitalized Patients with Covid-19. New Eng J Med NEJM oa2021436, 2020 Chow JH, Khanna, AK, Kethireddy, S, et al. Aspirin Use is Associated with Decreased Mechanical Ventilation, ICU Admission, and In- Saag MS. Misguided use of hydroxychloroquine for COVID-19. Jour Amer Med Assoc Published online November 9, 2020 Hospital Mortality in Hospitalized Patients with COVID-19 Anesthesia & Analgesia Pub ahead of print: Oct. 21, 2020 36 37

Need More Data Need More Data

• Ivermectin • Fluvoxamine – SSRI, immunomodulatory . Preliminary positive study in hospitalized patients . Proposed mechanisms . Good safety profile - Sigma-1 activation – reduces cytokine production . Animal preparations should not be used in humans . Good safety profile . Some concerns about neurotoxicity in inflammatory phase (due . Inexpensive to decrease in BBB) • Positive outpatient phase 2 STOP COVID trial • Results from more RCTs expected soon. • Phase 3 trial underway • NIH guidelines still recommend against use outside a clinical trial

Rajter JC, Sherman MS, Fatteh N, Vogel F, Sacks J, Rajter J. Use of ivermectin is associated with lower mortality in hospitalized patients with Lenze EJ, Mattar C, Zorumski CF et al. Fluvoxamine vs. placebo and clinical deterioration with symptomatic COVID-19. JAMA Published coronavirus disease 2019. Chest: Oct. 12, 2020 online November 12, 2020. 38 39

6 Question #4

Ms. W is being admitted to the hospital after presenting with 5 days of increasing shortness of breath, dry cough, chest pain, and fever. Her COVID-19 NAAT was positive, and she is requiring high flow O2 supplementation to maintain her O2 sats. In addition to starting dexamethasone, what other medicine may reduce time to recovery? COVID-19 Treatment

1. Monoclonal antibody therapy Inpatient Clinical Trials 2. Hydroxychloroquine 3. Azithromycin 4. Remdesivir 5. Lopinavir-ritonavir

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Usual Drug Development Process COVID-19 Clinical Trial & Response Team

• ACTT study group inclusion . March 21, 2020 (Saturday afternoon!): call received from NIH (Dr. John Biegel, PI) . RAPID response from: CTO, IRB, CTSA, FORU, Coordinator pool, OSP, UHS, COVID-19 ID, etc. . March 26, 2020: first patient enrolled! . >250 patients enrolled in 4 treatment ACTT trials! (>90% Hispanic) • CoVPN: Novavax Vaccine Trial (>120 pts) • Award UTHSA Presidential Team Award!!

ACTT: Adaptive COVID-19 Treatment Trial; CoVPN: COVID-19 Vaccine Prevention Network 43 44

N Engl J Med. 2020 Nov 5;383:1813‐1826

● Improved time to recovery: 10 vs. 15 Question #5 days (p<0.001) ● Reduced mortality: 6.7% vs. 11.9% ● Remdesvir EUA on May 1, 2020 One potential risk of using mRNA vaccines is that the mRNA of SARS-CoV-2 will be integrated into the host cell’s N Engl J Med. 2020 Dec 11:NEJMoa2031994 genome.

• Reduced time to recovery: 7 vs 8 days 1. True (p=0.03) • Reduced recovery for high flow oxygen: 2. False recovery 10 days vs 16 days • Fewer adverse events with baricitinib • Baricitinib EUA Nov 19, 2020

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7 Traditional & Accelerated Vaccine Development Timelines Strategies in Use

• Genetic vaccines . mRNA, DNA for SARS-CoV-2 genes . E.g. Moderna, Pfizer • Viral vector vaccines . Other viruses engineered to carry SARS-CoV-2 genes . E.g. Gam-Covid-Vac, Sputnik V, J&J, Astra Zeneca/Oxford • Protein-based vaccines . Contain SARS-CoV-2 proteins or parts of them . E.g. Novavax, Anhui Zhifei Longcom, Finlay Institute

• Inactivated or attenuated vaccines . Created from SARS-CoV-2 that has been weakened or killed . E.g. Sinovac, Wuhan Institute, Sinopharm

https://www.nytimes.com/interactive/2020/science/coronavirus-vaccine-tracker.html Krammer, F. SARS-CoV-2 vaccines in development. Nature 586, 516–527 (2020). https://doi.org/10.1038/s41586-020-2798-3 48 49

COVID-19 Real World Vaccine Efficacy Prevention Network

Novavax Vaccine • Israel – National Surveillance Data Trial: 30,000 • Observational study of Pfizer-BioNTech mRNA • By April 3, 2021: participants . 72.1% people age 16 or older – fully vaccinated . >10 million doses to >5.2 million people 176 participants • Efficacy results at 7 days s/p 2nd dose: locally/6 wks . 91.5% asymptomatic infection . 97% symptomatic infection UTHealthResearch.com . 97.2% hospitalization . 96.7% death • In ALL age groups, increased vaccine coverage correlated with decreased incidence of SARS-CoV-2 outcomes

Haas EJ et al. Lancet 2021;397:1819-29 51 52

UTHSA COVID Vaccine Numbers Real World Vaccine Efficacy

Uptake Providers 84% Others 70%

– individuals who received 1st dose and 2nd dose or scheduled to receive 2nd dose. Haas EJ et al. Lancet 2021;397:1819-29 3/14/21 53 54

8 Question #6 Vaccine Efficacy at UTHSA

A 42 y/o woman with no significant medical history presents to clinic with severe headache and nausea. She did receive the Janssen/J&J COVID-19 vaccine just over a week ago. She doesn’t have a fever or other localizing findings. Labs reveal platelets of 52,000/uL. This presentation is concerning for:

1. Vaccine-induced migraine headache 2. Thrombosis with thrombocytopenia 3. Breakthrough COVID-19 infection 4. Viral meningitis

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Cerebral Venous Sinus Thrombosis (CVST) with Thrombocytopenia Broader ACIP Review

• CVST is rare, not usually associated with thrombocytopenia • ACIP Review 4-14-21 of observed cases following Janssen COVID-19 vaccine . 6 cases in women age 18-48 yrs, all with thrombocytopenia • Not observed after 2 authorized mRNA vaccines . 182 million doses with no reported cases • Clinical features similar to those observed following AstraZeneca COVID-19 vaccine in Europe • Both are adenoviral vector-based platforms

https://www.cdc.gov/vaccines/acip/meetings/downloads/slides-2021-04/03-COVID-Shimabukuro-508.pdf

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Janssen/J&J COVID-19 Vaccine COVID-19 Vaccine Recommendations

• Initial pause on clinical use but then EUA re-instated • All people 12 yrs and older eligible for vaccine should get • Recommend counseling patients prior to vaccination about this rare but serious potential risk vaccinated • Would provide them with patient fact sheet • Would recommend mRNA vaccines (Pfizer, Moderna) for • Advises them to monitor for the following symptoms in the 1-2 weeks after vaccine receipt: women age 18-50 yrs old BUT Janssen/J&J vaccine still an . Shortness of breath, option for those unable to take mRNA vaccines . Chest pain, . Leg swelling, • Extremely few contraindications to available vaccines . Persistent abdominal pain, . Severe or persistent headaches or blurred vision, • mRNA vaccine platform has proven to be highly effective . Easy bruising or tiny blood spots under the skin beyond the site of the injection. and well tolerated – with millions of doses given now • Still an option for patients with appropriate counseling

https://www.cdc.gov/vaccines/acip/meetings/downloads/slides-2021-04/03-COVID-Shimabukuro-508.pdf https://www.cdc.gov/vaccines/acip/meetings/downloads/slides-2021-04/03-COVID-Shimabukuro-508.pdf

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9 Impact of SARS-CoV-2 Variants on Vaccine Efficacy Major Variants of Concern Selective Pressure for Immune Escape ● B.1.1.7 • “UK” variant • N501Y mutation in receptor-binding domain of spike protein = increased binding to ACE2 ● RNA-virus with low fidelity replication • Detection in UTHSA analysis ● Ongoing widespread transmission • B.1.351 • “South Africa” variant ● Partially effective immune response to natural infection • N501Y • E484K and K417N = immune escape to vaccine-generated antibodies • P.1 • “Brazil” variant • N501Y • E484K and K417T = immune escape to vaccine-generated antibodies • B.1.427/B.1.429 • “California” variant • L452R=increased ACE2 binding; higher rate of transmission • Detected from UTHSA sample 12/2020 62 63

Qatar Experience Pfizer COVID-19 Vaccine Cautionary Tale with Variants

• Vaccine scale up during 2nd and 3rd waves of COVID-19 • Viral genome sequencing Feb-Mar 2021: . 50% cases B.1.351 (South Africa) . 44.5% cases B.1.1.7 (UK) • Estimated vaccine efficacy 2 weeks s/p 2nd dose: . Any infection B.1.1.7: 89.5% . Any infection B.1.351: 75% . Severe, critical, or fatal disease: 97.4%

Abu-Raddad LJ et al NEJM May 5, 2021 DOI:10.1056/NEJMc2104974

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U.S. Experience – COVID-19 Vaccine COVID-19 Vaccine

• May 18, 2021 – 60% of adults in U.S. with at least 1 dose • U.S. is fortunate to have highly effective and available vaccines • Need to improve overall uptake of vaccine to reduce risk of future increase in cases • Still effective against current variants – especially for severe disease, hospitalizations, and death • Anticipate children < 12 yrs old being eligible late 2021-early 2022

These are the states with the highest and lowest vaccination rates – CNN 5-10-21 66 67

10 Take Home Points

• Crazy timeline of science • Incredible progress so far • Need to work against vaccine hesitancy • Continue research for effective therapies . Inclusion of vulnerable populations . Thanks for enthusiastic participation of our patients! [email protected] • No te rindas!! . Don’t give up!

Thank you! Photo and slide credit: Thanks, Dr. Patterson! 68

11 Notes