COVID-19: Update on Therapy and Vaccine

Development

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Learning Objectives

After attending this presentation, learners will be able to:

▪ List available effective treatment modalities for Covid-19

▪ Describe challenges to SARS-CoV-2 vaccine development

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Covid-19 U.S. Epidemiology, Diagnostic, and Pathogenesis Update

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Total U.S. Covid-19 Cases and Deaths

https://www.cdc.gov/covid-data-tracker

4,339,997 Cases 148,866 Deaths

0-3,8666173-17,416

82,530-165,934174,973-466,550

Last updated: July 29, 2020, 5:45 PM EDT.

18,725-34,99039,337-63,678

0-56102-335

2,924-6,4217162-23,512

409-839913-2,125

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Covid-19 Cases and Deaths Disproportionately Affect Black and Latinx Populations

Deaths by Race/Ethnicity

https://www.cdc.gov/coronavirus/2019-ncov/cases-updates/cases-in-us.html

Cases by Race/Ethnicity

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SARS-CoV-2 Transmission – Masks Save Lives!

• SARS-CoV-2 human-to-human transmission via– Droplet

– Aerosols

– Fomites (uncommon)

– Peak infectiousness during pre-symptomatic/early infection

• Masks – Reduce personal viral load exposure

– Reduce aerosols in the environment

– Lower likelihood of infection

– Less severe infection (lower viral load exposure) Cheng S, et al. JAMA Intern Med 2020;

Prather KA, et al. Science 2020

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Common COVID-19 Diagnostic Methods

Udugama et al. ACS Nano 2020; 14:3822; Lee et al. Front Immunol 2020; 11:879; Carter et al. ACS Cent Sci 2020; 6:591.

TestUsually

IndicatesConsiderations

Viral nucleic acid*

Current infection

Primary method for COVID-19 diagnosis; multiple RT-PCR kits available False negatives may result from improper sampling or handling, low

viral load, or rarely viral mutations SARS-CoV-2 RNA generally undetectable by ~ Day 14 following onset of

symptoms; prolonged in some cases

Serologic† Past infection

Provides a delayed but wider window of time for detection Useful for COVID-19 surveillance and identification of convalescent

plasma donors False negative—sensitivity varies by platform False positive due to cross-reactivity (other coronaviruses?)

Typical specimen sources: *upper (eg, nasopharyngeal, mid-turbinate nasal, oropharyngeal swabs) or lower (eg, sputum, bronchoalveolar lavage fluid, tracheal aspirates) respiratory tract, †blood serum or plasma.

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Diagnostic Trajectory of RT-PCR and Antibody Responses

• Our understanding of the magnitude and duration of antibody responses is limited

• IgG Ab titers appear to be higher in pts with more severe disease than mild-moderate disease –may relate to viral load and duration of infection

• Durability of IgG and neutralizing Ab responses is of intense interest for vaccine development

Bryant et al. Science Immunol 2020; 5:eabc6347; Long et al. Nature Med 2020

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Pathogenesis of SARS CoV-2 Infection• The SARS-CoV-2 RNA genome encodes spike, envelope,

membrane, nucleocapsid and other viral proteins

– Spike proteinSARS-CoV-2 entry via binding to ACE-2

receptor & TMPRSS2 cofactor (lung, oro-nasal, GI tract,

endothelial)

– Early initiation of inflammatory programmed cell

deathrelease of damage-associated proteins

recognized by alveolar macrophages,

endothelial/epithelial cells that when infected stimulate

release of proinflammatory cytokines

– IL-6, IP-10, MIP1⍺, MIP1β, MCP1recruit monocytes,

macrophages, cytotoxic T cellsproinflammatory loop

– Defective immune response vs. healthy immune

response (virus-specific T cells; neutralizing Ab)

Tay MZ et al., Nat Rev Immunol 2020

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Covid-19 Disease Classifications

Disease Classification Clinical Parameters Proportion of Patients

Asymptomatic or presymptomatic infection

Positive test for SARS-CoV-2 but no symptoms

80%Mild illness

Varied symptoms (eg, fever, cough, sore throat, malaise, headache, muscle pain) but no shortness of breath, dyspnea, abnormal imaging

Moderate illness SpO2 ≥ 94% and lower respiratory disease

evidenced by clinical assessment or imaging15%

Severe illness SpO2 < 94%, PaO2/FiO2 < 300, respiratory rate > 30

breaths/min, or lung infiltrates > 50%

Critical illness Respiratory failure, septic shock, and/or

multiorgan dysfunction 5%

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Factors Associated with Increased Mortality Among Hospitalized COVID-19 Patients

Prospective observational cohort study of hospital admissions in UK during February 6 - April 19, 2020 (N = 20,133)

Significantly increased risk of mortality among older age > 50 yrs, men, chronic comorbidities

‒ HTN, CVD, COPD, asthma, CKD, obesity, liver disease most common

Docherty et al. British Med J 2020; 369:m1985.

Multivariate Survival Analysis

HR (95% CI) P Value< 50 yrs

50-59 yrs 60-69 yrs

70-79 yrs ≥ 80 yrs Female sex

Chronic cardiac diseaseChronic pulmonary disease

Chronic kidney diseaseDiabetesObesity

Chronic neurological disorderDementia

MalignancyModerate/severe liver disease

2.63 (2.06-3.35)

4.99 (3.99-6.25)8.51 (6.85-10.57)

11.09 (8.93-13.77)0.81 (0.75-0.86)1.16 (1.08-1.24)

1.17 (1.09-1.27)1.28 (1.18-1.39)

1.06 (0.99-1.14)1.33 (1.19-1.49)1.17 (1.06-1.29)

1.40 (1.28-1.52)1.13 (1.02-1.24)

1.51 (1.21-1.88)

Characteristic

< .001

< .001< .001

< .001< .001< .001

< .001< .001

.087< .001.001

< .001.017

< .001

101 2 5

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COVID-19 in People Living with HIV

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Risk and Features of COVID-19 in Persons With HIV in the US

MGH series: 36 PWH with confirmed, 11 with probable COVID-19

‒ 77% non-Hispanic black, Hispanic/Latinx (vs 40% black, Hispanic/Latinx in HIV clinic overall)

‒ 85% had comorbidity associated with severe disease: obesity (33%), HTN (31%), DM (22%), hyperlipidemia (22%), chronic kidney disease (22%)

Mount Sinai Hospital System: case-control study

‒ PWH admitted with COVID-19 (n = 88) matched to HIV-negative group by age, race/ethnicity, sex, wk of COVID-19 hospitalization admission (n = 405)

‒ No differences in disease severity on admission (P = 0.15) or adverse outcomes (mechanical ventilation or death) with vs without HIV infection

Meyerowitz et al. AIDS 2020; [Epub]; Sigel et al. Clin Infect Dis 2020; [Epub].

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COVID-19 & HIV: Public Sector Data – Western Cape, SA

• 12,987 patients with COVID-19 in Western Cape, South Africa

• After adjusting for other risk factors, HIV increased mortality with COVID-19 by a factor of 2.75 and active TB by a factor of 2.58

• Older age, comorbidities were the major factors increasing the risk of COVID-19 deaths

• Only a modest effect of HIV (<10% of COVID-19 deaths were associated with HIV)

Davies MA. AIDS 2020 Virtual (Nordling Science Mag 2020)

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The Impact of the COVID-19 Response on PLWH in LMICs

• “Lockdowns have impacted both the transport of goods across the value chain of production and the distribution of HIV medicines”

• “Barriers to the supply chain and a forecasted economic shock indicate possible fluctuation in the availability of antiretroviral medicines and an increase in costs”

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Treatment of Covid-19 Disease

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Key Therapeutic Classes Under Investigation for Treatment of COVID-19

Barlow. Pharmacotherapy. 2020;40:416. McCreary. Open Forum Infect Dis. 2020;7:ofaa105. Sanders. JAMA. 2020;323:1824; Sheahan, et al. Sci Transl Med 2020

Antivirals Immunomodulators

Convalescent plasmaFavipiravir?

(Hydroxy)chloroquineIvermectin?

Lopinavir/ritonavirOseltamivir

RibavirinInterferons (lambda, beta)

RemdesivirEIDD-2801

CorticosteroidsIL-1 inhibitors (eg, anakinra)?

IL-6 inhibitors (eg, tocilizumab)Intravenous immunoglobulinJAK inhibitors (eg, baricitinib)

“Management strategies and treatment for patients with COVID-19 are rapidly evolving; the optimal agents

to treat infection or prevent progression to critical illness remain ill-defined.”

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Randomized Therapeutic Clinical Trials for Covid-19

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Remdesivir

• Remdesivir is a broad acting nucleoside analog RNA polymerase inhibitor

– EC50 of 0.137 – 0.77 µM against SARS-CoV-2 in Vero cells; nanomolar activity in human airway epithelial cells

• RDV has broad spectrum activity against filoviruses (Ebola, Marburg,

SARS-CoV, MERS-CoV) and paramyxoviruses (RSV, Nipah, and Hendra)

– Clinical and virologic efficacy against SARS-CoV-1 and SARS-CoV-2 in mouse and primate models

• Reduces lung viral loads, lung pathology, and clinical signs of pulmonary dysfunction

De Wit, et al. PNAS 2020; Sheahan et al., Nature Comm 2020; Pizzorno A, et al. (https://www.biorxiv.org/content/10.1101/2020.03.31.017889v1); Will iamson BN, et al. (https://www.biorxiv .org/ content/ 10.1101/ 2020.04.15.043166v2); Wang M, et al. Cell Research 2020

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Remdesivir• Generally favorable safety profile (based on healthy volunteers in

phase 1 studies and pts with acute Ebola disease)

– Treatment emergent AEs elevations in ALT, AST

• PK profile indicates high and persistent levels of active nucleoside triphosphate metabolites in PBMCs allows once daily dosing– t1/2 of active metabolite in PBMCs 32-48h with Cmax > 10 µM

– Plasma t1/2 0.66-1h after infusion

• Renally excreted; CYP3A4 inhibitor but significant DDIs unlikely due to rapid clearance after IV administration; no induction of enzymes or transporters

Gilead Investigator’s Brochure; 2020

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Adaptive COVID-19 Treatment Trial (DMID ACTT-1): Study Design

Multicenter, adaptive, randomized, double-blind, placebo-controlled phase 3 trial

Adult patients ≥ 18 yrs of age;

hospitalized with symptoms of COVID-19/SARS-CoV-2 infection and

≥ 1 of following: radiographic infiltrates; SpO2 ≤ 94% on room air or requiring supplemental oxygen or or requiring

mechanical ventilation(N = 1063)

Remdesivir IV QDDay 1 200 mg ; D2-D10 100 mg

Placebo IV QD

Beigel J, et al. New Engl J Med 2020; [Epub]. NCT04280705

*Day of recovery is first day patient satisfies 1 of these categories from ordinal scale: 1) hospitalized, not requiring supplemental oxygen, no longer requires ongoing medical care; 2) not hospitalized, limitation on activities and/or requiring home oxygen; or 3) not hospitalized, no limitations on activities.

Daily assessment to Day 29 for time to clinical

improvement while hospitalized;

if discharged, assessments at Days 15, 22, and 29

Day 10

Primary endpoint: time to recovery* by Day 29 according to ordinal scale Secondary endpoints: treatment-related improvements in 8-point ordinal scale at Day 15

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Results: Primary Outcome

• Shorter time to recovery in the

remdesivir group vs placebo

– 11 vs 15 days

– Rate ratio for recovery 1.32, 95%

CI, 1.13 to 1.55; p<0.001

• Outcomes similar for those

with a duration of symptoms

at time of randomization of

<10 days vs > 10 days

Beigel JH, et al. NEJM 2020

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Results: Primary Outcome by Subgroups

Ordinal Score 4; RR 1.38 Ordinal Score 5; RR 1.47

Ordinal Score 6; RR 1.20

Ordinal Score 7; RR 0.95

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Secondary Outcomes: Mortality & Day 15 Ordinal Scores

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Results: Key Subgroup Outcomes

• Recovery rate ratio was improved for remdesivir-treated pts overall and regardless of duration of symptoms prior to randomization

• Except for baseline ordinal score 5 subgroup, 95% CI overlapped for all other subgroups

• Confounding for indication or insufficient statistical power for higher and lower score subgroups?

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Safety Outcomes

• Fewer serious adverse events occurred in pts receiving remdesivir compared to placebo (21.1% vs. 27%)

– Most common SAEs were respiratory failure, hypotension, viral pneumonia, AKI

• Grade 3 or 4 adverse events occurred less frequently in the remdesivir group than placebo (28.8% vs. 33%)

– Most common AEs were anemia/decreased Hgb, AKI, decreased eGRF/Cr clearance, increased Cr, hyperglycemia, increased aminotransferases

– DVTs and PEs were relatively uncommon, occurring in 1.4% and 0.6%, respectively

• No deaths were attributed to study medications

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Other Remdesivir Randomized Trials

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China: Remdesivir vs. Placebo• Randomized, double-blind,

placebo-controlled multicenter trial– 237 pts 2:1 remdesivir vs placebo

• Terminated early due to outbreak controlled; statistically underpowered but no difference in primary outcomes

• Subgroup of symptoms < 10d median time to recovery was 18d for remdesivir vs 23d for placebo– HR 1.52; 95% CI 0.9 to 2.43

Wang Y, et al. Lancet 2020

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Remdesivir: 5 vs 10 Days Duration for Severe COVID-19

• Randomized, open-label, phase 3 trial in 397 hospitalized pts with SARS-CoV-2 pneumonia, RA O2 sat < 94%

– Pts randomized to 10d significantly worse baseline clinical status (p=0.02)

• Clinical improvement of > 2 points on the ordinal scale in 64% in 5d group vs 54% in 10d group (p=0.14)

Goldman JD, et al. NEJM 2020

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RECOVERY Trial: Dexamethasone Results

• Study Design: Randomized, open-label, adaptive platform trial

comparing different possible treatments with “usual care” in

hospitalized pts with Covid-19

– 176 National Health Service hospitals in UK

– Eligibility: Clinically suspected or lab confirmed SARS-CoV-2 infection

– Treatment: 2,104 pts randomly allocated to dexamethasone oral or

IV 6 mg/d for up to 10d vs. 4,321 concurrently allocated to usual

care

– Primary endpoint: 28d mortalityNew Engl J Med July 17, 2020 at NEJM.org

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RECOVERY: Randomization and Procedures

• Randomized 2:1 to usual SOC alone or SOC + dexamethasone or to one of

the other “suitable and available treatments being evaluated in the trial” (HCQ, LPV-

RTV, azithromycin, tocilizumab, convalescent plasma

• Web-based CRF at Entry (Demographics, level of respiratory support, major

comorbidities, treatment available at each site)

• Single on-line followup form at discharge, death or day 28 (adherence to

allocated treatment, receipt of other treatment, duration of hospitalization, respiratory

or renal support status, vital status)

• Secondary outcomes time to discharge, receipt and duration of

mechanical ventilation, ECMO, cause-specific mortality

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RECOVERY: Results

• Mean age 66.9 yrs in dexamethasone vs. 65.8 yrs in SOC; 36% women

– DM 24%; CVD 27%; chronic lung disease 21%

– At randomization 56% had > 1 comorbidity; 89% confirmed SARS-CoV-2, 16% on MV/ECMO, 60% on O2

• Median duration of dexamethasone 7d (8% of the usual care group also

received dexamethasone)

– 0-3% received HCQ, LPV/r, IL-6 antagonists or remdesivir; 24% in SOC and 25% in the dexamethasone group received azithromycin

– 4.5% in the dexamethasone and 6.4% in the SOC groups underwent a second randomization to tocilizumab vs SOC; 13 pts underwent 2nd randomization to convalescent plasma vs SOC

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RECOVERY: Primary Outcome Results

28d mortality:

• 22.9% in dexamethasone group vs. 25.7% in SOC (RR 0.83; 95% CI, 0.75-0.93; P < 0.001)

• 29.3% vs. 41.4% (RR 0.64 [95% CI, 0.51- 0.81]; P < 0.001) for those on MV at entry

• 23.3% vs. 26.2% (RR 0.82; 95% CI, 0.72-0.94 for those on O2 but not MV at entry

• Benefit primarily observed in pts with symptoms for more than 7d; no benefit and possible harm in those not receiving O2

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28-Day Mortality: Remdesivir ACTT-1 vs RECOVERY

ACTT-1 Remdesivir ACTT-1 Placebo RECOVERY Dex RECOVERY SOC

No O2

requirement (Ordinal score 4)

4.6% 5.6%17.8% 14.0%

Mortality Rate Ratio 1.19 (95% CI 0.91-1.55)

O2 requirement (Ordinal score 5)

4.3% 13.0% 23.3% 26.2%

High Flow O2

(ordinal score 6)23.3% 22.2% Mortality Rate Ratio 0.82 (95% CI 0.72-0.94)

MV or ECMO 22.7% 20.3% 29.3% 41.4%

Mortality Rate Ratio 0.64 (95% CI 0.51-0.81)

Overall 12.0% 15.2% 22.9% 25.7%

Overall Mortality Rate Ratio 0.79 0.83

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Vaccines for SARS CoV-2

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Vaccines: Opportunities and Challenges

• Multiple vaccine platforms

– Protein, mRNA, DNA, chimeric viruses, attenuated viruses, non-replicating viral vectors

• Challenges:– Correlates of

immunity?

– Durable immunity?

– Immunogenic in vulnerable populations

Sponsor Vaccine Construct Trial Phase Date

ModernaTX mRNA-1273 encoding Spike protein Phase 3 July 2020

Oxford-AstraZeneca ChAdOx1 adenovirus/Spike protein construct

Phase 3 Aug 2020

J&J/Janssen Ad5 Vector/Spike protein Phase 3 Sep 2020

Regeneron Monoclonal Ab cocktail Phase 3 Sep 2020

Biontech SE/Pfizer BNT162 RNA vaccine Phase 3 Aug 2020

Genexine GX-19 CoV NA vaccine Phase 1/2

Novavax Recombinant Spike Protein Nanoparticle

Phase 1/2

Symvivo bacTRL Spike protein Phase 1 Sep 2020

CureVac AG/CEPI CVnCoVA mRNA Phase 1

CanSino Ad5 Recombinant CoV Phase 1

Medicago Recombinant CoV-Like Particle vaccine

Phase 1

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Symptomatic People Make More Vigorous Immune Responses

Long, et. al., Nature Medicine 2020

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Natural Coronavirus Immunity May Not Be Durable

Long, et. al., Nature Medicine 2020

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Coronavirus Vaccine Immunity May Not Be Durable

Zhu, et. al. Lancet 2020; 395:P1845-54

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Conclusions

• Remdesivir is effective in reducing time to recovery and improving survival in select subgroups and should be used in those with moderate to severe Covid-19 (SpO2 < 94% on RA or requiring oxygen)

• Dexamethasone appears to improve survival for those with severe Covid-19 disease (mechanical ventilation or requiring O2)

• Prospective, randomized clinical trials recently completed with two immunomodulating agents - tocilizumab, baricitinib - results due in August

• Multiple vaccines are under active development

– As in HIV-1, the pathway to an effective coronavirus vaccine is likely to be a long and winding road

• ACTIV/Operation Warp Speed rapid platform trials evaluating antiviral BnAbs, novel direct-acting antiviral agents and multiple candidate vaccines

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Thank You!

To Be Continued in Microbiology Lab…

Question-and-Answer Session