COVID-19: Update on Therapy and Vaccine Development - PowerPoint Presentation

1. COVID-19: Update on Therapy and Vaccine DevelopmentConstance A. Benson, MDProfessor of Medicine and Global Public HealthUniversity of California San DiegoLa Jolla, California

2. Financial Relationships With Commercial EntitiesDr Benson has served on advisory and data safety monitoring boards for GlaxoSmithKline/ViiV Healthcare, received research grants awarded to her institution from Gilead Sciences, Inc., and serves as a consultant to NDA Partners, LLC. Her spouse has served as a consultant to CytoDyn, AbbVie and Sempra Energy; owns stock options in Antiva Biosciences and CytoDyn; has served on the board for Gilead Sciences, Inc., with payment remitted to his institution; and has served on data and safety monitoring boards for Gilead Sciences, Inc., and VIR. (Updated 07/27/20)

3. Learning ObjectivesAfter attending this presentation, learners will be able to: List available effective treatment modalities for Covid-19Describe challenges to SARS-CoV-2 vaccine development

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

5. Total U.S. Covid-19 Cases and Deathshttps://www.cdc.gov/covid-data-tracker4,339,997 Cases148,866 Deaths0-3,8666173-17,41682,530-165,934174,973-466,550Last updated: July 29, 2020, 5:45 PM EDT.18,725-34,99039,337-63,6780-56102-3352,924-6,4217162-23,512409-839913-2,125

6. Covid-19 Cases and Deaths Disproportionately Affect Black and Latinx PopulationsDeaths by Race/Ethnicityhttps://www.cdc.gov/coronavirus/2019-ncov/cases-updates/cases-in-us.htmlCases by Race/Ethnicity

7. SARS-CoV-2 Transmission – Masks Save Lives!SARS-CoV-2 human-to-human transmission viaDropletAerosolsFomites (uncommon)Peak infectiousness during pre-symptomatic/early infectionMasks Reduce personal viral load exposureReduce aerosols in the environmentLower likelihood of infectionLess severe infection (lower viral load exposure)Cheng S, et al. JAMA Intern Med 2020; Prather KA, et al. Science 2020

8. Common COVID-19 Diagnostic MethodsUdugama 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 IndicatesConsiderationsViral nucleic acid*Current infectionPrimary method for COVID-19 diagnosis; multiple RT-PCR kits availableFalse negatives may result from improper sampling or handling, low viral load, or rarely viral mutationsSARS-CoV-2 RNA generally undetectable by ~ Day 14 following onset of symptoms; prolonged in some casesSerologic†Past infectionProvides a delayed but wider window of time for detectionUseful for COVID-19 surveillance and identification of convalescent plasma donorsFalse negative—sensitivity varies by platformFalse 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.

9. Diagnostic Trajectory of RT-PCR and Antibody ResponsesOur understanding of the magnitude and duration of antibody responses is limitedIgG Ab titers appear to be higher in pts with more severe disease than mild-moderate disease – may relate to viral load and duration of infectionDurability of IgG and neutralizing Ab responses is of intense interest for vaccine developmentBryant et al. Science Immunol 2020; 5:eabc6347; Long et al. Nature Med 2020

10. Pathogenesis of SARS CoV-2 InfectionThe SARS-CoV-2 RNA genome  encodes spike, envelope, membrane, nucleocapsid and other viral proteinsSpike proteinSARS-CoV-2 entry via binding to ACE-2 receptor & TMPRSS2 cofactor (lung, oro-nasal, GI tract, endothelial)Early initiation of inflammatory programmed cell deathrelease of damage-associated proteins recognized by alveolar macrophages, endothelial/epithelial cells that when infected stimulate release of proinflammatory cytokinesIL-6, IP-10, MIP1⍺, MIP1, MCP1recruit monocytes, macrophages, cytotoxic T cellsproinflammatory loop Defective immune response vs. healthy immune response (virus-specific T cells; neutralizing Ab) Tay MZ et al., Nat Rev Immunol 2020

11. Covid-19 Disease ClassificationsDisease ClassificationClinical ParametersProportion of PatientsAsymptomatic or presymptomatic infectionPositive test for SARS-CoV-2 but no symptoms80%Mild illnessVaried symptoms (eg, fever, cough, sore throat, malaise, headache, muscle pain) but no shortness of breath, dyspnea, abnormal imagingModerate illnessSpO2 ≥ 94% and lower respiratory disease evidenced by clinical assessment or imaging15%Severe illnessSpO2 < 94%, PaO2/FiO2 < 300, respiratory rate > 30 breaths/min, or lung infiltrates > 50%Critical illnessRespiratory failure, septic shock, and/or multiorgan dysfunction5%

12. Factors Associated with Increased Mortality Among Hospitalized COVID-19 PatientsProspective 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 comorbiditiesHTN, CVD, COPD, asthma, CKD, obesity, liver disease most commonDocherty et al. British Med J 2020; 369:m1985.Multivariate Survival AnalysisHR (95% CI)P Value< 50 yrs50-59 yrs 60-69 yrs 70-79 yrs ≥ 80 yrs Female sexChronic cardiac diseaseChronic pulmonary diseaseChronic kidney diseaseDiabetesObesityChronic neurological disorderDementiaMalignancyModerate/severe liver disease2.63 (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< .00110125

13. COVID-19 in People Living with HIV

14. Risk and Features of COVID-19 in Persons With HIV in the USMGH series: 36 PWH with confirmed, 11 with probable COVID-1977% 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 studyPWH 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 infectionMeyerowitz et al. AIDS 2020; [Epub]; Sigel et al. Clin Infect Dis 2020; [Epub].

15. COVID-19 & HIV: Public Sector Data – Western Cape, SA12,987 patients with COVID-19 in Western Cape, South AfricaAfter adjusting for other risk factors, HIV increased mortality with COVID-19 by a factor of 2.75 and active TB by a factor of 2.58Older age, comorbidities were the major factors increasing the risk of COVID-19 deathsOnly a modest effect of HIV (<10% of COVID-19 deaths were associated with HIV)Davies MA. AIDS 2020 Virtual (Nordling Science Mag 2020)

16. 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”

17. Treatment of Covid-19 Disease

18. Key Therapeutic Classes Under Investigation for Treatment of COVID-19Barlow. Pharmacotherapy. 2020;40:416. McCreary. Open Forum Infect Dis. 2020;7:ofaa105. Sanders. JAMA. 2020;323:1824; Sheahan, et al. Sci Transl Med 2020 AntiviralsImmunomodulatorsConvalescent plasmaFavipiravir?(Hydroxy)chloroquineIvermectin?Lopinavir/ritonavirOseltamivirRibavirinInterferons (lambda, beta)RemdesivirEIDD-2801CorticosteroidsIL-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.”

19. Randomized Therapeutic Clinical Trials for Covid-19

20. Remdesivir Remdesivir is a broad acting nucleoside analog RNA polymerase inhibitorEC50 of 0.137 – 0.77 µM against SARS-CoV-2 in Vero cells; nanomolar activity in human airway epithelial cellsRDV 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 modelsReduces lung viral loads, lung pathology, and clinical signs of pulmonary dysfunctionDe 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); Williamson BN, et al. (https://www.biorxiv .org/ content/ 10.1101/ 2020.04.15.043166v2); Wang M, et al. Cell Research 2020

21. RemdesivirGenerally favorable safety profile (based on healthy volunteers in phase 1 studies and pts with acute Ebola disease)Treatment emergent AEs elevations in ALT, ASTPK profile indicates high and persistent levels of active nucleoside triphosphate metabolites in PBMCs  allows once daily dosingt1/2 of active metabolite in PBMCs 32-48h with Cmax > 10 µMPlasma t1/2 0.66-1h after infusionRenally 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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23. Adaptive COVID-19 Treatment Trial (DMID ACTT-1): Study DesignMulticenter, adaptive, randomized, double-blind, placebo-controlled phase 3 trialAdult 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 mgPlacebo IV QDBeigel 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 29Day 10Primary 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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25. Results: Primary OutcomeShorter time to recovery in the remdesivir group vs placebo11 vs 15 days Rate ratio for recovery 1.32, 95% CI, 1.13 to 1.55; p<0.001Outcomes similar for those with a duration of symptoms at time of randomization of <10 days vs > 10 daysBeigel JH, et al. NEJM 2020

26. Results: Primary Outcome by SubgroupsOrdinal Score 4; RR 1.38Ordinal Score 5; RR 1.47Ordinal Score 6; RR 1.20Ordinal Score 7; RR 0.95

27. Secondary Outcomes: Mortality & Day 15 Ordinal Scores

28. Results: Key Subgroup OutcomesRecovery rate ratio was improved for remdesivir-treated pts overall and regardless of duration of symptoms prior to randomizationExcept for baseline ordinal score 5 subgroup, 95% CI overlapped for all other subgroupsConfounding for indication or insufficient statistical power for higher and lower score subgroups?

29. Safety OutcomesFewer serious adverse events occurred in pts receiving remdesivir compared to placebo (21.1% vs. 27%)Most common SAEs were respiratory failure, hypotension, viral pneumonia, AKIGrade 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 aminotransferasesDVTs and PEs were relatively uncommon, occurring in 1.4% and 0.6%, respectivelyNo deaths were attributed to study medications

30. Other Remdesivir Randomized Trials

31. China: Remdesivir vs. PlaceboRandomized, double-blind, placebo-controlled multicenter trial237 pts  2:1 remdesivir vs placeboTerminated 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 placeboHR 1.52; 95% CI 0.9 to 2.43Wang Y, et al. Lancet 2020

32. Remdesivir: 5 vs 10 Days Duration for Severe COVID-19Randomized, 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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34. RECOVERY Trial: Dexamethasone ResultsStudy 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 UKEligibility: Clinically suspected or lab confirmed SARS-CoV-2 infectionTreatment: 2,104 pts randomly allocated to dexamethasone oral or IV 6 mg/d for up to 10d vs. 4,321 concurrently allocated to usual carePrimary endpoint: 28d mortalityNew Engl J Med July 17, 2020 at NEJM.org

35. RECOVERY: Randomization and ProceduresRandomized 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 plasmaWeb-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

36. RECOVERY: ResultsMean age 66.9 yrs in dexamethasone vs. 65.8 yrs in SOC; 36% womenDM 24%; CVD 27%; chronic lung disease 21%At randomization 56% had > 1 comorbidity; 89% confirmed SARS-CoV-2, 16% on MV/ECMO, 60% on O2Median 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 azithromycin4.5% 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

37. RECOVERY: Primary Outcome Results28d 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 entry23.3% vs. 26.2% (RR 0.82; 95% CI, 0.72-0.94 for those on O2 but not MV at entryBenefit primarily observed in pts with symptoms for more than 7d; no benefit and possible harm in those not receiving O2

38. 28-Day Mortality: Remdesivir ACTT-1 vs RECOVERYACTT-1 RemdesivirACTT-1 PlaceboRECOVERY DexRECOVERY SOCNo 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 ECMO22.7%20.3%29.3%41.4%Mortality Rate Ratio 0.64 (95% CI 0.51-0.81)Overall12.0%15.2%22.9%25.7%Overall Mortality Rate Ratio0.790.83

39. Vaccines for SARS CoV-2

40. Vaccines: Opportunities and ChallengesMultiple vaccine platformsProtein, mRNA, DNA, chimeric viruses, attenuated viruses, non-replicating viral vectorsChallenges:Correlates of immunity?Durable immunity?Immunogenic in vulnerable populationsSponsorVaccine ConstructTrial PhaseDateModernaTXmRNA-1273 encoding Spike proteinPhase 3July 2020Oxford-AstraZenecaChAdOx1 adenovirus/Spike protein constructPhase 3Aug 2020J&J/JanssenAd5 Vector/Spike proteinPhase 3Sep 2020RegeneronMonoclonal Ab cocktailPhase 3Sep 2020Biontech SE/PfizerBNT162 RNA vaccinePhase 3 Aug 2020 GenexineGX-19 CoV NA vaccinePhase 1/2 NovavaxRecombinant Spike Protein NanoparticlePhase 1/2 SymvivobacTRL Spike proteinPhase 1Sep 2020CureVac AG/CEPICVnCoVA mRNAPhase 1  CanSinoAd5 Recombinant CoVPhase 1 MedicagoRecombinant CoV-Like Particle vaccinePhase 1 

41. Symptomatic People Make More Vigorous Immune ResponsesLong, et. al., Nature Medicine 2020

42. Natural Coronavirus Immunity May Not Be Durable Long, et. al., Nature Medicine 2020

43. Coronavirus Vaccine Immunity May Not Be DurableZhu, et. al. Lancet 2020; 395:P1845-54

44. ConclusionsRemdesivir 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 developmentAs in HIV-1, the pathway to an effective coronavirus vaccine is likely to be a long and winding roadACTIV/Operation Warp Speed  rapid platform trials evaluating antiviral BnAbs, novel direct-acting antiviral agents and multiple candidate vaccines

45. Thank You!To Be Continued in Microbiology Lab…

46. Question-and-Answer Session