COVID-19 Vaccine, an Update Pharmaceries Webinar March 23Rd, 2021

COVID-19 Vaccine, an Update PharmaCEries webinar March 23rd, 2021

Fernanda Bonilla, MD Infectious Diseases Rania El-Lababidi, PharmD, EMHA, BCPS(AQ-ID), AAHIVP Senior Manager, Pharmacy Education and Training Co-Director, Antimicrobial Stewardship Program

Fulvio Salvo, MD Allergy and Immunology Learning Objectives

• Recognize the immunologic basis for SARS-CoV-2 vaccination and the importance of neutralizing antibodies associated with protection from infection

• Define the phases of vaccine development and the different platforms used to develop SARS-CoV-2 vaccines

• Discuss the immunogenicity and safety data for the different vaccine candidates Smallpox Control of mortality, morbidity and complications Eradication

Elimination

Mitigation of disease Sanitation severity Immunization

Prevention of infection

Protection of the Prevention unvaccinated of related population diseases Societal and cancer benefits Andrea et al. Vaccination greatly reduces disease, disability, death and inequity worldwide. Bulletin of the World Health Organization 2008 Sanitation Immunization

Variolation

• Early 18th century - Smallpox or Variola inoculation

Vaccination

• 1796 Edward Jenner – Cowpox or Variola vaccinia inoculation from milkmaids Value of Immunization

• Annual prevention of 6 million deaths worldwide • Global eradication of smallpox • Elimination of polio by wild viruses in the US

Ehreth J. The global value of vaccination. Vaccine. 2003 Adverse Effects

MMR Tetanus toxoid • Onset 10 d • Encephalitis in 1 in 2 million • Brachial neuritis 1 month after • Causal role not established • 1 per 100K recipients

Meningococcal vaccine Yellow fever • Anaphylaxis 1 in 500K doses • Vaccine-associated viscerotropic • GBS 1.25 in 1 million doses disease in 1 in 400K doses Immune response to COVID-19 A Complex Reality Immune Response to SARS-CoV-2

• Role of innate immunity, cellular adaptive immunity, and antibodies • Duration of natural immunity • Pre-existing immunity to other CoV • Risks related to partial immunity • Vaccine design rationale Immune response to a viral infection

Infection can be stopped here if neutralizing Ab are present

Prodromal Phase SYMPTOMS Recovery

Innate Immune Response Adaptive Immune Response

• Standard response to any infection • Tailored response to the infection

• Macrophage and neutrophils • Starts usually after 6-8 days produce cytokines and chemokines to contrast the virus and activate • Involves 2 main cell types with the immune system several subtypes: • B-cells • Antibodies can efficiently stop the • T-cells (CD4 & CD8) infection

Adapted from WHO Innate Immunity in COVID-19

Innate Immunity

• Port of entry is mainly through the mucosal surfaces of the respiratory tract • In early phase of infection SARS-CoV-2 suppresses activation of innate immune system by inhibiting IFN type I and III response. • Delayed activation of the immune system may explain the prolonged incubation period and increase the viral replication • Late-onset hyperinflammatory response is probably driven by activated proinflammatory macrophage and neutrophils T-cell mediated immunity

• Emerging evidences support a central role for T-cell mediated immune response to SARS-CoV-2. • 100% of convalescent patients has S protein-specific CD4 T- cell and 70% of CD8. Other antigens also induce specific T cell response (e.g. N and M proteins). • Tissue resident memory T-cells may be particularly important for disease protection • Priming of the immune response towards Th1 or Th2 may be important for disease severity and outcome T-cell mediate immunity: for how long?

• 23/23 patients recovered from SARS-CoV-1 infection still had T-cells reactive to SARS-CoV- 1 N protein after 17 years from infection • These T-cells also reacted to SARS-CoV-2

Le Bert, Nature 2020 SARS-CoV-2 structure and antibodies Antibodies

• SARS-CoV-2-specific IgM, IgG and IgA are detectable in patients’ serum starting from 1-2 weeks after infection. • Antibody levels correlate with magnitude of T-cell response • Higher levels are detected in patients with severe disease • Antibodies are produced against multiple epitopes • Antibody titers tend to decrease over time but specific epitopes and severity of the disease may account for the significant variation in duration of detectable Abs IgG anti-S IgG anti-N

Lumley, Clin Inf Dis 2021

Neutralizing Antibodies

Spike • High affinity antibodies directed against the S1-RBD are able to neutralize the virus • Other epitopes may also have protective effects: antibodies against S2 domain may block membrane fusion.

• Treatment of older patients with ACEr2 mild COVID-19 with high-titer convalescent plasma can decrease progression to more severe forms of disease. Spike Protein

RBD

S2 Do we have natural immunity against SARS- CoV-2?

• Other 4 coronaviruses are known to infect humans (besides SARS-CoV-1 and MERS-CoV) and cause approx. 15% of common cold cases • Cross-reactive antibodies and T-cells between other coronaviruses and SARS-CoV-2 are present, but are usually directed against more conserved epitopes (N protein or other non structural proteins, but also to S2 domain) • While antibody titers decline rapidly, memory T-cell may persist for much longer time Possible effect of cross-reactive T-cell on SARS-CoV-2 replication and infection

Model I: Central Memory T-Cell Infection less severe at individual level Possibly enhanced transmission due to high viral replication

Model II: Follicular Th-Cell More efficient ab-induction, less symptoms less viral load. Mild/moderate reduction of transmission

Model III: Tissue resident T-Cell Quicker response, symptoms significantly reduced Transmission reduced with lower viral load.

Lipsitch, Nat Rev Immunol 2020 Can inefficient immune response be harmful?

Antibody-dependent Enhancement of Infection or Inflammation • ADE of infection is a well-known phenomenon in other viral infection (e.g. Dengue) • Animal models showed potential for ADE also in CoV infections (mice) • Low titer non-neutralizing antibodies are at higher risk of inducing ADE What does the immunologist want from a good vaccine?

To be able to induce predictable antibody response to relevant epitopes (neutralizing antibodies)

To induce a T-cell response which is durable and beneficial (Th1 and not Th2)

To provide a protection against the disease and its transmission

To be safe and avoid vaccine-associated damage Immunological properties of main COVID- 19 vaccine candidate platforms

Jeyanathan, Nat Rev Immunol 2020 Immunological properties of main COVID-19 vaccine candidate platforms

Jeyanathan, Nat Rev Immunol 2020

Vaccine Development

SARS-CoV-2 vaccines in development, Krammer F, Nature 2020 Phases of clinical trials

Immunogenicity Safety Phases of clinical trials

Optimal vaccine schedule Immunogenicity Safety Phases of clinical trials

Efficacy Safety Immune response Optimal Vaccine schedule Vaccine Development

SARS-CoV-2 vaccines in development, Krammer F, Nature 2020 Emergency Use Authorization Vaccine platforms

Spike Protein Instructions

SARS-CoV-2 vaccines in development, Krammer F, Nature 2020 mRNA Vaccines

Vaccines that deliver a gene transcript into our cells to provoke an immune response • Snippets of viral mRNA: instruction for making proteins

• mRNA packed into a lipid envelop

• mRNA inside the cytoplasm interacts with a ribosome → starts making spike proteins

• S proteins elicit an immune response Vaccine platforms

Spike Protein Instructions

SARS-CoV-2 vaccines in development, Krammer F, Nature 2020 174 63 8 Preclinical Clinical Development vaccines in use

BioNtech/Pfizer Moderna Oxford/AstaZeneca Sinovac/Instituto Butuntan Wuhan Institute/Sinopharm Beijing Institue/Sinopharm Gamaleya Reasearch Institute CanSino Biologics Janssen Pharma Novavax

Candidates in clinical phase

https://www.who.int/publications/m/item/draft-landscape-of-covid-19-candidate-vaccines Factors related to vaccines platforms

• Effectiveness • Speed of development • Scalability • Complexity of distribution: - Storage requirements - >1 dose

https://emedicine.medscape.com/article/2500139 Inactivated Recombinant/ mRNA vaccines Adenovirus Vector Vaccine Adjuvant

Product BBIBP-CorV mRNA BNT162b2 ChAdOx1/ AD26.CoV2 rAd26-S NVX-CoV2373 1273 AZD1222 .S and rAd5- S Company Sinopharm Moderna/ BioNTech/ Oxford/ J&J Gemalaya Novavax NIAID Pfizer AstraZeneca Research Institute Series 0, 21 days 0, 28 days 0, 21 days 0, 28 days 1-dose 0, 21 days 0, 21 days

Ages > 18 years > 18 years 12-85 > 18 years > 18 years > 18 years 18-84 years Studied years* Phase of Phase III Phase III Phase III Phase III Phase III Phase III Phase III Development Doses per NR 10 5 10 5 NR 10 vial ○ Storage 2 – 8○C -20○C -70-20 + 10C ○forC 2 -20○C or Fridge -20○C Fridge weeks Fridge Stability NR Fridge: Fridge: 5d NR Fridge: 3 NR NR 30d RT: 6 hours mo RT: 6 RT: 6 h hours Inactivated Recombinant/ mRNA vaccines Adenovirus Vector Vaccine Adjuvant

Product BBIBP-CorV mRNA 1273 BNT162b2 ChAdOx1/ AD26.CoV2.S rAd26-S NVX-CoV2373 AZD1222 and rAd5-S

Company Sinopharm Moderna/ BioNTech/ Oxford/ J&J Gemalaya Novavax NIAID Pfizer AstraZeneca Research Institute Series 0, 21 days 0, 28 days 0, 21 days 0, 28 days 1-dose 0, 21 days 0, 21 days

Efficacy: 79.34% 94.5% 95% 79% 66% 91.6% 89.3% Confirmed COVID-19 Efficacy: 100% 100% 88.9% Pending 85% 100% 100% Severe COVID-19

Adjuvant Aluminum None None None None None Saponin-based adjuvant Matrix-M™

Source: COVID-19 vaccine tracker (shinyapps.io); Voysey M, Clemens S, Madhi S, et al. Single dose administration, and the influence of the timing of the booster dose on immunogenicity and efficacy of ChAdOx1nCoV-19 (AZD1222) vaccine. https://papers.ssrn.com/sol3/papers.cfm?abstract_id=3777268. ; www.jnj.com; Lugonov DY et al. Lancet 2021; DOI: https://doi.org/10.1016/S0140-6736(21)00234-8. Sinopharm

• BBIBP-CorV – Inactivated • Responsible Party: China National Biotec Group Company Limited

• EFFICACY: 79.34% • DOSE: 2 doses, 3 weeks apart, IM • January, 2020 Sinopharm begins development • June 2020 Phase 1/2 trial • APPROVED IN: United Arab Emirates, Bahrain, China • July 2020 - Phase 3 begins in UAE • EMERGENCY USE IN: Egypt, Hungary, Jordan • Dec. 2020 UAE full approval - efficacy 86 % • Dec. 30 Sinopharm efficacy 79.34% - approved in China

Xia S et al. Lancet Infect Dis. Oct 2020 A Study to Evaluate The Efficacy, Safety and Immunogenicity of Inactivated SARS-CoV-2 Vaccines (Vero Cell) in Healthy Population Aged 18 Years Old and Above - Full Text View - ClinicalTrials.gov Sinopharm

• Phase I - 192 participants - 2 doses of 2 μg, 4 μg, or 8 μg on days 0 and 28 • Phase II - 448 participants - Single-dose of 8 μg - Two-dose of 4 μg on days 0 and 14, 0 and 21, or 0 and 28100% Humoral responses on day 42

• All reactions were mild or moderate • 100% had neutralizing antibodies by day 42 • No serious adverse events • Higher neutralizing antibodies in the 2-dose, 4μg on days 0 and 21 or days 0 and 28

• Comirnaty (tozinameran or BNT162b2) mRNA vaccine • EFFICACY: 95%

• DOSE: 2 doses, 3 weeks apart, IM

• STORAGE: Freezer storage only at – Spike 94°F (–70°C) Protein Instructions

• APPROVED IN: Bahrain, Saudi Arabia, Switzerland. • EMERGENCY USE IN: Argentina, Australia, Canada, Chile, Colombia, Costa Rica, Ecuador, European Union, Iraq, Jordan, Kuwait, Lebanon, Malaysia, Mexico, Oman, Panama, Qatar, Serbia, Singapore, Switzerland, Tunisia, UAE, UK, USA. Emergency use validation from the World Health Organization. Pfizer/BioNTech

Efficacy

• Phase 1/2 RCT - 18-85 years-old with Placebo Arm Vaccine Arm adequate neutralizing antibody Confirmed 162 8 responses COVID-19 Severe COVID- 9 1 • In-vitro → new UK variant B.1.1.7 and 19 new South African variant B.1.351 • Phase 3 RCT • Adverse effects mild or moderate - 36,000 participants - 95% efficacy >7 days after 2nd dose - Fever 16% of < 55 years old - Anaphylaxis 5 per 1 million doses - 91.7% >65 y/o with comorbidities or obesity - 4 cases of Bell’s palsy - none in post-vaccine monitoring - ~ 52% after 1st dose

Wals et al. Safety and Immunogenicity of Two RNA-Based Covid-19 Vaccine Candidates. N Engl J Med. 2020 Polack et al. Safety and Efficacy of the BNT162b2 mRNA Covid-19 Vaccine. N Engl J Med. 2020 Dec Muik A et al. Neutralization of SARS-CoV-2 lineage B.1.1.7 pseudovirus by BNT162b2 vaccine-elicited human sera. https://www.biorxiv.org/content/10.1101/2021.01.18.426984v1 Moderna

mRNA vaccine • mRNA-1273 • National Institute of Allergy and Infectious Diseases (NIAID) and Moderna • EFFICACY: 94.5% • DOSE: 2 doses, 4 weeks apart, IM • STORAGE: 30 days with refrigeration, 6 months at –4°F (–20°C) • EMERGENCY USE IN: Canada, European Union, Israel, Switzerland, United Kingdom, United States Moderna Efficacy • Phase 1: Placebo Arm Vaccine Arm - 45 healthy 18-55 with adequate neutralizing antibodies Confirmed 185 11 COVID-19 Severe COVID- 30 0 • In-vitro neutralizing capabilities against 19 new UK variant B.1.1.7 and new South African variant B.1.135 (lower titers) • Phase 3 RCT - 30,000 participants • Adverse effects mild or moderate - 94.1% efficacy >14 days after 2nd dose - 86.4% >65 y/o - Fever 17% of < 65 years old - Severe fatigue, HA, myalgias 5-10% - 100% severe cases - Anaphylaxis 2.8 per 1 million doses - 80% after 1st dose at 28 days (2000 - 3 cases of Bell’s palsy only 1 dose)

Jackson et al. An mRNA Vaccine against SARS-CoV-2 - Preliminary Report. N Engl J Med. 2020 Anderson EJ, Rouphael NG et al. Safety and Immunogenicity of SARS-CoV-2 mRNA-1273 Vaccine in Older Adults. N Engl J Med. 2020 Widge et al. Durability of Responses after SARS-CoV-2 mRNA-1273 Vaccination. N Engl J Med. 2021 Baden et al. Efficacy and Safety of the mRNA-1273 SARS-CoV-2 Vaccine. N Engl J Med. 2020 Oxford/Astra Zeneca

• ChAdOx1 nCoV-19 or AZD1222 (also Non-replicating Viral Vector known as Covishield in India) Adenovirus • EFFICACY: 62% to 90%, depending on dosage • DOSE: 2 doses, 4 weeks apart, IM • STORAGE: Stable in refrigerator for at least 6 months

• EMERGENCY USE IN: Argentina, Bangladesh, Bhutan, Brazil, Dominican Republic, El Salvador, European Union, India, Maldives, Mexico, Morocco, Nepal, Pakistan, South Africa, United Kingdom Johnson&Johnson/Janssen

• Ad26.CoV2.S Ad26 replication-incompetent adenovirus vector • EFFICACY: 72% in US, 66% in Latin America, 57% in South Africa (B.1.351 • Phase 3 RCT: 45 000 volunteers variant) • Local and systemic side effects 9-20% - 85% Severe cases

• DOSE: 1 dose, IM EARLY USE IN: Russia • STORAGE: Up to two years frozen at –4° F (–20° EMERGENCY USE IN: Algeria, Argentina, Belarus, Bolivia, C), and up to three months refrigerated at 36–46° F Guinea, Hungary, Iran, Palestinian Authority, Paraguay, Serbia, Turkmenistan, United Arab Emirates, Venezuela (2–8° C)

Sadoff et al. Interim Results of a Phase 1-2a Trial of Ad26.COV2.S Covid-19 Vaccine. N Engl J Med. 2021 https://www.jnj.com/johnson-johnson-announces-single-shot-janssen-covid-19-vaccine-candidate-met-primary-endpoints-in-interim-analysis-of-its- phase-3-ensemble-trial Sputnik V

• Gam-Covid-Vac - Gamaleya Two replication-incompetent adenovirus Institute/Russian Direct Investment Fund vectors (Ad26 →Ad5) RDIF 3:1 Confirmed Efficacy • EFFICACY: 91.4% (19 866) COVID-19 (78) • DOSE: 2 doses, 3 weeks apart, IM Vaccine 14 964 16 91.6% st • STORAGE: Freezer storage. Developing After 1 dose an alternative formulation that can be Placebo 4 902 62 refrigerated (20 severe cases) EARLY USE IN: Russia • No unexpected adverse effects EMERGENCY USE IN: Algeria, Argentina, Belarus, Bolivia, Guinea, Hungary, Iran, Palestinian Authority, Paraguay, Serbia, Turkmenistan, United Arab Emirates, Venezuela

Logunov DY et al. Safety and immunogenicity of an rAd26 and rAd5 vector-based heterologous prime-boost COVID-19 vaccine in two formulations: two open, non-randomised phase 1/2 studies from Russia. Lancet. 2020 Logunov, DY et al. Safety and efficacy of an rAd26 and rAd5 vector-based heterologous prime-boost COVID-19 vaccine: an interim analysis of a randomised controlled phase 3 trial in Russia. Lancet 2021 Novavax

• NVX-CoV2373 • 2-dose protein-adjuvant (Matrix-M1) • DOSE: 2 doses, 3 weeks apart, IM • STORAGE: Stable in refrigerator • 89.3% effectiveness in UK trial (>50% cases UK variant) • 49.4% in South Africa (>90% cases are B.1.351 variant) - 60% efficacy in those HIV neg - A new version tailored with the variant is being developed • Phase 3 US and Mexico began Dec 2020 Phase 1 Keech et al. Phase 1–2 Trial of a SARS-CoV-2 Recombinant Spike Protein Nanoparticle Vaccine. NEJM 2020 https://ir.novavax.com/news-releases/news-release-details/novavax-covid-19-vaccine-demonstrates-893-efficacy- uk-phase-3 Immunomodulatory therapy and COVID-19 vaccination

Risks Benefits Immunomodulatory therapy and COVID-19 vaccination timing in Rheumatic disease

Medication Recommendation Hydroxychloroquine No modification to either this therapy or IVIg vaccination timing Glucocorticoids Sulfasalazine Leflunomide Mycophenolate Azathioprine PO Cyclophosphamide TNF IL-6R, IL-1 Methotrexate Hold MTX 1 week after each vaccine dose JAKi IV Cyclophosphamide CYC >1 week after each vaccine dose Rituximab Schedule vaccine at least 4 weeks prior to RTX Delay RTX 2-4 weeks after 2nd dose Real-world Data on Pfizer-BioNTech Vaccine • 596,618 vaccine recipients matched with unvaccinated controls • Study outcomes - documented infection with the severe acute respiratory syndrome coronavirus 2 (SARS- CoV-2), symptomatic Covid-19, Covid-19– related hospitalization, severe illness, and death Dagan N, Barda N, Kepten E, Miron O, Perchik S, Katz MA, Hernán MA, Lipsitch M, Reis B, Balicer RD. BNT162b2 mRNA Covid-19 Vaccine in a Nationwide Mass Vaccination Setting. N Engl J Med. 2021 Feb 24:NEJMoa2101765. Real-world Data on Pfizer-BioNTech Vaccine

Dagan N, Barda N, Kepten E, Miron O, Perchik S, Katz MA, Hernán MA, Lipsitch M, Reis B, Balicer RD. BNT162b2 mRNA Covid-19 Vaccine in a Nationwide Mass Vaccination Setting. N Engl J Med. 2021 Feb 24:NEJMoa2101765. Vaccine Efficacy vs Variants

• Serum Neutralization of Variant Strains of SARS-CoV-2 after the Second Dose of BNT162b2 Vaccine • Lower effectiveness against B.1.351 variant as compared to B.1.1.7 variant

Liu Y, Liu J, Xia H, Zhang X, Fontes-Garfias CR, Swanson KA, Cai H, Sarkar R, Chen W, Cutler M, Cooper D, Weaver SC, Muik A, Sahin U, Jansen KU, Xie X, Dormitzer PR, Shi PY. Neutralizing Activity of BNT162b2-Elicited Serum. N Engl J Med. 2021 Mar 8. Vaccine Efficacy vs Variants

• Neutralizing activity of the mRNA- 1273 vaccine • serum neutralization of the B.1.1.7 variant was not significantly reduced • Reduction in neutralizing activity by factor of 6.4 against the B.1.351

Wu K, Werner AP, Koch M, Choi A, Narayanan E, Stewart-Jones GBE, Colpitts T, Bennett H, Boyoglu-Barnum S, Shi W, Moliva JI, Sullivan NJ, Graham BS, Carfi A, Corbett KS, Seder RA, Edwards DK. Serum Neutralizing Activity Elicited by mRNA-1273 Vaccine. N Engl J Med. 2021 Mar 17. Vaccine Safety

• RCTs are not powered to detect rare events - Can only detect common adverse effects • Active and passive surveillance systems - VAERS (US) - EudraVigilance (EU) - VigiBase (WHO) - Vaccine Safety Datalink (VSD) - DOH Pharmacovigilance ACIP. COVID-19 Vaccine Safety Update. Available at: ACIP March 1, 2021 Presentation Slides | Immunization Practices | CDC. Anaphylaxis Pfizer – Moderna Reporting Rate BioNtech (Cases per 4.7 2.5 million doses administered)

Shimabukuro TT, Cole M, Su JR. Reports of Anaphylaxis After Receipt of mRNA COVID-19 Vaccines in the US-December 14, 2020-January 18, 2021. JAMA. 2021 Mar 16;325(11):1101-1102.

Delayed Vaccine Reactions • Phase 3 trial, delayed injection-site reactions occurred in 0.8% participants after the first dose and in 0.2% after the second dose • Case series of 12 patients with delayed large cutaneous reactions - Median onset of day 8 (4 – 11 days) - Appeared near the injection site - All twelve patients received subsequent second dose - Half of which had recurrence of the local reaction • Not considered a contraindication to continue the vaccine series

1. Blumenthal KG, Freeman EE, Saff RR, Robinson LB, Wolfson AR, Foreman RK, Hashimoto D, Banerji A, Li L, Anvari S, Shenoy ES. Delayed Large Local Reactions to mRNA-1273 Vaccine against SARS-CoV-2. N Engl J Med. 2021 Mar 3:NEJMc2102131. 2. Baden LR, El Sahly HM, Essink B, et al. Efficacy and safety of the mRNA-1273 SARS-CoV-2 vaccine. N Engl J Med 2021;384:403-416.

VSD Rapid Cycle Analysis (RCA) aims

• Monitor the safety of COVID-19 vaccines weekly using pre-specified outcomes of interest among VSD members • Assess each pre-specified outcome for a 1-21 and 1- 42 day risk interval • Describe the uptake of COVID-19 vaccines over time among eligible VSD members

ACIP. COVID-19 Vaccine Safety Update. Available at: ACIP January 27, 2021 Presentation Slides | Immunization Practices | CDC. • Preliminary results of VSD unvaccinated concurrent comparator analyses for either dose of the mRNA COVID-19 vaccines.

• No signals as of February 13.

ACIP. COVID-19 Vaccine Safety Update. Available at: ACIP March 1, 2021 Presentation Slides | Immunization Practices | CDC. Global Advisory Committee on Vaccine Safety (GACVS)

• The GACVS was established in 1999 by the World Health Organization to respond to vaccine safety issues of potential global importance

WHO | Global Advisory Committee on Vaccine Safety (GACVS) Safety of AstraZeneca COVID19 Vaccine