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 • 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. 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 S1 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 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