Immunizations Part 2 Session 18 PDF

Immunizations, Part 2 Session 18 MICRG 1553 Lisa Kronstad, Ph.D. [email protected] https://www.cdc.gov/vaccines/index.html October 2, 2024 Cholla D 1 Learning Objectives Be able to describe how inactivated vs. attenuated vaccines...

Immunizations, Part 2 Session 18 MICRG 1553 Lisa Kronstad, Ph.D. [email protected] https://www.cdc.gov/vaccines/index.html October 2, 2024 Cholla D 1 Learning Objectives Be able to describe how inactivated vs. attenuated vaccines are developed, examples of each platform, and their pros and cons Describe how the 1960's RSV vaccine candidate triggered enhanced respiratory disease and how this illustrates the importance of vaccine correlates of protection Identify the patient populations for which live attenuated vaccines are contraindicated Given a person seeking in uenza vaccination, be able to identify appropriate vaccine platform recommendation Describe how mRNA lipid nanoparticle (P zer/Moderna) COVID-19 vaccines elicit an immune response and how their ef cacy/safety pro le was established 2 fi fi fl fi Lecture Outline Oral Polio Vaccine as an example of an attenuated vaccine Inactivated Vaccine Candidate for RSV Inactivated In uenza Vaccines - new vaccines are urgently needed mRNA-based vaccines used for COVID-19 3 fl Ways to make an active vaccine Attenuated and "Killed/ Inactivated" vaccines are the historical modes of developing active vaccines 4 https://www.nature.com/articles/s41577-020-00479-7/ gures/2 fi Replication competent, attenuated vaccines "Live" Pathogen replication occurs, stimulates memory immune response Infection with vaccine strain induces mild or inapparent disease Attenuated vaccines are contraindicated in pregnancy and immunode ciency because they require an immune response to clear the infection It is safe to administer attenuated vaccines to people living with HIV with CD4 T cell count > 200 cells/mm3 5 Kuby Table 17-6 fi Empirically-derived attenuated vaccines Attenuation is done by passaging the pathogen in animal cell The Oral Polio Vaccine (OPV) was attenuated by passing in animal cells (monkey kidney cells) and replicates in gut- associated tissues 6 Principles of Virology, ASM Press Sabin Oral Poliovirus vaccine (OPV) Delivered orally (sugar drop) Generates transient intestinal immunity and durable systemic immunity Virus is shed up to a month and can circulate and persist for years in the environment and community Eliminated poliomyelitis (NOT poliovirus) from US in 197 Global eradication of poliomyelitis is nearly within reach https://www.cdc.gov/ u/prevent/nasalspray.htm 7 Principles of Virology, ASM Press fl Attenuation of poliovirus neurovirulence Changing only a few nucleotides eliminates the ability of the virus to cause paralysis Vaccine-attenuating mutations are found in 5’UTR of viral RNA in a highly structured location These changes are unstable and can revert to the original virulent form of the virus (wild type) 8 Reported cases of paralytic poliomyelitis 1961-2003 1 paralytic case / 1.4 million doses of OPV administered to children U.S. uses the inactivated polio vaccine (since 2000) to minimize the risk of vaccine-derived 9 paralytic poliomyelitis Polio in New York 2022 Paralytic case in New York caused by vaccine-derived Sabin OPV2 Low vaccination coverage Viral genomes found in local wastewater Solution: vaccinate with IPV! 10 Designed attenuated vaccines Molecular biology now permits attenuation to be done with precision New Oral Polio Vaccine (OPV) has a reduced ability to acquire mutations needed for replication in neuronal tissues 11 Lecture Outline Oral Polio Vaccine as an example of an attenuated vaccine Inactivated Vaccine Candidate for RSV Inactivated In uenza Vaccines - new vaccines are urgently needed mRNA-based vaccines used for COVID-19 12 fl Inactivated vaccines New: Sinovac COVID-19 vaccine CoronaVac Chemical procedures such as the use of formalin, beta-Propiolactone, or nonionic detergents Pathogen is replication-defective, antigenicity is intact, although may be compromised Safe in pregnant and immunode cient individuals 13 Kuby Table 17-6 fi No available active vaccine for RSV in children 14 https://www.youtube.com/watch?v=egGUL7igwTQ Vaccine Candidate for Respiratory Syncytial Virus Enhanced Respiratory disease (ERD) Clinical trial evaluated an RSV vaccine candidate in the 1960's - formalin-inactivate 80% of the children receiving the vaccine candidate vs. 5% of placebo experienced serious disease - 2 died The candidate resulted in priming of severe illness upon natural infection This tragedy stymied RSV vaccine development for 60 years 15 d : Vaccine for Respiratory Syncytial Virus Enhanced Respiratory disease (ERD) RSV vaccine candidate in the 1960's elicited pulmonary eosinophilia due to CD4+ T cells secreting TH2 cytokine Triggered production of non-neutralizing antibodie Correlates of protection remain unclear - likely involve CD4+ T cells secreting TH1 cytokines and neutralizing antibodies to the F protein 16 https://pubmed.ncbi.nlm.nih.gov/30107412/ s : s Correlates of Immune Protection Only responsible for what was said in class 17 Janeway Figure 11.15 Lecture Outline Oral Polio Vaccine as an example of an attenuated vaccine Inactivated Vaccine Candidate for RSV Inactivated In uenza Vaccines - new vaccines are urgently neede mRNA-based vaccines used for COVID-19 18 fl d Influenza Virus Vaccine against types A and B Inactivated In uenza vaccination is recommended for everyone >6 months old Live Attenuated In uenza Vaccine (LAIV) nasal spray vaccine available for ages 2-49 in immunocompetent, non-pregnant 19 individuals fl fl Influenza Virus Virology Hemagglutinin (HA) binds sialic acid to gain entry to host cells Neuraminidase (NA) cleaves HA-sialic acid to release viral particles 20 Shi et al. (2014) Nat. Rev. Micro Influenza Inactivate Virus Vaccine against types A and B 12,000-52,000 deaths/yr in the US due to in uenza virus Inactivated In uenza Vaccine (IIV) cornerstone of public health 4 strains - re-formulated annually Virus grown in embryonated chicken egg Formalin-inactivated virions Intramuscular Injection 75-100 million doses are manufactured each year in the US Correlate of Protection: serum antibodies to HA, NA 21 fl s fl Influenza Virus Vaccine challenges Effectiveness against symptomatic illness is carefully monitored each season: Flu vaccine reduced children’s risk of u-related PICU admission by 74% during u seasons from 2010-201 Current vaccine strategies represent the best way we have of protecting ourselves and others from in uenza-related morbidity and mortality 22 , https://www.cdc.gov/ u/professionals/vaccination/effectiveness-studies.htm fl fl fl 2 fl Selecting a seasonal influenza virus vaccine Surveillance of Southern Hemisphere informs strain selection 23 Developing a pandemic influenza virus vaccine Six months is too long for production - this is primarily why vaccines were not available until AFTER the peak of the 2009 in uenza pandemic 24 Krammer and Palese (2015) Nat. Rev Drug Discovery fl Influenza vaccines for older adults Patients aged 65 and older are eligible for two different inactivated in uenza vaccines: 1 - High-dose vaccine with 4- fold more antigen was shown to be 24% more effective in >65 age group 2 - Standard-dose IIV with an adjuvant are available for ≥ 65 age group. Adjuvants are added to some vaccines to enhance the immune response to vaccine antigen 25 fl Influenza vaccination reduces community spread Epidemiology: Widespread vaccination of children with IIV reduces mortality and illness in older adult Guinea pig model: Vaccination with IIV reduced transmission between animals The inactivated in uenza vaccine is only available after 6 months of age and in uenza vaccination is less effective in older adults - thus the most vulnerable populations rely on the immunity of the population and their healthcare providers https://jvi.asm.org/content/83/7/2803#ref-40 https://pubmed.ncbi.nlm.nih.gov/5433709/ 26 https://pubmed.ncbi.nlm.nih.gov/11259722/?dopt=Abstract fl fl s Lecture Outline Oral Polio Vaccine as an example of an attenuated vaccine Inactivated Vaccine Candidate for RSV Inactivated In uenza Vaccines - new vaccines are urgently needed mRNA-based vaccines used for COVID-19 27 fl Greatest effort to develop a vaccine in human history SARS-CoV-2 sequence deposited on January 12th 2020 - Tony Fauci was on the phone the next day with Moderna, Inc, to create a mRNA- based vaccine - a vaccine platform never before licensed to address the greatest infectious disease threat since 1918. Why? Ways to make an active vaccine Rapid and scalable manufacturing Excellent safety pro le (non-infectious, degraded by normal cellular processes) even in immunocompromised individuals Immunogenic - drives formation of memory B and T cells without anti- vector immunity 29 https://www.nature.com/articles/s41577-020-00479-7/ gures/2 fi fi A new class of vaccine - mRNA DNA encoding the antigen of interest (spike for COVID-19) Promoter for RNA polymerase to synthesize mRNA in vitro Packaged into lipid nanoparticles 30 SARS-CoV-2 Virology RNA virus surrounded by a lipid envelope decorated with the viral Spike protein - major vaccine candidate target Antibodies that bind to Spike prevent infection (neutralize) https://www.pnas.org/content/106/2/582 SARS-CoV-2 spike protein Spike binds to ACE2, cleaved at cell surface, spike undergo conformational change, antibodies to the post-fusion form aren't neutralizing/protective antibodies Prolines prevent conformational change - traps spike in pre-fusion form that has the epitopes needed to trigger protective antibodies 32 Principles of Virology, ASM Press mRNA-Vaccines Injected into muscle Dendritic cells take up mRNA-LNPs and synthesize viral Spike protein, which is then processed and presented DCs displaying viral peptides traf c to lymph node and present to T cells Generation of effector and memory B and T cells Dramatically reduce COVID-19 disease severity upon SARS-CoV-2 infection 33 fi Pfizer BNT162b2 COVID-19 Data Phase 3 data Transient high levels of antibodies reduce infection Long-term memory B and T cells reduce disease https://www.nejm.org/doi/suppl/10.1056/NEJMoa2034577/suppl_ le/nejmoa2034577_research-sum https://www.nejm.org/doi/full/10.1056/NEJMoa2034577 fi COVID-19 Active Vaccines available in the USA Licensed mRNA-based vaccines containing mRNA encoding for pre- fusion Spike surrounded by a lipid nanoparticle Comirnaty® Pfizer-BioNTech SpikeVax® Moderna EUA: Protein Subunit vaccine contains recombinant spike protein and an adjuvant Novavax https://www.cdc.gov/vaccines/covid-19/clinical-considerations /interim-considerations-us.html Global impact of the st year of COVID-19 vaccination; a mathematically modeling study. https://doi.org/10.1016/S1473-3099(22)00320-6. fi COVID-19 Active Vaccines available in the USA Pfizer/Moderna are available for ages >6 months Contraindications: History of a severe allergic reaction after a previous dose or to a component of the COVID-19 vaccine History of a diagnosed allergy to a component of the COVID-19 vaccine. Safe in immunocompromised individuals, however efficacy may be reduced Confers high rates of protection against severe disease and My 2-year-old receiving his second SpikeVax dose! death Vaccination began in late 2020 and is estimated to have averted at least 14 million deaths https://www.cdc.gov/vaccines/covid-19/clinical-considerations /interim-considerations-us.html Global impact of the st year of COVID-19 vaccination; a mathematically modeling study. https://doi.org/10.1016/S1473-3099(22)00320-6. fi Take Home Messages Attenuated vaccines have historically been made by passaging the virus in non-human cell types. These vaccines should not be administered to immunocompromised individuals and may pose a risk of reversion back to the virulent form. Oral Polio Vaccine (OPV) triggers mucosal and systemic immunity, protecting from paralysis, and leads to transient gut immunity Vaccines must generate the correct immune response; induction of a TH2 immune response to an inactivated RSV vaccine candidate triggered enhanced disease upon infection Inactivated vaccines are unable to replicate but can stimulate an immune response; they are safe in pregnant and immunocompromised individuals All individual over 6 months are eligible for inactivated In uenza vaccines, which are formalin- inactivated and confer critical protection from severe disease and reduce transmission to vulnerable individuals. 4-fold antigen or adjuvant vaccines should be offered to those ≥65 years The COVID-19 mRNA vaccines encode Spike that when expressed is stabilized in the pre-fusion conformation trigger a robust memory B and T cell response - lipid nanoparticle enhance uptake by cells Vaccines don't save lives - Vaccinations do! What will be your vaccine policy as a future pharmacist? How will you help best inform your patients about the risks and bene ts of vaccination? 37 fl End of Lecture SUPER happy to answer questions via e-mail, Teams or in person - feel free to e-mail me to set up of ce hours or stop by! 360-D Science Hall. Will return all e-mails within 24 hr period! 38 fi End of Lecture Vaccines don't save lives - vaccinations do! 39