COVID-19 Vaccines Lecture

COVID-19 Vaccines Patricia Fitzgerald-Bocarsly, PhD Professor, Pathology, Immunology and Lab. Medicine Rutgers NJMS [email protected] September 24, 2024  Passive Immunity: temporary protection Transfer of products of the imm...

COVID-19 Vaccines Patricia Fitzgerald-Bocarsly, PhD Professor, Pathology, Immunology and Lab. Medicine Rutgers NJMS [email protected] September 24, 2024  Passive Immunity: temporary protection Transfer of products of the immune response rather than inducing an active immune response Maternal IgG that crosses the placenta in third trimester, conferring protection to neonate Janeway, Ed. 10, 2022, Figure 13.5 2 Passive immunity: temporary protection MAb to respiratory syncytial virus (RSV) – given to preemies, who didn’t get benefit of maternal transfer of antibodies New RSV vaccine for pregnant mothers: antibody passes to fetus Pooled immunoglobulin for those with antibody deficiency Immune globulin or immune plasma helped individuals with Ebola virus Transfer of NK cells or T cells – e.g. CAR-T cells for cancer therapy What works in COVID-19? Convalescent plasma from individuals who have recovered from COVID-19 Some evidence it might help, pooled plasma from >1000 donors wasn’t effective Compassionate use approval from FDA Not all plasmas are equivalent: Improved by measuring virus neutralizing titer of the antibody Bottom line: not being used because of superiority of monoclonal antibodies 3 Monoclonal Antibody (Mab)Therapy Human MAb to the receptor-binding domain (RBD) of Spike protein Identified cells infected with SARS and SARS CoV-2 but not MERS Prevented replication in vitro of both SARS and SARS CoV-2 Three ”cocktails” of 2 mAbs had early emergency use authorization Regeneron (given to Trump) Eli Lily (given to Christie) Vir/Glaxo sotrovimab Because of shifting to omicron Variant Of Concern, decreased efficacy. Now available are Bebtelovimab, Tixagevimab plus cilgavimab with omicron BA.4 and BA.5. 4  Nanobodies from Llamas Winter the Belgian Llama Nanobodies Tiny antibodies 10 years to develop Need for COVID-19 vaccine was urgent Global COVID-19 pandemic has prompted unprecedented effort due to urgency: As of 11/9/22 US has had 98 M confirmed infections; (48 M a year before) US Deaths: 1.07M deaths; 2,500/week; (0.77M a year before) Unprecedented international effort for vaccine development, with leading candidates filing for approval just 10-11 months post identification of SARS-CoV-2 11  FDA Vaccine Approval Scheme Biologics Post- Animal Safety/ license marketing Safety Efficacy In vitro models efficacy application monitoring Placebo Placebo Data, controlled controlled production small large marketing study study review (30,000 Tested on plus subjects) Young, healthy 12  PRECLINICAL TESTING: Scientists test a new vaccine on cells and then give it to animals such as mice or monkeys to see if it produces an immune response. We have confirmed 87 preclinical vaccines in active development. Stages of PHASE 1 SAFETY TRIALS: Scientists give the vaccine to a small number of people to test safety and COVID-19 dosage as well as to confirm that it stimulates the immune system. Vaccine PHASE 2 EXPANDED TRIALS: Scientists give the Testing vaccine to hundreds of people split into groups, such as children and the elderly, to see if the vaccine acts differently in them. These trials further test the vaccine’s safety and ability to stimulate the immune system. 13  PHASE 3 EFFICACY TRIALS: Scientists give the vaccine to thousands of people and wait to see how many become infected, compared with volunteers who received a Stages of placebo. These trials can determine if the COVID-19 vaccine protects against the coronavirus. In June, the F.D.A. advised vaccine makers that Vaccine they would want to see evidence that Testing vaccines can protect at least 50 percent of those who receive it. In addition, Phase 3 (cont.) trials are large enough to reveal evidence of relatively rare side effects that might be missed in earlier studies. https://www.nytimes.com/interactive/2020/science/coronavir us-vaccine-tracker.html 14  EARLY OR LIMITED APPROVAL: China and Russia approved vaccines without waiting for the results of Stages of Phase 3 trials. Experts say the rushed process has serious risks. COVID-19 APPROVAL: Regulators in each country Vaccine review the trial results and decide whether to approve the vaccine or not. During a Testing pandemic, a vaccine may receive emergency (cont.) use authorization before getting final approval. UK approved use of Pfizer vaccine on 12/2/20 after 10 days review. 15 mRNA vaccines 1. Stabilized mRNA encapsulated in lipid bilayer injected into host 2. Taken up through host endocytic pathways into endosomes 3. mRNA escapes to cytoplasm 4. Directly translated non-replicating mRNA (NRM) at ribosome (Moderna and Pfizer) 5. Amplified (self-amplifying mRNA (SAM) 6. SAM translated at ribosome 7. Protein secreted, trans-membrane, or intracellular protein 8. Presented with MHC class I or secreted leading to activation of innate and adaptive responses 16  mRNA vaccines: NRM vs SAM mRNA vaccine type Mechanism Replication Non-replicating mRNA These vaccines deliver The mRNA does not synthetic mRNA encoding a replicate within the host specific antigen (usually a cells; it is translated into protein from the pathogen) protein and then degraded. directly into cells. The cells then translate this mRNA into the protein, which triggers an immune response. Self-amplifying mRNA These vaccines also deliver The self-amplifying mRNA mRNA, but the mRNA replicates in the host cells, includes additional genetic resulting in a higher elements that enable it to expression of the antigen replicate itself within the and potentially a stronger host cells. This means that a immune response. single dose of the vaccine can lead to the production of many copies of the mRNA. 17 Modifying bases in mRNA to reduce activation of dendritic cells through RNA receptors UnModifed mRNA given = innate receptors recognize and induce an inflammatory response. Pseudouridine made the mRNA vaccine safer because it decreased the inflammatory response. 18  mRNA vaccines: Moderna and Pfizer Antibody and T mRNA for Spike in lipid coat cell responses; memory SPIKE protein processed and Internalized by presented with MHC or fusion, delivering secreted and taken up by RNA to cytoplasm APC mRNA translated on ribosome 19 COVID-19 mRNA vaccine constructs Moderna designed their construct in 2 days after sequence of Spike was known! BioNTech was ready to go as well. mRNA contains conserved region of Spike and stabilizing elements, poly A tail Different lipid formulation and different stabilization of the mRNA lead to different storage requirements for Moderna and Pfizer/BioNTech, but testing has demonstrated that both mRNA vaccines are much more stable than previously thought 20 mRNA vaccine clinical trials: “First in humans” Moderna Pfizer 2 doses plus booster after 6 mo. 2 doses plus booster after 6 mo. Placebo controlled; different age Placebo controlled, different age groups and co-morbidities, ethnicities groups; children 12 years and up Endpoint: Symptomatic infection 1-2 Endpoint: Symptomatic infection 1-2 weeks or more after second injection weeks or more after second injection Compare cases in placebo vs. vaccine Compare cases in placebo vs. vaccine ~95% effective vs. placebo ~95% effective vs. placebo Some severe cases in placebo, none in Beat the min 50%. vaccine group No severe cases in either group Caveat: Clinical trials do not measure Caveat: Does not measure asymptomatic infection asymptomatic infections US EAU 12/18/20 US EAU 12/11/21; approved by FDA 8/23/21 21 Replicating Viral Vector and Non-replicating Viral vector vaccines also were looked into as a response to COVID-19. The use of replicating or non-replicating viral vectors. Insert piece of viral genome (spike gene in genome), then protein is transcribed and translated into Spike protein, generating an immune response. 22 Astra Zeneca/Oxford Adenoviral Vector Vaccine Were already working on Coronaviruses before SARS-CoV-2 Same adenovirus vector as newly released Ebola virus vaccine, so safety profile was established Included in clinical trial is testing for SARS-CoV-2 two weeks after 2nd immunization – so, trials pick up asymptomatic infections Math error meant a subset (2700 people) receive a half dose on first immunization, followed by full dose Used in UK and possible that it gives better/longer lasting T cell immunity that could account for more stable hospitalizations in England than in the rest of Europe??? (no proof) 23 Johnson and Johnson Adeno vector vaccine Trialed and EUA with one dose; later recommended two doses or mRNA boost. Rutgers participated in testing this vaccine Fall 2021: CDC recommended everyone with J & J vaccine receive a dose of one of the mRNA vaccines because of waning immunity and lower protection May 2023: J & J vaccine no longer available in the US 24 109 in human trials; 75 in preclinical animal studies Room for many vaccines and improvement in vaccines – 2nd and 3rd generation. E.g. whole cell vs. acellular pertussis, killed vs. live Polio vaccines; Herpes Zoster Vaccines – first generation was ~60% effective, newer one >90% effective 25 Novavax – likely to be used internationally and for those who can’t tolerate mRNA vaccines Protein subunit vaccines (Novavax) Protein subunit vaccine contains: SPIKE protein Lipids (cholesterol and Phosphatidylcholine) – allows SPIKE to enter cell Adjuvant: Fraction A and C of Quilaja Saponaria Molina extract Activates innate immune system Stabilizers: Keep the vaccine stable No preservatives Received EUA in 2022; replaced by updated version for 2024/25 season 26 COVID-19 Vaccines in the US – one dose 27 28  Current status of COVID-19 vaccines in fall of 2024 By the end of 2022, COVID-19 vaccines had prevented 18.5 million COVID-19 hospitalizations and 3.2 million COVID-19 deaths in the United States (https://covid.cdc.gov/covid-data-tracker/#variant-proportions) As of Oct. 28, 2023; ~6.5M hospitalizations, ~1.15M deaths in US As virus evolved, waning Vaccine Effectiveness (VE) Point mutations at Receptor Binding Domain on spike that accumulate are able to mutate rapidly. New vaccine needed annually. SARS-CoV-2 XBB-sublineage variants, which, by September 2, 2023, accounted for >99% of sequenced SARS-CoV-2 specimens in the United States. Approved vaccine for fall of 2023 targets this strain; recommended for individuals 6 months and up mRNA vaccine from Pfizer or Moderna Safe for immunodeficient individuals Omicron XBB.1.5 updated protein vaccine from Novavax – adjuvanted (from bark of a Chilean Tree) Spike protein vaccine; further updated for fall of 2024 29 Recommendations for Fall of 2024 2.3% of US deaths due to COVID-19 as of 9/14/24 and 4.1/100,000 hospitalized Received previous doses of a COVID-19 vaccine Ages 6 months–4 years 1 or 2 doses of 2024–2025 mRNA vaccine from the same manufacturer as administered for initial vaccination, depending on the vaccine and the number of prior doses Ages 5–11 years 1 dose of 2024–2025 Moderna OR 1 dose of 2024–2025 Pfizer-BioNTech Ages 12 years and older 1 dose of 2024–2025 Moderna (Omicron variant KP.2) OR 1 dose of 2024–2025 Pfizer-BioNTech (Omicron variant KP.2) OR 1 dose of 2024–2025 Novavax (Omicron variant JN.1 strain) Note that KP.2, KP.2.3, KP.3 and KP.3.1.1, as well as LB.1 are circulating with ~half of infections in Sept. 2024 with KP.3.1.1 but KP-2 vaccine is protective. KP-1 and -2 were FLiRT variants based on amino acid changes in Spike protein. 30  How do we know a vaccine is working? Measurement of virus-specific antibody (IgG) titer from blood serum by ELISA assay: Abcam.com 31  T cell activation: Principle of the IFNg release assay + T cell activation looking for interferon gamma release by memory cells that are going to get activated and release interferon gamma.  COVID-19 IFN release assay COVID-19 IFNg release assay Individuals with natural PBMC stimulated with infection will have a SARS-CoV-2 SARS-CoV-2 high interferon gamma non-spike peptides spike peptides release to SARS-CoV-2 non-spike peptides and spike peptides. SARS-CoV-2 infected SARS-CoV-2 vaccinated will have a high interferon gamma Vaccinated release when stimulated with spike peptides. Naïve 0 50 100 150 200 250 0 50 100 150 200 250 Naïve individuals (no vaccine or natural IFNγ (pg/ml) infection) will have no interferon gamma release.  How do we know a vaccine is working? Measure ability of serum antibody to neutralize pseudotyped virus or live virus – i.e. prevent ability of the serum antibody to prevent infection of susceptible cells Measure length of time antibody levels (titers) stay high in the serum Measure antigen-specific T cell responses Real-world efficacy: Prevention of symptomatic infection Prevention of severe disease/hospitalization Prevention of death Currently, the majority of hospitalizations with COVID-19 are non-vaccinated individuals but are seeing vaccine breakthrough cases; 9/10 deaths in >65 y.o. 34  Challenges to Developing a Vaccine Time to develop – typically, a new vaccine takes 10 years; we needed this immediately. Geared up production before Clinical Trials done. Combine Phase 1/2 or 2/3; Speed up phase 3. Live virus challenge to human donors? Which ones? Many initial vaccines get replaced by improved ones What kind of response do we need? Antibody? T cell-mediated immunity? How will we demonstrate efficacy? How long will immunity last? Do we need boosters? Can virus mutate and escape? Do we need new vaccines periodically? Yes – anticipate annual updated vaccines What about immunosuppressed individuals? 35  Challenges to Developing a Vaccine (cont.) Presence of animal hosts: Smallpox eliminated because there is no animal reservoir, but wild bats harbor Coronaviruses (500 species of coronaviruses isolated!!) What level of penetration do we need to get herd immunity? Reason for concern: unvaccinated or under vaccinated people From the Washington Post Editorial Board 12/2/20: citing disinformation and conspiracy theories: “Will New COVID Vaccine Make You Transhuman?” “This vaccine will not only ‘mark’ you like a cattle,” reads another website, “you will be injected with nano particules [sic] that will make you a Perfect antenna for the 5g frequencies.” 36