Vaccine Therapeutics PDF

Vaccine therapeutics ©FierceBiotech Christina Sakellariou, PhD Department of Immunotechnology November 2024 [email protected]  Lecture’s...

Vaccine therapeutics ©FierceBiotech Christina Sakellariou, PhD Department of Immunotechnology November 2024 [email protected]  Lecture’s objectives Understand the need for vaccination in the general population What is a vaccine, why is herd immunity needed Prophylactic and therapeutic vaccines: what are the differences and what the applications of each Vaccine types: understand the difference between them, mechanism of action, advantages/limitations and remember some examples of each To be able to elaborate and discuss which vaccine type would be more fitting to target specific pathogens or cancer mRNA vaccines and cancer vaccines: to be able to describe the mechanism of action, limitations, challenges and future directions Department of Immunotechnology, Lund University  Terminology A vaccine is a biological preparation that provides active acquired immunity to a particular infectious disease. Vaccines can be prophylactic (to prevent a future infection), or therapeutic (to fight a disease that has already occurred, such as cancer). The purposes of vaccination are to limit the spread of infectious diseases and protect those who cannot be vaccinated. Department of Immunotechnology, Lund University  Vaccines stimulate a protective immune response Department of Immunotechnology, Lund University Generation of immune response: step by step 1) Vaccine injected into muscle 2) Protein Ag taken up by DCs (activated through pattern recognition receptors by danger signals in the adjuvant) 3) Trafficked to draining lymph nodes 4) Peptide presentation- MHC -> T cell activation + signalling (by soluble Ag) through B cell receptor ➔ T cells drive the B cell development in the LN ➔ Maturation of the Ab response increases Ab affinity and induces different Ab isotypes ➔ Production of short-lived plasma cells, secrete vaccine protein- specific Abs, increase the serum Ab levels. ➔ Memory B cells are produced ➔ Long-lived plasma cells that can produce Abs for decades, travel to bone marrow niches ➔ CD8+ memory T cells: proliferate rapidly when Pollard, A.J., Bijker, E.M. 2021 encountering a pathogen ➔ CD8+ effector T cells eliminate infected cells Brief history of vaccination 1796; Edward Jenner - Variolae vaccinae (smallpox of the cow) 1885; Louis Pasteur- rabies vaccine; introduced the term vaccination from vacca (Latin, cow) in honor of Edward Jenner Introduced live attenuated (weakened) forms of the disease-causing bacterium: Immunized sheep against anthrax 1897; live attenuated cholera vaccine 1904; inactivated anthrax vaccine for humans 1930s; yellow fever and influenza vaccines 1980; global eradication of smallpox and near-total elimination of polio 1990s: mRNA vaccines start being investigated Between 2000 and 2018, measles vaccinations prevented 23M deaths, while polio vaccines decreased the number of children paralyzed by the disease by 99% since 1988. Department of Immunotechnology, Lund University Global scale of vaccines Department of Immunotechnology, Lund University Herd immunity Herd immunity gives population scale immunity when critical level of vaccination has been achieved Pollard, A.J., Bijker, E.M. 2021 Department of Immunotechnology, Lund University  Herd immunity Virus spread stops when the probability of infection drops below a critical level This critical level is virus- and population- specific o population % that needs to be vaccinated to achieve herd immunity is 80-85% for polio and 90-95% for measles (highly contagious) None of the vaccines is or will be 100% effective For example – In order to achieve the critical level of infection to be 80% we need to vaccinate approximately 89% of population effectiveness of the smallpox vaccine is ~90% critical level of infection is 80% 80% divided by 90% is 89% Department of Immunotechnology, Lund University  Prophylactic and therapeutic vaccines Prophylactic Therapeutic ❑ Engage the immune system to fight off a disease in the ❑ Strengthen immune system to fight an existing infection future ❑ Confer protection against a pathogen or disease by building ❑ Designed for treatment of cancer, some infectious diseases immunity (e.g. HIV, HepB, dengue fever), and neurodegenerative diseases (e.g. Parkinson’s, Anzheimer’s). Coax B cells to produce pathogen-specific antibodies Antibodies bind to a specific antigen “marking” the pathogen for destruction by the immune system Examples: polio, measles, smallpox Examples: Sipuleucel-T (DC-based therapeutic vaccine) for prostate cancer. 2022: Moderna: phase I trial - mRNA vaccine for HIV TherVacB: vaccine candidate for HepB which may benefit 3% of 2023: GSK conducting a phase II trial for HSV (interrupted as of world population already infected with HepB and cannot benefit 09/2024) from other prophylactic vaccines (3-year clinical trial started in 2022). Department of Immunotechnology, Lund University Vaccine types Killed whole organism Live attenuated Outer membrane vesicle Nucleic acid Subunit (purified protein, rec. protein, polysaccharide, peptide) Pathogen Toxoid Protein-polysaccharide conjugate Bacterial vector Antigen presenting cell Virus-like particle Viral vector Department of Immunotechnology, Lund University Live attenuated vaccine: weakened or inactivated Live attenuated Mechanism of action: live or weakened form of the pathogen Advantages: strong and long-lasting (lifelong immunity possible with 2 doses) Limitations: a. risk of reverting to pathogenic form; b. increased risk of infection for immunocompromised patients; c. new versions cannot be developed rapidly Licensed vaccines using this technology: Measles, mumps, rubella, yellow fever, influenza, oral polio, typhoid, Japanese encephalitis, rotavirus, BCG, varicella zoster Department of Immunotechnology, Lund University Inactivated: killed whole organism Mechanism of action: non-living pathogen Killed whole organism Advantages: lower possibility of adverse side effects Limitations: multiple booster shots needed; Not as strong as live attenuated vaccines Licensed vaccines using this technology: Whole-cell pertussis, polio, influenza, Japanese encephalitis, rabies, hepA Department of Immunotechnology, Lund University Influenza A virus Classified by subtypes based on properties of hemagglutinin (H or HA) and neuraminidase (N or NA) surface proteins. 18 HA subtypes 11 NA subtypes Subtypes named by combining H and N numbers Graphics: https://www.cdc.gov/flu/about/viruses/types.htm Department of Immunotechnology, Lund University Inactivated Influenza vaccine Vaccine: virus grown in embryonated chicken eggs, formalin or detergent- inactivated or chemically disrupted virions 60% effective Envelope proteins change each year: new strains must be selected in the first few months for manufacture Department of Immunotechnology, Lund University Selecting an Influenza virus vaccine Outer membrane vesicle vaccines Outer membrane vesicle Mechanism of action: OMVs are used to present antigens for vaccination; derived from the parent strain of a Gram- pathogen, where the antigens needed are naturally expressed in the outer membrane in their native conformation Advantages: least challenging, as antigens are available in the outer membrane of a pathogen Limitations: issues with consistency of yields, immunogenicity, toxicity, and loading. Licensed vaccines using this technology: Group B meningococcal strains Department of Immunotechnology, Lund University Subunit (purified protein, rec. protein, peptide, polysaccharide) Subunit (purified protein, recomb. protein, Mechanism of action: employs part of the pathogen (e.g. outer coating) polysaccharide, peptide) o Break virus into components, immunize with purified components o Clone viral gene, express in bacteria, yeast, insect cells, cell culture, purify protein o Antigen is usually a capsid or membrane protein Advantages: robust and targeted; safe and can be given to immunocompromised patients; recombinant DNA technology is fast; no use of infectious virus or viral genomes Limitations: poor immunogenicity without adjuvants - boosters may be necessary; expensive Licensed vaccines using this technology: Pertussis, influenza, hepatitis A and B, meningococcal, pneumococcal, typhoid Department of Immunotechnology, Lund University Protein-polysaccharide conjugate (subunit type vaccine) Protein-polysaccharide conjugate Mechanism of action: some bacteria are coated with polysaccharides to avoid immune cell recognition; the vaccines are prepared by attaching a protein conjugate (carrier) to the polysaccharide, which following injection it will educate the body to recognize the polysaccharide as harmful. Advantages: robust immune response- induction of higher antibody concentrations, for a longer time; high immunogenicity in young children Limitations: carrier protein induces immune response to itself Licensed vaccines using this technology: Haemophilus influenzae type B, pneumococcal, meningococcal, typhoid Department of Immunotechnology, Lund University Virus-like particle (VLP; subunit type vaccine) Virus-like particle Mechanism of action: mimic the organization and conformation of authentic native viruses, but lack the viral genome Advantages: Most VLPs consist of structurally identical capsid proteins arranged in a repetitive quasicrystalline pattern, which can crosslink multiple BCRs to provide a stimulatory advantage over other types of subunit vaccines; non-infectious = safe -> Crosslinking of BCRs is important for inducing a robust humoral response Limitations: mostly liquid formulations which may pose safety and storage issues; expensive; boosters may be needed Licensed vaccines using this technology: Human papillomavirus, hepatitis B virus, hepatitis E virus, Department of Immunotechnology, Lund University Human Papilloma Virus (HPV) vaccine HPV: o >90% of sexually active population has HPV o The body naturally clears the virus within 2 years of infection o Certain high-risk HPV types can cause cancer; others cause warts HPV vaccines: Gardasil® (Merck): types 6, 11, 16, 18 produced in S. cerevisiae Gardasil-9® (Merck): types 6, 11, 16, 18, 31, 33, 45, 52, 58 Cervarix® (GlaxoSmithKline): types 16, 18 produced in insect cells Ideally should be given before becoming sexually active Davies and Schiller 2004. Nat. Mic. Antigen-presenting cell vaccine Antigen presenting cell Mechanism of action: ex vivo manufacturing or generation of APCs; in situ recruitment and reprogramming of endogenous APCs (tested on DCs) Goal: to harness T cell antitumor immunity by the presentation of tumor-associated-antigens (TAAs) Advantages: boosts anti-tumoral immunity; Limitations: persistent viral infection may evade immune clearance by impairing T-cell function Licensed vaccines using this technology: DC-based: Sipuleucel-T for Prostate cancer Department of Immunotechnology, Lund University Process of generating whole cell DC vaccine Gardner, Pulido and Ruffell (2020) Bacterial vector Bacterial vector Mechanism of action: use of live bacteria as a vector to deliver heterologous antigens to stimulate the host immune response. Bacteria are genetically modified (recombinant bacteria) with inactive pathogenic components, to attenuate bacteria toxicity. Advantages: inexpensive; non-integrative properties; highly immunogenic; easy to manufacture: reduced purification difficulties of the target antigen Limitations: Generation of neutralizing antibodies restricts the efficacy of repeated therapy; potential immunodominance to the vectors; potentially toxic =>Immunodominance: the immunological phenomenon in which immune responses are mounted against only a few of the antigenic peptides out of the many produced. Licensed vaccines using this technology: experimental stage Department of Immunotechnology, Lund University Viral vector Viral vector Mechanism of action: Delivery of a harmless virus that encodes for the antigen of a pathogen Advantages: Robust and targeted; does not require additional adjuvants; can be used for a wide range of infections Limitations: Effectiveness can be reduced by previous exposure to vector; not suitable for immunocompromised patients Licensed vaccines using this technology: Ebola, SARS-CoV-2 Department of Immunotechnology, Lund University Toxoid Mechanism of action: uses toxins made by pathogens Toxoid Advantages: targeted vaccines; led to the first combination vaccines Limitations: boosters may be necessary Licensed vaccines using this technology: diptheria, tetanus Department of Immunotechnology, Lund University Nucleic acid (mRNA, DNA) Nucleic acid Mechanism of action: uses genetic material to code for antigenic protein Advantages: Effective against multiple viral pathogens; easily adaptable; does not contain viral material; no risk of causing the disease, fast manufacturing times Limitations: mRNA degrades quickly and is unstable; leads to unwanted immune responses/adverse side effects Licensed vaccines using this technology: SARS-CoV-2 Department of Immunotechnology, Lund University Case no 1: mRNA vaccines History of mRNA vaccines Hou et al. (2021) Department of Immunotechnology, Lund University How do mRNA vaccines work? mRNA vaccines: Employ a single-stranded RNA molecule found in all cells Do not enter the cell nucleus or alter the DNA Do not contain material from the original pathogen (as in other vaccines) Mechanism of action: i. mRNA vaccines code for a viral protein that is usually found on the outer surface of the virus => they cannot cause the disease they protect against ii. mRNA vaccine is injected into the body iii. Ribosomes (in the cytoplasm) translate the mRNA blueprint into viral protein – cell moves the protein to the outer surface of its membrane iv. T cells recognised the viral protein v. Antibody production is initiated Image: Anne Seeger, SCNAT (CC BY 4.0)  Issue Potential solution mRNA vaccine challenges 1. o large mRNA molecules (Covid vaccine: 2000-4000 nucleotides) pose a risk in effectively transporting the mRNA into host cells o Current delivery system: lipid complexes, lipid nanoparticles Currently investigated: polymers and lipid-polymer hybrid nanoparticles (increased safety, stability, efficiency, lower costs) Increasing efficiency by adding adjuvants (create stronger immune responses) 3. Inflammation o Host immune system is stimulated o Impurities in ss mRNA vaccines Filtration methods to purify mRNA samples Department of Immunotechnology, Lund University Future of mRNA vaccines Infectious diseases: e.g. HIV introducing neutralizing antibodies towards broad HIV antigens (VRC01, N6) through a mRNA vaccine mRNA vaccines coding for VRC01 protected mice against HIV e.g. Influenza Moderna: phase 3 clinical trial for one of its HA-encoding mRNA vaccine candidates pipeline: mRNA vaccine for flu and Covid-19 (one shot) Exploration studies for: Zika virus, Ebola, rabies, respiratory syncytial virus (acute lower respiratory infection) Case no 2: cancer vaccines Prophylactic and therapeutic cancer vaccines Prophylactic cancer vaccines: Gardasil®, Gardasil-9®, Cervarix®, HEPLISAV-B® (HBV-related liver cancer) Can prevent viral infection which can cause cancer Therapeutic cancer vaccines (TCV): Bacillus Calmette-Guérin (early-stage bladder cancer), Provenge® (prostate cancer) Help the immune system recognise, target and eliminate cancer cells Do not target the underlying cause of cancer Target commonly expressed antigens Personalised TCVs: ie. autologous therapy: using antigens expressed by a patient’s individual tumor Department of Immunotechnology, Lund University Personalised cancer vaccines ❑ Prepared from autologous tumor cells and tumor-derived cellular products due to the expression of unique (i.e. neoantigens) and shared (i.e. tumor-associated antigens) antigens on individual patient’s tumors ❑ Help to elicit antitumor responses that are relevant and beneficial to the patients Fritah, et al. 2022 Key challenge: tumor evasion and immunosuppressive TME! Department of Immunotechnology, Lund University Future perspectives Key challenges to be overcome: ▪ Identification of novel vaccine vectors and antigens -> strong and broad T cell responses ▪ Improve methods of antigen delivery (e.g. liposomes, polymeric particles, immunostimulating complexes etc.) ▪ Improve methods for vaccine delivery (e.g. microneedle patches – improved thermostability, safer) ▪ Identification of complementary mechanisms of action that will overcome immune system suppression ▪ Development of strategies that induce antibody response with anti-tumor activity e.g. multi-site injections enhanced TAA-specific antibodies compare with single injections (Mould et al. 2017) New vaccine development for unmet needs: ▪ Group B Streptococcus vaccines are currently in trials of maternal vaccination, with the aim of inducing maternal antibodies that cross the placenta and protect the newborn passively ▪ Combat hospital-acquired infections Particularly with antibiotic-resistant Gram+ bacteria (e.g. Staphylococcus aureus) that are associated with wound infections and intravenous catheters and various Gram- organisms Requirements for an effective vaccine ▪ Induction of an appropriate immune response ▪ Induction of protective immunity in the population ▪ Vaccinated person must be protected against disease caused by a virulent form of the pathogen ▪ Just getting “a response” is not enough (like producing antibodies only) ▪ Safety: no disease, minimal side effects ▪ Protection must be long-lasting ▪ Low cost (3000 (depending on incidence of infection) Therapeutic dose Milligram range Microgram range Number of doses or subject Multi= regular injections daily or weekly for years 1-4 Need for combination or needle-free delivery No Yes Basis for product target profile Structure activity relation Complex immunology (e.g. T cell response, systemic B cell responses, mucosal immune responses) Average development time 8-12 years, decreasing 15-20 years Success rate 1 in 6 when reaching toxicology studies and clinical trials < 1 in 10 when entering clinical trials Main features bill of testing PK and PD Efficacy, Safety Repeated toxicology Repeated toxicology Cost 1000 Euro / gram Biological Drug Products: Development and strategies: p 413, Table 13.1 Recommended reading 1. Pollard, A.J., Bijker, E.M. A guide to vaccinology: from basic principles to new developments. Nat Rev Immunol 21, 83–100 (2021). https://doi.org/10.1038/s41577-020-00479-7 2. Fritah, H., Rovelli, R., Chiang, C. L., & Kandalaft, L. E. (2022). The current clinical landscape of personalized cancer vaccines. Cancer treatment reviews, 106, 102383. https://doi.org/10.1016/j.ctrv.2022.102383 3. Morse, M. A., Gwin, W. R., 3rd, & Mitchell, D. A. (2021). Vaccine Therapies for Cancer: Then and Now. Targeted oncology, 16(2), 121–152. https://doi.org/10.1007/s11523-020-00788-w 4. Biological Drug Products: Development and strategies: Part 3 Vaccines Department of Immunotechnology, Lund University