Harnessing the Immune System to Prevent Cancer: Basic Immunologic Mechanisms & Their Application to Clinical Trials of Vaccines Part 2: The Vaccines Barbara K. Dunn NCI/Division of Cancer Prevention August 3, 2020 Harnessing the Immune System to Prevent Cancer: Basic Immunologic Mechanisms and Therapeutic Approaches that are Relevant to Cancer Prevention
I. Basic immunologic mechanisms II. Application to prevention & treatment of cancer 1. Antibodies: as drugs 2. Vaccines: general principles & your vaccine trials & more… I) Vaccines to prevent cancers caused by infectious agents II) Vaccines to prevent non-infection associated cancer (directed toward tumor associated antigens) Harnessing the Immune System to Prevent Cancer: Basic Immunologic Mechanisms and Therapeutic Approaches that are Relevant to Cancer Prevention
I. Basic immunologic mechanisms II. Application to prevention & treatment of cancer 1. Antibodies: as drugs “passive immunity” 2. Vaccines: general principles & your vaccine trials & more… I) Vaccines to prevent cancers caused by infectious agents “active II) Vaccines to prevent immunity” non-infection associated cancer (directed toward tumor associated antigens) Harnessing the Immune System to Prevent Cancer: Basic Immunologic Mechanisms and Therapeutic Approaches that are Relevant to Cancer Prevention
I. Basic immunologic mechanisms II. Application to prevention & treatment of cancer 1. Antibodies:Focus as on drugs the Antigen “passive !immunity” 2. Vaccines: general principles & your vaccine trials & more… I) Vaccines to prevent cancers caused by infectious agents “active II) Vaccines to prevent immunity” non-infection associated cancer (directed toward tumor associated antigens) DCP CONSORTIUM VACCINE TRIALS
MAY2013-01-01 MUC 1/COLON Non-infection associated cancer MAY2013-02-01 VACCINE/HCV LIVER Infection associated cancer MAY2016-08-01 MUC-1/LUNG Non-infection associated cancer
MDA2014-04-02 VADIS/BREAST Non-infection associated cancer
Infection associated NWU2015-06-02 HPV 9-VALENT/TRANSPLANT cancer
UAZ2014-03-01 PROSTVAC/PROSTATE Non-infection associated cancer Infection associated UAZ2015-05-01 HPV-9-VALENT/PEDIATRICS cancer
UWI2014-03-01 WOKVAC/BREAST Non-infection associated cancer Vaccines - “active immunity” Adaptive Immune System KEY COMPONENTS OF VACCINES Antigen comes from the specific component: the nonspecific component: the thing you want to destroy: cancer cell, pathogen the Antigen the Adjuvant Peptide- long vs short
Epitope (antigenicGenetic determinant vaccines:) = the partprotein of an antigen that is•DNA recognized (encodes by athe protein) immune system (antibodies,•RNA B vaccines cells, T cells); main Viralimmunogenic-like part of the vaccine Protein/ VLP Pentamer of a protein •Viral vector Adjuvants = agents added to vaccine formulations that Cell-based enhance the immunogenicity vaccines of antigens in vivo Vaccines - “active immunity” Adaptive Immune System KEY COMPONENTS OF VACCINES the specific component: the nonspecific component: the Antigen/Epitope the,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, Adjuvant Peptide-
long vs short Platform technology Genetic vaccines: protein •DNA (encodes a protein) •RNA vaccines Viral-like Protein/
VLP platform Pentamer of a protein •Viral vector Adjuvants = agents added to vaccine formulations that Cell-based enhance the immunogenicity vaccines of antigens in vivo Vaccines - “active immunity” Adaptive Immune System KEY COMPONENTS OF VACCINES Antigen comes from the specific component: the nonspecific component: the thing you want to destroy: cancer cell, pathogen the Antigen the Adjuvant Peptide- Antigenlong vs short Genetic vaccines: protein •DNA (encodes a protein) •RNA vaccines Viral-like Protein/ VLP Platform Pentamer of a protein 1)Safety •Viral vector 2)Reactogenicity Adjuvants3)Immunogenicity= agents added: Endpoints:to vaccine formulations-seroconversion:Ab that Cell-based enhance the-neutralization:Ab immunogenicity vaccines of antigens- CD4,in vivo CD8 Tcell Vaccines - “active immunity” Adaptive Immune System KEY COMPONENTS OF VACCINES the specific component: the nonspecific component: the Antigen the Adjuvant Peptide- long vs short
Epitope (antigenicGenetic determinant) vaccines: = the Adjuvant non- partprotein of an antigen that is•DNA recognized (encodes by athe protein) immune system (antibodies,•RNA B vaccines cells, T cells)specific stimulation to TargetsViral-like a specific Protein/ immune system = VLP antigen INNATE Pentamer= ADAPTIVEof a protein •Viral vector Adjuvants = agents added How do we pick the ■ Nonto vaccine-specific formulations Immuno- that Cell-based Modulatorsenhance the = INNATE immunogenicityonly antigen/epitope tovaccines target? of antigens in vivo Harnessing the Immune System to Prevent Cancer: Basic Immunologic Mechanisms and Therapeutic Approaches that are Relevant to Cancer Prevention I. Overview: Context of immunologic mechanisms: Elicitscarcinogenesis a specific response from the body’s own immune system: II. Structure/physicalFocus components on the Antigen and ! hierarchy of the immune system I. How immunologic mechanisms are used in medical interventions to treat and prevent cancer 1. Antibodies as drugs “passive immunity” 2. Vaccines: general principles & your vaccine trials I) Vaccines to prevent cancers caused by infectious agents “active II) Vaccines to prevent non-infection immunity” associated cancer (directed toward tumor associated antigens) Vaccines to prevent cancers caused by infectious agents
Targets a specific How do we pick antigen the = ADAPTIVE antigen/epitope to target? The infectious agent is FOREIGN/NON-SELF
→pick the antigen from this! JH February 13, 2018 HBV Vaccine HCV Vaccine example of antigen(s) derived from infectious agents, HBV, HCV Vaccines to prevent cancers caused by infectious agents
Pathogenesis of Hepatitis B Virus-Associated Cancer
Infects 350-400 million people (5% world population) Chronic HBV Carriers - incidence of HCC (hepatocellular carcinoma) ranges from 70% to 90% and nearly 100% in children Chronic HBV infection and high HBV DNA levels are a strong predictor for cirrhosis and HCC (irrespective of other viral and biochemical factors)
Viral Viral Chronic Precancer Liver exposure infection Viral conditions Cancer infection
Prophylactic vaccine Focus on the Antigen! HBV Vaccines (hepatitis B virus)
HBV vaccine – FIRST vaccine in How do we pick the humans for cancer prevention (1981) antigen/epitope to target? -the Antigen: hepatitis B surface antigen The infectious agent is FOREIGN/NON- (HBsAg) = a viral envelope protein SELF →pick the antigen from this! • Pre-exposure prophylaxis/prophylactic vaccine • Vaccination with hepatitis B surface antigen (HBsAg) = a viral envelope protein – made from recombinant DNA, produced in yeast • Recombivax HB (Merck), Engerix-B (GSK), Elovac B (Human Biologicals Institute, Genevac B (Serum Institute), Shanvac B, etc. DCP CONSORTIUM VACCINE MAY2013-02-01 Therapeutic HCV vaccine
Infection associated cancer chronic HCV infection
example of antigen(s) derived from infectious agent, HCV
no preventive vaccine for HCV Vaccines to prevent cancers caused by infectious agents Pathogenesis of Virus-Associated Cancer *Therapeutic from an infectious disease standpoint; actually prophylactic from a cancer standpoint Vaccines
Viral Viral Chronic Precancer Cancer exposure infection Viral conditions infection
Prophylactic Therapeutic vaccine vaccine DCP CONSORTIUM VACCINE Phase I Trial of a therapeutic DNA Vaccine for MAY2013-02-01 Chronic Hepatitis C Virus (HCV) Infection No therapeutic vaccine for HCV and HBV WHY VACCINE FAILURE? IMPAIRED T CELL RESPONSES
CHRONIC HCV INFECTIONS immunoediting
96.
-
54:1286 J. Hepatology 2011, Hepatology J. immunoediting
T-Cell Exhaustion MAY2013-02-01 Therapeutic HCV vaccine Infection associated cancer
antigen
NS3 NS4B DNA plasmid vaccine NS5a platform chronic genotype 1 HCV infection w/plasma HCV RNA>10,000 IU/ml ↓ HCV genotype 1a/1b consensus DNA vaccine: encoding HCV NS3, NS4A; NS4B, NS5A Day 0; Weeks 4, 12, 24 ↓ 1o Endpoint: safety, AEs; immunogenicity: change HCV-specific IFN-Ɣ (wk 26) Translational Endpoints: virologic response (decrease in HCV RNA level) HPV Vaccines example of antigen(s) derived from infectious agent, HPV HPV Vaccines human papilloma virus - >100 strains: Some cause cancer -14 high risk Some cause warts Causes: ~100% of cervical cancers + head and neck cancers anal cancers L1 differs among strains Vaccines to prevent cancers caused by infectious agents VLP (L1s)
HPV VACCINES (HUMAN PAPILLOMAVIRUS)
How do we pick the Prophylactic (3 FDA Approved HPV vaccines) antigen/epitope to target? The infectious agent is -the Antigen: virus-like particles (VLP) from FOREIGN/NON-SELF →pick the antigen from major capsid proteins L1 = strain specific this! ●Bivalent/Quadrivalent subunit vaccines (HPV 16 and 18 – 70% of cervical cancers) Cervarix® (GSK-bivalent) (HPV 6 and 11 – majority of genital warts) Gardasil ® (Merck-quadrivalent) Vaccines 98% effective preventing high-grade cervical lesions Approved: ● Nonavalent vaccine (V503, Merck) (FDA approval Dec 2014) females 9-26 HPV 6/11/16/18/31/33/45/52/58–Gardasil 9® males 9-15 ●Bivalent (HPV 16 and 18)(Xiamen Innovax Biotech Co) John Schiller’s lectures-July 2018 (China: approved Jan 2,2020) - Cecolin July 21,2020 Vaccines to prevent cancers caused by infectious agents Pathogenesis of HPV-Associated Cancer & Vaccines to Prevent Cervical Cancer
Cervical Viral Viral Chronic Precancer Cancer exposure infection Viral conditions infection
Cervarix: HPV 16, 18 Prophylactic Lasker~DeBakey Clinical Medical Gardasil: HPV 16, 18, 6, 11 vaccine Gardasil 9: HPV 6/11/16/18/ Research Award: John Schiller & 31/33/45/52/58 Douglas Lowy DCP CONSORTIUM VACCINE NWU2015-06-02 HPV 9-valent/Transplant
Infection associated cancer Transplant Vaccine
example of antigen(s) derived from infectious agent, HPV Vaccines to prevent cancers caused by infectious agents HPV – HUMAN PAPILLOMAVIRUS
Adult solid organ transplant recipients Immunosuppression
Increased risk of developing several malignancies, especially causally linked to carcinogenic HPV infection: Squamous cell carcinoma of: anogenital region [vulva, cervix, penis, vagina] naso/oropharynx
Engels 2011 JAMA 306:1891 NWU2015-06-02 Protocol Version 3.8, July 18, 2019SCHEMA : Immunogenicity of Nonavalent HPV Vaccine Administered Prior To Renal Transplantation in Adults: A Prospective, Single-Arm, Multi-Center Clinical Trial
Adults planning renal transplant ↓ Gardasil® 9 HPV ≥1 dose L1 VLP ↓ 30 days prior to transplantation ↓ ↓ 1o Objective: immunogenicity: HPV type-specific seroconversion at 12 months post-tx INFECTIOUS AGENTS AND CANCER PREVENTION
Control Infectious Agent(s) Vaccines – prophylactic / therapeutic Antiviral therapy
Control Infection Prevent Cancer Focus on the Antigen! Harnessing the Immune System to Prevent Cancer: Basic Immunologic Mechanisms and Therapeutic Approaches that are Relevant to Cancer Prevention
I. Overview of these immunologic mechanisms II. Structure/physical components of the immune system III. How immunologic mechanisms are used in medical interventions to treat and prevent cancer 1. Antibodies as drugs --- “passive immunity” 2. Vaccines: general principles – “active immunity” I. Vaccines to prevent cancers caused by infectious agents II. Vaccines to prevent non-infection associated cancer (directed
toward tumor associated antigens) Focus on the Antigen the on Focus Vaccines to prevent cancers not caused by infectious agents The antigen is from Targets a specific How do we pick ALTERED SELF antigen the antigen/epitope = ADAPTIVE cells→ tolerance = to target? self vs non-self! Selection of appropriate antigen Self Nonself/ in non-infection-associated cancers, Anti Foreign, gen Unwanted the antigens are modified normal antigens, Antigen taken from cancer cells cancer cell Concern is: Prevent autoimmune responses Self We do not want the immune system to attack Tolerance Anti signals gen the normal cells (don’t want toxicity), We only want the immune system to attack But want anti-cancer responses Nonself/ Attack Foreign, the cancer cells, Unwanted signals Antigen which have modified normal antigens Vaccines to prevent non-infection associated
Self Nonself/ Foreign, cancer: the Antigen Anti Unwanted gen Antigen Mechanism of Tumor Antigen:
• Tumor Associated Antigens (TAAs)/ neoantigens → “self”- antigens or normal cellular proteins that become immunogenic during the malignant process • Mechanisms by which normal cell protein becomes aberrant in cancer (“abnormal-self”) 1-acquisition of mutations (melanoma antigen MAGE1) 2-overexpression of cancer associated proteins (breast cancer HER2/NEU) 3-post-translational modifications (abnormal glycosylation (colon cancer antigen MUC-1) DCP CONSORTIUM VACCINE MAY2013-01-01 MUC 1/Colon
Non-infection associated cancer Colorectal Cancer Vaccine example of antigen with abnormal post-translational modification Colorectal Cancer - MUC-1 Muc1 Expression in Cancers: Normal Muc1
Mucins = large glycoproteins:
O-linked carbohydrates/ polypeptide core Oligosaccharides: Glycosylated MUC1
Transmembrane glycoprotein
Immunohistochemical analysis of paraffin-embedded human colon carcinoma, using MUC1 (VU4H5) Mouse mAb. Colorectal Cancer - MUC-1
Tumor-associated O-linked antigen: oligosaccharides Post-translational modification
Basal Expression in normal ductal epithelial cells: Overexpressed & aberrantly glycosylated in --most adenocarcinomas, inflammatory diseases, Pancreas, Breast, Lung, Gastrointestinal tract e.g. inflammatory bowel disease (IBD)JH February 13, 2018 Colorectal Cancer - MUC-1 COLORECTAL CANCER IMMUNOPREVENTION TARGETING MUC-1 Vaccination against MUC1 prevents the development of dysplasia and CACC. (A) Percentage of untreated (n=13) and adjuvant treated (n=9) mice with dysplasia at 16 weeks of age.
TnMUC1: 100-mer dysplasia peptide (five tandem repeats of 20–amino acid sequence
tumors
Untreated mice-many tumors
Beatty et al., Cancer Prev Res (Phila). 2010 April; 3(4): 438–446. DCP CONSORTIUM VACCINE MAY2013-01-01 MUC 1/Colon example of antigen with post-translational modification
Randomized, Double-Blind, Placebo-Controlled Trial of MUC1 Vaccine in Patients with Newly Diagnosed Advanced Adenomas
≥ 1 advanced adenoma ↓ ↓ MUC1 vaccine (peptide) placebo ↓ weeks 0, 2, 10, 53 ↓ ↓ Endpoints: Immunogenicity: IgG anti-MUC1 antibody titer Week156- adenoma recurrence
Endpoints: immunogenicity – adenoma recurrence DCP CONSORTIUM VACCINE MDACC2014-04-02 VADIS 1/Breast UWI2014-03-01 WOKVAC/Breast
Non-infection associated cancer Breast Cancer Vaccines
examples of antigen that is overexpressed in cancer Breast Cancer - HER2/NEU, IGF1R, IGFBP-2 3 antigens overexpressed in breast cancer
IGFBP-2+ DCIS
• Overexpressed in hyperplasia /DCIS • LUMINAL: ER+ HER2+ DCIS IGFIR+ hyperplasia
• Overexpressed DCIS, ER- • HER2+ • Overexpressed in hyperplasia/DCIS Disis • LUMINAL AND TN: ER-HER2- Breast Cancer - HER2/NEU, IGF1R, IGFBP-2-positive BREAST CANCER IMMUNOPREVENTION TARGETING [ HER2/NEU + IGF1R + IGFBP-2 ]
Vaccination to prevent disease onset
) Interferon- 2 Tumor-free No Ag Protected 100 1 Irr secreting cells Multi-Ag neu Vaccine ELISpot assay 80 IGFBP2 p<0.001
p=0.0009 Antigens IGF1R 60 Mix PHA HER2 40 IGFBP-2 0 IGF-IR 200 400 600 800 ELISPOT, spots per well (SPW); Gad et al., 2011
Percent Tumor Freel Tumor Percent 20 p=0.0002 SPW No Ag Unprotected Control Irr IGFIR+ hyperplasia 0 HER2+ DCIS neu 0 10 20 30 40 50 IGFBP2 p<0.001 Animals ages (weeks)
Antigens IGF1R
Mix (CADRG/PREVENT Cancer Program Cancer (CADRG/PREVENT 100 survival PHA 3 HER2/IGFBP2/ IFG-IR Vaccine 0 Disis 80 • Overexpressed DCIS, ER200- • Overexpressed400 600 800in hyperplasia/DCIS - - • HER2+ • LUMINALSPW AND TN: ER HER2 60 No Ag Adjuvant IGFBP-2+ DCIS Tg-MMTVneu Control Irr • Hyperplasia-DCIS-IDC 40 Control neu • neu, IGFBP-2, IGF-IR high, ER low, PTEN low
Percent survival IGFBP2 • Resistant to chemotherapy, neuMoAb 20 ns
p=0.0012 Antigens IGF1R Mix 0 0 10 20 30 40 50 PHA Tri-antigen Animal age ( weeks) 8 epitope vaccine 0 • Overexpressed in hyperplasia200 /DCIS400 600100% homology800 • LUMINAL: ER+
Data courtesy of Dr. Mary Dr. of courtesy Data SPW Vaccinated at 18 weeks, n=15/group ELISPOT,Park et spots al Ca perRes, well 2008; (SPW); Cecil Gadet al, et 2011 al, 2011 MDACC2014-04-02 UWI2014-03-01 VADIS 1/BREAST WOKVAC/Breast
DCIS on CORE Bx non-metastatic node+ HER2neg NED ↓ ↓ (in remission) VADIS (Nelipepimut-S Peptide vaccine: WOKVAC (DNA plasmid-based HER2 9aa) vaccine: IGFBP-2,HER2,IGF-1R) ↓ ↓ 3 monthly vaccinations 3 monthly vaccinations ↓ ↓ 1o Endpoint: safety 1o Endpoint: safety 2o Endpoint: immunogenicity: Th1, Th2 2o Endpoint: immunogenicity: Th1, Th2 SUM UP: NON-INFECTION ASSOCIATED CANCER PREVENTION
Vaccines – target a TAA The antigen derives from an altered cellular protein/TAA/ neoantigen – Concern Prevent about “self” versus Cancer “non-self” ●Why are vaccines more promising in Sum Up: cancer prevention (vs treatment)? immunoediting Evaluate vaccines in the states of: “minimal residual disease” and Cancer Prevention: WHY ? Vaccination early in disease process:
→ Intact immune system (active immunity) prevention → Permissive microenvironment treatment → Pre-cancers are smaller lesions → Immune mechanisms in early lesions involve + CD4 T H , IFNγ, Antibodies & Cytotoxic T-Lymphocytes (CTL) that fight cancer COVID-19 AND VACCINES
Union of Concerned Scientists Vaccines - “active immunity” Adaptive Immune System KEY COMPONENTS OF VACCINES the specific component: the nonspecific component: the Antigen/Epitope the,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, Adjuvant Peptide-
long vs short Platform technology Genetic vaccines: protein •DNA (encodes a protein) •RNA vaccines Viral-like Protein/
VLP platform Pentamer of a protein •Viral vector Adjuvants = agents added to vaccine formulations that Cell-based enhance the immunogenicity vaccines of antigens in vivo Vaccines - “active immunity” Adaptive Immune System KEY COMPONENTS OF VACCINES the specific component: the nonspecific component: the Antigen the Adjuvant Peptide- long vs short platform
Epitope (antigenicGenetic determinant) vaccines:= the partprotein of an antigen that is•DNA recognized (encodes by athe protein) immune system (antibodies,•RNA B vaccines cells, T cells); main Viralimmunogenic-like part of the vaccine Protein/ VLP Pentamer of a protein •Viral vector Adjuvants = agents added to vaccine formulations that Cell-based enhance the immunogenicity vaccines of antigens in vivo SARS-COV-2 Antigen: Spike glycoprotein (S) Figure 1. The SARS-CoV-2 Virion and Its Proteins. Although all the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) proteins are potential drug targets, some are likely to be more easy to find a drug against, in part because they play principal roles in the viral lifecycle and also lack human protein homologues. Examples include the spike glycoprotein, the papain-like protease, the chymotrypsin-like main protease, and the RNA-dependent RNA polymerase. A list of the Worldwide Protein Data Bank identifiers of the structures shown is provided in the Supplementary Appendix, available with the full text of this article at NEJM.org. ACE2 denotes angiotensin-converting enzyme 2, NSP nonstructural protein, ORF open reading frame, and RdRP RNA- dependent RNA polymerase. Parks, Smith, How to Discover Antiviral Drugs Quickly N Engl J Med (June 4, 2020); 382:2261 SARS-COV-2 Antigen: Spike glycoprotein (S)
Schematic representation of the novel SARS-CoV-2 viral capsid. The coronavirus spike (S) protein mediates membrane fusion by binding to cellular receptors. S spike binds cell’s receptor for angiotensin-converting enzyme (ACE2) and mediates virus entry into cell.
Amawi et al. Therapeutic Delivery (May 2020) platform ALL PHASES of VACCINE CANDIDATES FOR COVID-19
adenovirus vector US$ AZ
SF9 baculovirus- recombinant protein nanoparticles
US$
mRNA-1273 Developing Covid-19 BNT-162b2 Vaccines at Pandemic Speed Lurie et al. NEJM Mar 30, 2020 platform ALL PHASES of VACCINE CANDIDATES FOR COVID-19
adenovirus vector US$ Main Categories of Vaccine PlatformsAZ (summarized by Dr. Anthony Fauci, July 31 during congressional testimony) SF9 baculovirus- Nucleicrecombinant acid (DNA, RNA) Peptideprotein (protein) nanoparticles
Modified virus US$
mRNA-1273 Developing Covid-19 BNT-162b2 Vaccines at Pandemic Speed Lurie et al. NEJM Mar 30, 2020 RNA platforms
Amplifying RNA Vaccine Development Fuller, Berglund NEJM June 18, 2020 CD4 vs CD8 and TH1 vs TH2
CD4+ CD8+
(APC)
Antibody- dependent enhancement TH2
(Humeral immune response); Syndrome of vaccine-enhanced CD4+ respiratoryCD8+ disease ≠ Covid-cytokine storm, Cellular (T 1 or T 2) (CTL) immune H H Multisystem Inflammatory Syndrome-children response IL-2, IFNƔ IL-4 JUNE 16, 2020 VACCINE STATUS FROM “OPERATION WARP SPEED” OWS Operation Warp Speed (goal:300mil doses) Where Fed Govt/HHS has put its $$:
March 30 –HHS $$456mil → Johnson & Johnson /Jansson → Phase I April 16 –HHS $$483mil → Moderna/NIAID → [NEJM July 14 → Phase I] May 21 –HHS $$1.2bil → AstraZeneca/Oxford → [Lancet July 20 → Phase I/II] Phase III (~this summer) July 7 - HHS $$1.6bil →Novavax (Gaithersberg) July 22-Fed Govt $$1.95bil→Pfizer/BioNTech100mil doses July 31-Fed Govt $$2.1bil→ Sanofi/GSK 100mil doses New Eng J Med July 14,2020
(Moderna/NIAID) Jan 10: genome posted Mar 11: WHO:pandemic First-in-human trial Mar.16: 1st vacc. pt. July 14: Interim analysis: No serious toxicity #2>#1, 250μg>lower
phase I, dose-escalation, open-label trial 45 healthy adults n=15 n=15 n=15 mRNA-1273 25μg → 100μg → 250μg lipid nanoparticle encapsulated mRNA ↓ ↓ ↓ 1st- Day 1 SARS-CoV2 spike (S-2P) glycoprotein ↓ ↓ ↓ 2nd-Day 29 Day 57: immunogenicity: ELISA: Receptor binding assay →→→→→ →seroconversion: IgGvsS-2P PsVNA:neutralization assay; PRNT:plaque reduction →→→→→ ~~convalescent (+responses: CD4/Th1-humans; CD8,CD4/Th1-mice) serum safety: adverse event (local, systemic) reactogenicity: (short-term immunologic adverse reactions) July 20,2020
(AstraZeneca/Oxford) Jan 10: genome posted Mar 11:WHO:pandemic Phase I / II RCT phase I / II, single(pt)-blind RCT July 20:preliminary report 1077 healthy (18-55y) adults AZD1222/ No serious toxicity 1:1 - ChAdOx1 nCoV-19:control ChAdOx1 nCoV-19 Double immunity 5 × 1010 viral particles ↓ chimpanzee adenovirus-vectored vaccine ↓ Day 0: 1st dose ↓ SARS-CoV2 spike glycoprotein ↓ Day 28: booster dose ↓ ↓ (n=10) immunogenicity: Double Immunity: ELISA: seroconversion:anti-spike IgG (↑day 28→boost after 2nd dose) humeral & Live neutralizing antibody (↑day 28, boost); PRNT, MNA, Marburg VN cellular Spike-specific T-cell responses (ELISpot:IFNɣ) (↑day 14) safety: no serious adverse event (+local, systemic AEs) reactogenicity: (short-term immunologic adverse reactions) FURTHER VACCINE UPDATES Ongoing: Phase II trial of mRNA-1273 in 600 healthy adults, evaluating doses of 50 µg and 100 µg (ClinicalTrials.gov NCT04405076); Moderna/NIAID July 22: BioNTech/Pfizer vaccine BNT162b2 30 µg (full-length spike mRNA); early data:+neutralizing Abs; July27 Phase IIb/III n=30,000 July 16:Oxford/AstraZeneca ChAdOx1nCoV19(AZD1222) Phase I trial prelim:↑antibodies+↑killerTcells(LancetJuly20) plan: ongoing PhII; 2-3wks ago (July) Phase III trial Later in July 2020:Moderna & Pfizer & AstraZeneca:large trials July 27: Moderna/NIAID (NEJM July 14): Phase III trial st mRNA-1273 100 μg dose n=30,000: 1 patient July 31: plan Sept: Sanofi/GSK: begin human testing →→OPERATION WARP SPEED→→ Coronavirus Vaccine Tracker SARS-CoV-2 genome posted January 10, 2020 June 10, 2020 PRECLINICAL PHASE I PHASE II PHASE III APPROVAL
125 7 7 1 0
Vaccines not yet Testing safety Expanded Large-scale Vaccines in human trials and dosage safety trials efficacy test approved for use By Jonathan Corum and Carl Zimmer, New York Times, June 10, 2020
Vaccines approved August 3, 2020 for limited use ~???
140 18 12 6 1
By Jonathan Corum. Denise Grady, Sui-Lee Wee, Carl Zimmer, New York Times, updated July 22, 2020 HARNESSING THE IMMUNE SYSTEM TO PREVENT CANCER: VACCINES
DCP CANCER Immunoprevention Acknowledgements:
Asad Umar
Margaret Wojtowicz
FIN JoAnne Rinaudo
Vik Sahasrasbuddhe [email protected] Maggie House
TRI group