(Astrazeneca), Pfizer, Diassess, Novavax, Merck, GSK, Regeneron, Janssen, Novartis

11/19/2018

Joseph Domachowske MD, FAAP Professor of Pediatrics Professor of Microbiology and Immunology SUNY Upstate Medical University Syracuse, NY

 Consultant: Sanofi Pasteur, Medimmune

 Research: Sanofi Pasteur, Medimrnune (AstraZeneca), Pfizer, Diassess, Novavax, Merck, GSK, Regeneron, Janssen, Novartis

1 11/19/2018

 Attendees will list the steps required and general timeline needed to move a preclinical vaccine idea to a vaccine that is available for widespread use

 Attendees will describe strategies for immunization and disease prevention

Smallpox Diphtheria Polio Measles H. Flu b Tetanus Pertussis

Pre‐vaccine Morbidity 29,005 21,053 16,316 530,217 20,000 580 200,752

Recent reported 00118731 26 28,639 cases in US

% Decrease 100% 100% >99% >99% >99% 96% 86%

CDC. Impact of Vaccines in the 20th and 21st century. Pink Book, Appendix E. 2015

2 11/19/2018

Vaccines licensed for use in the US Adenovirus Japanese Rotavirus encephalitis virus Diphtheria, tetanus, Measles, mumps, Smallpox acellular pertussis rubella H. influenzae type bMeningococcal Typhoid ACWY Hepatitis AMeningococcal B Varicella Hepatitis B Pneumococcal Yellow Fever

Human Polio Zoster papillomavirus Influenza Rabies Cholera

3 11/19/2018

 Highly regulated process  Can take 10‐15 years from concept to recommendation  Most vaccines do not make it past pre‐clinical or early clinical trials (phase I)

Vaccines Years to approval Varicella 25‐30 LAIV 25‐30 HPV* 14‐16 Rotavirus* 14‐16 Pediatric combination 10‐12 vaccines

* Excluding early pre‐clinical work

Douglas RG. (2008). The Vaccine Industry. In Plotkin’s Vaccines. (p39). Elsevier

4 11/19/2018

 Limited‐use product  10‐15 years before

Drivers of marketing vaccine . Uncertain demand in market development . Incorporation into immunization program Demand for ▪ Clinical Technically vaccine in ▪ Economic feasible market

Vaccine development

Clinical Process Assay development development development

•Vaccine effect on patients • Vaccine prep by regulatory • Specific testing methods: • Safety, efficacy, requirements • Purity immunogenicity • Vaccine lots • Stability • Phase I, II, III clinical trials • Consistent manufacturing • Potency methods •Assays for immunologic endpoints

5 11/19/2018

Vaccine Development

Pre‐clinical PhaseI Phase II Phase III File Phase IV

1‐10 years 2‐3 years 2‐5 years

Vaccine concept

Identification of antigens

Lab assays, animal models

6 11/19/2018

IND Application

Manufacturing process Pre‐clinical data

Vaccine composition Proposed clinical trials plan

Vaccine safety

Vaccine potency

Vaccine efficacy

Vaccine purity

Small studies Primary outcome •healthy subjects (~50) •Safety •Short‐term Phase I

Other measures Subjects at low risk • Prelim Immunogenicity for infection •Vaccine dosing

7 11/19/2018

 RSV . 12‐17 month old, RSV sero‐positive infants . Safety, reactogenicity, immunogenicity . Dose escalation, with safety assessments . Precursor to studying vaccination in sero‐negative infants

Longer, larger Proof of concept • ~2 years • Immunogenicity • 1,000 subjects •At‐risk population Phase II

Expanded data Double‐blinded, •Safety placebo controlled, randomized •Vaccine dosing

8 11/19/2018

 RSV monoclonal antibody, extended half life  Healthy pre‐term infants, 29‐34 6/7 weeks  Entering first RSV season

 Efficacy: reduction in medically attended respiratory infections due to RSV

Large‐scale Assess • 1000s of subjects •Safety •At‐risk for infection • Efficacy •Several years • Immunogenicity Phase III

Clinical endpoints Randomized, placebo‐ Immunologic response controlled, blinded

9 11/19/2018

 RSV F nanoparticle vaccine . Healthy third‐trimester pregnant women . Immunologic endpoints ▪ Pregnant women ▪ Cord blood ▪ Newborns . Clinical endpoints –infants for 2 years . Safety data collected

Biologics License Application (BLA) submission Submit safety/efficacy to FDA

Vaccines and related Biologic Product Advisory Committee Review data with VRBPAC

18‐24 months Pre‐approval inspection of vaccine production

10 11/19/2018

FDA ACIP

Decides on Reviews data in context of current licensure needs

Restricted to Makes vaccine study population recommendation

FDA label indication ACIP recommendation Tdap – one dose and done Tdap every pregnancy Tdap for people aged 10‐64 years Tdap for all 7years and older Quadrivalent meningococcal –one Quad mening – 2 doses for all dose teens MenB 10‐24 years of age MenB 10 years and older for those at risk Influenza vaccine not specifically Influenza vaccine during licensed for use during pregnancy pregnancy

11 11/19/2018

 Post‐licensure surveillance . Safety surveillance ▪ VAERS, Vaccine Safety Data Link, manufacturer reports ▪ Case‐controlled studies when ‘Red Flags’ appear ▪ Look for rare adverse events . Long‐term efficacy evaluation ▪ During outbreaks, ongoing epidemiologic data collection . Manufacturer production activities

 Cost of developing new vaccine $231 million in 1991  $800 million in 2010 . Research and development costs of failed products . Post‐licensure clinical studies . Improvements in manufacturing processes

12 11/19/2018

Private Vaccine Companies

Government NGO agencies Gates CDC, FDA, DOD, Foundation, USAID, NIH PATH

Contributions to Vaccine R&D

 Highly regulated  Single set of rules applied to all vaccines  Regulations of manufacturing process  Regulations of clinical trials  Complicated, costly, with more failures than successes

13 11/19/2018

 Clinicaltrials.gov . Search: vaccine . 6,670 registered vaccine trials . 1,100 open vaccine trials . 642 trials actively recruiting

14 11/19/2018

clinicaltrials.gov

15 11/19/2018

universal flu vaccine

group B strep

Meningococcal ABCWY

RSV

Ebola

MERS‐CoV

Ebola Tuberculosis

Pneumococcus RSV

Hepatitis C HIV

Malaria Universal flu

Meningococcal ACWY CMV

Shigella Rabies

Hexavalent peds Tdap

16 11/19/2018

Men pneumococcus ACWY

rotavirus VZV C. diff

MMR Ebola Flu RSV

17 11/19/2018

Virus attachment to host cell

Virus entry into host cell

cdc.gov

Types A, B, C •A, B: most of human disease •C: uncommonly causes human disease

Influenza A •H1, H2, H3; N1, N2 •Seasonal epidemics

Vaccination is most effective method for disease prevention

18 11/19/2018

IIV: intradermal, Trivalent, IM quadrivalent

A (H1N1) A (H3, N2) LAIV: intranasal B Cell‐based

Egg‐based Recombinant

CDC and WHO provide candidate vaccine viruses

Egg‐based: Virus Cell‐based: Virus Recombinant: HA protein isolated injected into inoculated into from wild‐type virus and combined fertilized hen’s egg mammalian cells with proteins to grow in insect cells

virus virus FDA testing, incubate for virus containing inactivated approval, replication fluid harvested and purified shipment

19 11/19/2018

Vaccine efficacy ~30‐60%

Most effective when vaccine strains closely match circulating viruses

Circulating strains change yearly

Do not protect against pandemics

 Universal influenza vaccine???

Goals At least 75% effective Protects against multiple types of influenza A (pandemic strains included ) Duration over a year Suitable for all age groups www.niaid.nih.gov/diseases‐conditions/universal‐influenza‐vaccine‐research

20 11/19/2018

• Current vaccines induce antibody to HA head • Changes frequently

Lofano, Giuseppe & Kumar, Arun & Finco, Oretta & Del Giudice, Giuseppe & Bertholet, Sylvie. (2015). B Cells and Functional Antibody Responses to Combat Influenza. Frontiers in immunology. 6. 336. 10.3389/fimmu.2015.00336.

• More conserved • Vaccine to induce antibody to stalk

21 11/19/2018

nanoparticles

4 H subtypes into one vaccine

DNA‐based vaccine “prime” [phase 1, 2] • More conserved • Vaccine to induce antibody to stalk M‐001: antigenic peptides from many strains [phase 2]

22 11/19/2018

 F glycoprotein . Mediates fusion reaction  delivery of virus capsid core contents into cell . Disrupting activity would ▪ reduce virus entry into cell ▪ protect host from infection . Highly conserved among strains

 Infants . Active immunization . Passive immunization  Pregnant mothers . RSV Ab efficiently transferred across placenta . High cord blood RSV Ab levels lower incidence of severe RSV LRTI . Passive immunization

23 11/19/2018

 Formalin inactivated‐RSV vaccine  Infants 2‐7 months of age  Enhanced disease . Hospitalizations: 80% of vaccinated vs 5% placebo . 2 deaths from RSV infection among vaccinated

 Thought to be due to . Ab produced: non‐neutralizing and did not inhibit fusion . Inflammatory CD4 T‐cell driven cytokine response

Live Attenuated

Whole Inactivated

Particle based

Subunit

Nucleic Acid

Vectors

Immuno‐ prophylaxis

24 11/19/2018

ID genetic sequence of RSV F protein

Clone gene into baculovirus

Engineered baculovirus Spodoptera frugiperda (Fall armyworm) infects the SF9 cells

‐ Only infects insects ‐ Engineered to express RSV F proteins genes of interest produced ‐ Used to infect Sf9 cells to efficiently produce desired protein Transported to surface, extracted, purified

 Safe and inexpensive  Chimpanzee adenovirus  High capacity . Related to human adenovirus . Infect cells . Low neutralizing antibodies in . Express encoded antigens human population  Induce immune response  Adenovirus type 5

. Most common human Genetically engineered recombinant CHAd155

Adenovirus serotype Same vector used in ebola vaccine . 30% + Ad Ab  less immunogenic Non-alum composition fibre  Can express multiple proteins core

Double stranded DNA Target RSV genes

25 11/19/2018

 Passive protection  Palivizumab . Prevention of RSV . Licensed in 1998 . Monthly injections during RSV season . Costly

 recombinant human IgG1 kappa monoclonal antibody  Targets prefusion F  Derived from D25 (human mAb with 100x YTE technology substitutes 3amino acids in the Fc region of IgG. greater potency than palivizumab in vitro  YTE technology

26 11/19/2018

 Rigorous regulations in vaccine development . Significant amount of time and money to ensure safe and effective vaccines  Novel vaccine strategies are being developed to improve disease prevention  New vaccines are becoming available in the US and worldwide