Future of vaccine development and commercialization

Holly S. Sellers, MS, PhDPoultry Diagnostic and Research Center

College of Veterinary Medicine

University of Georgia, Athens, GA

hsellers@uga.edu

Expectations of vaccines…

• Prevent and reduce disease and production losses

• Increase resistance to infection

• Reduce virus replication and shedding• Reduce transmission to susceptible

birds• Reduce environmental contamination

• Cannot• Eradicate disease• Sterilizing immunity

Important considerations of vaccination programs• Type of production system

• Level of protection needed

• Presence of regional diseases• Severity

• Cost

• Post-vaccinal reactions versus production loss

• Is vaccine available?https://thepoultrysite.com/articles/spray-vaccination-of-dayold-chicks-at-the-hatchery

Viral vaccines at a glance…

• Conventional• Killed whole virus

• Live attenuated virus

• Recombinant• Reverse genetics

• Vectored

• DNA

• Subunit

Conventional live vaccines

• Attenuation of pathogenic virus• SPF embryo or cell culture passages

until reduced pathogenicity

• Time consuming

• Types of live vaccines • Tissue culture origin (TCO)

• Chicken embryo origin (CEO)

• Mass administration • Hatchery – in ovo, spray, subcutaneous

• On farm – spray, water, eye drop

Inactivated/killed vaccines

• Killed/adjuvant vaccines

• Enhance immune response without infection• Water-in-oil (WO)

• Oil-in-water (OW)

• Water-in-oil-in water (WOW)

• Aluminum salts

Recombinant vaccines

• Replicating virus (Vector) + gene/s that code for protective immunogenic proteins (Field virus)• Fowlpox (FP)

• Cellular immunity

• Herpesvirus of turkeys (HVT) –serotype 3 Marek’s disease virus• Persistent, systemic infection• Stimulates humoral and cell mediated

immunity

• Newcastle disease virus (NDV)• Mucosal immunity• Interference with maternal antibodies

HVTFPND

Field virus Vector Virus

Inserted gene

Expressed protein

Clone geneof interest

=IMMUNE RESPONSE AGAINST PROTECTIVE ANTIGEN, NOT WHOLE FIELD VIRUS

Slide courtesy of Dr. Darrell Kapczynski – USDA/NPRC

Recombinant vaccines

• Success of recombinant vaccines depends on• Safety

• Efficacious

• Cost effectiveness

• Mass administration

Current commercial recombinant viral vaccines for poultry

Company Virus Vector

Boehringer-Ingelheim Trovac NDV FP

CEVA Vectormune FP ND FP

CEVA Vectormune FP LT FP

CEVA Vectormune FP LT AE FP

Boehringer-Ingelheim VAXXITEK HVT+IBD HVT

Boehringer-Ingelheim NEWXXITEK HVT+ND HVT

Boehringer-Ingelheim PREVEXXION RN Chimera

CEVA Vectormune HVT ND & SB1 HVT

Merck Animal Health Innovax MDV HVT

*No commercial endorsement implied

Company Virus Vector

Merck Animal Health Innovax ND SB HVT

CEVA Vectormune HVT+IBD HVT

CEVA Vectormune HVT+IBD & SB1 HVT

CEVA Vectormune ND HVT

Merck Animal Health Innovax ND ILT HVT

Merck Animal Health Innovax LT SB HVT

Merck Animal Health Innovax LT HVT

Merck Animal Health Innovax ND IBD HVT

CEVA Ultifend ND IBD HVT

Boehringer-Ingelheim VAXXITEK HVT+IBD+ND HVT

*No commercial endorsement implied

Recombinant vaccines for Avian Influenza Virus (AIV)• Many exist worldwide in areas where AIV

is endemic• In U.S. conditional licenses were issued for

several recombinant AIV vaccines during/after the 2014-2015 high path AI outbreak• Zoetis - Reverse engineered/killed

• US H5 – modified cleavage site• Boehringer-Ingelheim – Fowlpox/H5• Alphavirus RNA particle - GyrFalcon/U.S./2014• CEVA – HVT-H5 – Swan/Hungary/2006 • AgriLabs - DNA vaccine H5

• Platforms to accommodate changes in H5 to match outbreaks

Technologies for current and future vaccine development

Recombinant vaccinesReverse genetics• Construction of avian influenza

reassortant vaccine viruses

• Reverse engineered (RE) vaccines in China for AIV H5N1• RE-1 A/goose/Guangdong/1/1996

• RE-2

• RE-3 A/bar-headed goose/Qinghai/3/2005

• RE-4 A/chicken/Shanxi/2/2006

• RE-5 A/duck/Anhui/1/2006

• RE-6 A/duck /Guangdong/1332/2010

• HA cleavage site altered from high path to low path

Deletion mutants

• ILTV with gG deletion

• Live virus

• Protection against clinical signs of disease following challenge with virulent ILTV

• Stimulates systemic, mucosal and cellular immune responses

• Less pathogenic than live ILTV whole virus vaccines

Virus like particles (VLPs)

https://www.creative-biolabs.com/virus-like-particles-vlps-for-vaccine-development.html

Pushko, et. al., Virology, 2017

DNA vaccines

• Antigen-encoding gene is cloned into a non-replicating expression plasmid

• Host cells take up plasmid and express the antigen

• Easy to manipulate plasmid/switch genes

• Stable

• Humoral and cellular immunity

• DIVA compatible

Lee, L.Y.Y., et al, Front Imm, 2018

RNA particle vaccines

• Alphavirus -based replicon particles used as expression system • Accurate production of native proteins• Replication-defective nature • Only capable of a single infection cycle

• RPs not shed from vaccinated animals -> cannot spread to unvaccinated animals

• Platform used for custom vaccines for swine influenza [Sequivity – Merck]

• A conditional license for avian influenza H5

https://www.alphavax.com/alphavaccine-platform.html

“Omics” approach to vaccines

• Genome derived/epitope driven vaccines

https://epivax.com/immunogenicity-assessment/ivax-web-based-vaccine-design

Microarray Scan

(Double Spots)

Data Analysis

Antigen Sequence

Overlapping Peptides

Peptide Microarray

Secondary Antibody

Target Antibody

Post vaccine

Post challenge

Epitope = Consensus Motif

Epitope mapping

Research priorities for vaccine development

Research needs

• Research priorities were assembled by the American Association of Avian Pathologists (AAAP) research priorities committee

• Annual survey of veterinarians in• Association of Veterinarians in Broiler Production (AVBP)

• Association of Veterinarians in Egg Production (AVEP)

• Association of Veterinarians in Turkey Production (AVTP)

• Association of Poultry Primary Breeder Veterinarians (APPBV).

• Purpose to communicate applied research needs of industry to researchers and funding agencies

Vaccines topped list of priorities across sectors • Infectious bronchitis virus (IBV)

• Improved vaccines, enhanced safety characteristics

• Cross-protective

• Reovirus• Develop efficacious and innovative live and inactivated vaccines

• Provide protection against current and emerging strains

• Autogenous vaccines (custom made vaccines)• Improve speed and efficiency of production

• Develop more efficient methodologies to select viral and bacterial isolates

Working closely with industry• Isolate, identify and characterize viruses from clinical cases

• Track emergence of new viruses

• Evaluate protection/cross protection afforded by current commercial vaccines

• Maintain database with diagnostic results for tracking viruses over time and location

• Isolates for autogenous vaccines • Avian reoviruses, Infectious bursal disease viruses, Adenoviruses

• Attenuate new viruses that emerge or continue to cause disease in the field• Infectious bronchitis virus (GA08)• Takes time

Commercialization through partnerships with Universities• Pathways for new vaccine

development• R&D• Acquisition of company with

technology/vaccines • Acquisition of vaccine/technology

from a University

• Universities with competitive research programs have Innovation teams/departments that facilitate technology/intellectual property for licensing • @ UGA -> Innovation Gateway

In the next 5-10 years• Adjuvant technologies will be incorporated into vaccines – cytokines,

nanoparticles, toll like receptor ligands

• Continued development of recombinant platforms

• Vaccine advancements

• License of nucleic acid vaccines, VLPs, subunit and synthetic are on the horizon

• Conventional vaccines will continue to serve the poultry industry in an important role

• Vaccine licensure: Time from application to field use will decrease.

Thanks for your attention!