Vaccines and their thermostability-Challenges in formulation and potential

solutionPawan Dulal, DPhil (Oxon)

Rabies vaccine projectJenner Institute

University of OxfordPawan.dulal@ndm.ox.ac.uk

1

Presentation outline

• Very brief introduction to vaccines

• Structural complexities

• Problems with vaccines available in Nepal

• Thermostabilisation technology we have been developing at the Jenner Institute

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Introduction

• Vaccines are a biological preparation that improve immunity against a particular disease

• Agents that resemble a disease-causing microorganism

Vaccines

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Types of conventional vaccines

Types Preparation Structural complexity of vaccines

KilledVirulent micro-organism destroyed with chemicals,

heat, irradiation or antibiotics

Attenuated Live but weakened

Toxoid Inactivated toxic compounds that cause illness

Subunit Protein subunit

Conjugate Polysaccharide outer coat of bacteria linked with

protein to make them immunogenic

Virus

Bacteria

Conjugate

Subunit

Protein

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Epidemiological bulletin-2016Veterinary Epidemiology Centre (VEC)

Poultry diseases in Nepal

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Disease Vaccine type

Infectious bursal disease Inactivated/attenuated whole virus Recombinant subunit

Coccidiosis Live attenuated parasite

Fowl pox Live / killed virus

Newcastle disease virus Live /inactivated virus

Fowl typhoid Live/ inactivated bacteria

Fortunately vaccines againstthe majority of diseases exist

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Products need the ‘cold chain’

Disease Storage Product

Infectious bursaldisease

2-8oC Lyophilised

Coccidiosis 2-8oC Liquid

Fowl pox 2-8oC Lyophilised

Newcastle diseasevirus

2-8oC Lyophilised

Fowltyphoid

2-8oC, DNF Liquid

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• Example 1 Newcastle disease vaccines– Produced in eggs, formulated with allantoic fluid and

skimmed milk

– Lyophilised requires cold chain

• Example 2 Coccidiosis– Live sporulated oocysts produced in SPF chicks

formulated with adjuvants such as Montanide in phosphate buffered saline.

– Liquid requires cold chain

Manufacturing process adds complexities too

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Better formulation and thermostabilityis important for transport

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..and during vaccination

Image credit: https://freenewsman.com & declara.com

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Thermostability=most successful vaccination campaigns

• Only two diseases have been eradicated by immunisation: one a disease of humans, smallpox, and the other rinderpest or cattle plague

• In both cases development of thermostable vaccine formulations -key to the success of the programmes

-Journal of Pharmaceutical Sciences. 2013, 102(1)

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Route to thermostability stopped/slowed down chemistry

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Optimised liquid formulations– Antioxidants, pH buffering salts, sugar, amino acids, surfactants,

chelating agents, organic solvents• But do not completely remove stress related degradation …

Dry formulations• To immobilise the product in amorphous sugar glass

• Lyophilisation/freeze drying- most common method

• Spray drying

Thermostable strains• Newcastle disease I2 strain

Different approaches used

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Sugar-matrix thermostabilisation-a novel drying method

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Drying mechanism- hypothesis

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High thermostability of viral vectored vaccine against malaria

Alcock, 2010AdHu5- TIP-GFP16

Stability of Modified Vaccinia Virus-Ankara

Alcock, 2010MVA- TIP-GFP

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Thermostability of Rift Valley fever vaccine

ChadOx1-GnGc- Rift valley fever Dulal, 2016

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Preclinical-rabies vaccine

ChadOx2-RabG Chuan, 2018

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– Non-enveloped attenuated virus vectors (adenovirus vectored vaccines)

– VLPs (HPV)

– Complex adjuvants containing immunomodulatory functions+subunit vaccines (R21+MatrixM)

– Highly labile virus vectored vaccine (baculovirus)

One size fit for all?

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Summary….Continued

• Cheap ingredients < few cents• Smaller doses possible• No process optimisation “in

most cases”– Generic method– Only two excipients– Simpler– Shorter – More efficient than lyophilisation,

spray drying and spray-freeze drying

All desirable characteristics of a vaccine for backyard and

small scale poultry farmers

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Next steps

• Adopting the technology to veterinary vaccines will be relatively easier after GMP production of human vaccines

• Will be testing more veterinary vaccines using the technology

• Certainly hope to resume NDV thermostabilisation work that had to be paused

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• Jenner Institute-Sandy Douglas

-Adam Ritchie

-Tom Merritt

-Sofiya Fedosyuk

-Adrian Hill

-Rebecca Ashfield

-Sarah Gilbert

-Ali Turner, Claire Powers & VVCF

• KWTRP, Kilifi, Kenya• George Warimwe

Thank you

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• U of Oxford Clinical Bio-manufacturing Facility

-Richard Tarrant

-Emma Bolam

-Eleanor Berrie

-Abdou Tahiri-Alaoui