MICR5817 L6: Animal Models for Vaccine Development

Vaccine development is a slow, complex, and costly process:

-How long does it take to develop a human vaccine?

-How many vaccines make it to market? What is the cost?

-10 to 12 years (from the pre-clinical stag

-Less than

True or False: Vaccines are mostly used in healthy people to PREVENT disease, so clinical trials must demonstrate the vaccine is safe and effective

True

Who must review vaccines to ensure safety and efficacy before recommended for human use?

Scientists, doctors, policy-makers, regulatory authorities

What government organizations conduct safety monitoring?

-European Medicines Agency (EMA)

-U.S. Food and Drug Administration (FDA)

-Therapeutic Goods Australia (TGA

-Other national public health institutes.

When does the first safety test for vaccines happen?

-Before human trials

-At the pre-clinical development stage.

True or False: The FDA can approve drugs that are tested in only non-animal studies (including those that use lab-grown tissues or computer models) before being tested in clinical trials with humans.

True

(Insert Image P6) Describe some key milestones in Vaccine Development

1) Vaccine Design

2) Preclinical Testing (Animal)

3) Clinical: Phase I, II and III

(Insert Image P7) Describe the steps involved in Vaccine Development and why it takes so long to develop a vaccine

(Insert Image P8) Describe the Vaccine Life Cycle

(Insert Image P9) Describe the Vaccine Discovery Phase

-More like 10-15 years of laboratory research (private industry and/or university)

-COVID vax development was 1 year.

-CEPI recently launched their 100-day vax development ambition

What is this?

-Antigen Research and Identification

-Understanding the disease, the pathogenesis and the immune mechanisms of protection.

-Proof of concept: Vaccine candidate is evaluated for safety and efficacy profile using in vitro and in vivo tests.

What is involved in the 1. Vaccine Discovery Phase?

i. Vaccine candidate(s) selection (vaccine design lecture from A/Prof Alma Fulurija)

ii. Demonstrate immunogenicity (usually in mice)

iii. Test efficacy and safety in disease model (if available)

(Insert Image P9) Describe the development of Vaccine Forumlations

(Insert Image P9) Describe the in vivo testing with animal models

What animal models are good and bad for studying Cdiff?

-Guinea pigs are good

-Mice and rats are bad

-Chinchillas have big ears, good for ER but hard to get into Australia

(Insert Image P11) What are Pros of using a Mouse?

-Ease of Use

-Availability of reagents

-Genetic manipulation

(Insert Image P11) What are Cons of using a Mouse?

-Lack of fever response

-Sub strain variation, lots of issues

(Insert Image P11) What are Pros of using a Guinea Pig?

-Relevance to human disease

-Febrile dose-response

(Insert Image P11) What are Cons of using a Guinea Pig?

-Cost

-Cumbersome

-Lack of reagents

-Limited strain selection

(Insert Image P11) What are Pros of using a Monkey?

-Relevance to human disease

-Febrile dose-response

(Insert Image P11) What are Cons of using a Monkey?

-Cost

-Cumbersome

-Ethical considerations

-Infrastructure requirements

True or False: Usually mice or rat safety data is enough to go into adults without including monkeys

True

Which animals are bad for studying the immune system?

-Guinea pigs and rabbits

-Harder to find antibodies against them

(Insert Image P12) Describe some examples of animal immunogenicity experiment design

-Give antigen/vaccine candidate multiple times

-Higher antibody titre, like a 2-3 dose booster shot for babies

-Challenge with disease you're protecting against

(Insert Image P13) How was the mouse model used to test a vaccine?

-3 Dose vaccine candidate against ear infections

-Tail vein blood from mouse = vein blood in arm

-Use ELISA to measure mice antibodies

(Insert Image P14) What were the results of the Murine Serum IgG response to NTHI intranasal vaccine?

Murine serum increase in protective IgG antibodies against antigen that causes ear infections

What is this?

-The safety testing before use in humans

-This is rigorous and highly regulated

Pre Clinical Vaccine Development Phase

What is this?

-In depth testing of the vaccine candidate's safety in lab and animal models (local and systemic toxicity), follows regulatory guidelines.

-Adjuvant for the formulation of the vaccine candidate are selected

Safety Study

What 3 steps are involved in a Safety Study?

1. Defining a Quality Control System for Vaccine Production

2. Establishing the Safety Profile of the Vaccine Before Testing in Humans

3. Application for approval for Human Trials (REGULATORY & ETHICS APPROVAL)

Which step of a Safety Study is this?

-Scientists have shown proof-of-concept (feasibility)

-Manufacturer must establish a QC approach candidate vaccine

-Follows 'Good Manufacturing Practice' (GMP) rules and National medicines agency's guidelines (FDA, TGA, EMA)

-Vaccine is "released" after validation, toxicity testing can begin

Defining a Quality Control System for Vaccine Production

Which step of a Safety Study is this?

-Panel of animal toxicity studies must be performed

-Toxicity studies are designed to mimic the intended use in clinic

-Include: Relevant animal species, dosing schedule, method of vaccine administration

Establishing the Safety Profile of the Vaccine Before Testing in Humans

Which step of a Safety Study is this?

-Production process is developed

-Toxicity studies are completed

-The sponsor can apply for approval to their competent authority

-If approved, clinical trials can start

Application for approval for Human Trials (REGULATORY & ETHICS APPROVAL)

What is this?

-Agent causes the majority of pneumonia + meningigitis in world

-Commonly carried by many people, over 100+ serotypes

-1/3 of people have it in nose

-Especially kids in daycare/crowded settings

Streptococcus pneumoniae

Name another bacteria responsible for causing pneumonia (besides Streptococcus pneumoniae)

Hemophilus influenzae

Describe a problem with previous pneumococcal vaccines

-Replacement

-Vaccine protects against certain types, then others come and takes over

True or False: A study in Papua New Guinea showed that children carried 61 types of pneumococcus and up to 5 types at once

True

(Insert P16) Describe the gamma-irradiated whole cell pneumococcal vaccine: from discovery to clinical trials

-Vax covers 20 serotypes

-Goal: Universal protection

-Take pneumococcus, gamma radiate it to sterilize and create wholesale vaccine

How does ear infection happen and why would a nasal spray prevent it?

-Ear infections start up the nose with bacteria

-Ear infections travel up Eustachian tubes and cause infection behind eardrum

-Nasal vaccine sprays up nose, prevents ear infection

(Insert Image P20) Describe the differences between these ear drums after seeing them in an otoscope

1) Healthy

2) Has pus behind it

3) Bulging eardrum, pressure pushes it out. After multiple infections, undergo grommet surgery

4) Balance the pressure with a grommet

Describe how ear infection during Otitis Media (OM) causes pressure buildup

If infection persists, pus builds up and comes out of the ears

Describe how OM (Otitis Media) affects children in WA

-1 in 4 children suffer recurrent AOM/chronic OMEI

-1 in 2 Aboriginal children have OM-associated hearing loss by 6 months of age

List some Risk Factors for Otitis Media

1) Under 5yrs old

2) Day-care attendance

3) Siblings

4) Family history

True or False: Otitis Media is the main reason for childhood antibiotics and surgery

True

What is the main reason for childhood GP visits, antibiotics and surgery worldwide?

Otitis Media

Where is Otitis Media prevalent?

-High, middle and low-income countries

-First Nation peoples at high risk

What are some consequences of Untreated Otitis Media causing sticky glue behind your ears?

1) Hearing loss

2) Speech delay

3) Poor life-course

What bacteria is associated with all Otitis Media?

Nontypeable Haemophilus influenzae (NTHi)

True or False: There are NO therapies for Nontypeable Haemophilus influenzae (NTHi) OM prevention

True

What is this?

-Nasal spray using commensal bacteria

-Prevent childhood ear infections

-Need to understand nasopharyngeal microbiome

-Similar to probiotic for nose but w/ more clinical evidence

Spritz OM

Describe the results of the study on Spritz OM efficacy

-Single intranasal dose of Spritz-OM reduces amount of NTHi colonisation

-Prevent bacteria getting behind ears and causing OM ear infections in mice

How was SpritzOM developed?

-Took friendly bacteria, put it onto respiratory cells

-Can prevent infection from main pathogen

-Faster recovery with Spritz-OM after IAV infection