Viral Vaccines Flashcards by Claire Delargy

WHO states the 2 most significant developments which have improved the health of children are:

Clean water
Vaccination

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Variolation

Ancient method
Recovered patients had life-long immunity
Material from infected individuals given to healthy people may result in milder disease and subsequent protection
10 fold reduction in disease incidence
2-3% died
Eg smallpox virus

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Smallpox vaccine

Edward Jenner
Dairy maids infected with cowpox (mild disease) - resistant to smallpox
1796 - inoculated 8 year old boy with fluid from dairy maid cowpox posture; 6 weeks later exposed to smallpox => no symptoms

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Why was global eradication possible for Smallpox?

Virus biology
- no animal reservoir
- lifelong immunity
- no overt symptoms
- one serotype
- good vaccine (vaccinia virus)

Global commitment
- Governments
- WHO (1965)

1979 - 1/2 viruses eradicated ever

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In what year was MMR vaccine introduced in the UK?

1988

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3 examples of live attenuated vaccines

MMR
Polio
Influenza
Smallpox

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3 examples of inactivated/whole vaccines

Hep A
Rabies
Japanese encephalitis
(Influenza)

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Distribution of vaccines requires strict ______________ control of vaccine stock.

Temperature

(Difficult in hot climates in resource poor countries)

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Whole inactivated vaccines

Virus grown in cell culture or eggs
Extract
Chemical inactivation e.g. formaldehyde

No possibility of infection - control
Duration of protective immunity generally less than live attenuated vaccines

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Inactivated vaccines - split

Virus grown in cell culture or eggs
Lyse culture
Extract virus vaccine antigen eg F surface protein in Influenza
Purify vaccine antigen

No possibility of infection
Duration if immunity less than for live attenuated vaccines
E.g.influenza HA = vaccine target of interest

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Subunit vaccines

Recombinant subunit vaccines

Identify potential vaccine antigens
Obtain cDNA copies of genes
Antigen gene cloned into expression vector
Antigen expression in suitable cells (eukaryotic, bacteria, yeast)
Antigen purification
Vaccine formation - add adjuvants
-> modulates immune response

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Adjuvants

Greatly enhances immune response to antigens
e.g. aluminium hydroxide

ISCOMs (immune stimulating complexes); oil/water emulsions and toll-like receptor agonist = undergoing research

Influenza no adjuvants in adults
Influenza adjuvants needed in elderly

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_______ __________ ______________ leads to herd immunity.

High vaccine uptake - 90%

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How do vaccines modulate the acquired immune system?

Vaccine antigen introduced to body (Mucosal or Parenteral) -> Viral antigen taken up by APCs -> present antigen to B and T cells in correct conformation in LNs -> Clonal expansion of epiptope-specific memory B and T cells ->
Accelerated response to virus upon infection -> protection from disease due to Tc cells and neutralising Abs

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Most common vaccine adverse events

Injection site hypersensitivity
Injection site oedema
Rash
Myalgia
Fever
Headache

VAERS US, 1990-2001

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What does VAERS stand for?

Vaccine Adverse Events Reporting System

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Eczema vaccinatum

Smallpox vaccine adverse events
Frequency => 10-42 cases/million vaccinees

Vaccines versus therapeutics

Healthy individuals
Mass administration
Disease prevention
Low risk tolerance
Low cost

Vaccines versus therapeutics

Sick individuals
Targeted administration
Disease treatment
High risk tolerance
High cost

Obstacles to vaccination in infancy

Immune system not fully mature
Maternal antibody restricts live vaccines
False contraindications
Parental fears
Adverse publicity

Vaccine contra-indications

Acute illness
Definite severe or generalised reaction to preceding dose
Avoid live vaccines in pregnancy
Care with live vaccines in immunocompromised patients

Do multiple vaccines overwhelm immune system?

Childs immune system can cope with 11000 immunological challenges at once
<0.1% of the immune system is used after MMR

Does the MMR vaccine cause autism?

Population based study in Denmark 1991-1998
N = 537,303 kids
MMR vaccine = 440,655
316 autistic children
442 autistic spectrum
No increased risk with vaccine

MMR vs autism in Japan
Stopped giving MMR vaccine
No change in incidence of autism

Synthetic peptide vaccines

Synthesis of chemically defined antigens

Require:
- antigen purification
- carrier protein conjugation - provide helper T-cell epitopes (essential for B-cell activation, memory and Ab production e.g. tetanus toxoid)

Recombinant subunit vaccines are:

Novel expression systems or Novel formulations

Recombinant viral vaccines typically involve: (2)

Reverse genetics (influenza, RSV) Multi-valent antigen expression vectors

Major challenges for viral vaccines

Viral quasi-species and antigenic variability - influenza Overcoming poor immunogenicity of WT viral antigens - RSV Formulations - induction of sufficiently strong, long lasting, and safe immune responses Live attenuated vs subunit Mucosal vs parenteral

Viral quasi-species

Population structure of viruses with a large number of variant genomes. Result from high mutation rates as mutants arise continually and change in relative frequency as viral replication and selection proceeds

Example of inactivated/split vaccine

Influenza

3 Examples of subunit vaccines

Hep B HPV SARS - CoV- 2

Virus attenuation and considerations

Repeated passage in non-natural cells -> reduced ability to replicate in natural host - cell culture adaption. Induce sub-clinical infection AND induce protective immune responses - Usually long lasting Complicating risk - Reconversion to wild-type - Contaminating infectious agents in cell culture - Cold chain

Herd immunity

Sufficient number of vaccinated people to protect those unvaccinated eg immunocompromised (can’t cope with live unattenuated virus) or those with allergies (eg egg proteins)

All medical interventions carry risks of adverse events so should calculate:

Vaccine risk/benefit ratio Low disease morbidity and mortality = low risk acceptable High disease morbidity and mortality = higher risk acceptable

Serious adverse events of vaccines

Life threatening illness Death

Future Vaccines

Synthetic peptides Recombinant subunit vaccines Recombinant viral vaccines

Carrier proteins

Conjugated to peptide antigens which provide helper T cell epitopes - Essential for B cell activation, memory and Ab production Eg Tetanus toxoid and Diptheria toxoid

Polio

Generally benign 1% flaccid paralysis Vast amount of people infected Dime for polio research Live tenanted vaccine no longer used in favour of inactivated vaccine

Polio London patient

Individual travelled to London Had been given live attenuated vaccine,no longer used in England Virus was shedded and found in sewerage Live attenuated vaccine no longer used as there is a small possibility of virus returning to WT ->excreted into waste-water -> infectious

What do you want in a vaccine?

Sub-clinical infection with no symptoms Stimulate the immune response without pathology

Groups who should not be given live attenuated vaccine

HIV patient Cancer patient Allergies ->allergy to egg protein

Efficacy of MMR vaccine

90-92% => herd immunity