Manipulating immune responses to control infectious disease

methods to boost innate immune response (2)

PRR agonists

cytokines

methods to suppress innate immune response (2)

PRR antagonists

anti-cytokine therapies

innate immunity - imiquimod

TLR7 agonist → used to boost innate immunity

Topical treatment used in treatment of some virus infections (eg. HPV) and some melanoma (eg. superficial basal cell carcinoma)

imiquimod - side effects (2)

Fever, flu-like symptoms

Blisters, skin redness, skin scabbing

septicaemia to septic shock - transition cause

strong inflamamtory resposne and thrombotic and fibrinolytic response

septicaemia to septic shock - transition steps (5)

1. LPS binds to monocytes → lipid A segment interacts with cell TLR-4

2. Inflammatory response

• Monocytes produce inflammatory cytokines inc. IL-1, IL-6 and TNF-a → bind to endothelial cells and stimulate inflammatory response inc. transmigration of innate immune cells

• Chemotaxis, adhesion, superoxide production and degranulation cause damage to the endothelial cells

3. Thrombotic and fibrinolytic response

4. Damage to endothelial cells causes loss of fluid in tissues, fall in BP and circulatory collapse -> difficult to reverse

5. Multi-organ failure

septic shock - thrombotic and fibrinolytic response (5)

1. Monocytes produce tissue factor

2. Tissue factor activates coagulation and thrombin

3. Thrombin activation leads to fibrin production

4. Fibrin forms clots between and on endothelial cells

5. Disseminated intravascular coagulation

suppressing innate immunity - septic shock

TLR-4 antagonists in trial for septic shock -0> block over-exuberant immune responses

strategies to stimulate adaptive immunity (2)

Passive immunisation -> deliver products of B cells

Active immunisation -> deliver appropriate antigen/s to induce and activate T and B cells

passive immunisation - uses

Mainly suitable for serum antibodies -> not good for protecting mucosa

immediately available but not long lasting

passive immunisation - contents

antibodies only

T cells originating from another individual will express different MHC molecules

sources of antibodies used in passive immunisation (3 categories)

• antimals → immunised animals, monoclonal ab (limited number of admin unless constant region is “humanised”

• blood bank serum → eg. Hep A and varicella zoster virus

• recombinant human antibodies → eg. HIV and RSV

active immunisation - meaning

induction of components of wild type immune response

active immunisation - advantages (3)

Long lived -> naturally boosted

Can involve humoral and cellular immunity

May be able to target specific tissue locations -> eg. mucosal immunity

active immunisation - disadvantages (2)

Takes time to induce

Variable in very young and very old

features of ideal vaccines (7)

• Be safe

• Provide protection

• Be cost effective

• Be stable

• Be easy to administer

• Have few side effects

• Able to achieve herd immunity

vaccine design - implications of pathogen profile

Type of pathogen and disease it causes

possible virulence factors to target

vaccine design - implications of location of immunity (3)

Which immune components to activate and where -> eg. injected vaccine will not induce mucosal immunity

Humoral or cellular immunity

Memory response?

vaccine design - implications of vaccine design concept (3)

Type of vaccine

Antigen selection

Adjuvants or delivery systems

vaccine design - implications of challanges and considerations (2)

Safety and efficacy concerns

Side effects or limitations

current types of vaccines - list (4)

live attenuated organisms

subunits of purified pathogen

killed micro-organsims

virus like particles

current types of vaccines - live attenuated organisms

living organisms modified to lose pathogenicity but not immunogenicity

Empirically attenuated -> eg. TB and MMR vaccine

Rationally attenuated -> eg. rotavirus vaccine

current types of vaccines - subunits of purified pathogen examples (2)

influenza vaccines 

acellular pertussis

current types of vaccines - killed micro-organisms examples (2)

polio vaccine

old pertussis vaccines

current types of vaccines - virus-like particles

self assembled viral capsid proteins made by recombinant technology

Eg. capsid proteins of HBV and HPV

lvie attentuated vs killed/ extracted antigens - delivery

live attenuated: oral, injfection, parenteral

killed/ extracted antigens: usually parenteral

lvie attentuated vs killed/ extracted antigens - duration

live attenuated: long lived

killed/ extracted antigens: short duration → requires boosters

lvie attentuated vs killed/ extracted antigens - living?

live attenuated: replicate → determines site and quantitiy

killed/ extracted antigens: no-replciation → needs repeated high doses

lvie attentuated vs killed/ extracted antigens - stability (efficacy)

live attenuated: labile

killed/ extracted antigens: relatively stable

lvie attentuated vs killed/ extracted antigens - stabiluty (genetic)

live attenuated: reversion to virulence

killed/ extracted antigens: avirulence

lvie attentuated vs killed/ extracted antigens - antigens

live attenuated: multiple antigens present

killed/ extracted antigens: restricted number of antigens

main goal of an ideal vaccine

mimic or improve features of the antibody response induced by infection

achieved through inducing efficient B cell activation

achieving B cell activtation in ideal vaccine - requirement

requires activated T cells → vaccine must contain epitopes that can also be recognised by T cells

Without T cell activation, antigen binding to BCR results in only IgM produced and no memory cells

interaction via CD40L and CD40 and cytokines induces:

1. Isotype switching

2. High affinity antibodies

3. Induction of memory B cells

adjuvants - def

substances added to vaccines to enhance, prolong or modify immune response to the antigen

adjuvants - example mechansims (3)

Enhance immune response to antigen by promoting antigen uptake and presentation

Stimulate innate immune pathways by activating innate immune cells through PRRs

Improve development of adaptive immunity by shaping type of response and creating a depot effect that slows antigen release

considerations for designing a vaccine for a new respiratory virus (4)

1. Which antigen would you use

2. Where does immunity need to act

3. Which immune response is required

4. Would you include an adjuvant