Vaccine Development I

Srabasti J Chakravorty

“Immunisation is a right of every child

in the 21st century”
 Vaccines: A global Issue

WHO/Europe
help countries strengthen infectious
disease control programmes

Current major initiatives :

• safe immunization
• introduce new & underused antigens
• eliminating measles
• prevention of congenital rubella infection
• maintaining a poliomyelitis-free Europe
Diseases that can be controlled by vaccines:
Poorly infectious
Antigens relatively invariant

Diseases that are difficult to control by vaccines:

highly infectious
antigenic variation
Animal or environmental reservoirs of
infection
 Aim of Vaccination

Induce specific immunity to:

Prevent microbial invasion

Eliminate microbes

Neutralize microbial toxins

Major types of pathogens confronting the immune system
 Vaccine Preventable Diseases

WHO Global Immunization Vision and Strategy 2006-2015.

Global immunization coverage 2013

WHO: Fact sheet N°378 Reviewed November 2014

Antibody - mediated host defense
Host defense against intracellular VIRAL infection
 History of Vaccines

Variolation:
smallpox immunisation
infect with scab material to induce immunity
disease - in less-dangerous form
Turks, Chinese, African

 England: in 1721 by Lady Mary Wortley Montagu

 Massachusettes: Cotton Mather
N. America after 1721 and S. America in 1728

1842 - illegal
Smallpox vaccine: Edward Jenner 1796
 Milkmaids with cowpox - lovely skin

 8yrs old James Phipps

 James resisted a smallpox challenge

 “cow-pox protects the human

constitution from the infection of
smallpox” :
Efficiency of Vaccines
Efficiency of Vaccines
 Molecular era 1970-1990

• Hepatitis B vaccine (1981):

– recombinant DNA technology
– first used to protect select target populations
– now throughout developing world

• First anti-cancer vaccine

• Pneumococcal and Hemophilus influenza

b subunit vaccines.
 The Future

• Glycoconjugate vaccines, rotavirus

vaccine, human papilloma virus vaccine
and herpes zoster vaccine.

• HIV/AIDS vaccines, malaria vaccines,

tuberculosis vaccines, anti-cancer
vaccines, anti-addiction vaccines anti-
fertility vaccines, therapeutic vaccines.
Immune System
Criteria for Vaccine activity

1. Antibody titre

2. CD4+ T cell activity

3. CD8+ T cell activity

 Immunologic Memory
the basis for prophylactic immunization
 Activating Agents (Immunogens)

Molecules
• Peptide/proteins, Polysaccharides Nucleic
acids, Lipids

Microrganisms
• Bacteria, Viruses, Fungi, Protozoa,
 Artificial Methods of Immunity

Active immunization
– patient mounts a protective immune
response

Passive immunization
–acquires immunity through transfer of
antibodies
 Active Immunization

Vaccine types

• Attenuated (live) vaccines

- MMR, VZV, Flu

• Inactivated (killed) vaccines

- Polio, HAV, Flu

• Toxoid vaccines
 Active Immunization
Attenuated (live) vaccines

• use pathogens
• mild infections
• active microbes
• strong immune response
• effective with one dose
• contact immunity
• hazardous
 Active Immunization
Inactivated (killed) vaccines

• Whole agent vaccines

- deactivated whole microbes

• Subunit vaccines
- antigenic fragments of microbes (HBV)

• safer than live vaccines

• Antigenically weak

• Often contain adjuvants

 Inactivated Vaccines

 viruses
 bacteria

 protein-based
• toxoid
• subunit

• polysaccharide-based
• pure
• conjugate
 Adjuvants

[INSERT TABLE 17.1]

 Function of Adjuvants
• Rapid Response

• Vaccine Response Broadening

• Vaccines for elderly

• Therapeutic vaccines

• New T cell vaccines

• Reduced number of Immunizations

• Dose Sparing
 Mechanisms of Action of Adjuvants
Muscle tissue
1. Depot Formation
2. Cytokine & Chemokine secretion
3. Immune cell recruitment in tissue

Blood vessel
APC 5. Maturation of APCs

4. Antigen uptake through PRRs

6. Antigen
presentation

7. Activated APCs traffic to lymph nodes 8a. B cell responses

Lymph Node

8b. CD8 T cell

responses
Awate et al. Front Immunol. 2013; 4: 114.
 Active Immunization
 Toxoid vaccines

• modified toxins
• Useful for some bacterial diseases
• antibody-mediated immunity
• Require multiple doses
 Active Immunization

 Recombinant gene technology

• Research attempts to make vaccines that

are more effective, cheaper, and safer

• A variety of recombinant DNA techniques

can be used to make improved vaccine
Recombinant Gene Technology

[INSERT FIGURE 17.2]

 Viral vectors
Engineer HIV genes into another non-pathogenic virus

Vaccinia
Canarypox
Fowlpox
VEE
AAV
MVA
NYVAC
Adenovirus

Disadvantages:
• difficult to produce high titer recombinant virus
• may have pre-existing immunity to vector and/or will
develop immunity after vaccination
 DNA plasmid vectors

Stevenson 2004. Immunological Reviews 199: 5-8.

Disadvantages:
limited response after repeat doses, integration, DNA Ab
Pantaleo & Koup Nature Medicine  10, 806 - 810 (2004)
 Active Immunization
 Vaccine safety
• Problems associated with immunization

– Mild toxicity
– Pain or general malaise
– anaphylactic shock
– virulence
– autism, diabetes, and asthma
 Passive Immunization

Administration of antiserum

immediate protection against a recent infection

or an ongoing disease
 Passive Immunization
Limitations

• antibodies against many antigens

• serum sickness

• May be contaminated with virus

• Antibodies degraded quickly

• May be overcome through development

of hybridomas
 Hybridoma

[INSERT FIGURE 17.4]

 Passive vs Active

[INSERT FIGURE 17.5]

 WHO:
Properties of an Ideal Vaccine

• Safe
• Affordable
• Heat stable
• Effective - single dose
• Applicable to a number of diseases
• Administered by a mucosal route
• Suitable for administration early in life
 In 2001: only 37% of children fully immunised
63% mothers don’t know child’s vaccine needs
37% children receive all 5 rounds of immunization

http://www.path.org/files/Uganda_immunization_advocacy.pdf
 Supplementary Reading

The business of making vaccines. Cormac Sheridan

Nature Biotechnology 23, 1359 - 1366 (2005)
http://www.nature.com/nbt/journal/v23/n11/fig_tab/nbt1105-1359_T1.html

Immunology textbooks:
Janeway's immunobiology / Kenneth Murphy
Cellular and Molecular Immunology / Abbas, Abul K.

Oberdan et al 2011; Perspectives in Vaccinology, Volume 1.

Stevenson 2004; Immunological Reviews 199: 5-8.

Pantaleo & Koup 2004; Nature Medicine  10, 806 – 810

Awate et al. Front Immunol. 2013; 4: 114

InvivoGen: http://www.invivogen.com/review-vaccine-adjuvants
Immune System