VACCINE

DEVELOPMENT

Presented to: Dr Saima Akram

Presented by: Aqsa Anwar
MSc biotechnology (4th )
Roll no: 04
contents
■ Introduction
■ Milestones in vaccine development
■ Concept of vaccination
■ Types of vaccines
■ Basic steps of vaccine production
■ DNA vaccines
■ Clinical development
■ Limitations of current vaccines
■ Flucelvex
■ malaria
What is vaccine?

“A vaccine is a biological preparation that improves immunity to

a particular disease. A vaccine typically contains an agent that
resembles a disease-causing microorganism, and is often made
from weakened or killed forms of the microbe, its toxins or one of
its surface proteins. The agent stimulates the body's immune
system to recognize the agent as foreign, destroy it, and
remember it, so that the immune system can more easily
recognize and destroy any of these microorganisms that it later
encounters”
Milestones in vaccine development
■ 1798: Edward Jenner invented smallpox vaccine
■ 1885: Louis Pasteur developed the first vaccine to protect humans against rabies
■ 1927: BCG vaccine recognized
■ 1955: Dr. Jonas Salk’s inactivated polio vaccine licensed, beginning the decline of polio worldwide.
■ 1963 : Dr. Albert Sabin introduced trivalent oral polio vaccine The first measles vaccine licensed
■ 1971 : The MMR vaccine licensed.
■ 1982 : Hepatitis B vaccine becomes available. Blumberg & Millman Irwing
■ 1995 : Varicella vaccine is licensed. Hepatitis A vaccine licensed. Acellular pertussis vaccine licensed.
■ 2003: The first live attenuated influenza vaccine(FLUMIST) licensed for use in people from 5 to 49 years of
age.
■ 2005: FDA licenses the meningococcal conjugate vaccine to prevent invasive meningococcal diseases
(MENATRA).
■ 2006: FDA licenses the HPV (GARDASIL) and Rotavirus vaccines (Rota Teq).
■ 2008: Two dose rotavirus vaccine (ROTARIX) approved
■ 2009: Influenza A (H1N1) vaccine approved.
Concept of vaccination
Types of vaccines
■ Whole-Organism Vaccines
a) Killed (Pertussis, Cholera, Rabies, Influenza)
b) Live Attenuated (BCG, OPV, Measles, Mumps, Rubella)
 Purified macromolecules as vaccine
a) Toxoids (diphtheria, tetanus)
b) Cellular fractions
c) Capsular polysaccharides (pneumococcal)
d) Cell wall polysaccharides (meningococcal)
e) Surface antigens (hepatitis B polypeptides)
■ Newer approaches
a) Recombinant vaccines
b) DNA vaccines
c) Multivalent subunit vaccines
 According to microorganisms
a) Bacterial (BCG, cholera, typhoid, toxoids)
b) Viral (OPV, MMR, rabies, hepatitis)
c) Rickettsials (epidemic typhus)
 According to indication
a) Preventives
b) therapeutics
Basic steps of vaccine production
DNA vaccines
■ DNA vaccines are third generation vaccines,
and are made up of a small, circular piece of
bacterial DNA (called a plasmid) that has been
genetically engineered to produce one or two
specific proteins (antigens) from a micro-
organism. The vaccine DNA is injected into
the cells of the body, where the "inner
machinery" of the host cells "reads" the DNA
and converts it into pathogenic proteins.
■ Advantages:
• Cheaper, safe and easier to produce.
• Large rapid GMP manufacturing capabilities.
• No need to handle infectious pathogens during
production.
• Can elicit both humoral & cell mediated
immunity.
Clinical development
Pre-IND stage
■ Identification of components and antigens
■ Preclinical testing
a) to rule out overt toxicity
b) identify potential toxic effects that might occur during the clinical trial and reversibility of the
toxicity
 Requirements for preclinical toxicity studies depend on
a) vaccine’s potential risk/benefit consideration
b) target population
c) available clinical data from the use of related products
d) availability of animal models
Investigational new drug stage

a) Phase I ( safety and immunogenicity studies)

b) Phase II (safety dose ranging study)
c) phase III (large scale safety)
Phase I:
• in small numbers (e.g. 20-100) of healthy adults, approximately 1 year.
• to evaluate vaccine safety and immunogenicity.
• includes study of dose and route of administration.
• Information about the induction of cell-mediated immunity, the cross reactive antibodies
and/or interaction pre-existing antibodies which might affect immune system is also
obtained.
Investigational new drug stage
■ Phase II
• Initial trials examining safety, effectiveness (immunogenicity) dose range &
pharmacokinetics.
• In several hundred volunteers forming the target groups, like, children, adults or those at risk
of exposure to pathogens.
• 1-3 years
• To obtain preliminary estimates on rates of common adverse events
 Phase III
• provides the critical documentation of the vaccine’s safety and effectiveness needed to
a) evaluate the risk/benefit relationship
b) to support licensure
• typically enrol several thousand subjects.
• 3-5 years.
• Manufacturing reproducibility is typically addressed by evaluation of lot consistency and
ensuring process validation.
Post approval stage

■ Necessary component of vaccine-safety monitoring.

■ Done in large populations over longer periods of time.
■ Important objectives:
I. to monitor increase in known reactions.
II. to identify rare adverse reactions not detected during pre-licensure studies.
Special concerns

■ A small risk of infection with active or live - attenuated micro-organisms.

■ Participants in control groups or when subjected to ineffective vaccines run a risk of
contracting the disease.
■ Risks associated with vaccines produced by recombinant DNA techniques are not
completely known.
■ Post trial access to the vaccine should be available to the control group. But, children in
control arm may cross the age when vaccine is protective.
■ When a trial of HIV preventive vaccine is being conducted, positive serology may result
after the vaccination.
Limitations of current vaccines
• Single disease prevention
• Require Multiple doses
• Not 100 % effective
• No sustained Protection
• Though less, but have adverse reactions
• Most are not safe in pregnancy and immunodeficiency
• Biological & environmental stability- difficult
• Cost effectiveness
• Risk of infection with live-attenuated micro-organisms
Flucelvax (influenza vaccine)

■ Inactivated trivalent cell-culture-derived vaccine against A (H1N1, H3N2) & B

subtypes.
■ For active immunization in adults aged 18 years and older
■ Single 0.5 ml I.M. injection
■ The FDA approval of Flucelvax was based on,
a) RCT during the 2007-2008 influenza season in 11400 adults
b) aged 18 - 49 years showed an 83.8% efficacy rate
 Adverse events reported: injection site reaction, headache, fatigue
malaria
Pre-erythrocytic vaccines:
Prevent clinical manifestation.

Erythrocytic vaccines:
Prevent invasion of RBC by merozoites and speed parasitized RBC clearance
Decrease the symptom severity.

Transmission blocking vaccines:

Block human to human transmission.
 Malaria
■ Effective immunity
■ Currently in preclinical stage
 Malaria
RTS,S/AS02A
 Pre-erythrocytic subunit vaccine.
 Fusion of surface CSP antigen with the HBsAg, formulated with
 the AS02 adjuvant system.
 Acceptable side-effect profile and immunogenicity confirmed in
 children 6 weeks of age or older.
 Phase3 trialin 15,460 children in two age categories:
 6 to 12 weeks of age and 5 to 17 months of age, showed
 protection against clinical and severe malaria up to 18 months
 after vaccination.