Unique
Approaches to Vaccine Development Formulation and Delivery
Patil SM*, Maske AP Sapkale GN and Kure AB
ASPM’s. K. T.Patil Collage of Pharmacy
Osmanabad- 413 501(MS) INDIA.
ABSTRACT:
A Vaccine is a preparation, which is used to
stimulate immune system, improves immunity to a particular disease. Vaccine can
be prophylactic or therapeutic. Most vaccine registered for use is designed to
prevent or control acute human infections. The conventional approaches to
vaccine Research and Development are as Isolation and Characterization of
disease causing organism, to discover methods to effectively immunize and
protect susceptible host and to develop assay to measure immune response and
identity immune correlates of protection, Manufacturing and Preclinical
development, Clinical and Field testing in humans. New approaches to vaccine
development are as use of anti-idiotype antibody preparation to mimic B-cells
epitops, Synthesis of oligo or polypeptides that reflect naturally occurring a
sequence of protein of pathogen. rDNA Transfection of cells with inserted
DNA/CDNA into genome of other viruses and bacteria. New prophylactic and therapeutic
vaccines will prevent and potentially cure disease. New delivery systems for
human vaccines are being developed to enhance cellular and Mucosal immunity, as
well as ease of use, advances in current vaccines such as conjugated
pneumococcal vaccines for adults, nasal spray vaccines for Influenza and adult
a cellular pertussis vaccine will provide an efficient way to of longlasting
protective immunity. There is as of today no TH1 adjuvant efficient in humans.
Such adjutants are needed to develop powerful therapeutic vaccines against
cancer or chronic infectious diseases. New vaccine delivery technology will
provide easier delivery routs such as transcutaneous, depot, nasal, and oral
delivery without compromising efficacy.
KEY WORDS: Vaccines, development, delivery,
approaches.
INTRODUCTION:
Need
for development of vaccines:
2/3 of the world’s people live in the
developing world. Millions die unnecessarily each year from diseases that are
currently treatable or preventable, WHO estimates that 1.4 million of deaths
among children under 5 years were due to diseases that could have been
prevented by routine vaccination, This represents 14% of global total mortality
in children under 5 years of age, For every six mothers giving birth today in
sub-Saharan Africa, one will lose her child before it is five. That is 4.5
million babies dying from preventable diseases, of which about 2 million are
vaccine preventable. Just 3 diseases – AIDS, TB and malaria – kill 6 million
people annually Vaccine Preventable diseases kill 1.7 million children
annually.
Need
of innovative delivery technologies:
To vaccinate a child against the most common
childhood illnesses costs just $30 a head, and yet in 37 million children
worldwide did not receive this basic level of protection in their first year of
life. Globally, 50% of all vaccines bought go to waste through temperature
damage, contamination during reconstitution and wastage.
Enough to protect 10 million more children. Regulatory environment
requires to develop vaccine that are very well defined in molecular terms,
Vaccines of past designed to stimulate against surface molecules of bacteria or
virus, new generation vaccine are designed to elicit cellular immune responses,
Improving vaccine administration either for the physician, for patient, towards
pain-free and safe needle-less devices
Global
Infectious diseases: Mortality and Causes of child deaths globally Diphtheria:
Diphtheria is a bacterial infection caused by Corynebacterium diphtheria, transmitted from person to person through close physical and
respiratory contact. It can cause infection of the nasopharynx, which may lead
to breathing difficulties and death
Pertussis:
Description: Pertussis, or whooping cough, is a disease of the
respiratory tract caused by bacteria that live in the mouth, nose, and throat.
The disease is most dangerous in infants. Pertussis spreads very easily from
child to child in droplets produced by coughing or sneezing
Prevention: Inactivated whole cell WP or a
cellular AP - at least 3 primary doses, given
by the intramuscular route, combined with diphtheria and tetanus toxoid
Tetanus:
Description: Tetanus is acquired through exposure to the spores of the
bacterium Clostridium
tetani The disease is caused by the action of a potent neurotoxin produced
during the growth of the bacteria in dead tissues, People of all ages can get
tetanus. But the disease is particularly common and serious in newborn babies.
This is called neonatal tetanus. Most infants who get the disease die.
Prevention: Toxoid as DTP, DT, TT or Td - at least three primary doses given by
the intramuscular route
Measles:
Description: Measles is a highly contagious vaccine-preventable disease caused by
the measles virus, a member of the genus Morbillivirus in the family paramyxoviridae.
It spreads by droplets or direct contact with nasal or throat secretions of
infected persons; less commonly by airborne spread or by articles freshly
soiled with secretions of nose and throat. Measles is one of the most readily
transmitted communicable diseases and Probably the best known and most deadly
of all childhood rash/fever illnesses
Prevention: Live attenuated viral measles vaccine - one dose given by the
intramuscular or subcutaneous route, with opportunity for second dose at least
one month after the first.
Mumps:
Description: Mumps is an infection caused by a virus. It is sometimes called
infectious parotitis, and it primarily affects the salivary glands. Mumps is
mostly a mild childhood disease. It most often affects children between five
and nine years old. Mumps virus can infect adults as well. When it does,
complications are more likely to be
Serious. Mumps virus is present throughout the world. It is spread by
airborne droplets released when an infected person sneezes or coughs and by
direct contact with an infected personPrevention: Live
attenuated viral mumps vaccine - one dose given subcutaneous, usually in MMR
Rubella
and Congenital Rubella Syndrome (CRS):
Description: Rubella is an infection caused by a virus. Congenital rubella
syndrome
(CRS) is an important cause of severe birth defects. Deafness is the
most common, but CRS can also cause defects in the eyes, heart, and brain.
Rubella is spread in airborne droplets when infected people sneeze or cough.
Once a person is infected, the virus spreads throughout the body in about five
to seven days. During this time, pregnant women may pass the virus on to their
fetuses
Prevention: Live attenuated viral rubella vaccine - one dose given by
the intramuscular or Subcutaneous route as monovalent, MR or MMR.
Haemophilus
influenza type b (Hib):
Description: Haemophilus
influenza type b (Hib) is one of the six related types of bacterium. The Hib
bacterium is commonly present in the nose and throat. Bacteria are transmitted
from person to person in droplets through sneezing, coughing. Infected children
may carry Hib bacteria without showing any signs or symptoms of illness, but
they can still infect others. The risk of disease is highest for children
between Six months and two years of age.
Prevention: Hib conjugate vaccine - two or three doses in the primary
series
Hepatitis
B:
Description: a virus that affects the liver causes Hepatitis B. Adults
who get hepatitis B usually recover. However most infants infected at birth
become chronic carriers i.e. they carry the virus for many years and can spread
the infection to others. The virus is carried in the blood and other body
fluids. It is usually spread by contact with blood.
Prevention: Recombinant DNA or plasma-derived hepatitis B vaccine -
three doses given By the intramuscular route into upper thigh of infant and
deltoid muscle of adult.
Poliomyelitis:
Description: Poliomyelitis, or polio, is a crippling disease caused by
any one of three related viruses, poliovirus types 1, 2 or 3. The only way to
spread poliovirus is through the faecal/oral route. The virus enters the body
through the mouth when people eat food or drink water that is contaminated with
faeces. The virus then multiplies in the intestine, enters the bloodstream, and
may invade certain types of nerve cells, which it can damage or destroy.
Polioviruses spread very easily in areas with poor hygiene
Prevention: Live oral polio vaccine (OPV) - four doses in endemic countries or
Inactivated polio vaccine (IPV) given by injection - two-three doses depending
on country schedule.
Meningitis:
Description: Meningococcal meningitis is an infection of the brain and spinal cord.
It is caused by the bacterium Neisseria meningitidis (the
meningococcus). The disease is divided into several types. Types A, B, C, Y and
W135 cause most cases of meningoccal meningitis. More recently types Y and W135
are gaining importance. Transmission of bacteria is from person to person
through airborne droplets from the nose and throat of infected people. Prevention: Purified bacterial capsular polysaccharide (AC, AC/W135, Y)
- one dose or purified bacterial capsular polysaccharide conjugated to a
protein (only serogroup C available) - three doses for infants, one dose for
older children.
Tuberculosis:
Description: Tuberculosis (TB) is caused by the bacterium Mycobacterium
tuberculosis which usually attacks the lungs. Not everyone who is infected with
tuberculosis bacteria develops the disease. TB spreads rapidly, especially in
areas where people are living in Crowded conditions, have poor access to health
care, and are malnourished. Prevention: Immunization of infants with Bacille
Calmette-Guérin vaccine (BCG) can protect against TB meningitis and other
severe forms of TB in children less than five years old. BCG Vaccine is not
recommended after 12 months of age because the protection provided is variable
and less certain
Yellow
Fever:
Description: Yellow fever is caused by the yellow fever virus, which is
carried by mosquitoes. It is endemic in 33 countries in Africa
and 11 countries in South America. The yellow
fever virus can be transmitted by mosquitoes, which feed on infected animals in
forests, then pass the infection when the same mosquitoes feed on humans
traveling through the forest.
Prevention: Live viral yellow fever vaccine - one dose of 0.5 ml
subcutaneously
Vaccine
development -New Vaccine Strategies:
Purified (Subunits) Antigen vaccine e.g. Hepatitis B, Haemophillus
influenza type b, Rotavirus, foot-and-mouth diseaseConjugate vaccines e.g. meningitis,
pneumonia Recombinant antigen vaccines e.g. Hepatitis B, malaria Synthetic
peptide vaccines e.g. . Parasites (malaria), bacteria (diphtheria and cholera)
toxins, viruses (HIV).Recombinant vector vaccines e.g. investigated for
hepatitis B virus, herpes simplex, Influenza virus, and HIVDNA vaccines e.g.
purified preparation of plasmid DNA vaccines, especially for Immune deficient
recipients.
Types
of Vaccines:
Vaccines containing killed microorganisms like Vaccines against flu,
cholera,
bubonic
plague, and hepatitis A Vaccines containing live, attenuated
virus microorganismsYellow fever,
measles,
rubella,
and mumps.
Toxoids
Vaccines include tetanus
and diphtheria
Subunit
Combination Vaccines, DNA and Recombinant DNA Vaccines, Conjugate Vaccines,
Subunit Vaccines
New
devices for vaccine administration:
Mini needles (Macro flux micro
projection array)- Various antigens, Needle-less injection Spring powered
(Advantajet, Injex, Vitajet 3, Medi-Jector),HepAandB, Flu antigens, Gas powered
(Biojector 2000, Penjet, J-Tip, Powderject system)
Factors
effecting vaccine development:
1-Identification of protective antigen
2-Pathogenesis of infection and evasion of protective responses
3-Simple inexpensive animal model that mimics the human model
4-Antigenic diversity Integration of DNA/cDna intohostcell genome
Delivery
technologies for human vaccines towards the rational design of adjuvant and
formulations:
Adjuvant Mechanisms
1-Influence antigen processing and trafficking
2-Activate immune cells
3-Influence magnitude and quality of immune response
Adjuvant Types-Immunostimulants, Vehicles, Surfactants, Particulates,
Conjugates,“Molecular”Antigen particulate formulations.
Vaccine
delivery:
1:Vesicles
Micro particulates of proteins,
lipids, carbohydrates, polymers
Passive or active targeting
Eg. Liposomes
2:Controlled Release
Nearly independent of
environmental conditions (pH)
Pumps ,Synthetic polymeric
materials
3:Diffusion
4:Chemical
reaction (degradation/cleavage)
Solvent
activation (swelling/osmotic effects.
5:Polymers degradable.
6-Ocusert,,Norplant
7-Problems -variable release rates
8-Protein
particle size, loading, protein solubility, molecular weight
9-Polymer
composition, size/shape of matrix, protein stability
Vaccine
Delivery – Routes:
-Intramuscular, Subcutaneous, Intradermal, Intranasal, Oral/Enteric,
Transdermal, Other.
Advantages
of Mucosal Delivery Systems:
Oral or intranasal products avoid theneed for needles/syringes or
skilled health care personnel for administration.,Live, attenuated bacterial
vaccines have been particularly effective against intracellular pathogens (e.g.
BCG, Ty21a) and require less knowledge of immune protective mechanisms.
Challenges
For Mucosal Delivery Systems:
Lack of available clinically proven adjutants (e.g. could increase.The
small window Between immunogenicity and reactogenicity). Lack of knowledge of
specific protective Immune mechanisms may limit the use of targeted subunit
delivery methods, Attenuation of
bacteria for use as live vaccines - difficult to balance between good
immunogenicity, Low reactogenicity, and limited shedding in stool,
Manufacturing consistency of live bacterial vaccines offers unique challenges
retaining high viability, stabilization of lyophilized
CONCLUSION:
New
prophylactic and therapeutic vaccines will prevent and potentially cure
disease. New delivery systems for human vaccines are being developed to enhance
cellular and Mucosal immunity, as well as ease of use, advances in current
vaccines such as conjugated pneumococcal vaccines for adults, nasal spray
vaccines for Influenza and adult a cellular pertussis vaccine will provide an
efficient way to of longlasting protective immunity. There is as of today no
TH1 adjuvant efficient in humans. Such adjutants are needed to develop powerful
therapeutic vaccines against cancer or chronic infectious diseases. New vaccine
delivery technology will provide easier delivery routs such as transcutaneous,
depote, nasal, and oral delivery without compromising efficacy.
ACKNOWLEDGEMENT:
Authors are sincerely thankful to Principal and
management of ASPM’s K.T.Patil College Of Pharmacy, Osmanabad for providing
facility.
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