Buynak Synopsis Vaccines

1
Buynak Synopsis Vaccines

• Medicinal Chemistry
• Donlene Mallon
• SMU

2
Viruses

• A virus is a submicroscopic obligate parasitic
  particle that infects cells in biological
  organisms.
• Viruses are non-living particles that can only
  replicate when an organism reproduces the
  virulent RNA or DNA.
• Among other things, viruses do not move,
  metabolize, or decay on their own. Viruses are
  obligate intracellular parasites that lack the
  cellular machinery for self-reproduction.
• Viruses infect eukaryotes and prokaryotes such as
  bacteria bacteriophages.
• Typically viruses carry a small amount of
  genetic material, either in the form of RNA or
  DNA, but not both, surrounded by some form of
  protective coat consisting of proteins, lipids,
  glycoproteins or a combination.
• The viral genome codes for the proteins that
  constitute this protective coat, as well as for
  those proteins required for viral reproduction
  that are not provided by the host cell.

3
Viruses

• Viral nucleic acid can be DNA or RNA. It can be
  single or double stranded, circular or linear,
  with most being linear.
• The nucleic acid is protected from physical,
  chemical and enzymatic damage by a protein coat
  called a Capsid.
• Many viruses have a second envelope surrounding
  the Capsid on which there are spikes with
  antigenic determinants.
• This outer surface of the virus is responsible
  for host cell recognition. Initially viral
  proteins on the outer surface will attach to the
  hosts receptor molecules. A simplified viron is
  illustrated below.

4
Life Cycle

• ? Attachment, sometimes called absorption The
  virus attaches to receptors on the host cell
  wall.
• Injection The nucleic acid of the virus moves
  through the plasma membrane and into the
  cytoplasm of the host cell. The capsid of a
  phage, a bacterial virus, remains on the outside.
  In contrast, many viruses that infect animal
  cells enter the host cell intact.
• Transcription Within minutes of phage entry into
  a host cell, a portion is transcribed into mRNA,
  which is then translated into proteins specific
  for the infecting phage.
• Replication The viral genome contains all the
  information necessary to produce new viruses.
  Once inside the host cell, the virus induces the
  host cell to synthesize the necessary components
  for its replication.
• Assembly The newly synthesized viral components
  are assembled into new viruses.
• Release Assembled viruses are released from the
  cell and can now infect other cells, and the
  process begins again.

5
Vaccines

• Take advantage of the immune system to kill
  disease-causing microbe
• Have nearly eliminated diseases that killed
  hundreds of thousands of people in the 19th and
  early 20th century
• Vaccines protect the whole community, since if
  your immune system is trained to kill a disease,
  you will not be contagious for long, thus you
  will not be able to spread the disease to
  unvaccinated individuals.
• The word vaccine comes from the Latin word
  vaccinus, which means pertaining to cows

6
Origin of Vaccines

• Smallpox was the first disease people tried to
  prevent by purposely inoculating themselves with
  other types of infections. Inoculation is
  believed to have started in India or China before
  200 BC. Physicians in China immunized patients by
  picking off pieces from drying pustules of a
  person suffering from a mild case of smallpox,
  grinding the scales to a powdery substance, and
  then inserting the powder into the person's nose
  in order for them to be immunized. In 1718, Lady
  Mary Wortley Montague reported that the Turks
  have a habit of deliberately inoculating
  themselves with fluid taken from mild cases of
  smallpox. Lady Montague inoculated her own
  children in this manner. In 1796, during the
  heyday of the smallpox virus in Europe, an
  English country doctor, Edward Jenner, observed
  that milkmaids would sometimes become infected
  with cowpox through their interactions with dairy
  cows' udders. Cowpox is a mild relative of the
  deadly smallpox virus. Building on the
  foundational practice of inoculation, Jenner took
  infectious fluid from the hand of milkmaid Sarah
  Nelmes. He inserted this fluid, by scratching or
  injection, into the arm of a healthy local eight
  year old boy, James Phipps. Phipps then showed
  symptoms of cowpox infection. Forty-eight days
  later, after Phipps had fully recovered from
  cowpox, Jenner injected some smallpox-infected
  matter into Phipps, but Phipps did not later show
  signs of smallpox infection

7
The Immune System

• Usually takes more than a week to learn how to
  fight off an unfamiliar microbe
• Certain microbes are so powerful (virulent) that
  they can overwhelm your bodys natural defenses
• Once your immune system is trained to resist a
  disease, you are said to be immune to it
• When you get sick and (hopefully) recover, you
  receive naturally acquired immunity
• Vaccines provide artificially acquired immunity
  and thus represent a less risky way to become
  immune

8
The Immune System Macrophages

• Macrophages Literally big eaters, white blood
  cells that engulf foreign organisms.
• Macrophages recognize what is foreign by
  identifying its antigens
• Macrophages save the antigens, and carry them
  back to the lymph nodes, where immune system
  cells congregate
• Macrophages show the antigens to specialized
  white blood cells, called lymphocytes

9
The Immune System Lymphocytes

• Lymphocytes swing into action when they see the
  foreign antigens
• Lymphocytes Come in Two types T Cells and B
  Cells
• T Cells come in two types cytotoxic T cells and
  helper T cells
• Cytotoxic T cells are also called killer T
  cells. They latch onto the foreign invader and
  release chemicals that destroy it.
• Helper T cells assist in activating killer T
  cells and also work with B cells
• B Cells secrete antibodies secrete antibodies
  that bind to the antigens on the surface of the
  invader
• Antibodies provide a signal to macrophages and
  other defensive cells to come and eat the
  invader.

10
The Immune System Memory Cells

• Following the disease, some of the defensive B
  cells and T cells are converted into memory
  cells.
• Memory B cells can quickly divide into plasma
  cells and make more antibody if needed
• Memory T cells can quickly divide and grow up
  into a disease fighting army.

11
(No Transcript)
12
Vaccines

• Vaccines contain a weakened form of the microbe
  that doesnt cause disease or reproduce
• Vaccines stimulate the macrophages, which present
  the antigens to T and B cells
• The mock infection is rapidly cleared, and you
  are left with a supply of memory T cells and B
  cells to protect you against of future infection
  of this type

13
One type of vaccine Live attenuated vaccines

• Live attenuated vaccines contain a version of the
  living organism that has been weakened the lab so
  it cant cause disease
• Since these vaccines are close to the actual
  infection, they elicit strong immune system
  responses and usually confer lifelong immunity
  with only one or two doses
• Downside live attenuated vaccines could
  potentially revert to a virulent form and cause
  disease. For this reason, they are not given to
  people with weakened immune systems (e.g. cancer
  patients, or those infected with HIV)
• Downside must be refrigerated to stay potent
• Hard to create live attenuated vaccines to treat
  bacterial infections (since bacteria have
  thousands of genes and are harder to tame)

14
Live Vaccines

• 1. Live attenuated organisms
• Organisms whose virulence has been artificially
  reduced by in vitro culture under adverse
  conditions, such as reduced temperature. This
  results in the selection of mutants which
  replicate poorly in the human host and are
  therefore of reduced virulence.  Replication of
  the vaccine strain in the host reproduces many of
  the features of wild type infection, without
  causing clinical disease.  Most successful viral
  vaccines belong to this group.
• The immune response is usually good - when the
  virus replicates in the host cells, both antibody
  as well as cell mediated immune responses are
  generated and immunity is generally long lived.
   Often, only a single dose is needed to induce
  long term immunity.

15
Live Vaccines

• 3. Live recombinant vaccines
• It is possible, using genetic engineering, to
  introduce a gene coding for an immunogenic
  protein from one organism into the genome of
  another (such as vaccinia virus). The organism
  expressing a foreign gene is called a
  recombinant. Following injection into the
  subject, the recombinant organism will replicate
  and express sufficient amounts of the foreign
  protein to induce a specific immune response to
  the protein.
• Attributes
• Good immune response
• Both Cell Mediated Immunity and antibody
  responses.
• Immunity is long lived
• Single dose
• Safety
• Danger of reversion to virulence, or
• Severe disease in immunocomprised
• Stability
• Organisms in the vaccine must remain viable in
  order to infect and replicate in the host
• Vaccine preparations are therefore very sensitive
  to adverse storage conditions
• Maintenance of the cold chain is very important.
• Expense
• Cheap to prepare

16
Type of vaccine Inactivated or killed vaccines

• In inactivated vaccines, the disease-causing
  microbe is killed with chemicals, heat, or
  radiation
• The dead microbes cant mutate back to a virulent
  form and dont require refrigeration
• Downside these vaccines stimulate a weaker
  immune response and may require several
  additional doses (or booster shots)

17
Killed (inactivated) vaccines

• Attributes
• Immune response
• poor  only antibody - no cell immediated immune
  response.
• response is short-lived and multiple doses are
  needed.
• may be enhanced by the incorporation of adjuvants
  into the vaccine preparation (see below)
• 1. Safety
• Inactivated, therefore cannot replicate in the
  host and cause disease.
• Local reactions at the site of injection may
  occur.
• 2. Stability
• Efficacy of the vaccine does not rely on the
  viability of the organisms.
• These vaccines tend to be able to withstand more
  adverse storage conditions.
• 3. Expense
• Expensive to prepare

18
Killed (inactivated) vaccines

• When safe live vaccines are not available, either
  because attenuated strains have not been
  developed or else because reversion to wild type
  occurs too readily, it may be possible to use an
  inactivated  preparation of the virulent organism
  to immunize the host.
• The organism is propagated in bulk, in vitro, and
  inactivated with either beta-propiolactone or
  formaldehyde. These vaccines are not infectious
  and are therefore relatively safe. However, they
  are usually of lower immunogenicity and multiple
  doses may be needed to induce immunity. In
  addition, they are usually expensive to prepare.
• Subcellular fractions
• When protective immunity is known to be directed
  against only one or two proteins of an organism,
  it may be possible to use a purified preparation
  of these proteins as a vaccine. The organism is
  grown in bulk and inactivated, and then the
  protein of interest is purified and concentrated
  from the culture suspension. These vaccines are
  safe and fewer local reactions occur at the
  injection site. However, the same disadvantages
  of poor immunogenicity and the need for multiple
  boosters applies.
• Recombinant proteins
• Immunogenic proteins of virulent organisms may be
  synthesized artificially by introducing the gene
  coding for the protein into an expression vector,
  such as E-coli or yeasts. The protein of interest
  can be extracted from lysates of the expression
  vector, then concentrated and purified for use as
  a vaccine. The only example of such a vaccine, in
  current use, is the hepatitis B vaccine.

19
Type of Vaccine Subunit Vaccines

• Subunit vaccines dispense with the entire microbe
  and just use important parts of it the antigens
  that stimulate the immune system
• The chances of an adverse reaction to the vaccine
  are lower
• Downside identifying the precise antigens which
  best stimulate the immune system is difficult and
  time-consuming
• It may be possible to manufacture the antigen
  molecules using recombinant DNA technology

20
Subunit Vaccines

• Immune response can be stimulated by one or a set
  of viral proteins.
• This was first demonstrated by hepatitis B and
  influenza vaccines
• These can be a lot safer than attenuated or
  inactivated vaccines
• The subunits included are determined by
  identifying which proteins the antibodies
  recognize.
• Subunits vaccines
• Composed solely of purified protein
• can be delivered to body by means of a
  nonpathogenic virus, bacteria, etc

21
Type of vaccine Toxoid Vaccines

• Toxoid vaccines are used when a bacterial toxin
  (i.e. a harmful chemical given off by the
  microbe) is the main cause of the illness
• The bacterial toxins are inactivated by treating
  them with a solution of formaldehyde
• These detoxified toxins are called toxoids and
  are safe for use in vaccines
• The immune system produces antibodies that lock
  onto and block the toxin.

22
Type of Vaccine Conjugate Vaccines

• Sometimes microbes contain an outer coating of
  polysaccharides that hide the antigens so that
  younger childrens immune system cant recognize
  them
• Scientists overcome this obstacle by linking
  antigens that a child can respond to to the
  polysaccharides
• That way, the childs immune system will become
  trained to respond to the foreign polysaccharides

23
Type of vaccine DNA Vaccines

• DNA vaccines would use the naked DNA from a few
  genes of the invading organism
• Those genes would be introduced into the body,
  taken up by some of the cells
• Those host cells would then produce the antigens
  molecules, allowing them to be displayed and
  stimulating the immune system
• The hosts own cells would become the
  vaccine-making factory
• Still experimental, but being tested against
  malaria, influenza, herpes, and HIV
• In another version, called a vector vaccine the
  DNA is ferried into the host cells by harmless
  viruses

24
Type of Vaccine Combination Vaccine

• Several vaccines are combined into one dose
• DTP diphtheria, tetanus, pertussis
• MMR measles, mumps, rebella

25
Adjuvants

• Certain substances, when administered
  simultaneously with a specific antigen, will
  enhance the immune response to that antigen. Such
  compounds are routinely included in inactivated
  or purified antigen vaccines.
• Adjuvants in common use
• Aluminium salts
• First safe and effective compound to be used in
  human vaccines.
• It promotes a good antibody response, but poor
  cell mediated immunity.
• Form precipitate with antigen, making complex
  more antigenic
• 2. Liposomes and Immunostimulating complexes
  (ISCOMS)
• 3. Complete Freunds adjuvant is an emulsion of
  Mycobacteria, oil and water
• Too toxic for man
• Induces a good cell mediated  immune response.
• 4. Incomplete Freund's adjuvant as above, but
  without Mycobacteria.
• 5. Muramyl di-peptide
• Derived from Mycobacterial cell wall.
• 6. Cytokines
• IL-2, IL-12 and Interferon-gamma.
• Possible modes of action
• By trapping antigen in the tissues,  thus
  allowing maximal exposure to dendritic cells and
  specific T and B lymphocytes.
• By activating antigen-presenting cells to secrete
  cytokines that enhance the recruitment of
  antigen-specific T and B cells to the site of
  inoculation.

26
Timeline of Vaccines

• 18th century
• 1796 First vaccine for smallpox, first vaccine
  for any disease
• 19th century
• 1882 First vaccine for rabies
• 20th century
• 1932 First vaccine for yellow fever
• 1945 First vaccine for influenza
• 1952 First vaccine for polio
• 1954 First vaccine for Japanese encephalitis
• 1957 First vaccine for adenovirus-4 and 7
• 1962 First oral polio vaccine
• 1964 First vaccine for measles
• 1967 First vaccine for mumps
• 1970 First vaccine for rubella
• 1974 First vaccine for chicken pox
• 1977 First vaccine for pneumonia
• 1978 First vaccine for meningitis
• 1981 First vaccine for hepatitis B
• 1992 First vaccine for hepatitis A

27
DNA Vaccines

• DNA vaccines are at present experimental, but
  hold promise for future therapy since they will
  evoke both humoral and cell-mediated immunity,
  without the dangers associated with live virus
  vaccines.
• The gene for an antigenic determinant of a
  pathogenic organism is inserted into a plasmid.
   This genetically engineered plasmid comprises
  the DNA vaccine which is then injected into the
  host.  Within the host cells, the foreign gene
  can be expressed (transcribed and translated)
  from the plasmid DNA, and if sufficient amounts
  of the foreign protein are produced, they will
  elicit an immune response.
• in recent years a new type of vaccine, created
  from an infectious agent's DNA called DNA
  vaccination, has been developed. It works by
  insertion (and expression, triggering immune
  system recognition) into human or animal cells,
  of viral or bacterial DNA. These cells then
  develop immunity against an infectious agent,
  without the effects other parts of a weakened
  agent's DNA might have. As of 2006, DNA
  vaccination is still experimental, but shows some
  promising results.

28
Vaccines in General Use

• Measles
• Live attenuated virus grown in chick embryo
  fibroblasts, first introduced in the 1960's. Its
  extensive use has led to the virtual eradication
  of measles in the first world. In developed
  countries, the vaccine is administered to all
  children in the second year of life (at about 15
  months). However, in developing countries, where
  measles is still widespread, children tend to
  become infected early (in the first year), which
  frequently results in severe disease. It is
  therefore important to administer the vaccine as
  early as possible (between six months and a
  year). If the vaccine is administered too early,
  however, there is a poor take rate due to the
  interference by maternal antibody. For this
  reason, when vaccine is administered before the
  age of one year, a booster dose is recommended at
  15 months.

29
MeaslesUnited States, 1950-2002

• Vaccine Licensed

30
Vaccines in General Use

• Mumps
• Live attenuated virus developed in the 1960's.  
  In first world countries it is administered
  together with measles and rubella at 15 months in
  the MMR vaccine.
• The current "Jeryl Lynn" strain of the mumps
  vaccine was developed by Dr. Maurice Hillman from
  the mumps virus that infected his 5-year-old
  daughter (whose name was Jeryl Lynn). This
  vaccine, combined with rubella or both rubella
  and measles vaccines (MMR), has been widely used
  worldwide (300 million doses given) since it was
  approved by the FDA in 1967.

31

• MumpsUnited States, 1968- 2002

32
Vaccines in General Use

• Polio
• Two highly effective vaccines containing all 3
  strains of poliovirus are in general use
• The killed virus vaccine (Salk, 1954) is used
  mainly in Sweden, Finland, Holland and Iceland.
• The live attenuated oral polio vaccine (Sabin,
  1957) has been adopted in most parts of the
  world  its chief advantages being low cost, the
  fact that it induces mucosal immunity and the
  possibility that, in poorly immunized
  communities, vaccine strains might replace
  circulating wild strains and improve herd
  immunity.  Against this is the risk of reversion
  to virulence (especially of types 2 and 3) and
  the fact that the vaccine is sensitive to storage
  under adverse conditions. - Orimune
• The inactivated Salk vaccine is recommended for
  children who are immunosuppressed.
• 3 types of live polio virus, magnesium chloride,
  amino acid, polysorbate 80, purified water,
  neomycin, sulphate, streptomycin, penicillin and
  monkey kidney cell cultures.

33

• PoliomyelitisUnited States, 1950-2002

34
Vaccines in General Use

• Rubella
• Live attenuated virus. Rubella causes a mild
  febrile illness in children, but if infection
  occurs during pregnancy, the fetus may develop
  severe congenital abnormalities. Two vaccination
  policies have been adopted in the first world. In
  the USA, the vaccine is administered to all
  children in their second year of life (in an
  attempt to eradicate infection), while in
  Britain, until recently, only post pubertal girls
  were vaccinated.  It was feared that if the
  prevalence of rubella in the community fell, then
  infection in the unimmunized might occur later -
  thus increasing the likelihood of infection
  occurring in the child-bearing years.  This
  programme has since been abandoned in Britain and
  immunization of all children is the current
  practice.
• MMR live measles virus, live mumps virus, live
  rubella virus, chick embryo, human foetal cells,
  neomycin, sorbitol, gelatine.

35

• RubellaUnited States, 1966-2002

36
Vaccines in General Use

• Rabies
• No safe attenuated strain of rabies virus has yet
  been developed for humans. Vaccines in current
  use include
• The neurotissue vaccine - here the virus is grown
  in the spinal cords of rabbits, and then
  inactivated with beta-propiolactone. There is a
  high incidence of neurological complications
  following administration of this vaccine due to a
  hypersensitivity reaction to the myelin in the
  preparation and largely it has been replaced by
• A human diploid cell culture-derived vaccine
  (also inactivated) which is much safer.
• There are two situations where vaccine is given
  a) Post-exposure prophylaxis, following the bite
  of a rabid animalA course of 5-6 intramuscular
  injections, starting on the day of exposure.
  Hyperimmune rabies globulin may also administered
  on the day of exposure.
• b) Pre-exposure prophylaxis is used for
  protection of those whose occupation puts them at
  risk of infection with rabies  for example,
  vets, abbatoir and laboratory workers. This
  schedule is 2 doses one month apart ,and a
  booster dose one year later. (Further boosters
  every 2-3 years should be given if risk of
  exposure continues).

37
Virus Vaccine Brand Name Type Route
Hepatitis A Havrix Inactivated Intramuscular
Hepatitis A VAQTA Inactivated Intramuscular
Hepatitis B Recombivax Subunit Intramuscular
Hepatitis B Engerix-B Subunit Intramuscular
Influenza Fluzone Whole Inactivated Intramuscular
Influenza Fluzone, FlueShield Split-Virion Intramuscular
Influenza Fluvirin Subunit Intramuscular
Japanese Encephalitis JE-Vax Inactivated Subcutaneous
Measles Attenuvax Live Attenuated Subcutaneous
Mumps Mumpsvax Live Attenuated Subcutaneous
Polio Orimune Inactivated Salk Subcutaneous
Polio IPOL, Poliovax Live Attenuated Sabin Oral
Rabies HDCV Inactivated Intramuscular
Rabies RVA Inactivated Intramuscular
Rabies RabAvert Inactivated Intramuscular
Rotavirus RotaShield Live Attenuated Oral
Rubella Meruvax II Live Attenuated Subcutaneous
Varicella-Zoster Varivax Live Attenuated Intramuscular
Yellow Fever YF-Vax Live Attenuated Subcutaneous