VIRAL VACCINES

CURRENT PRACTICES
Dr.T.V.Rao MD

DR.T.V.RAO MD

WHAT ARE VIRUSES

Viruses are intracellular parasites unable to survive without a living host Non-living ?; do not follow Kochs Postulates They cannot reproduce or metabolize on their own because they lack the self-machinery to do so Obligatory replicate inside host cells using host metabolism A single infectious virus particle is termed a Virion that acts as the vehicle for transmission

All viruses consist of either double- or singlestranded DNA or RNA that is linear or circular (or fragmented)
DR.T.V.RAO MD

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.
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.

Viruses infect eukaryotes and prokaryotes such as bacteria; bacteriophages.

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.
DR.T.V.RAO MD

HISTORICAL BEGINNING
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
DR.T.V.RAO MD

ORIGIN OF VACCINES
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

DR.T.V.RAO MD

BASIC STRATEGIES IN VACCINATION

DR.T.V.RAO MD

VACCINES [BACKGROUND]
Vaccine comes from the Latin word vacca which pertains to cows Based on the practice of variolation which was inoculating healthy individuals with weak forms of smallpox

1st Vaccine (1796): Edward Jenner inoculated milkmaids with cowpox to confer protective immunity against smallpox.
1st Attenuated Vaccine (1885): Louis Pasteur developed a vaccine to protect against rabies; vaccine is made from viable virus with reduced virulence (lower degree of pathogenicity).

DR.T.V.RAO MD

VACCINES [BACKGROUND]
Most damage to a cell is done too early before any clinical symptoms of disease appear. Treatment becomes difficult, therefore, prevention is preferred over post-exposure vaccines. The Main Idea: Vaccines contain a weak form of a virus/microbe that is not pathogenic Vaccines are used to protect a large number of people fight against epidemics and pandemics. Good vaccines elicit a secondary immune response that will eliminate the pathogen.

DR.T.V.RAO MD

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 1945First vaccine for influenza 1952 First vaccine for polio 1954 First vaccine for Japanese encephalitis 1957 First vaccine for adenovirus-4 and 7
DR.T.V.RAO MD

TIMELINE OF VACCINES
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 1998 First vaccine for rotavirus
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VACCINES BASICS
The principle of vaccination is to induce a "primed" state in the vaccinated subject so that, following exposure to a pathogen, a rapid secondary immune response is generated leading to the accelerated elimination of the organism and protection from clinical disease. Success depends on the generation of memory T and B cells and the presence in the serum of neutralizing antibody.

Attributes of a good vaccine

1.Ability to elicit the appropriate immune response for the particular pathogen: Tuberculosis - cell mediated response most bacterial and viral infections - antibody

2. Long term protection ideally life-long 3. Safety vaccine itself should not cause disease 4. Stable retain immunogenicity, despite adverse storage conditions prior to administration 5. Inexpensive
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VACCINES IMITATE AN INFECTION

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
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THE IMMUNE SYSTEM & RESPONSE AND VACCINES

Once vaccinated, the immune system takes a week and upwards to begin fighting off the organism. Immunity is conferred once the immune system is trained to resist a certain disease a vaccine is developed for Artificially Acquired Immunity is provided Childhood vaccinations are highly encouraged against: Measles, Mumps, Rubella, Polio, Hepatitis A & B, Diphtheria, Pertussis, Tetanus, Chicken Pox, HIB, Rotavirus, Meningococcal disease, and Influenza.
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THE IMMUNE SYSTEM & RESPONSE

Macrophages: white blood cells that detect and engulf viral antigens; microbes are carried to lymphocytes Within lymph nodes, T and B cells are activated T cells: able to recognize virus infected cells early in infection period and release cytotoxins to destroy them B cells: secrete antibodies that bind antigens on the virus surface. This coats the virus and prevents infection. B-cells can also recognize virus infected cells late in infection Ideally, good vaccines evoke both T and B cells Antibodies will activate macrophages to engulf viral antigens
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VACCINE TYPES

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LIVE (ATTENUATED) VACCINES

Consist of a live form of the virus that has been artificially weakened; select for mutants that will cause wild-type infection without onset of disease Usually only takes 1 or 2 doses to confer life long immunity (childhood vaccines). Must be careful of the small chance of reversion to a more virulent form

Elicit good immune response, inexpensive, but must be cautiously stored to maintain viability
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INACTIVATED VACCINES
Using heat, radiation or chemicals a virus is killed and is no longer infectious

WHY USE AN INACTIVATED VIRUS?

Attenuated strains have yet to be developed Reversion to virulent forms is a high occurrence Requires no refrigeration The downside is that the immunogenicity is lowered and multiple doses will be required (i.e. booster shots) Adjuvants: administered simultaneously to enhance immune response

Combination vaccines: DTP and MMR

More expensive to prepare

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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.
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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-yearold 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.
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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.
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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.
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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. a) Post-exposure prophylaxis, following the bite of a rabid animal:

There are two situations where vaccine is given:

A 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).
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VACCINES IN GENERAL USE

Influenza
Repeated infections with influenza virus are common due to rapid antigenic variation of the viral envelope glycoproteins. Antibodies to the viral neuraminidase and haemagglutinin proteins protect the host from infection. However, because of the rapid antigenic variation, new vaccines, containing antigens derived from influenza strains currently circulating in the community, are produced every year. Surveillance of influenza strains now allows the inclusion of appropriate antigens for each season.The vaccines consist of partially purified envelope proteins of inactivated current influenza A and B strains.

Individuals who are at risk of developing severe, life threatening disease if infected with influenza should receive vaccine. People at risk include the elderly, immunocompromised individuals, and patients with cardiac disease. In these patients, protection from disease is only partial, but the severity of infection is reduced . DR.T.V.RAO MD 25

VACCINE IN SPECIAL CIRCUMSTANCES

Varicella-Zoster virus
A live attenuated strain of varicella zoster virus has been developed. It is not licensed in South Africa for general use, but is used in some oncology units to protect immuno-compromised children who have not been exposed to wild-type varicella zoster virus. Such patients may develop severe, life threatening infections if infected with the wild type virus.

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VACCINES IN SPECIAL CIRCUMSTANCES

Yellow Fever

The 17D strain is a live attenuated vaccine developed in 1937. It is a highly effective vaccine which is administered to residents in the tropics and travelers to endemic areas. A single dose induces protective immunity to travelers and booster doses, every 10 years, are recommended for residents in endemic areas.
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HEPATITIS B VACCINATION EMERGING NEED IN VACCINATION

Hepatitis B
Two vaccines are in current use: a serum derived vaccine and a recombinant vaccine. Both contain purified preparations of the hepatitis B surface protein.

The serum derived vaccine is prepared from hepatitis B surface protein, purified from the serum of hepatitis B carriers. This protein is synthesised in vast excess by infected hepatocytes and secreted into the blood of infected individuals. A vaccine trial performed on homosexual men in the USA has shown that, following three intra-muscular doses at 0, 1 and 6 months, the vaccine is at least 95% protective.
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NEWER VACCINES FOR HEPATITIS B INFECTIONS

A second vaccine, produced by recombinant DNA

technology, has since become available. Previously, vaccine administration was restricted to individuals who were at high risk of exposure to hepatitis B, namely: infants of hepatitis B carrier mothers, health care workers, homosexual men and intravenous drug abusers. However, hepatitis B has been targetted for eradication , and since 1995 the vaccine has been included in the universal childhood immunization schedule. Three doses are given; at 6, 10, and 14 weeks of age. As with any killed viral vaccines, a booster will be required at some interval (not yet determined, but about 5 years) to provide protection in later life from hepatitis B infection as a venereal disease.

HEPATITIS B Hepatitis B virus gene, aluminium hydroxide, mercury,

formaldehyde. For the genetically engineered vaccine: aluminium hydrochloride, sodium chloride and mercury
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ROTATEQ AND ROTAVIRUS INFECTIONS

Rotateq is a live, oral Pentavalent vaccine that contains five rotaviruses produced by reassortment. The rotavirus A parent strains of the reassortants were isolated from human and bovine hosts. Four reassortant rotaviruses express one of the outer capsid, VP7, proteins (serotypes G1, G2, G3, or G4) from the human rotavirus parent strain and the attachment protein VP4 (type P7) from the bovine rotavirus parent strain. The fifth reassortant virus expresses the attachment protein VP4, (type P1A), from the human rotavirus parent strain and the outer capsid protein VP7 (serotype G6) from the bovine rotavirus parent strain. In February 2006 approved RotaTeq for use in the United States.

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WHO RECOMMENDS THE ROTAVIRUS VACCINE

WHO recommends that rotavirus vaccine for infants should be included in all national immunization programmes. In countries where diarrhoeal deaths account for 10% of mortality among children aged <5 years, the introduction of the vaccine is strongly recommended. WHO recommends that the first dose of either RotaTeq or Rotarix be administered at age 615 weeks. The maximum age for administering the last dose of either vaccine should be 32 weeks.
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HPV HUMAN PAPILLOMAVIRUS

Genital HPV most common sexually transmitted infection in US Cause of cervical cancer, genital warts, anal & penile cancer By the age of 50, 80% of women will have contracted at least 1 strain of the virus Fortunately, many strains can be cleared by immune system before symptoms occur HPV vaccine is a preventative measure against initial infection
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HPV HUMAN PAPILLOMAVIRUS

HPV Human Papillomavirus Types 16 and 18 cause 70% of the cases of cervical cancer and types 6 and 11 cause 90% of genital warts HPV Vaccine, Gardasil, protects against these strains Pap smears are still recommended since there are over 100 HPV strains identified, many of which can also cause cancer

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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 non-pathogenic virus, bacteria, etc
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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 .

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RECOMBINANT VACCINES
Recombinant vaccines are those in which genes for desired antigens are inserted into a vector, usually a virus, that has a very low virulence. The vector expressing the antigen may be used as the vaccine, or the antigen may be purified and injected as a subunit vaccine. The only recombinant vaccines currently in use in humans is the Hepatitis B Virus (HBV) vaccine, and HPV which is a recombinant subunit vaccine Hepatitis B surface antigen is produced from a gene transfected into yeast cells and purified for injection as a subunit vaccine. This is much safer than using attenuated HBV, which could cause lethal hepatitis or liver cancer if it reverted to its virulent phenotype. Recombinant DNA techniques can also be used to make safer attenuated pathogen vaccines.
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VACCINES A METHOD OF PREVENTION

Influenza

Nearly 40,000 deaths and 115,000 hospitalized yearly in US

Educated guess on most probable form of virus Also comes in nasal spray of attenuated form New vaccines must always be produced due to high antigenic variation At risk individuals (elderly, Immunodeficient) should be vaccinated

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HUMAN IMMUNODEFICIENCY VIRAL VACCINES

Currently in use: subunit, recombinant, and DNA vaccines Method: Inhibit fusion to host cell Inhibit reverse transcriptase Stops any viral integration into host cells Targets functional HIV viral proteins Viral exit form host cell is stopped HIV continuously mutates and recombines to escape effects of vaccine It can also be transmitted as a free virus

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WHY HIV IS A HARD TARGET

Spread both sexually and blood so need both mucosal immune responses and systemic Probably transmitted both as cell-free virus and cell associated and therefore probably need both neutralizing antibody AND T-cell mediated immune response Worst of all, our own immune systems cant stop the replication of the virus Here, the viruss evolution is the central issue maybe it will never be possible to generate immune protection against the virus

Ignoring this, for the moment, you then still would need to contend with the tremendous genetic diversity of the virus

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VACCINES A SOURCE OF CONTROVERSY

Some health critics say vaccination benefits are exaggerated. Claim that vaccines are not solely responsible for reducing mortality rates of any one disease. Opponents find that even vaccinated individuals still contract disease Adverse effects (although RARE) can be worse than the naturally occurring disease Vaccine schedules are not designed for multiple exposure to immunogens at young ages Some diseases and conditions (leukaemia, MS, SIDS) have increased with the use of vaccinations Some vaccines contain mercury, formaldehyde, neomycin, and other toxic chemical components
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DO NOT NEGLECT VACCINATION

Vaccines still most effective preventative measure you can take to protect yourself from disease Remains one of the most affordable methods Not only are you protecting yourself, you are protecting everyone around you.

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 Programme Created by Dr.T.V.Rao MD for Medical and Health Care Workers in the Developing World
Email doctortvrao@gmail.com

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