VACCINES
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.
Vaccines in general use include: LIVE vaccines;
and KILLED
vaccines
Vaccines are available for:
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.
Potential drawbacks to these vaccines include:
the danger of reversion to virulence and
the possibility of causing extensive disease in immunocompromised individuals.
2. Heterologous vaccines
Closely related organism of lesser virulence, which shares many antigens with the virulent organism. The vaccine strain replicates in the host and induces an immune response that cross reacts with antigens of the virulent organism. The most famous example of this type of vaccine is vaccinia virus: Both cowpox virus and vaccinia virus are closely related to variola virus, the causitive agent of smallpox. The eighteenth centuary physician, Edward Jenner observed that milkmaids who had been infected with cowpox virus were immune to smallpox. Widespread use of vaccinia virus as a vaccine has lead to the world-wide eradication of smallpox.
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.
Good immune response
Safety
Stability
Expense
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.
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.
1. Safety
2. Stability
3. Expense
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.
1. Aluminium salts
2. Liposomes and Immunostimulating complexes (ISCOMS)
3. Complete Freunds adjuvant is an emulsion of Mycobacteria, oil and water
4. Incomplete Freund's adjuvant as above, but without Mycobacteria.
5. Muramyl di-peptide
6. Cytokines
By activating antigen-presenting cells to secrete cytokines that enhance
the recruitment of antigen-specific T and B cells to the site of
inoculation.
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.
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.
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. This is not a legal requirement in South Africa.
Live attenuated virus. Rubella causes a mild febrile illness in children, but if infection occurs during pregnancy, the foetus 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.
Two highly effective vaccines containing all 3 strains of poliovirus are in general use:
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.
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.
A vaccine for hepatitis A has been developed from formalin-inactivated ,
cell culture-derived virus.
Two doses, administered one month apart, appear to induce high levels of
neutralising antibodies. The vaccine is recommended for travellers
to third world countries, and indeed all adults who are not immune to hepatitis
A.
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 travellers to endemic areas. A single dose induces protective immunity to travellers and booster doses, every 10 years, are recommended for residents in endemic areas.
No safe attenuated strain of rabies virus has yet been developed for humans. Vaccines in current use include:
There are two situations where vaccine is given:
a) Post-exposure prophylaxis,
following the bite of a rabid animal:
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).
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.
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.
These notes were prepared by Diana Hardie
for Virology Lectures to 3rd Year Medical Students
in
theDepartment
of Medical Microbiology, University of Cape Town.
Illustrations and layout by Linda Stannard, updated November, 1999.