Classification of Vaccines : Live Attenuated Vaccines, Inactivated Vaccines and Recombinant Vaccines
There are two basic types of vaccines: live attenuated and inactivated. The characteristics of live and inactivated vaccines are different, and these characteristics determine how the vaccine is used.
Live attenuated vaccines are produced by modifying a disease-producing (“wild”) virus or bacterium in a laboratory. The resulting vaccine organism retains the ability to replicate (grow) and produce immunity, but usually does not cause illness. The majority of live attenuated vaccines available in the United States contain live viruses. However, two live attenuated bacterial vaccines are available in the United States (Ty21a and BCG). BCG is not used as a vaccine, but as a treatment for bladder cancer.
Inactivated vaccines can be composed of either whole viruses or bacteria, or fractions of either. Fractional vaccines are either protein-based or polysaccharide-based. Protein-based vaccines include toxoids (inactivated bacterial toxin) and subunit or subvirion products. Most polysaccharide-based vaccines are composed of pure cell wall polysaccharide from bacteria. Conjugate polysaccharide vaccines contain polysaccharide that is chemically linked to a protein. This linkage makes the polysaccharide a more potent vaccine.
Live Attenuated Vaccines
Live vaccines are derived from “wild,” or disease-causing, viruses or bacteria. These wild viruses or bacteria are attenuated, or weakened, in a laboratory, usually by repeated culturing. For example, the measles virus used as a vaccine today was isolated from a child with measles disease in 1954. Almost 10 years of serial passage using tissue culture media was required to transform the wild virus into attenuated vaccine virus.
To produce an immune response, live attenuated vaccines must replicate (grow) in the vaccinated person. A relatively small dose of virus or bacteria is administered, which replicates in the body and creates enough of the organism to stimulate an immune response. Anything that either damages the live organism in the vial (e.g., heat, light) or interferes with replication of the organism in the body (circulating antibody) can cause the vaccine to be ineffective.
Although live attenuated vaccines replicate, they usually do not cause disease such as may occur with the “wild” form of the organism. When a live attenuated vaccine does cause “disease,” it is usually much milder than the natural disease and is referred to as an adverse reaction.
The immune response to a live attenuated vaccine is virtually identical to that produced by a natural infection. The immune system does not differentiate between an infection with a weakened vaccine virus and an infection with a wild virus. Live attenuated vaccines produce immunity in most recipients with one dose, except those administered orally. However, a small percentage of recipients do not respond to the first dose of an injected live vaccine (such as MMR or varicella) and a second dose is recommended to provide a very high level of immunity in the population.
Live attenuated vaccines may cause severe or fatal reactions as a result of uncontrolled replication (growth) of the vaccine virus. This only occurs in persons with immunodeficiency (e.g., from leukemia, treatment with certain drugs, or human immunodeficiency virus [HIV] infection).
A live attenuated vaccine virus could theoretically revert to its original pathogenic (disease-causing) form. This is known to happen only with live (oral) polio vaccine.
Active immunity from a live attenuated vaccine may not develop because of interference from circulating antibody to the vaccine virus. Antibody from any source (e.g., transplacental, transfusion) can interfere with replication of the vaccine organism and lead to poor response or no response to the vaccine (also known as vaccine failure). Live attenuated vaccines are fragile and can be damaged or destroyed by heat and light. They must be handled and stored carefully.
Currently available live attenuated viral vaccines are measles, mumps, rubella, vaccinia, varicella, zoster (which contains the same virus as varicella vaccine but in much higher amount), yellow fever, rotavirus, and influenza (intranasal). Oral polio vaccine is a live viral vaccine but is no longer available in the United States. Live attenuated bacterial vaccines are bacille Calmette-Guérin (BCG—not currently available in the US) and oral typhoid vaccine.
Inactivated Vaccines
Inactivated vaccines are produced by growing the bacterium or virus in culture media, then inactivating it with heat and/ or chemicals (usually formalin). In the case of fractional vaccines, the organism is further treated to purify only those components to be included in the vaccine (e.g., the polysaccharide capsule of pneumococcus).
Inactivated vaccines are not alive and cannot replicate. The entire dose of antigen is administered in the injection. These vaccines cannot cause disease from infection, even in an immunodeficient person. Inactivated antigens are less affected by circulating antibody than are live agents, so they may be given when antibody is present in the blood (e.g., in infancy or following receipt of antibody-containing blood products).
Inactivated vaccines always require multiple doses. In general, the first dose does not produce protective immunity, but “primes” the immune system. A protective immune response develops after the second or third dose. In contrast to live vaccines, in which the immune response closely resembles natural infection, the immune response to an inactivated vaccine is mostly humoral. Little or no cellular immunity results. Antibody titers against inactivated antigens diminish with time. As a result, some inactivated vaccines may require periodic supplemental doses to increase, or “boost,” antibody titers.
Currently available whole-cell inactivated vaccines are limited to inactivated whole viral vaccines (polio, hepatitis A, and rabies). Inactivated whole virus influenza vaccine and whole inactivated bacterial vaccines (pertussis, typhoid, cholera, and plague) are no longer available in the United States. Fractional vaccines include subunits (hepatitis B, influenza, acellular pertussis, human papillomavirus, anthrax) and toxoids (diphtheria, tetanus). A subunit vaccine for Lyme disease is no longer available in the United States.
Polysaccharide Vaccines
Polysaccharide vaccines are a unique type of inactivated subunit vaccine composed of long chains of sugar molecules that make up the surface capsule of certain bacteria. Pure polysaccharide vaccines are available for three diseases: pneumococcal disease, meningococcal disease, andSalmonella Typhi. A pure polysaccharide vaccine for Haemophilus influenzae type b (Hib) is no longer available in the United States.
The immune response to a pure polysaccharide vaccine is typically T-cell independent, which means that these vaccines are able to stimulate B cells without the assistance of T-helper cells. T-cell–independent antigens, including poly saccharide vaccines, are not consistently immunogenic in children younger than 2 years of age. Young children do not respond consistently to polysaccharide antigens, probably because of immaturity of the immune system.
Repeated doses of most inactivated protein vaccines cause the antibody titer to go progressively higher, or “boost.” This does not occur with polysaccharide antigens; repeat doses of polysaccharide vaccines usually do not cause a booster response. Antibody induced with polysaccharide vaccines has less functional activity than that induced by protein antigens. This is because the predominant antibody produced in response to most polysaccharide vaccines is IgM, and little IgG is produced.
In the late 1980s, it was discovered that the problems noted above could be overcome through a process called conjugation, in which the polysaccharide is chemically combined with a protein molecule. Conjugation changes the immune response from T-cell independent to T-cell dependent, leading to increased immunogenicity in infants and antibody booster response to multiple doses of vaccine.
The first conjugated polysaccharide vaccine was for Hib. A conjugate vaccine for pneumococcal disease was licensed in 2000. A meningococcal conjugate vaccine was licensed in 2005.
Recombinant Vaccines
Vaccine antigens may also be produced by genetic engineering technology. These products are sometimes referred to as recombinant vaccines. Five genetically engineered vaccines are currently available in the United States. Hepatitis B, human papillomavirus (HPV), and influenza (one brand) vaccines are produced by insertion of a segment of the respective viral gene into the gene of a yeast cell or virus. The modified yeast cell or virus produces pure hepatitis B surface antigen, HPV capsid protein, or influenza hemagglutinin when it grows. Live typhoid vaccine (Ty21a) is Salmonella Typhi bacteria that have been genetically modified to not cause illness. Live attenuated influenza vaccine has been engineered to replicate effectively in the mucosa of the nasopharynx but not in the lungs.
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