Production of modern vaccines
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 virtu – ally 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 reac – tions as a result of uncontrolled replication (growth) of the vaccine virus. This only occurs in persons with immunodefi – ciency (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., transpla – cental, 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). Measles vaccine virus seems to be most sensitive to circulating antibody. Polio and rotavirus vaccine viruses are least affected. Live attenuated vaccines are fragile and can be damaged or destroyed by heat and light. They must be handled and stored carefully.
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 polysac – charide 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 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, and Salmonella Typhi.
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 polysaccharide 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.
Vaccine antigens may also be produced by genetic engi – neering technology. These products are sometimes referred to as recombinant vaccines. Four genetically engineered vaccines are currently available in the United States. Hepatitis B and human papillomavirus (HPV) 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 produces pure hepatitis B surface antigen or HPV capsid protein 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.
Production of Hepatitis Vaccine
Hepatitis B vaccine is a vaccine that prevents hepatitis B. The first dose is recommended within 24 hours of birth with either two or three more doses given after that. This includes those with poor immune function such as from HIV/AIDS and those born premature. It is also recommended for health-care workers to be vaccinated. In healthy people routine immunization results in more than 95% of people being protected.
Blood testing to verify that the vaccine has worked is recommended in those at high risk. Additional doses may be needed in people with poor immune function but are not necessary for most people. In those who have been exposed to the hepatitis B virus but not immunized, hepatitis B immune globulin should be given in addition to the vaccine.The vaccine is given by injection into a muscle.
n 1963, the American physician/geneticist Baruch Blumberg discovered what he called the “Australia Antigen” (now called HBsAg) in the serum of an Australian Aboriginal person. In 1968, this protein was found to be part of the virus that causes “serum hepatitis” (hepatitis B) by virologist Alfred Prince. The American microbiologist/vaccinologist Maurice Hilleman at Merck used three treatments (pepsin, urea and formaldehyde) of blood serum together with rigorous filtration to yield a product that could be used as a safe vaccine. Hilleman hypothesized that he could make an HBV vaccine by injecting patients with hepatitis B surface protein. In theory, this would be very safe, as these excess surface proteins lacked infectious viral DNA. The immune system, recognizing the surface proteins as foreign, would manufacture specially shaped antibodies, custom-made to bind to, and destroy, these proteins. Then, in the future, if the patient were infected with HBV, the immune system could promptly deploy protective antibodies, destroying the viruses before they could do any harm.
The first large-scale trials for the blood-derived vaccine were performed on gay men, in accordance with their high-risk status. Later, Hilleman’s vaccine was falsely blamed for igniting the AIDS epidemic. But, although the purified blood vaccine seemed questionable, it was determined to have indeed been free of HIV. The purification process had destroyed all viruses—including HIV. The vaccine was approved in 1981.
The blood-derived hepatitis B vaccine was withdrawn from the marketplace in 1986 when Pablo DT Valenzuela, Research Director of Chiron Corporation, succeeded in making the antigen in yeast and invented the world’s first recombinant vaccine. The recombinant vaccine was developed by inserting the HBV gene that codes for the surface protein into the yeast Saccharomyces cerevisiae. This allows the yeast to produce only the noninfectious surface protein, without any danger of introducing actual viral DNA into the final product. This is the vaccine still in use today.
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