Vaccines

I. For the most part, the body is protected by the barriers presented by the skin and mucous membranes. For those pathogens that breach this first line of defense the response of the nonspecific and specific immune systems come into play. Protection from bacterial pathogens is mainly accomplished by phagocytosis and destruction via the complement cascade. Both of these nonspecific mechanisms are greatly facilitated by the presence of antibodies (the product of a specific immune response). Viral pathogens are neutralized by antibody and certain viruses are also destroyed by the complement cascade once antibody has bound to the virus. To rid the body of virus-infected cells requires the action of cytotoxic T lymphocytes. Generally speaking, when a pathogen is introduced into the body, the body reacts by increasing the number of lymphocytes (B cells, helper T cells, and cytotoxic T cells) that recognize that pathogen and by increasing the antibody titer (concentration of antibodies in the body fluids) against a particular pathogen. The increased numbers of cytotoxic T cells lead to destruction of virally infected cells while increased numbers of helper T cells aid in activating and focusing all aspects of the body's defenses against the invading pathogen.

A. Increasing the number of lymphocytes, which react to a pathogen and the subsequent rise in antibodies against the pathogen, is referred to as active immunity. The proliferation of lymphocytes is usually due to the recognition of antigens from the pathogen by the lymphocytes. As previously discussed, this leads to rapid cell division and large increases in the number of lymphocytes which will recognize the pathogen. B lymphocytes will then secrete antibodies and increase the antibody titer against that pathogen.

1. Active immunity that results from infection with the pathogen is referred to as natural active immunity. During the initial exposure to a pathogen, development of natural active immunity only occurs late in the acute phase and during the convalescent phase of a disease caused by the pathogen. Though the specific immune reaction is delayed during the initial infection, the immunological memory generated during this infection prevents subsequent infections from progressing to the acute phase of disease and may prevent any infection whatsoever by the same pathogen. In many cases, natural active immunity against that pathogen lasts for the rest of a person’s life.

2. Administering a vaccine to a person allows their lymphocytes to be stimulated without suffering the disease. This is referred to as artificial active immunity. Depending on the type of vaccine used, artificial active immunity can lead to the stimulation of all types of lymphocytes or to only the B cells and helper T cells. The immunity acquired from vaccines sometimes will last a lifetime but often it wanes leaving the person susceptible to the pathogen. To provide protective levels of lymphocytes and antibodies the same vaccine will often need to be given repeatedly. The second dose and all subsequent doses of a vaccine are referred to as boosters.

B. In certain cases, antibody titers are increased without stimulating B cells to undergo clonal expansion. This is referred to as passive immunity. Passive immunity does not last long (several weeks to several months at the most).

1. Natural passive immunity occurs when antibodies are passed from mother to fetus via the placenta or from mother to neonate via breast milk. These antibodies will help protect the infant during the first six months of life. The antibody titer will slowly diminish to the point where protective titers no longer are present in the baby’s blood. At this point the baby is susceptible to infection by pathogens that they had been previously protected against.

2. In certain cases, purified antibody preparations containing antibodies that will bind to a specific pathogen or toxin (these preparations are known as gamma globulin or antitoxins) are given to patients. This is referred to as artificial passive immunity. This is usually done when it is known that an unvaccinated patient has been exposed to a pathogen. The immediate increase in antibodies helps the body fight infection by this pathogen. Once again, this protection is short-lived.

II. As mentioned earlier, vaccines allow for the development of active immunity. Over the years various types of vaccines have been developed. Long before any understanding of the specific immune system existed, the Chinese would intentionally expose susceptible persons to the ground-up scabs from a smallpox victim. The scabs contain proteins from the smallpox virus (along with some active virus) and exposure to these smallpox proteins allowed a person to develop protective levels of antibodies and T cells. If successful, this would protect the person from infection with the often-deadly smallpox virus. But this frequently led to the person contracting full-blown smallpox. In 1796, Edward Jenner, an English physician, noticed that milkmaids who had contracted cowpox from their contact with the utters of cows seldom contracted smallpox. This led him to use the cowpox virus as a vaccine against smallpox. It is now known that the proteins on the surface of the cowpox virus are very similar to those found on the surface of the smallpox virus. From these humble beginnings, the practice of vaccination has become one of the most effective and economical ways to control infectious disease. Now many types of vaccines are in use and several new modes of vaccination are being developed.

A. A killed whole vaccine consists of a preparation of the pathogenic bacteria or virus which has been killed or inactivated by radiation, formalin or other means. This type of vaccine is easily prepared and can be handled liberally (no refrigeration is usually necessary). Little or no stimulation of cytotoxic T cells occurs with this type of vaccine and repeated boosters are often needed.

B. A modified (attenuated) live vaccine consists of a live bacteria or an active virus that has lost its capacity to cause disease. The pathogen actually infects the patient and the full range of lymphocytes is stimulated. This generates a more robust immune protection especially in the case of viruses. Often immunity lasts a lifetime. In rare cases, the modified pathogen reverts to full pathogenicity and causes disease.

C. Subunit vaccines consist of a protein or carbohydrate from the bacterial or viral pathogen. The bacteria or virus is broken apart (and thus killed) and the components of the pathogen separated. Only one or a few of the components are injected into the patient. Like killed vaccines these require multiple doses.

D. The problem with many subunit vaccines stems from the inability to completely purify the component that is wanted from other proteins or polysaccharides produced by the pathogen that might cause side effects. Current biotechnology allows a single gene to be transferred from a pathogen to a harmless yeast or bacterial cell. This is referred to as genetic recombination. The recombinant yeast or bacteria will produce the protein from the pathogen. By growing this recombinant strain in large vats, vast amounts of the protein will be produced. This protein can be purified with little or no risk of purifying other proteins or carbohydrates that might cause disease. This purified protein can then be given in the same manner that a subunit vaccine would be given. This type of vaccine is referred to as a recombinant vaccine.

E. In those cases in which it is not the growth of a bacterial pathogen but the release of toxins from that pathogen that leads to disease, development of antibodies that will bind to the toxin will often protect the patient from disease even if they are infected with the pathogen. Vaccines that are derived from the toxin and thus lead to the development of antibodies against the toxin are referred to as toxoid vaccines. The toxoid vaccine consists of chemically modified bacterial toxin. The chemical modifications eliminate the pathogenic effect of the toxin. This toxoid is injected into the patient and the patient develops a high titer against the toxin. If the patient is infected with the pathogen and the toxin is released, antibodies will bind to it and stop it from causing disease.

F. Currently, there are many strategies being explored to help harness and direct the immune system to better fight infection. We will concentrate only a few of these emerging vaccine strategies.

1. It has been demonstrated that eucaryotic cells will take up DNA from the environment and use that DNA to make proteins. By injecting DNA that codes for proteins usually found on pathogens, our cells can be induced to make these proteins. Subsequently, our immune system reacts to these proteins as it would any antigen. This is especially helpful in that the cytotoxic T lymphocytes can be stimulated in this manner. This type of vaccine is currently being referred to as a DNA vaccine or naked DNA vaccine. Enclosing the DNA in a phospholipid bilayer "bag" (referred to as a liposome) has been shown to increase the uptake of the DNA in certain cell types.

2. Immune protection against certain viruses requires the proliferation of cytotoxic T lymphocytes. This requires the presentation of viral antigens (complexed with MHC I) on the surface of normal cells of the body. This cannot be accomplished by simply injecting the protein into the body. If the viral pathogen is not easily attenuated to a nonpathogenic state or if it readily reverts to full pathogenicity, a modified-live vaccine will not be feasible for this pathogen. Recently, genes that code for the surface proteins of pathogenic viruses have been transferred to nonpathogenic viruses. Infection with this recombinant virus leads to the production of proteins from the pathogenic virus by normal cells within the vaccinated person’s body. This leads to the stimulation and proliferation of the cytotoxic T lymphocytes that will react with the pathogenic virus. This is referred to as a recombinant virus vectored vaccines or simply a virus vector vaccine.

G. Many vaccines require that the immune system be signaled to pay attention to the materials deposited at the vaccination site. To alert the macrophages and other types of WBC’s substances known as adjuvant are added to the vaccine. These substances elicit a strong inflammatory response and thus alert the body to the presence of the material at the site of vaccination.

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