Immunoprophylaxis

Immunoprophylaxis against viral illnesses includes the use of vaccines or antibody-containing preparations to provide immune protection against a specific disease.

Active Prophylaxis (Vaccines)

Active immunization involves administering a virus preparation that stimulates the body's immune system to produce its own specific immunity. Viral vaccines now available for use include the following types: (1) attenuated live viruses; (2) killed viruses; (3) recombinant produced antigens. A vaccinee is a person who has been vaccinated.

Immune Response to Vaccines: Vaccination evokes an antibody response and stimulates T lymphocytes. Vaccine effectiveness is assessed in terms of percentage of recipients protected and the duration and degree of protection. Most effective viral vaccines protect more than 90 percent of recipients and produce fairly durable immunity.

Passive Prophylaxis

Passive immunity is conferred by administering antibodies formed in another host. Human immunoglobulins remain a mainstay of passive prophylaxis (and occasionally therapy) for viral illnesses; they are usually used to protect individuals who have been exposed to a disease and cannot be protected by vaccination.

Sanitation and Vector Control

Many viral diseases are controlled by reducing exposure to the virus by (1) eliminating nonhuman reservoirs, (2) eliminating the vector, and (3) improving sanitation.

Antiviral Chemotherapy

There are three types of antiviral agents: (1) virucidal agents, which directly inactivate viruses, (2) antiviral agents, which inhibit viral replication, and (3) immunomodulators, which boost the host immune response.

Interferons

Virus-infected cells and cells induced with other agents, e.g., double-stranded polynucleotides, can secrete proteins called interferons, which protect normal cells from viral infection. Therapeutic administration of interferon alpha has proven effective for several human viral illnesses.

Cytokines

Cytokines are molecules produced by cells which modify the biological responses of the same or other cells.

Active Prophylaxis (Vaccines)

The viral vaccines currently approved for use in the United States are listed in TABLE 51-1. These products are of three types:

Table 51-1

Viral Vaccines Approved for Use in the United States.

Immune Response to Vaccines

Vaccination evokes an antibody response which is, in turn, a measure of the effectiveness of the vaccine in stimulating B lymphocytes. Antiviral antibodies are classified as IgA, IgM, or IgG and can be measured by various techniques. Some antibody categories (IgA and IgM) are normally more abundant in respiratory and intestinal secretions; others (mainly IgG) are more abundant in the circulatory system.

Vaccines also stimulate T lymphocytes, leading to cell-mediated responses that influence protection. Antibody assays are now routine laboratory procedures, but measuring cellular immunity in vitro usually requires the utilization of complex laboratory techniques. In general, despite the complexities of the immune system, resistance to the vaccine-preventable viral diseases often correlates well with the presence of circulating antiviral antibodies, which are easily measured.

Effectiveness is a key concern with any vaccine. Here the standard for comparison is usually the immunity conferred by the natural disease; an example of an exception is rabies. Both epidemiologic and laboratory methods are used to generate comparative data. Vaccine-induced immunity can be defined by the percentage of recipients protected, the projected duration of protection, and the degree of protection. Most viral vaccines considered effective protect more than 90 percent of recipients, and the immunity produced appears to be fairly durable, lasting several years or more. However, vaccines usually do not induce an immunologic response entirely comparable to that seen in the natural disease. Immunity to viral diseases should not be thought of as absolute. Persons immune due to the natural infection, as well as, vaccinees, sometimes experience subclinical reinfection if exposed. Evaluating the protection conferred by a vaccine often involves measuring the frequency and extent to which subclinical reinfection can override vaccine-induced resistance.

Often, upon revaccination or reinfection, a boost in IgG antibodies is observed with little or no detectable IgM response, suggesting prior exposure with antibody priming. Such anamnestic responses may be seen in individuals who lack detectable antibody prior to reexposure. Therefore, the absence of measurable antibody may not mean that an individual is unprotected.

Immune responses to viral vaccines may be influenced by a number of factors related to the vaccine as well as to the host. As already discussed, the magnitude and duration of immunity differ significantly between live and killed vaccines. The immune response to vaccines can be enhanced by adding adjuvant substances such as aluminum salts (e.g., hepatitis B vaccine). The route of administration of a vaccine can also influence the immunogenicity of some vaccines. Also, maternal antibodies acquired transplacentally can interfere with responses to measles, mumps, and rubella (MMR) vaccine, as demonstrated by lower response rates when the vaccine is administered earlier than 15 months of age. In this case, it is thought that the antibodies interfere with the post-vaccination replication of these live vaccine viruses in the host.

Vaccine Production

Because viruses are obligate intracellular parasites, all viral vaccines contain substances derived from the cells or living tissues used in virus production. Technical advances have improved production methods. One can think of generations of vaccines: those prepared in the tissues of an inoculated animal are the first generation (e.g., smallpox vaccine from the skin of a calf), products from the inoculation of embryonated eggs are the second generation (e.g., inactivated influenza virus vaccine), and tissue culture-propagated vaccines are the third generation (e.g., poliomyelitis, measles, mumps, and rubella vaccines). The vaccine generation indicates the production methodology, sophistication, and relative purity. Third generation vaccines usually contain the least host protein and other extraneous constituents, but they have been the most difficult to produce. Advances in biotechnology, i.e., recombinant DNA-derived subunit vaccines, now serve as the cornerstone for a fourth generation of vaccines and have led to the development and licensure of a recombinant hepatitis B vaccine. In addition, exciting new technologies such as polynucleotide vaccines are now being tested in animal studies for several viral diseases.

Developing new vaccines

The past success with developing highly effective viral vaccines has been considerable. To develop a new vaccine, researchers must first identify and then produce the virus (or virus components) in quantity under circumstances acceptable for vaccine preparation. Normally this means production of virus or virus components in cell cultures, embryonated eggs, or tissues of experimental animals or humans, or through nucleic acid recombinant technology. Finding an acceptable production system can be a problem, especially in developing inactivated viral vaccines, because a high concentration of antigen is needed. As already mentioned, production of specific viral proteins by recombinant DNA procedures is providing a solution to many of these problems. A final consideration is the clinical importance of the virus. Normally, it must cause a disease of some severity and there must be an identifiable at-risk target population before consideration is given to developing a vaccine.

However, there are still important indications for which there is no effective vaccine. From a public health perspective an important example for which there is no effective vaccine available is human immunodeficiency virus type 1 (HIV-1). Some of the challenges for the development of an HIV-1 vaccine include the following: (1) the type of immune response required to prevent HIV-1 infection is unknown; (2) there is no animal model for AIDS caused by HIV-1; (3) there are multiple types or clades of HIV-1 which may require the development of a multivalent vaccine; (4) even within a clade, there is considerable viral antigen variation; (5) some successful traditional approaches to viral vaccines, such as live attenuated viruses, pose considerable potential safety risks to the vaccinee.

Passive Prophylaxis

The use of immunoglobulin preparations remains a mainstay of passive prophylaxis (and occasionally of therapy) for viral illnesses. Passive immunoprophylaxis is most often recommended in one of these situations: (1) when exposure has occurred, or is expected to occur very soon, and time does not allow for vaccination and the development of an adequate post-vaccination immune response; (2) when no effective vaccine exists; (3) when an underlying illness precludes a satisfactory response to vaccination. Although once derived exclusively from animal sources, most immunoglobulins are now manufactured from human sources. Table 51-2 lists the types of immunoglobulins approved for use in the United States.

Table 51-2

Approved Products Currently Used for Passive Immunization and Immunotherapy Against Viral Disease in the United States.

Standard immunoglobulin is produced by pooling plasma obtained from thousands of donors and contains antibodies to a number of common viruses. Specific immunoglobulins are produced from donors with high titers of antibodies to specific viruses, often selected following immunization with the relevant vaccine.

Combination Therapy

The use of multiple drugs with different mechanisms of action is being studied as a method of improving clinical effectiveness. Such combinations may offer advantages over monodrug therapy such as improved antiviral activity, preventing or delaying the development of drug resistance, and use of lower, less toxic doses. Combinations of various antiviral agents have been extensively studied for HIV. In addition, approaches investigated for HIV have included combining a cytokine with one or more antiviral agents. Combination therapy has been effective in the treatment of diseases caused by other infectious agents (e.g., Mycobacterium tuberculosis and Pseudomonas aeruginosa).

Discovering New Drugs

New drugs with novel mechanisms of action are being sought and developed. Some of these have displayed considerable antiviral activity in human clinical trials, e.g., protease inhibitors for HIV-1.

Evaluating Available Drugs for New Indications

Interleukin-2, a cytokine currently approved for treating renal cell carcinoma, has shown considerable immunomodulatory activity in some HIV-1 infected patients in early human studies.