Passive Immunization Involves Transfer of Preformed Antibodies

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Jenner and Pasteur are recognized as the pioneers of vaccination, or induction of active immunity, but similar recognition is due to Emil von Behring and Hidesaburo Kitasato for their contributions to passive immunity. These investigators were the first to show that immunity elicited in one animal can be transferred to another by injecting it with serum from the first (see Clinical Focus, Chapter 4).

Passive immunization, in which preformed antibodies are transferred to a recipient, occurs naturally by transfer of maternal antibodies across the placenta to the developing fetus. Maternal antibodies to diphtheria, tetanus, streptococci, rubeola, rubella, mumps, and poliovirus all afford passively acquired protection to the developing fetus. Maternal vaccination even in the United States is an indication of the difficulty of the task. Even if we assume that suitable vaccines have been developed and that compliance is universal, the ability to produce and deliver the vaccines everywhere is a profound challenge. The World Health Organization (WHO) has stated that the ideal vaccine would have the following properties:

■ Affordable worldwide

■ Effective after a single dose

■ Applicable to a number of diseases

■ Administered by a mucosal route

■ Suitable for administration early in life

Few, if any, vaccines in common use today conform to all of these properties. However, the WHO goals can guide us in the pursuit of vaccines useful for worldwide application. They further aid us in setting priorities, especially for development of the vaccines needed most in developing countries. For example, an HIV/AIDS vaccine that meets the WHO criteria could have an immediate effect on the world AIDS epidemic, whereas one that does not will require further development before it reaches the populations most at risk.

Immunization saves millions of lives, and viable vaccines are increasingly avail-

able. The challenge to the biomedical research community is to develop better, safer, cheaper, easier-to-administer forms of these vaccines so that worldwide immunization becomes a reality.

Estimated annual deaths worldwide of children under 5 years of age, by pathogen

Pathogen

Deaths (millions)

Pneumococcus* Measles

Hemophilus (a-f, nst)

Rotavirus**

Malaria

Pertussis

Tetanus

Tuberculosis

*Pathogens shown in bold are those for which an effective vaccine exists. ** A licensed vaccine is being tested for possible side-effects.

SOURCE: Adapted from Shann and Steinhoff, 1999, Lancet 354 (Suppl II):7—11.

antibodies present in colostrum and milk also provide passive immunity to the infant.

Passive immunization can also be achieved by injecting a recipient with preformed antibodies. In the past, before vaccines and antibiotics became available, passive immunization provided a major defense against various infectious diseases. Despite the risks (see Chapter 16) incurred by injecting animal sera, usually horse serum, this was the only effective therapy for otherwise fatal diseases. Currently, there are several conditions that warrant the use of passive immunization. These include:

■ Deficiency in synthesis of antibody as a result of congenital or acquired B-cell defects, alone or together with other immunodeficiencies.

■ Exposure or likely exposure to a disease that will cause complications (e.g., a child with leukemia exposed to varicella or measles), or when time does not permit adequate protection by active immunization.

■ Infection by pathogens whose effects may be ameliorated by antibody. For example, if individuals who have not received up-to-date active immunization against tetanus suffer a puncture wound, they are given an injection of horse antiserum to tetanus toxin. The preformed horse antibody neutralizes any tetanus toxin produced by Clostridium tetani in the wound.

Passive immunization is routinely administered to individuals exposed to botulism, tetanus, diphtheria, hepatitis, measles, and rabies (Table 18-2). Passively administered antiserum is also used to provide protection from poisonous snake and insect bites. Passive immunization can provide immediate protection to travelers or health-care workers who will soon be exposed to an infectious organism and lack active immunity to it. Because passive immunization does not activate the immune system, it generates no memory response and the protection provided is transient.

For certain diseases such as the acute respiratory failure in children caused by respiratory syncytial virus (RSV), passive

Common agents used for passive immunization

TABLE 1B-1

Type

Acquisition of passive and active immunity

Acquired through

TABLE 18-2

Passive immunity

Active immunity

Natural maternal antibody

Immune globulin*

Humanized monoclonal antibody

Antitoxin*

Natural infection

Vaccines*

Attenuated organisms

Inactivated organisms

Purified microbial macromolecules

Cloned microbial antigens

Expressed as recombinant protein

As cloned DNA alone or in virus vectors

Multivalent complexes

Toxoid§

*An antibody-containing solution derived from human blood, obtained by cold ethanol fractionation of large pools of plasma; available in intramuscular and intravenous preparations.

TAn antibody derived from the serum of animals that have been stimulated with specific antigens.

*A suspension of attenuated live or killed microorganisms, or antigenic portions of them, presented to a potential host to induce immunity and prevent disease.

§A bacterial toxin that has been modified to be nontoxic but retains the capacity to stimulate the formation of antitoxin.

immunization is the best preventative currently available. A monoclonal antibody or a combination of two monoclonal antibodies may be administered to children at risk for RSV disease. These monoclonal antibodies are prepared in mice but have been "humanized" by splicing the constant regions of human IgG to the mouse variable regions (see Chapter 5). This modification prevents many of the complications that may follow a second injection of the complete mouse antibody, which is a highly immunogenic foreign protein.

Although passive immunization may be an effective treatment, it should be used with caution because certain risks are associated with the injection of preformed antibody. If the antibody was produced in another species, such as a horse, the recipient can mount a strong response to the isotypic determinants of the foreign antibody. This anti-isotype response can cause serious complications. Some individuals, for example, produce IgE antibody

Disease

Agent

Black widow spider bite Botulism Diphtheria Hepatitis A and B

Measles

Rabies

Respiratory disease

Snake bite Tetanus

*Respiratory syncytial virus

Horse antivenin

Horse antitoxin

Horse antitoxin

Pooled human immune gamma globulin

Pooled human immune gamma globulin

Pooled human immune gamma globulin

Monoclonal anti-RSV*

Horse antivenin

Pooled human immune gamma globulin or horse antitoxin specific for determinants on the injected antibody. Immune complexes of this IgE bound to the passively administered antibody can mediate systemic mast cell degranulation, leading to systemic anaphylaxis. Other individuals produce IgG or IgM antibodies specific for the foreign antibody, which form complement-activating immune complexes. The deposition of these complexes in the tissues can lead to type III hypersensitive reactions. Even when human gamma globulin is administered passively, the recipient can generate an anti-allotype response to the human immunoglobu-lin, although its intensity is usually much less than that of an anti-isotype response.

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