Advances in DNA vaccines

Nurse Practitioner, Jan 2002 by Simmerman, James Mark

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Abstract

Extraordinary advances in biotechnology make DNA vaccines the most promising area of vaccinology. This article reviews the public health impact of vaccines in the 20th century, summarizes immunologic concepts, and updates the status of DNA vaccine development and its impact on clinical practice.

Immunization ranks among the most important health advances of the 20th century.2 With the exception of safe drinking water, vaccinology has more effectively reduced mortality than any other modality (see Table 1).1 Sustained immunization programs, in countries that have them, have reduced many infectious diseases to rare occurrences. Immunization programs affect economic development and represent a contract between individuals and society.3

Vaccine Impact

Measles incidence in the United States exemplifies vaccine efficacy. Without vaccination, measles will infect nearly every person by adolescence.4 Before the vaccine was introduced in 1963, measles epidemics occurred every 2 to 3 years.5 State requirements that children be vaccinated before school admittance has helped increase vaccination coverage and reduced measles incidence.6

Low levels of measles transmission occurred through the mid-1980s with an average of 2,900 cases reported each year during 1983 to 1988.7 From 1989 to 1991, measles incidence increased to 55,622 reported cases,8 the majority of which were in children who had not been vaccinated.

This epidemic prompted the Centers for Disease Control and Prevention (CDC) and state health agencies to ensure vaccination at the recommended age. In 1989, the Advisory Committee on Immunization Practices and the American Academy of Pediatrics recommended that U.S. children receive two doses of measles vaccine, because some outbreaks had occurred in schools with high coverage levels but only a single dose of the vaccine.9,10

Increased vaccination and implementing a mandatory second dose of measles, mumps, rubella vaccine caused a dramatic decline in cases (see Table 2). In fact, epidemiologic evidence suggests that measles is no longer endemic in the United States. This means that new cases are imported from countries where measles remains endemic.11

Although measles is so rare in the U.S. that most clinicians have probably not managed a case, in the rest of the world it causes 1 million deaths annually in children age 5 and younger, mostly in Africa.12 The United States must continue vaccination requirements in this country until the threat of virus importation is eliminated.

These statistics point to a critical need for a measles vaccine that is noninvasively administered to infants in the presence of maternal antibodies. Recent research suggests that an oral DNA vaccine may meet this need, potentially saving millions of lives.13

Vaccine-Induced Immunity

Vaccines present the immune system with proteins or carbohydrate molecules. Specialized cells recognize and process these molecules, resulting in long-term immune responses. Vaccines can deliver immunogenic molecules in the form of whole, killed organisms; live, attenuated microbes; purified subunit proteins; recombinant proteins; and, in the future, DNA expression vectors that stimulate human cells to make foreign antigens. Immunity is categorized as innate or adaptive. Both types are essential for survival, but vaccines work primarily to stimulate specific, acquired (adaptive) immune responses.

Innate Immunity

Innate immunity, also called nonspecific or nonadaptive, results from specialized cells such as neutrophils and macrophages whose primary role is phagocytosis of foreign cells. The innate immune system also includes C-reactive proteins and complement cascade proteins. It is a rapid, first-line generalized response against pathogens that results in inflammation, chemotaxis, and localization of infection. Certain cells of the innate immune system also function as antigenpresenting cells (APCs), enabling T-lymphocyte-mediated immune recognition in the adaptive immune system.

Adaptive Immunity

The adaptive immune system, also called specific or acquired, differs from the innate system in two ways: memory and specificity. This system can identify foreign antigens (virus, bacteria, pollen, fungus, and tumor cells) with precision and then develop memory cells that will circulate for many years, providing a rapid and effective immune response to subsequent exposure.

The acquired immune system recognizes particular antigenic determinants known as epitopes rather than entire virions or bacterial cells. Epitopes are distinct structural molecules often located on the surface of the pathogen. To develop a vaccine, researchers must identify these discrete, immunogenic epitopes, produce them accurately and efficiently, and then design safe and effective mechanisms to deliver them to the human immune system.

The adaptive immune system contains two classes of lymphocytes: B cells responsible for humoral or antibody responses and T cells that regulate immune responses and activate direct, cell-mediated immunity (CMI). B cells originate in the bone marrow, mature in lymph nodes, and possess specialized immunoglobulin (Ig) receptors that identify and react with epitopes. These interactions stimulate a series of transformations in the B cell that end in the formation of plasma cells, which are able to secrete five immunoglobulin classes or isotypes of antibody molecules (IgG 1-4, IgA 1-2, IgM, IgD, IgE). Each immunoglobulin isotype has biologic functions and antibodies reacting to a multitude of antigens that may circulate simultaneously.