The Development of Polio Vaccines

Overview

Poliomyelitis, also known as infantile paralysis, is an acute viral infection that can invade the nervous system and cause paralysis. Where the disease is common, most infections probably go unnoticed or result in mild symptoms, such as fever, sore throat, headache, vomiting, and stiffness of the neck and back. Before the introduction of preventive vaccines, poliomyelitis was one of the most feared childhood diseases. During some epidemic years, over 10,000 paralytic cases occurred in the United States alone. Such epidemics formed the basis for the image of polio as the great crippler of children and exerted a profound influence on the direction of medical research. The history of poliomyelitis demonstrates the value of immunization. In 1981 about twenty years after the use of the polio vaccines became widespread, the number of recorded cases in the United States reached a record low of only six cases. By the end of the twentieth century, the global eradication of polio was considered a practical goal. In the wealthy, industrialized nations, diseases such as diphtheria, measles, mumps, pertussis, and rubella have been virtually eliminated or radically reduced. Nevertheless, fewer than half of all American children under the age of two are properly immunized.

Background

Although therapy for many diseases has improved, from the public health point of view vaccines are the most powerful and appropriate tools for preventing epidemic diseases. Whenever a large portion of a population has been vaccinated, the community achieves a form of protection against epidemics known as "herd immunity" because the number of susceptible people is significantly reduced. Advances in biotechnology have made possible the design of safer and more effective vaccines. Edward Jenner (1749-1823) introduced the term vaccination in the late eighteenth century to distinguish his method of inducing immunity to smallpox from older, more dangerous methods. Vaccines are made in a variety of ways, depending in part on the nature of the organism and the disease it causes. Weakened microbes, killed microbes, animal viruses that are not virulent in humans, and toxins are the most common components of the vaccines that have been in use throughout the twentieth century. Weakened live-virus vaccines have been used against rabies, mumps, measles and rubella, and poliomyelitis. Similar techniques are being used to create new vaccines against rotaviruses, respiratory syncytial virus, parainfluenza, and influenza viruses. Killed-virus vaccines are being used against poliomyelitis, whooping cough, and influenza.

The Development of Polio Vaccines

Overview

Background

In the battle against poliomyelitis, the Salk and Sabin polio vaccines have both been very successful, but they also illustrate the advantages and disadvantages of killed and live attenuated vaccines. Killed vaccines are generally easier to develop, but live vaccines induce longer-lasting protection. Albert Sabin (1906-1993) carried out pioneering research on poliomyelitis and developed a live attenuated vaccine for the prevention of the disease. Contrary to the prevailing views about the means of transmission of the polio virus, Sabin proved that the virus was spread by the fecal-oral route rather than the nasal route and that the virus multiplied in the human intestinal tract. By 1936, Sabin and his associates had been able to isolate and propagate the poliomyelitis virus in laboratory cultures of human embryonic nervous tissues. Sabin believed that long-lasting immunity could best be established with a live attenuated vaccine because antibodies to the virus were found in survivors of the disease many years after infection. The live vaccine could be administered by mouth, but the virus might spread from those who had been vaccinated to others who had not. During a period in which unvaccinated people might easily encounter the wild virus, the benefits of using the attenuated virus might outweigh the dangers. When the disease is rare, however, the transmission of even an attenuated form of the polio virus to non-immune people could be dangerous. Eventually, American epidemiologists found that the use of the live vaccine was associated with a small, but real, risk of paralytic polio.

Before Sabin perfected his vaccine, Jonas Salk (1914-1995) had developed a killed-virus vaccine that had to be administered by injection. A nationwide trial of the Salk vaccine in 1954 was successful. As a result of the Salk vaccine program, the incidence of paralytic polio in the United States decreased dramatically by 1961. The National Foundation for Infantile Paralysis, which had supported Salk's research, was committed to the Salk vaccine and unwilling to sponsor any other vaccines. The World Health Organization (WHO), however, supported tests of the oral polio vaccine in Mexico, Czechoslovakia, and the Soviet Union. In 1985 WHO began an effort to eradicate polio worldwide by the year 2000, but there is little likelihood that the goal will be achieved before 2040.

Impact

Advances in the sciences of virology, bacteriology, immunology, and molecular biology have led to new approaches in the construction of vaccines. Public health policies and procedures have been transformed by the development of vaccines against more than 20 infectious diseases. At least 15 new or improved vaccines were developed between 1980 and 2000. Experimental vaccines may offer enhanced protection against influenza, pneumococcal pneumonia, pertussis, rubella, rabies, bacterial meningitis, hepatitis B, and adenovirus-associated respiratory disease. New vaccine technologies also offer hope of ameliorating the effects of autoimmune disorders and allergies.

Microorganisms contain proteins called "antigens" that stimulate the host's immune response, resulting in the synthesis of proteins called "antibodies" that bind to the microbes and help destroy them. In addition, "memory cells" are produced and remain in the blood stream, ready to mount a quick response against subsequent infections by the same microbe. Vaccines have been made by using a portion of the disease-causing organism that contains the antigens that trigger the immune response. Such cell-free vaccines are generally safe but they may not induce long-lasting immunity. For microbes that produce toxins, vaccines can be prepared by changing the dangerous toxin into a harmless "toxoid." Improved vaccines against whooping cough (pertussis), for example, are made up of inactivated pertussis toxin. Based on Jenner's use of cowpox against smallpox, scientists have adopted a similar approach in the battle against rotaviruses, which are the leading cause of infant diarrhea, and parainfluenza viruses, which cause severe respiratory tract infections in children. Recently, biotechnology and genetic engineering techniques have been used to design "subunit vaccines," which are based on isolation of the genes that code for selected subunits of the genome of the infectious agent. The selected genetic material can then be produced in large quantities by growing it in bacteria or yeast host cells. Subunit vaccines are now available for meningitis, pneumonia, typhoid, and hepatitis B. Subunit vaccines for respiratory syncytial virus and parainfluenza virus infections are currently under development.

Some bacteria, such as those that cause pneumonia and meningitis, have an outer coat that protects them from the human immune response. When the outer coat of the pathogen is linked to proteins or toxins from another organism, the result is a combined, or conjugate, vaccine. In 1986 the first conjugate vaccine was licensed to protect against Haemophilus influenzae type b (Hib), the major cause of bacterial meningitis in babies and young children. By the end of the twentieth century, the widespread use of improved versions of this vaccine had virtually eliminated Hib meningitis in the United States.

Scientists have used genetic engineering technology to isolate specific genes and insert them into the DNA of certain microbes or mammalian cells grown in the laboratory. Such cells become "factories" for the mass production of the antigen that is the selected gene product. The antigen can then be separated from other material by the use of a monoclonal antibody that recognizes the antigen. A vaccine for the hepatitis B virus has been created through this approach.

Scientists can also insert genes for desired antigens into the DNA of related, but harmless, viruses such as the vaccinia virus or selected strains of bacteria. This approach is being used to develop novel vaccines for the viruses that cause hepatitis B, influenza, rabies, and AIDS. Another approach undergoing testing is the weakening of a dangerous microbe, such as the cholera bacillus or the herpes virus, by removing specific genes. The engineered microbes can produce immunity but not disease. One experimental DNA vaccine for AIDS involves isolating selected genes from the virus and injecting them into individuals. If these genes can enter host cells and cause the synthesis of viral proteins, these foreign proteins might elicit an immune response, which would protect the host against subsequent infection by the microbe. Some scientists believe that the creation of wholly synthetic vaccines made by isolating the gene that encodes for an appropriate antigen will be possible. Selected amino acid sequences of the resulting antigen (a protein molecule) could be synthesized and used as vaccines for malaria and diarrheal diseases.

Malaria parasites and the mosquitoes that serve as their vectors (means of transmission) are very ancient. The disease infects about 500 million people each year and claims about 2.7 million victims. Although the disease has resisted efforts to control it, during the second half of the twentieth century researchers acquired a great deal of information about various strains of malaria parasites and their characteristic antigens. Much of the malaria genome has been sequenced and chromosome mapping of the genome is nearly complete.

Progress towards anti-malaria vaccines has been slow—for both scientific and geopolitical reasons—but during the 1990s several promising experimental vaccines were being tested. New malaria vaccines are based on recombinant technology—a protein from the malaria parasite fused to hepatitis B surface antigen (HBsAg)—and highly effective adjuvants. (Adjuvants are substances added to vaccines to enhance the immune response.) Although experimental vaccines have not undergone rigorous field trials, research on these vaccines has provided insights into the immunological requirements for further improvements. Among the many obstacles to the development of a broadly effective malaria vaccine is the highly variable nature of the parasite's surface proteins. A vaccine that does well in limited clinical trials might not be effective against all variants of the parasite, and the duration of immunity is also problematic. The problems caused by variability in the malaria parasite are much more complex than those involved in working with the three major types of polio viruses.

Immunization is widely acknowledged as the most cost effective of all public health interventions. WHO estimates that vaccines for common infectious diseases, costing only pennies per dose, could save millions of lives and billions of dollars each year. According to WHO, however, 20% of the world's children, living mainly in the poorest countries, remain unprotected against polio, measles, diphtheria, pertussis, rubella, and other infectious diseases. Every year about 8 million children worldwide die from diseases that are preventable through the use of vaccines.

LOIS N. MAGNER