Zinsser Develops an Immunization Against Typhus

Date 1930

Hans Zinsser demonstrated clinical differences in forms of typhus and developed an effective vaccine against the disease.

Locale Harvard University, Cambridge, Massachusetts

Key Figures

• Hans Zinsser (1878-1940), American bacteriologist and immunologist
• Howard T. Ricketts (1871-1910), American bacteriologist
• John Franklin Enders (1897-1985), American immunologist

Summary of Event

As a bacteriologist and immunologist, Hans Zinsser was interested in the epidemiology of infectious diseases. During an outbreak of typhus in Serbia in 1915, he traveled with a Red Cross team in order to study the clinical and pathological aspects of the disease. He made subsequent trips to the Soviet Union in 1923, Mexico in 1931, and China in 1938. His observations supported the commonly held belief that typhus was caused by an organism, the rickettsia, isolated and named by Henrique da Rocha-Lima in 1916 for Howard T. Ricketts. The organism was known to be borne by a louse or a rat flea and transmitted to humans by way of a bite. The unsanitary living conditions resulting from poverty and overcrowding provided an atmosphere conducive for the spread of the disease.

The rickettsia are microorganisms whose shapes range from rod to sphere. Within the carrier’s body, the rickettsia stimulate the cells of endothelial tissue to use phagocytosis (that is, to eat) so that the microorganism can enter and live in the cytoplasm of the endothelial cells, which line the gut of the insect. The rickettsia multiply within the tissue and pass from the insect body with the feces. Because the internal cells of the insect are destroyed, the insect dies within three weeks of becoming infected with the microorganisms.

As the flea or louse feeds on a human, it causes an itch; scratching of the itch may result in a break in the skin. This, in turn, provides an opportunity for the rickettsia-laden feces to enter the body. Dried, airborne feces can be inhaled. Once within the human host, the rickettsia invades endothelial cells associated with blood vessels and causes an inflammation of the blood vessels. The resulting cell death leads to tissue death. In a few days, the infected host exhibits symptoms such as a rash, severe and sudden headache, rise in temperature, photophobia (visual intolerance to light), vertigo, tinnitus (ringing in the ears), deafness, and an altered mental state, which gives the disease its name, typhus (from the Greek meaning cloudy or misty). Left untreated, the patient dies within nine to eighteen days.

Typhus was first described in Europe in the fifteenth century. It is among the oldest diseases known to be caused by the rickettsia. Medical science now recognizes three clinical forms: the epidemic louse-borne form, the Brill-Zinsser form, and the murine, or rodent-related, form. The epidemic louse-borne or classical form is the severest manifestation of the disease. Rickettsia prowazekii is the causative agent and is carried by the human body louse Pediculus humanus. The Brill-Zinsser form presents symptoms similar to but milder than the epidemic type. It involves the reactivation of the organism within the host cells, indicating that the host had encountered the epidemic form earlier. The murine form is caused by Rickettsia typhi (previously called Rickettsia mooseri), which is borne by a rat flea. This variety also presents symptoms that are milder than the epidemic type. The pathology of murine typhus closely resembles that of Rocky Mountain spotted fever, which is caused by Rickettsia rickettsii.

When Zinsser began his work on typhus, the information that existed concerning the disease was in a chaotic state. Zinsser sought to organize the information and bring order to the study of the disease. Zinsser and his colleagues, including John Franklin Enders, Hermann Mooser, and M. Ruiz Castañeda, sought to establish the relation of one form of typhus to the others. In 1898, an endemic form of typhus prevalent among immigrants in New York City had been described. The endemic form was called Brill’s disease. Mooser, in the late 1920’s, proved that the causative agent of Brill’s disease was Rickettsia mooseri and that the organism was carried by the rat flea. The endemic form became known as the murine form, and the causative agent was later renamed as Rickettsia typhi.

In the 1930’s, Zinsser suggested that there were actually two forms of the disease being described by Brill: one that was associated with rodents (murine form) and another that had its own causative agent and was a reactivation of an organism picked up at an earlier time when the patient was exposed to the epidemic disease present in many European countries at that time. He demonstrated that Rickettsia prowazekii was the agent involved in both the European epidemic version and the reactivated version, which was known as Brill’s disease. As a result of Zinsser’s effort to distinguish the two types of typhus disease, it was renamed Brill-Zinsser disease.

Because he had analyzed the mechanism of the Weil-Feliz diagnostic test for rickettsial diseases, Zinsser was aware that the disease-causing organism had an antigenic component, most likely a polysaccharide. In 1932, Zinsser and Castañeda identified agglutinins, or antibodies, in the blood serum of typhus-infected patients with the murine and the classical forms. Although earlier attempts at preventing typhus by means of passive immunity were not satisfactory, Zinsser saw immunity as a viable solution to the problem of typhus. He determined that a large number of dead microorganisms was necessary to induce an immunity that would be effective. He and his colleagues set out to develop a method of growing organisms in large quantities by using tissue culture. The method started by infecting chick embryo yolk sac tissue with rickettsia. The infected tissue was used to inoculate large quantities of normal chick tissue. The infected tissue was then grown on the surface of agar in flasks. This provided Zinsser and his team with the quantities of microorganisms needed to produce the desired vaccine. The type of immunization Zinsser was proposing is known as passive immunity. The infecting organisms have markers on their cell surfaces known as antigens. The antigens are capable of eliciting an immune reaction regardless of whether the cell is living, weakened, or dead. The reaction involves recognition of the antigen by cells called macrophages and cells called B cells. The B cells produce antibodies that are capable of destroying the invading organism directly or attracting more macrophages to the area so that they can destroy the organism. B cells also produce “memory cells,” which remain in the blood in order to trigger a rapid second response if there is a subsequent infection. Because the vaccine contains weakened or dead organisms, the person experiences a mild reaction to the vaccine but is not at risk of contracting the disease.

Significance

Typhus is still prevalent in many areas of the world. Where it does persist, the disease is nurtured by poverty and overcrowded, unsanitary living conditions. Many countries that have experienced severe drought report high incidences of typhus. Epidemic typhus has not been reported in many countries for some time. The last report of the epidemic in the United States was in 1921. Endemic or murine typhus occurs more frequently. The incidence in the United States is low, with about fifty cases per year being reported. Because the organism is susceptible to antibiotics, such as tetracycline and chloramphenicol, reported cases can be treated; therefore, the mortality rate is low.

Zinsser’s work on the treatment and prevention of the disease had important impacts. By creating an orderly classification of the typhus diseases and identifying causative agents and vectors, Zinsser and his coworkers contributed significantly to the understanding of the disease, which in turn enabled attempts to discover a cure and establish preventive measures. Louse and rodent control and improved sanitation helped to prevent the spread of the disease.

Zinsser’s idea to grow large quantities of the rickettsia to make a vaccine led him to investigate tissue culture as a quick and reliable method of securing a good yield of the desired microorganism. The attention focused on the tissue culture method and inspired researchers to modify and improve the technique so that now the use of tissue culture is a standard effective laboratory procedure.

Zinsser’s greatest contribution to medicine was the development of a vaccine for typhus. This disease has a place not only in the history of medicine but also in the history of the world. Battles and wars were lost because louse-infected armies fell victim to typhus. Invading armies carried the disease across national boundaries; Europe witnessed an uninterrupted series of epidemics throughout the eighteenth and nineteenth centuries. The vaccine that Zinsser and his team developed ensured that even if wars continued and armies were subjected to undesirable living conditions, the possibility of contracting typhus would be greatly reduced. The vaccine also provided a safeguard for the poor in crowded cities. People who were forced by financial circumstances to live in densely packed housing, where they might easily become infected by lice or rat fleas, gained protection against typhus once the vaccine became available.

Because Zinsser looked to immunology for protection against typhus, he also had an impact on the growing science of immunology and its application to medicine. Vaccines have been developed against many pathogenic organisms, and their use has obliterated many diseases that were once commonplace. Zinsser was one of the pioneers in applying the principles of immunity to health care.

Zinsser was also an inspiring teacher whose students and associates appreciated his approach to science and his concern for the human condition. Unfortunately, he died before he had a chance to see all the benefits that accrued from the production of his vaccine against typhus. Today, the incidence of typhus is negligible, although small outbreaks of Q fever have been reported in the United States and Australia, and Rocky Mountain spotted fever has been reported in the United States.

Bibliography

Duma, Richard J., et al. “Epidemic Typhus in the United States Associated with Flying Squirrels.” Journal of the American Medical Association 245 (June 12, 1981): 2318-2323. Flying squirrels have been added to the list of rickettsia vectors. Suggests that most cases of typhus in the United States involve contact with squirrels.

Joklik, Wolfgang K., Hilda P. Willet, and D. Bernard Amos, eds. Zinsser’s Microbiology. 20th ed. East Norwalk, Conn.: Appleton & Lange, 1995. Presents excellent descriptions of the rickettsia organism and typhus disease. Highlights Zinsser’s contributions to the immunology of the disease.

Olitsky, Peter K. “Hans Zinsser and His Studies on Typhus Fever.” Journal of the American Medical Association 116 (January 8, 1941): 907-912. Comprehensive recitation of the highlights of Zinsser’s life and career. Describes Zinsser as a humanist and philosopher as well as a scientist. Includes a summary of the typhus research available when Zinsser began his work in 1930.

Strong, Richard P. “Obituary: Hans Zinsser.” Science 92 (September 27, 1940): 276-279. Written by a great admirer of Zinsser. Lauds the nonscientist side of Zinsser’s life, including his publication of poetry and other literary works under a pseudonym. Reveals the deep feelings of admiration many of Zinsser’s students and colleagues had for him.

Zinsser, Hans. Rats, Lice, and History. 1935. Reprint. New York: Black Dog & Leventhal, 1996. Classic volume presents what Zinsser calls a biography of a disease. Begins with his views on science and its relation to art and then provides a detailed account of epidemics and their influence on history. The last five chapters address the history of typhus. Highly readable; a must for anyone interested in history as well as science.

Zinsser, Hans, Harry Plotz, and John F. Enders. “Scientific Apparatus and Laboratory Methods: Mass Production of Vaccine Against Typhus Fever of the European Type.” Science 91 (January 12, 1940): 51-52. A firsthand account of the problems encountered and the modifications made in the development of a method to grow organisms in large quantities. Clearly written and accessible to nonscientists.