The similarity in the pathogenic properties of human and swine influenza virus for ferrets led Elkeles (1) to attempt the transmission of the human agent to swine. He found that very young pigs (2 to 6 weeks old) , developed a mild illness when the virus from man was given intranasally under light ether narcosis. At autopsy these animals sometimes showed scattered dark red bronchopneumonic areas of consolidation in the upper lobes of the lung. When cultures of either swine or human influenza bacilli were added to the virus at the time of its administration, the swine developed a more severe illness. The clinical picture was characterized by a low grade fever, apathy, loss of appetite, and sometimes cough. At autopsy varying degrees of bronchopneumonia were encountered. Virus, pathogenic for ferrets,

could be recovered from the pneumonic lungs. It thus appeared that Elkeles had produced a disease somewhat resembling swine influenza by the administration to young pigs of human influenza virus mixed with influenza bacilli of either human or swine origin. This observation made more credible the theory that swine influenza may have arisen as the result of the infection of swine in 1918 from human sources (2 - 4).

The question of the pathogenicity of human influenza virus for swine was of such importance that it seemed to warrant further investigation. The present paper reports our experience in the transmission of human influenza virus to swine.

Experimental - The Infection of Swine with Human Influenza Virus Alone

The PR 8 (Francis (5)) and WS (Smith, Andrewes, and Laidlaw (6)) strains of the human influenza virus were used in our experiments. No diflqculty was encountered in establishing either strain in swine 6 to 14 weeks of age. Older or younger animals were not tried. All animals were inoculated intranasally using the same methods employed in earlier studies of swine influenza (7, 8). The instillations were made with a Luer syringe without needle by pressing the tip of the syringe into the external nares. It was not necessary to anesthetize swine in order to induce infection with human influenza virus alone, although animals infected under ether narcosis exhibited somewhat more extensive pulmonary lesions at autopsy than those inoculated without anesthetic.

The WS virus was transferred 2, and the PR 8 virus 5, serial passages in swine before the experiments were discontinued. 10 per cent suspensions of infected mouse lung (5, 9) in physiological saline served as the source of virus for the first swine inoculation in each of the passage series and, after the first swine passage, similar suspensions of infected swine lung were used to inoculate swine of subsequent passages. 6.5 cc. of virus suspension was administered to each animal.

The disease produced in swine by human influenza virus was clinically very mild and, apart from a transient and indefinite malaise, no constant symptoms

were observed. It was sometimes difficult to be certain on antemortem examination that the animals had actually been infected. In most cases there was no significant elevation in temperature though a few had fever on the afternoon of the day following inoculation. 4 animals were kept under observation for 3 weeks or longer and made uneventful recoveries. 8 others were killed either by stunning and bleeding or by chloroforming on the 3rd or 4th day after inoculation and these exhibited the following picture at autopsy. There was a scattered, patchy, lobular atelectasis of one or more of the anterior lobes of the lung (Figs. 1 and 2). On cut section the involvement about the bronchi was seen to be more extensive than was apparent from the uncut surface. The involved lung was a reddish purple in color, beefy in appearance, felt rubbery, and was moist. A rather scant glassy tenacious mucous exudate could sometimes be pressed from the cut bronchi.

Histologically in involved areas of lung the alveolar walls were folded, greatly thickened, and infiltrated with large numbers of mononuclear cells (Figs. 3 and 4). Capillaries in the alveolar walls were dilated and packed with red blood cells. The partially collapsed alveoli themselves were either free of cells or contained at the most an occasional desquamated epithelial cell or a few lymphocytes. Polymorphonudear leucocytes were conspicuously absent. There was a pronounced perlbronchial round cell infiltration. The bronchial epithelium was, in places, fragmented and partially desquamated, and the cilia were either denuded or badly matted together. Some bronchi contained a scant, mixed lymphocytic and polymorphonuclear leucocytic exudate. Lymph channels in the interlobular septa were sometimes dilated and the septa themselves thickened and loosely infiltrated with mononuclear cells.

The trachea, bronchi, and lungs of swine infected with human influenza virus were in most instances bacteriologically sterile. The few animals from whose respiratory tracts organisms could be cultivated showed no evidence that their disease had been modified by the bacterial contaminant.

Influenza virus was demonstrated in the lung lesions of all passage swine by the inoculation of mice (5, 9). No evidence was obtained that serial transmission of the virus in swine modified its pathogenicity for mice. Also, the pathogenicity of the virus for swine appeared to remain constant through the number of serial passages to which it was submitted. It was of interest that the areas of swine lung that appeared free of lesions were also free of virus.

The symptoms and pathology observed in swine infected with human influenza virus were indistinguishable from those of the filtrate disease (10) produced in swine by the intranasal administration of swine influenza virus alone.

The Infection of Swine with Human Influenza Virus and H. influenzae suis

Sixteen swine have been inoculated intranasally with mixtures of human influenza virus and the bacterium, H. influensae suis (11). These animals were included in two serial passage experiments. One series, started with virus from infected ferret lung (6), was continued for 5 passages, and the other, initiated with virus from infected mouse lung, was carried through 3 passages in swine before being discontinued. 6.5 cc. of 10 per cent virus suspension to which had been added 0.5 co. of a 24 hour horse blood culture (11) 1 of H. influenzae suis, strain 18, was given intranasally to each animal. It was known from other experiments conducted at the same time as those under discussion that this culture of H. influenzae suis, in combination with swine influenza virus, was capable of producing characteristic influenza in swine (10).

In 11 of the 16 swine inoculated with mixtures of human influenza virus and H. influenzae suis the resulting illness was definitely more severe than that caused by the virus alone. This enhancement was evident both clinically and at postmortem examination. The temperature reactions were similar to those seen in swine influenza although nsuaHy the fever was less persistent. Seldom was it maintained for longer than 3 days, whereas 5 to 6 day fevers are not uncommon in swine influenza. Fever, while it lasted, was high, exceeding 41°C. on 1 or [...]

[...]

Summary

Swine inoculated intranasally with human influenza virus alone develop an ill defined, mild, and usually afebrile illness of short duration. At postmortem the anterior lobes of the lungs of such animals contain scant, scattered areas of lobular atelectasis. Transmission of the virus for 5 serial passages through two groups of swine

failed noticeably to enhance its pathogenicity for this species. The disease produced in swine by infection with human influenza virus alone is indistinguishable clinically and pathologically from that caused by infection with swine influenza virus alone. Transmission of human influenza virus from swine to swine by contact succeeded in only one of four attempts.

Swine inoculated intranasally with a mixture of human influenza virus and H. influenzae suis usually develop a febrile, depressing illness similar to mild swine influenza. The pneumonia encountered in such animals at autopsy is similar to but less extensive than that seen in swine influenza. In some animals H. influenzae suis fails to become established and the disease then seen is identical with that caused by human influenza virus alone.

The human influenza virus recovered after 5 serial transfers in swine was immunologically the same as that with which the experiments were begun.

• Born July 15, 1900 in Gas City, Indiana

• Died October 1, 1969 (aged 69), in Ann Arbor, Michigan

• Nationality United States

• Alma mater Yale University

• Known for development of vaccine against influenza virus A and B

• Awards : Medal of Freedom in 1946

• Scientific career Fields : virology, influenza research

• Institutions : University of Michigan

• Doctoral advisor : Francis Gilman Blake

• Doctoral students : [Dr. Jonas Edward Salk (born 1914)]

Thomas Francis Jr. (July 15, 1900 – October 1, 1969) was an American physician, virologist, and epidemiologist. Francis was the first person to isolate influenza virus in the United States, and in 1940 showed that there are other strains of influenza, and took part in the development of influenza vaccines.

Life

Francis grew up in New Castle in western Pennsylvania, graduated from New Castle High School in 1917 and Allegheny College on scholarship in 1921, and received his medical degree from Yale University in 1925. Afterwards he joined an elite research team at the Rockefeller Institute, first doing research on vaccines against bacterial pneumonia, later he took up influenza research. He became the first American to isolate human flu virus. From 1938 to 1941 he was professor of bacteriology and chair of the department of the New York University College of Medicine.

In 1941 he was appointed director of the Commission on Influenza of the Armed Forces Epidemiological Board (AFEB), a position which enabled him to take part in the successful development, field trial, and evaluation of protective influenza vaccines. Later that year Francis received an invitation from Henry F. Vaughan to join the newly established School of Public Health at the University of Michigan.

At the University of Michigan, Francis established a virus laboratory and a Department of Epidemiology that dealt with a broad range of infectious diseases. When [Dr. Jonas Edward Salk (born 1914)] came to that university in 1941 to pursue postgraduate work in virology, Francis was his mentor and taught him the methodology of vaccine development. During this time at the University of Michigan, Francis and Salk, along with other researchers, deliberately infected patients at several Michigan mental institutions with the influenza virus by spraying the virus into their nasal passages.^[2] Salk's work at Michigan ultimately led to his polio vaccine.

In 1947 Francis was awarded one of the first Michigan distinguished professorships, the Henry Sewall University Professor of Epidemiology. In addition to his work at the School of Public Health, Francis joined the pediatrics faculty at the University's Medical School.

As director of the University of Michigan Poliomyelitis Vaccine Evaluation Center, Francis designed and led an unprecedented $17.5 million nationwide field trial to test the vaccine. Conducted by a staff of more than 100 people from the University of Michigan, the year-long trial involved 1.8 million children in the U.S., Canada, and Finland and an enormous network of community volunteers. The results of the study were announced in Rackham Auditorium of the University of Michigan on April 12, 1955, and signaled an era of hope and success in combating infectious diseases and, more broadly, in the development of large-scale efforts for the good of society.

In 1933, Francis married Dorothy Packard Otton, and they had two children. He died in 1969 in Ann Arbor, Michigan.

Quotation (Francis on his work): "Epidemiology must constantly seek imaginative and ingenious teachers and scholars to create a new genre of medical ecologists who, with both the fine sensitivity of the scientific artist, and the broad perception of the community sculptor, can interpret the interplay of forces which result in disease."^[3]

Honors

• He was awarded the Medal of Freedom in 1946.

• He was honored with the Lasker Award in recognition of his distinguished contribution to the knowledge of influenza in 1947^[4]

• He was elected to the Polio Hall of Fame, which was dedicated in Warm Springs, Georgia in January 1958 in recognition of his polio research work.

• Posthumous recognition in 2005 by dedicating the Thomas Francis Jr. Medal in Global Public Health at Michigan^[5]

Further reading

• Lambert, SM; Markel, H (2000). "Making history: Thomas Francis, Jr, MD, and the 1954 Salk Poliomyelitis Vaccine Field Trial". Archives of Pediatrics & Adolescent Medicine. 154 (5): 512–7. doi:10.1001/archpedi.154.5.512. PMID 10807305.

• Smith, JS (1992). "Suspended judgment. Remembering the role of Thomas Francis, Jr. In the design of the 1954 Salk Vaccine Trial". Controlled Clinical Trials. 13 (3): 181–4. doi:10.1016/0197-2456(92)90001-G. PMID 1320555.

• Paul, JR (1974). "Thomas Francis, Jr". Biographical Memoirs of the National Academy of Sciences. 44: 57–110. PMID 11615644.

• Salk, J (1970). "The restless spirit of Thomas Francis, Jr., still lives: the unsolved problems of recurrent influenza epidemics". Archives of Environmental Health. 21 (3): 273–5. doi:10.1080/00039896.1970.10667238. PMID 4926858.

• Griffin, HE (1970). "Thomas Francis, Jr., MD: epidemiologist to the military". Archives of Environmental Health. 21 (3): 252–5. doi:10.1080/00039896.1970.10667234. PMID 4926854.

• Paul, J (1970). "Thomas Francis, Jr., MD, as a clinician--1900-1969". Archives of Environmental Health. 21 (3): 247–51. doi:10.1080/00039896.1970.10667233. PMID 4926853.

• Wegman, Myron E. (1970). "Thomas Francis, Jr.: an appreciation". Archives of Environmental Health. 21 (3): 230–6. doi:10.1080/00039896.1970.10667230. PMID 4926851.

• Macleod, CM (1970). "Thomas Francis, Jr., MD, 1900-1969". Archives of Environmental Health. 21 (3): 226–9. doi:10.1080/00039896.1970.10667229. PMID 4926850.

• "Infectious Diseases Society of America Bristol Award for distinguished achievement in the field of infectious diseases awarded to Thomas Francis, Jr., M.D. At the seventh meeting of the Society in Washington, D.C., October 25, 1969". The Journal of Infectious Diseases. 121 (2): 240–1. 1970. doi:10.1093/infdis/121.2.240. PMID 4905649.

• Mcdermott, W (1970). "Thomas Francis, Jr., 1900-1969". Transactions of the Association of American Physicians. 83: 16–8. PMID 4927289.

Publications

• Experimental septicemia; a method for its production in dogs Yale University (1925) OCLC 42288247 (M.D. Thesis)

• PubMed listed papers

References

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This article includes a list of general references, but it remains largely unverified because it lacks sufficient corresponding inline citations. Please help to improve this article by introducing more precise citations. (September 2009) (Learn how and when to remove this template message)

• ^ Furman, Bess (January 3, 1958). "New Hall of Fame Hails Polio Fight". The New York Times. Retrieved April 8, 2020.

• ^ Meiklejohn, Gordon N., M.D. "Commission on Influenza." in Histories' of the Commissions Ed. Theodore E. Woodward, M.D., The Armed Forces Epidemiological Board, 1994

• ^ "Thomas Francis, Jr., MD". University of Michigan. Archived from the original on May 15, 2009. Retrieved September 26, 2009.

• ^ "Award description". Lasker Foundation. Retrieved September 26, 2009.

• ^ "About the Medal". University of Michigan. Retrieved December 28, 2015.