野口英世著

Journal of Experimental Medicine

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E T I O L O G Y OF Y E L L O W FEVER.
V.

PROPERTIES OF BLOOD S E R U M OF YELLOW FEVER PATIENTS IN
PxELATION TO LEPTOSPIRA ICTEROIDES.
BY HIDEYO NOGUCHI, M.D.

(From the Laboratories o/ The Rockefeller Institute for Medical Research.)(Received for publication, May 2, 1919.)
Following the isolation of Leptospira icteroides from a case ofyellow fever a series of experiments was instituted with a view toestablishing the relation between the organism and the disease. As
stated elsewhere, 1 the organism reproduces in experimental animals
all the symptoms and lesions observed in man. From the standpoint of immunity the question arose whether or not the serum ofyellow fever convalescents would have a specific influence upon theorganism.
Blood was drawn from the median basilic vein of the patient andthe serum mixed with Leptospira icteroides in the form of organ
emulsion from infected guinea pigs or culture and injected into theperitoneal cavity of a normal guinea pig. After a period of 30 minutes to 1 hour the fluid was drawn from the peritoneal cavity bymeans of a sterile capillary pipette and examined under the darkfield microscope (Pfeiffer's phenomenon). The animals were allowed
to live until the results of the inoculations were evident. As
Table I shows, in some of the experiments, in which the amount of theinfectious emulsion or culture used was too large, no certain protection of the animal from the final fatal infection was obtained with theserum of convalescents, notwithstanding the fact that such serum
produced a definite Pfeiffer phenomenon in the peritoneal cavity.
When a smaller quantity of the infecting material was used in combination with convalescent serum most of the animals were saved,
while the controls with serum from patients not suffering from
1Noguchi, H., J. Exp. Med., 1919, xxix, 585.
9

10ETIOLOGY OF YELLOW FEVER.

V

TABLE I.
Effect of S e r u m f r o m Yellow Fever P a t i e n t s u p o n L e p t o s p i r a icteroides.

Case No.

[ Sex. ]Age.[Severity of infection.

Result.

299 ill ild ec°vered

Died in 8 days.
Survived.

23
1914Control.

""~ccc23 Severe.
21 Malaria.

~c"

Died in 7 days.,~¢gg

711Severeecove,ed

129F.
M.

gc

Died in 6 days.
"~c84

Severe. Recovered.
Mild.
Severe.
Mild.
Moderate.

""

Mild.

"~c"

c¢

Severe.
Moderate,"(also malaria).
Mild.

Recovered.

stSurvived.

""
Diagnosis (?). Recovered.

Control.

16
26
29
1930
31
23
32
33
820

~g 720th
22nd
15th
7th
14th
13th

12th

<~-b" 10"All these serewereseparated
fromthe clot in 48
hrs. and thenkept on ice for
2 to 4 wks.
when
theyweretested.
The negative
results
withthe sere ofCases 26 and29 may be due
to deterioration throughage.

HIDEYO NOGUCHI

11

yellow fever, and with saline solution died with the typicalsymptoms.
The mtmber of cases studied (eighteen) was limited, owing to thepressure of more urgent problems under investigation at the sametime. I t seems, however, to have been sufficient to establish thespecific reaction which exists between Leptospira icteroides and theserum of yellow fever convalescents (fifteen positive, 83 per cent).
In the case of one patient the serum did riot have any effect upon
the organism when tested on the 2nd day of the illness but wasprotective on the 10th day.
Sera from malarial patients in no case showed any action antagonistic to Leptospira icteroides. The malarial patients were all
mountaineers and consequently non-immune to yellow fever. The
negative results obtained with sera derived from doubtful cases ofyellow fever, all so mild as to make it difficult to recognize the disease, might have been due to the absence of antibodies, or, if there
were any, to the fact that they were too weak to produce a definite
reaction under the experimental conditions, or, a not impossible
assumption, to the existence of a variation among many strains.
As will be described later, ten normal sera from healthy, non-immune
soldiers2 were also examined before the vaccination of the latterwith killed cultures of Leptospira icteroides, but none of them had
any effect upon the organism.
SUMMARY.

The serum from a number of persons recovering from yellow feverin Guayaquil was s.tudied with a view to establishing its possible
immunological relationship with a strain of Leptospira icteroi~es derived from one of the yellow fever patients. For this purpose theserum of convalescents was mixed either with an organ emulsion ofa passage strain, or with a culture of the organism, and inoculated
intraperitoneaily into gtfinea pigs.
I am indebted for these specimens to Dr. Carlos A. Mifio, Assistant Directorof the Department of Health at Quito, to Dr. E. Salgado V., also of the Department of Health, and to Dr. Victor M. Bayas, Surgeon of the "Bolivar"Regiment.

12E T I O L O G Y OF Y E L L O W

FEVER.

VThe Pfeiffer reaction was first studied, and then the animals wereallowed to live until the controls, inoculated with the same emulsion or culture of Leptospira icteroides but without the serum, orwith serum from patients suffering from other diseases than yellow
fever, had died of the experimental infection with typical symptoms
A positive Pfeiffer phenomenon was observed in fifteen of the eighteen
convalescent cases studied, or approximately 83 per cent. Sera
from ten non-immune soldiers and from two malaria patients gave
uniformly negative results. Protection from an ultimate fatal infection was afforded some of the guinea pigs which received theserum of yellow fever convalescents, while the control animals
succumbed to the infection with typical symptoms. In one instance,
in which the serum was tested on the 2nd and the 10th days of disease, a Pfeiffer reaction was demonstrated, as well as protective
property against the infection, in the specimen from the 10th but
not in that from the 2nd day.
From the foregoing observations of immunity reactions it appears
highly probable that Leptospira icteroides is etiologically related toyellow fever.