野口英世著

Journal of Experimental Medicine

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ETIOLOGY OF YELLOW FEVER.
IV.

THE ACQUIRED Im~ltrNITY oF GIYIN'EA PIGS AGAINST LEPTOSPIRA ICTE1ROIDES AFTER THE INOCULATION OF BLOOD
OF YELLOW FEVER PATIENTS.
BY HIDEYO NOGUCHI, M.D.

(From the Laboratories of The Rockefeller Institute for Medical Research.)(Received for publication, May 2, 1919.)
Most of the attempts to transmit yellow fever by inoculating theblood of patients into various animals have ended in failure. As
stated elsewhere1 out of 74 guinea pigs, in only eigtlt were the results
positive, and in other species of animals they were all negative. I tshould be emphasized that for the purpose of transmission cases wereselected which were still in the early stage of the disease, previous
investigators having pointed out the fact that the virus may nolonger exist in the peripheral blood after the 3rd day of the illness.
In the present study the guinea pigs which failed to manifest thetypical symptoms, or any symptoms at all, were kept under daily observation for many weeks. On a later date, througl~ temporary
shortage of normal guinea pigs, they were inoculated, together withseveral normal guinea pigs, with a virulent organ emulsion, rich in
the leptospira, from a guinea pig experimentally infected with theorganism, in order to prepare a large amount of organ emulsion for thepurpose of immunizing two donkeys against the virus. A great
many of the guinea pigs remained perfectly well, while most of thenormal animals, as well as those which had been previously inoculated with the blood of malarial patients, ~ came down with an experimental infection.
1Nognchi, H., J. Exp. ]fled., 1919, xxix, 565.
2 In a country where a~stivo-autumnal parasites infest the population manytimes a malarial patient is brought to the Yellow Fever Hospital on thechance that the case is one of early yellow fever. All these cases were used forthe experiments on the transmissionof yellowfever without the loss of time which
would have been caused by waiting for a diagnosis, for which a day or two might
be required.

ETIOLOGY OF Y E L L O W FEVEI~.

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6~ T I O L O G Y OF Y E L L O W]~'F.V~R.

IV

Apparently some of the guinea pigs previously inoculated with theblood from yellow fever cases were refractory to the subsequent inoculation with a known virulent organ emulsion. As shown in Table I,
those which resisted the infection were found to have had a febrilereaction of varying degree and duration on about the 5th day after
the injection of the blood. This. seemingly unimportant fever reaction must have been tl~e result of a very mild abortive infection totally unsuspected on account of the absence of the main symptom, thejaundice. This fact is proved, in m y opinion, by the acquired resistance of an animal which, when a sufficient quantity of a passage
strain of Leptospira icteroides is introduced, is so susceptible. Thereis reason to believe that the strains of Leptospira icteroides as theyoccur in man are on the whole less virulent to the guinea pig and areincapable of producing a fatal infection from the beginning except inrare instances. It may be recalled here that with one strain (Case 2)
the organism did not become thoroughly adapted to the guinea pig
until it had been passed through three generations in this animal. ~A complete, or nearly complete refractoriness or resistance to
Leptospira icteroides was demonstrated in sixteen guinea pigs previously inoculated with the blood of yellow fever patients, representing nine out of fourteen cases of yellow fever. Four out of six guineapigs injected with the blood of two other.yellow fever patients died,and two survived. In this group the protection was present in someof the guinea pigs only. In a doubtful case one of the two guinea pigs
resisted a subsequent infection. On the other hand, of six guinea pigs,
which received the blood of three patients, all died with the typicalsymptoms and lesions when tested later with a virulent passage strainof Leptospira icteroides. Of ten, which received injections of bloodfrom four malarial patients, all proved to be susceptible to a later
inoculation with the same strain of Leptospira icteroides that wasused in the foregoing experiments.
Of the guinea pigs representing the yellow fever group, those which
had had a febrile reaction several days after the injection of theblood are the ones which acquired the immunity against the inoculation of Leptospira icteroides. There seems to exist some relation
between the febrile reaction and the acquired immunity. In several
instances, moreover, these guinea pigs showed a suspicious trace ofI~IDEYO NOGUCItI

7

jaundice in the scleras some time after the height of fever had passed,
but the disease had failed to advance further. If the animals had
been killed at the proper time and transfers made to normal guinea
pigs the virulence of the causative orgarfism might have been gradually increased to reproduce the disease more completely in later
passages. As a matter of fact it was possible to accomplish this in
one instance (Case 2).
The injection of blood from some cases of typical yellow fever into
guinea pigs caused a rise of temperature in about 5 days similar tothat of other cases, and there was even a suspicion of a trace oficterus in the scleras, yet no protection against a later infection witha passage strain of Leptospira icteroides (Case 1) could be demonstrated. Perhaps this lack of protection may be explained byassuming the strain variations among different strains of the leptospira.
Another point of interest brought out in this series is that the injection of organ emulsions obtained from fresh postmortem material(Case 27) conferred upon guinea pigs sufficient protection against a
subsequent infection to prevent its being fatal, although these animals showed fever and jaundice. It is possible that the emulsion
contained a certain amount of the antigen and produced a mildimmunity, or a limited amount of the immune bodies.
SLTMMARY.

The majority of guinea pigs inoculated with the blood of yellow
fever patients escaped a fatal infection.
There were a number of instances in which the inoculation ofyellow fever blood induced in these animals a temporary febrile reaction on the 4th or 5th day, followed in some cases by slight jaundice, but with a rapid return to normal. Most of these guinea
pigs when later inoculated with an organ emulsion of a passage strainof Leptospira icteroides resisted the infection. On the other hand,the animals which had previously been inoculated with the blood ofmalaria patients or normal guinea pigs died of the typical experimental infection after being inoculated with the infectious organemulsion.

8ETIOLOGY OF YELLOW FEVER.

IVIt appears from the results just described that a number of nonfatal, mild, or abortive infections follow the inoculation of bloodof yellow fever patients into guinea pigs. The fact that such animals manifested refractoriness to a subsequent attempt to infectwith a highly virulent passage strain of Leptospira icteroides is anindication, judging from the reciprocal immunity reaction, that they
actually passed through an infection with the same organism, or astrain closely related to it, as that which was used for the second
infection experiment