From the results of the experiments presented it is evident that in guinea pigs an early administration of immune rabbit serum will suppress the infection; that is, if it is given within the period of incubation, the effect being proportionately greater the earlier the serum is administered. Almost no beneficial effect is observed when the serum is given after the onset of the disease. In the animals inoculated with 10 to 100 M.L.D. the incubation period is shorter than when 1 M.L.D. is injected; nevertheless 1 cc. of the immune serum saved the animals as late as 96 hours from the time of the introduction of the virus into the system. When administered within 24 hours in the case of 100 M.L.D. and within 48 hours in the case of 10 M.L.D., the serum completely neutralized the virus, and the animals escaped infection altogether. On the other hand, the same quantity of the serum only modified the infection into a non-fatal one when given a day or two later. In the animals which were inoculated with 1 M.L.D. the incubation period was a day or two longer, and the neutralizing effect of the serum was much more powerful. Here animals were saved as late as 5, 6, and 7 days and with a much smaller quantity of the serum (0.1 cc.).
As to the usefulness of such an immune serum in human cases, the relative susceptibility of man and the guinea pig must first be considered. In a large number of experimental infections carried out with guinea pigs in the past 6 years almost never has a naturally refractory animal been encountered. The mortality is nearly 80 per cent with most strains, although as low as 50 per cent with some. The strain used in the present study caused death in nearly 80 per cent of the animals. Hence the susceptibility of guinea pigs is at least as great as that of man, in whom the mortality in the Bitter Root Valley is estimated to be about 70 per cent.
The relative length of the incubation period in guinea pig and in man is another point which requires analysis. In guinea pigs it varies somewhat according to the number of passages, being as short as 3 days when 100 M.L.D. or more of an adapted virus are inoculated. On the other hand, when the infection is the result of 1 M.L.D. or the bite of an infected tick, the incubation period is much longer, being 5, 6, or 7 days in the former and 7 to 8½ days in the latter instance, as with the present strain. In man the infection is brought on by the bite of an infected tick, and the period of incubation varies from 3 to 10 days but is usually 7 days; i.e., it is about the same as in guinea pigs infected with 1 M.L.D. Hence we may regard the susceptibility of man and the guinea pig as nearly equal.
The final point to be considered is the quantity of the immune serum that may be recommended for use in human cases. To prevent the infection in a guinea pig weighing 500 gm., 0.1 cc. of the serum was sufficient. This quantity protected the animal against 1 M.L.D. even as late as 5, 6, or 7 days. Calculated on this basis, 16 cc. of the serum would be required for a man weighing 80 kilos (about 160 pounds); that is, 16 cc. of an immune rabbit serum, administered before onset of the disease, should theoretically be sufficient to save a man of average weight against an infection brought about by the bite of an infected tick or by a laboratory accident. It would probably be best to administer the serum intravenously. The titer of the immune serum should be previously determined in guinea pigs, and 1 cc. should neutralize 100 M.L.D. completely and 0.1 and 0.01 cc. render the infection non-fatal. Such a serum is easily produced in rabbits (a rabbit weighing 2,500 gm. will yield 50 to 60 cc. of the serum) and probably will remain active a year or longer when kept at refrigerator temperature.
ETIOLOGY OF YELLOW FEVER