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The relation between dengue and rift valley fever
157 TRANSACTIONS OF THE ROYAL SOCIETY OF TROPICAL MEDICINE AND HYGIENE.
Vol. X X V I .
No. 2. August, 1932.
T H E R E L A T I O N B E T W E E N D E N G U E A N D R I F T VALLEY FEVER. BY
G. 3I. F I N D L A Y , Wellcome Bureau of Scientific R~search, London.
In a recent communication DINGER and SNIJDERS(1931) showed that monkeys which have recovered from dengue are subsequently immune to infection with yellow fever though immune dengue serum has no virieidal action on the virus of yellow fever. To the immunity against yellow fever conferred by dengue is due, it is suggested, the fact that epidemics of yellow fever have not been recorded in the Dutch East Indies. The similarity of Rift Valley fever to both dengue and yellow fever made it possible that this disease might also immunize against either yellow fever or dengue. Experiments recorded by FINDLAY and DAUBNEY (1931) and by FINDLAY (1932) showed, however, that monkeys which had recovered from yellow fever were as susceptible to Rift Valley fever as control monkeys while human immune yellow fever serum had no viricidal action on the virus of Rift Valley fever. FINDLAY (1932) also found that the serum of a patient recovered from dengue had no viricidal action on the Rift Valley fever virus. Nevertheless it appeared to be of interest to determine whether monkeys which had actually suffered from dengue were immune to Rift Valley fever or vice versa. Through the kindness of Professor SNIJDERSand Professor HOFFMANN of Amsterdam, to whom my most sincere thanks are due, it was possible to examine this question, since they generously placed at my disposal supplies of active dengue virus in the form of dried human serum from a patient with dengue. Unfortunately although monkeys are susceptible to dengue the disease is, as a rule, " inapparent " and is unaccompanied by fever or by any other sign of illness except occasionally a leucopenia appearing on the fifth or sixth day after injection and involving especially the polymorphonuclear leucocytes. In addition, as BLANC, CAMINOPETROS,DUMAS and SAENZ (1929) have pointed out, dengue cannot be transmitted by passage from monkey to monkey as is the case with yellow fever and Rift Valley fever, though blood from the monkey with dengue is infectious for man. A study of dengue fever virus thus necessitates the employment of human volunteers. Such volunteers were,
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T H E R E L A T I O N B E T W E E N D E N G U E AND R I F T VALLEY FEVER.
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however, forthcoming through the kindness of Dr. G. CARMICHAEL LOW, Dr. N. HAMILTON FAIRLEY and Dr. C. C. WORSTER-DROUCHTto whom I owe a debt of gratitude since they made it possible for cases of cerebrospinal syphilis to be inoculated with dengue virus as an alternative to malaria therapy. Unfortunately the first patient inoculated with the equivalent of 1 c.c. of human serum containing active dengue virus failed to show any rise in temperature, though on the sixth day after injection there was a fall in the total leucocyte count from 10,000 to 5,000 per c.mm. Blood removed on this day and injected into Volunteer 2 failed to produce any reaction whatsoever. A further supply of active dengue serum having been obtained, Volunteer 3 received an injection of 0.5 c.c. while a similar amount was injected subcutaneously into a normal monkey (Silenus rhesus = Jl~lacacus rhesus). The patient reacted on the fifth day after injection with fever, which lasted three days and was followed by a further attack of fever on the twelfth day. The monkey showed no significant rise of temperature, but on the sixth day' there developed a leucopenia involving especially the polymorphonuclear leucocytes as shown in the Table. Fourteen days after the first injection Monkey 1 received 0.5 c.c. of the serum of Volunteer 3 which had been dried and kept in vacuo at 0 ° C. This injection gave rise neither to fever nor leucopenia. Two other normal rhesus monkeys, Nos. 2 and 3, were also inoculated with the serum of Volunteer 3; no fever or other reaction occurred though No. 2 exhibited a slight leucopenia. Blood was removed from Monkey 3 on the seventh day after inoculation and 0.5 c.c. of its blood was injected into Volunteer 4 who began a febrile reaction on the fifth day following the injection. His blood on that day was injected into Monkeys 2 and 3 fourteen days after their first injection ; no temperature or leucopenia followed. Each of these three monkeys thus received two injections of dengue virus at intervals of fourteen days. Three weeks after the second injection all three monkeys received 0.5 c.c. of blood from mice which had died from Rift Valley fever. Monkey 1 showed a rise of temperature thirty-six hours, Monkevs 2 and 3, forty-eight hours after injection. Blood from these three monkeys removed on the first day of fever was injected into mice which all died within seventy-two hours of injection with the pathological changes characteristic of Rift Valley fever. Previous infection with dengue virus had therefore no effect in preventing the development of Rift Vallev fever in rhesus monkeys. In order to determine whether previous infection with Rift Valley fever had any effect on subsequent infection with dengue virus, three rhesus monkeys which had suffered from Rift Valley fever six months previously were employed. To test their immunity to Rift Valley fever, they were each first injected with 0.5 c.c. of blood from mice which had died from Rift Valley fever, _No fever or other reaction occurred. Fourteen days later each monkey received ().5 c.c. of serum from Volunteer 3. No fever occurred but, as in the other monkeys inoculated with dengue virus, a leucopenia occurred in two of the monkevs
160
THE RELATION BETWEEN DENGUE AND RIFT VALLEY FEVER,
on the fifth, sixth and seventh days after injection. Blood was removed from these three monkeys on the sixth day after inoculation. Volunteer 5 was injected subcutaneously with 1 c.c. of blood from the monkey which had failed to show any leueopenia. Four and a half days after his inoculation he began a febrile reaction which lasted for three days. Blood was removed on the first day of fever and ten mice were injected subcutaneously with 0.5 c.c. of the blood. These mice remained in good health ; ten days after their injection with dengue virus they each received (1.5 c.c. of blood from mice which had died from Rift Valley fever. Five normal mice were similarly injected as controls. All the mice died within ninety-six hours of their inoculation with the pathological appearances characteristic of Rift Valley fever. These experiments show that in rhesus monkeys immunity to Rift Valley fever does not prevent the appearance of dengue virus in the blood six days after inoculation, nor in mice does the previous injection of dengue virus prevent or delay death from Rift Valley fever. CONCLUSIONS.
Rhesus monkeys immunized against dengue were not immune to Rift Valley fever, nor were monkeys immunized against Rift Valley fever subsequently immune to dengue. Mice injected with dengue virus were not immune to Rift Valley fever virus. REFERENCES. BLANC, G., CAMINOPETROS,J., DUMAS,J., ~ SAENZ,A. (1929). Compt. rend. de l'Acad. des Sci., clxxxviii, 468. DINCER, J. E., & SNIJDEttS, E.P. (1931). Xrch.f. Schiffs- ~. Trop.-Hyg., xxxv, 497. F1NDLAY, G . M . (1932). Trans. Roy. Soc. Trop. Med. ~ [t3'g., xxv, 229. FINDLAY, G. M., & DAUBNEY,R. (1931). Lancet, ii, 1350.
Vol. X X V I .
No. 2. August, 1932.
T H E R E L A T I O N B E T W E E N D E N G U E A N D R I F T VALLEY FEVER. BY
G. 3I. F I N D L A Y , Wellcome Bureau of Scientific R~search, London.
In a recent communication DINGER and SNIJDERS(1931) showed that monkeys which have recovered from dengue are subsequently immune to infection with yellow fever though immune dengue serum has no virieidal action on the virus of yellow fever. To the immunity against yellow fever conferred by dengue is due, it is suggested, the fact that epidemics of yellow fever have not been recorded in the Dutch East Indies. The similarity of Rift Valley fever to both dengue and yellow fever made it possible that this disease might also immunize against either yellow fever or dengue. Experiments recorded by FINDLAY and DAUBNEY (1931) and by FINDLAY (1932) showed, however, that monkeys which had recovered from yellow fever were as susceptible to Rift Valley fever as control monkeys while human immune yellow fever serum had no viricidal action on the virus of Rift Valley fever. FINDLAY (1932) also found that the serum of a patient recovered from dengue had no viricidal action on the Rift Valley fever virus. Nevertheless it appeared to be of interest to determine whether monkeys which had actually suffered from dengue were immune to Rift Valley fever or vice versa. Through the kindness of Professor SNIJDERSand Professor HOFFMANN of Amsterdam, to whom my most sincere thanks are due, it was possible to examine this question, since they generously placed at my disposal supplies of active dengue virus in the form of dried human serum from a patient with dengue. Unfortunately although monkeys are susceptible to dengue the disease is, as a rule, " inapparent " and is unaccompanied by fever or by any other sign of illness except occasionally a leucopenia appearing on the fifth or sixth day after injection and involving especially the polymorphonuclear leucocytes. In addition, as BLANC, CAMINOPETROS,DUMAS and SAENZ (1929) have pointed out, dengue cannot be transmitted by passage from monkey to monkey as is the case with yellow fever and Rift Valley fever, though blood from the monkey with dengue is infectious for man. A study of dengue fever virus thus necessitates the employment of human volunteers. Such volunteers were,
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159
however, forthcoming through the kindness of Dr. G. CARMICHAEL LOW, Dr. N. HAMILTON FAIRLEY and Dr. C. C. WORSTER-DROUCHTto whom I owe a debt of gratitude since they made it possible for cases of cerebrospinal syphilis to be inoculated with dengue virus as an alternative to malaria therapy. Unfortunately the first patient inoculated with the equivalent of 1 c.c. of human serum containing active dengue virus failed to show any rise in temperature, though on the sixth day after injection there was a fall in the total leucocyte count from 10,000 to 5,000 per c.mm. Blood removed on this day and injected into Volunteer 2 failed to produce any reaction whatsoever. A further supply of active dengue serum having been obtained, Volunteer 3 received an injection of 0.5 c.c. while a similar amount was injected subcutaneously into a normal monkey (Silenus rhesus = Jl~lacacus rhesus). The patient reacted on the fifth day after injection with fever, which lasted three days and was followed by a further attack of fever on the twelfth day. The monkey showed no significant rise of temperature, but on the sixth day' there developed a leucopenia involving especially the polymorphonuclear leucocytes as shown in the Table. Fourteen days after the first injection Monkey 1 received 0.5 c.c. of the serum of Volunteer 3 which had been dried and kept in vacuo at 0 ° C. This injection gave rise neither to fever nor leucopenia. Two other normal rhesus monkeys, Nos. 2 and 3, were also inoculated with the serum of Volunteer 3; no fever or other reaction occurred though No. 2 exhibited a slight leucopenia. Blood was removed from Monkey 3 on the seventh day after inoculation and 0.5 c.c. of its blood was injected into Volunteer 4 who began a febrile reaction on the fifth day following the injection. His blood on that day was injected into Monkeys 2 and 3 fourteen days after their first injection ; no temperature or leucopenia followed. Each of these three monkeys thus received two injections of dengue virus at intervals of fourteen days. Three weeks after the second injection all three monkeys received 0.5 c.c. of blood from mice which had died from Rift Valley fever. Monkey 1 showed a rise of temperature thirty-six hours, Monkevs 2 and 3, forty-eight hours after injection. Blood from these three monkeys removed on the first day of fever was injected into mice which all died within seventy-two hours of injection with the pathological changes characteristic of Rift Valley fever. Previous infection with dengue virus had therefore no effect in preventing the development of Rift Vallev fever in rhesus monkeys. In order to determine whether previous infection with Rift Valley fever had any effect on subsequent infection with dengue virus, three rhesus monkeys which had suffered from Rift Valley fever six months previously were employed. To test their immunity to Rift Valley fever, they were each first injected with 0.5 c.c. of blood from mice which had died from Rift Valley fever, _No fever or other reaction occurred. Fourteen days later each monkey received ().5 c.c. of serum from Volunteer 3. No fever occurred but, as in the other monkeys inoculated with dengue virus, a leucopenia occurred in two of the monkevs
160
THE RELATION BETWEEN DENGUE AND RIFT VALLEY FEVER,
on the fifth, sixth and seventh days after injection. Blood was removed from these three monkeys on the sixth day after inoculation. Volunteer 5 was injected subcutaneously with 1 c.c. of blood from the monkey which had failed to show any leueopenia. Four and a half days after his inoculation he began a febrile reaction which lasted for three days. Blood was removed on the first day of fever and ten mice were injected subcutaneously with 0.5 c.c. of the blood. These mice remained in good health ; ten days after their injection with dengue virus they each received (1.5 c.c. of blood from mice which had died from Rift Valley fever. Five normal mice were similarly injected as controls. All the mice died within ninety-six hours of their inoculation with the pathological appearances characteristic of Rift Valley fever. These experiments show that in rhesus monkeys immunity to Rift Valley fever does not prevent the appearance of dengue virus in the blood six days after inoculation, nor in mice does the previous injection of dengue virus prevent or delay death from Rift Valley fever. CONCLUSIONS.
Rhesus monkeys immunized against dengue were not immune to Rift Valley fever, nor were monkeys immunized against Rift Valley fever subsequently immune to dengue. Mice injected with dengue virus were not immune to Rift Valley fever virus. REFERENCES. BLANC, G., CAMINOPETROS,J., DUMAS,J., ~ SAENZ,A. (1929). Compt. rend. de l'Acad. des Sci., clxxxviii, 468. DINCER, J. E., & SNIJDEttS, E.P. (1931). Xrch.f. Schiffs- ~. Trop.-Hyg., xxxv, 497. F1NDLAY, G . M . (1932). Trans. Roy. Soc. Trop. Med. ~ [t3'g., xxv, 229. FINDLAY, G. M., & DAUBNEY,R. (1931). Lancet, ii, 1350.