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3 to- 4 8o 0C!S ARMY MEDCAL RESEARCH LABORATORY

REPORT NO. 594

ACTIVEi IIMUNIZATICH OF A HUMAN AGAINSTNAJA I4AA VENOM

C.) A Prelliminay Report

I~Copt Herschel H. Flowers. VC

II

,,,, ,,,,....

SEULAEIO * SEW•LOPINT WUUAA 12 Nov'ember 14•3

COOT

Report Suabmitted S September 1963

Author

Capt Herschel H. Flowers. VC Pathology Division(OVU)

The animals used in Ihis study were handled in accordance with the"Principles of Laboratory Animal Cars" established by the NationalSociety for Medical Research.

Omal~ifod requesters may obtain copies of this report from DDC.

Foreign amoumee~meat and dissemination of this report by DDCis liMUted

| III

RUPORT NO. 5S4

ACTIVE IMMUNIZ.T3N OF A HUMAN AGAINSTNAJA NAJA VENOM

A Preliminary Report

Cape Herschel H. Flowers. VC

Pathology DivisionUS ARMY MEDiCAL RESEARCH LABORATORY

Fort Knox, Kentucky

II November 1963

In-House Laboratory Initiated Research and DevelopmentDA Project No. 3A013001A814

USAWRL Report No. 394

DA Project No. 3A01 3001AG14

ABSTRACT

ACTIVE IMMUNIZATION or A HUMAN AGAINST

NAJA NAJA VENOM

A Preliminary Report

OBJECT

To determine whether or not a human subject could be immunizedagainst the bite of the Indian cobra (NJi aja . To study the develop-ment and titer of neutralising antibodies produced. To determine anypathological conditions produced by the injections during the course of

immunization.

RESULTS

Tests demonstrated the theoretical neutralization potential of thesubject's circulating globulin to be approximately 100 mug Naja r.&J.venom. Examination of the subject during and after the course of theimmunization schedule revealed development of no pathological con-ditions.

CONC LUSIONdS

Using venomis with little or no local toxicity, it appears that man

may be safely immunized.

APPROVE-MFRED D.-AURE&RColonel. VCDirector, Pathology Division

APPROVED-SVEN A. BACHColonel, MCDirector

ACTIVE IMMUNIZATION OF A HUMAN AGAINSTNAJA NAJA VENOM

A Preliminary Report

Because of the complexity of venom proteins and their greatlocal and systemic effects, active immunization has been confined toanimals utilized in the production of commercial antivenins. In this&tudy the feasibility of a safe and practical method of immunization ofman against snakebite has been explored.

Parrish and Pollard (f) found that immunity against the effectof snakebite did not exist among 14 human subjects, each of whom hadbeen bitten two or more times by Crotalid snakes. However, the de-velopment of a persistent immunity might not be anticipated in thisgroup because envenomation occurred from ,-year to 14-year inter-vals, and the members of the group were also treated with antiveninsfollowing snakebite. The first observation of active immunizationagainst snakebite was reported by Haast and Winer (Z). A subject(human) was given repeated injections of crude cobra venom over aperiod of Z-I/Z years. A maximal irjection oi 40 mg of venom wastolerated, and this quantity of venom is lethal in the absence of im-munity. Immunological tests were not performed with the serum orglobulin to determine the degree of protection afforded by these in-jections, but the 40 mg immunizing dose of venom he tolerated issignificant.

Wiener (3) described in one human subject the titer rise andpersistence effected by repeated .je,,tions of Australian Tiger Snakevenom. This subject survived the bite of a snake of this species withlittle difficulty subsequent to his immunization.

In this laboratory, in an attempt to measure the development ofneutralizing antibodies, a human subject was given 17 injections con-taining increiasing amounts of Indian cobra (Naja nasa) venom. Venomsolutions were passed through a mill.pore filter and then added to anequal volume of a 4% Sodiunm Alsinate adjuvant.* The 17 injectionswere given over a period of S months (Fig. i). Ten ml of blood waswithdrawn from the subject after the 4th. 7th, and 10th injections.Five hundred ml of blood was withdrawn after the I1th injection, and

eIodium Alignate Adjivant, Colab Laboratories, Box 66. Chicago

Heights. Illinois.

•:: _

I liter afte- the 17th. Globulins were separated from serum by am-monium sulfate precipitation. and the antivenin titer was determinedby neutral.ation of Naja naJa venom in lb-ZO Gm Swiss mice. Iden-tical neutralization tests were conducted by a commercial laboratoryJFig. Z).

The results o1' this study show a development of active immuniza-tion against cobra venom. One ml of the globulin solution neutralized3( mouse LDr,0 * (. Z44 nig venom). Since it required 100 mnl of whole

biocad to produce I Gm of the crude globulin, it is estimated on a bloodvolume basis if-at -10 Gm are present in the subject's circulation. This..irculating glub-ialn alone therefore should neutralize a dose of 100 mngcobra venom. This calculation does not take into account the extra-vascular globulins present in the area of envenomation, which them-selves are capatt.e of venom neutralization.

The subject receiving r-ibra venom was Lnder observation by aphysician. Periodic Wlood and blood chemistry examinations were con-dticted to determine possible pathological conditions arising from theinjections. Examination of the subject during and after the injectionsindicated the absence of pathological response to the venom except forlocal swelling andi pain which persisted from I to 3 days in the aro.aof injection. fur a 2-week period after the I 'eth injection of ven-z-n.the subject 's blood pressure was elevated slightly.

The potential advantages cGf active immunization of man againaitenvenomation have been recognized for many years. The presence oflocally necrotizing enzymes in some venoms still presents a formidableobstacle. However, in venoms with little or no local toxicity it appearsthat man may be safely immunized.

ACKNOWLEDGEMENT

The author gratefully acknowledges Wyeth L~aboratories.Marietta. Pennsylvania. for their assistance ini neutralization test..descr~hed in this report.

REFERENCES

I. Parrish, Henry M. and C. B. Pollard. Effects ofrepeated poisonouis snakebites in man. Amer. 3.Med. Sci.. March 19S9. pp. 277-286.

Z. flaasr, William E. and Melvin L. Winer. Complete andspontaneous recovery from a bite of a blue krait snake

(Bungarus coeruleus). Amer. 3. Trop. Med. and Hyg.4: 1135, 1955.

3. Wiener. Saul. Active immunization of man against thevenom of the Australian Tiger Snake (Notechis scutatus).Med. 3. Australia. 1: 6S8. 1961.

3

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Norverd Unit. Medical Lib.rar. Sestoo. Mass..

Indieeo Unit. Hudicek Cooler Liborar. kodieempolk.. led.

Iedious Dolt. Set~ok of Hudieilmo UbreIT. 1loaeI891*0. 1ed.

Jefferson Madioek Cokioqo. Library. lhiled"kphio. Pt.

J6641 Hupkio Mmiv. 90106 Hudioel Librery. Hiltieoro. 0.

gmone state Mmiv. Depovtwwaot of Popebekeqp. flbettes. gern.

Loeo Lisd" Setw, Mite Smaerkel Modieel Librery. Lee Aeel,*t. Calif.

MEDICAL COLLEGE 'SCHOOL L133*HIES AND DEPTS Cost.

DISTUINUwsUU

*arqu.sto Ussy. Uedis.-.lDorntl Library. 1111tawb... I&*.

11"acel Collwoq of Vistqsio. Tornpksrne.UrCom Library. Nichb...d. Va..

H.. Vork Acod.., of Mpdscsrn Library. Now Yorb. N. V.

Me. Valk Urns.. Collegeof Medicirne. N...oorch Divisoed. Noe York. N. V.

loan Tech :.A*. College of Eaqr. Research D40tairia. Nee Tecb. H. Y.

X" other Usi.. Modsa1a Co~olr Library. Now Vorb. P. V.

11.:tb..efret Urns.. Dopart..rnt at Psychology. Eveatoto. 111.

Horth..oo,., Una.. 1m,46-o1 School Library. Chico"o. 111.

Ohso State V.A.. (b.essr. Abistract. service. Colernobu. Ohio

Ohio state Usiv. Esqr l:.persrn.t Stoties,. Syst... Research Croap. Ceirnabuf. Ohio.

Ohio SO*t. Us&.. Prnycholirnqrnattes Leobrdtsry. Columbus. Olson.

obs. Stat. Usiv. "se.arch Coolerg, Avietasor Pmyeboioqy Laboraorya. Coiarnbae. Ghte.

Ohio sltat Us&.. School of optesetry. Columbsoe. Ohio.

OhAo State Urns.. Tepaas Library. Colrno..rn. Ohio

Nerds. Urns,. D.Partsost of Poycbeloqy. Lafayette. 10d.

Push Gd&sol Coll.". Libmary. Cb~scaq.. Ill.

St. Losso Ursaw. od.sca1 Sebool Library. St. Leaser. Urn.

Stanford Urns.. Los. Mowdical Library. Palo Alto. Calif.

Stat. Unit, of lose.. C11.4. of H0scsrno Li4brary. ton. City. lose..

Stat. Urns, of logo. Uste Hoopl. Vopt of Otolavyrnq 6 Nax&IllofcjoalSorg. logo City. los..

Slot. Urs&. so Neo York. Amrnotborniolovy Uopartrn-ot. Brooklyrn, N. V.

Star* Urns. of 19" York. 11dital Library. D..rntomer Medical Cosnt.#. Brooklyrn. N. V.

Tooas N-dsaee Coat., Lsbrary. ).son. M. )*a** Library Nldq. Novet**. Torn.

Taft. Urs.w. Noeo. Eeqsrno.rsrq lotforoatsiso Arnalyst* S.v,v5~. M*Afo#d. Massrn

T.alarn Urs.v. Schrool of ~st. No. Or barns. La.

Voodrndthst Urns,. Hospital Lihrary. Basrnssabarn. Ala.

Ursiv of Aabovoa. 11" teal Coot., Library. firessaqaos. Ale.

Urnwsof Arbornoag. 0-dicot Cost.r Library. Latti. Reek. Ark.

Urs.v go Nosffel.. ~pavtorne~t of parnybollqy. 3sf tifle. 11. Y.

Urs.w of Urnlfals. 06*lth 3-sooo.* Library. Ea fole. N1. V.

Urni. of Calhforsti. 15.oismt-a1l Lsbro.y. La. Arnqol.s. Ceti#.

Us&* of Cbss-aqo. fledlfts.t Laboratory. Chicago. Ill.

Uca, of Clrncta.1it. C611.46 it medicinoe. 9.1tfrtato I.Cb. cloiasistit. at.;,

Unit. of rjsrdae. col1ege of Nwdsirn.. GA,.oa.mlo. ro..

Urs.w of Georgia. UDplortoornt of Poyelsotoqj. Athos@n. o

MCOICAL COLLEGE/SCNOOL LIDNARIES AND DEPIS Cost.

3.1. of lIlliesi.. Dweete iv ision. Library. Urbe... Ill.

Vale *6 Illinois. Sp sea u Sweiop Clial . Cbemplqm. Ill.

3.1. of 1111..'.. 1roalAog .o..reb Laoeratory. urbeam. 111.

Onto. ofgmeem. CIoed~eiq ftdloel Library. gas*. Cipy. gas.

3.iv of iem.... PafrbIwqp Dev..t...t. lbmbettim. Kms.

DRAW .I Eosoebyh. ftypolelw 3.peremet. Lo..qtom. Ky.

3.1. of L..l..illl. WdA..h Library. LoieOlsl~o. Ky.

3.5. *I Eoryload. Poeleh Sciences Llbroip. saitti.r.. Md.

u~s. of Mimi. school .6 sditia.. D"prt... at Op~bib~lsq. *I *I. ria.3.1. of Mimi. School .f Bodicise. boertemm of Popebol~q. Corel Cable*. rI..

Univ of Michigan. O...,.1 LAb,.ep of Serbial £ Decuests. A". Arbor. Rich.

3.5. of El-maoe.. Serial* Division L-bret. Ul....p.A.. Mis..

Onto of 81..i..Lppi. Radical Coster. UMolead Medicel Library. Jackson. P....

Vmiv 91 Ml....ri. Radical Library. C.I..bi.. No..

Ymi..of 9.Iemb.. College *I EMditis. Library. U0ob.. No..

So. 6 .th Carolina. Di. .6 U..tb Affair.. 5....isl MOOP Library- CbOPOI Mill. Vs.

3..6Obl.&.... awieal Coster Library. abiobo.. cipy. Ohi..

Usiv of Ovoj... odico~l School Library. P.,ti..d. Ore..

Date of f0vq... Depert.. of Dermat~olog. Petised. Or..

U.Av .o PIittburgh. D~pariinsai . Porch.5.qy sd Redlolqp. Plettb.,q&. Pa..

Usiu .f Pittburgh. *toli Ub~rq e lmS. Pit bo . P.t.N..

Uiniv .6 pocb~oir. Dpaprimmmt of Psychology. ..h..ter. 0. T.

Vaiv. *I Mob~otor. licieS of 40dieA.. 6 D.entitry- E..bo.Io,. 9. 1.

Vale of Rochester. strong mameilel N..Pitl. owioomro. P. I.

Uni1.of S..th.,m Califoumie. School .6 Nodlicis Liburar. La. Lagol.. Calif.

W3S1 of Sestbere California. sat1.te Library. Lom. Angeles. Calif.

U~s. of Sooth Debate. NadIO.! I.Ah,.,p. V.,.ilI02. S. D.

fti.of Tso" "....km No-9Moeilul Library. losphl.. TP.m

3.1.061 Toss@. Tb. N~dleblelogt Loboratoip. Austle. Tom.

Role.O6 Thu... Pedltal 3,eob~ Library. Colv.oieo. ?ON.

Palo .1 T*wo.. St.e*"& S kewisq Clio,. Lseodi. Too

Saiv *1 Utah. Lhibrar ON ESdIVOl .0o. Sol*"" L41Wo. City. stab.

Vale. of oromi. Celle"o .1 UMdloig Library. 009hlaqtm. It.

%V.A of wirgisid. USh..l of NWiGIm.. miesitaustioo. cholotto~ill. Vs..

:1i *1V1141.1W7ILbay si eptl loltovle o

u. ig of flosei.. Madleal Leolre. ULibay. Natonsl. vier~t.eyio

bwI * Nof arimel. Po16boi." Dotedlmot D eriees.efinings vi..g.one Stat ieSlav. bweith Librmry. Detroit. lsheti. S .barof ViergisoSag. &WigiSiest Castr ewr . owmidiom. Wi.weV& b iy o Sabooemim Pof ieiWs Studio. Sooili... Laboraor. Tie. Nvs on

l.A..o SIAy. Dopesslmme of per".ioew. Cmesimmoti. able

Aw"oommose Sept. Not' I Lmeading Lib.rar for SolA, AToo. States SM. Yorkshire. Uyleudbofelaoo, fbam... 1%w orevalsSee *I Aseuire. Al to. sAsst Mid At eowb.. Lemim. IEmqieodSwtilo Atmp Spllalm Unieson Giftie.. Switimb taboeme. gsmbiagle. D. C.

bu~tAsi b" Staff OWile... wejles FImoilem Ste. Altos F. P. tillm. wembimytem. D.C.Coemdies Usaesoe Woear.. Ollago * of b. Serve*& Caorel. lumbimytom. 6. C.Omeltet beltr "a too@. Royal Cement Move. Alto: lioter Alesoomd. Lmedee. bqieedCommbodo P. N. Ovmmm.A. mid coCha ft Iae. Deame.. ltuna. Fresnmo

"(Ofman aaeeenlb Meaimer. Canedies jiact Steff. 9meisimqem. 3. C.Dr. Dateiti 3. Slouvenes. *ir flymio Sort. Th. last tofaee aneili. vlimiAu. r~itead

Dt. :an orsii. Dept of 1i101ie0". Loeolimesb esmo. Steeo"Is. Isomdesft. G. U. Wyndham. mbrinp 4 Popuieel Lob. is. a oxPs. chmer a stage. Jeiommemimy. S. atries

Eiehil bmmime" cutslog ml. 5w ThO Nat'l loot of Animal Smeisj. Tab". Japanc~oisol do Semidel Slalaing. V. "oDitent. Atlas coeots r. C. Siaab.. dommm. ftegompcerails militar Allevioboefdorl ministry of Dmles"o. obeiaegleo. D. C.lose of Clialwa.. lap..r surget. Atlas Or. Lieie. Proen., Do.. Cmoeieeolow4ielost of leper SOd'aSetq. Alto: Dr. Beel Siol?. sir Snay of Montreal. wastreel. Croedlanst Of Pbymieloqp. oinl so Pies. Atllas Giotepp. miumemi. PlO*. ItalyLabratory of CeewreA Pmebiolef Tborapy. Altos Prof Zooms N. ft". Usog. ftigimoNedlo.i elobe.. Library. bulveormiy of Albertt@. Edtemose. Albert*. CanadaOnl ood bear. Doepotmesl of belsn Analgey. Allos Dr. 5. 1. Lied. Onlord. byimiaProf S. asmat~i. il. toot as cannotim riolooinem. nsmteyidmo. SnugeyProf A. 1. Diltobbers. J. 3. Theepo.. flymotl Lo. Sorb. 614y. Morke. bq9madProf 0. N. VMey Ay of U. Staffordshire. Soob. Stefferdoiiro. CeqimodProf 3. A. r. stoeyme"u ressity ot Sa. bayv of bOwsoro One. Lamos". &at. Coond"Moyci Air rorme toot of Avistio mid. A&tins Dr. G. I. DpI ord. srme she *0. byimeodSoyal Air orare loot *I Avialles mid. &ties Lt. 3. C. Gaipsewd. rFmbecub... EqimodAwyei Seeiot? ol Moild.. Libyary. Leaden Cegland

lbuy of *"omb, Cateio mid 2mbool. Altos Dv. Allen C. bottm. Leedem. Out. Comm

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