Vaccines Agaist Arthropods

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A m. J . T ro p. M ed . H vg ., 5 0(6 ) S up pl., 1 99 4, p p. 8 796Copyright 0 994 by The American Society of Tropical Medicine and Hygiene

VACCINES AGAINST ARTHROPODSBRIAN H. KAY AND DAVID H. KEMP

Queensland lnstitutef Medical Research,Royal BrisbaneHospi tal,Brisbane,Australia;C omm onw ealth Scientific Industrial Research O rganization, D ivision of Tropical AnimalProduction, Long Pocket Laboratories, Indooroopilly, Australia

Abstract. The possibility of vaccinating hosts against blood-feeding arthropods usingantigens derived from salivary gland, gut, and other tissues is reviewed. These vaccinesdirected against vector arthropods also have the potential to effect the arthropods capacityto transmit pathogens, and this is distinct from transmission-blocking vaccines that useantigens derived from pathogens. Antigen extracts have been used in attempts to vaccinateagainst fleas, lice, keds, flies, mosquitoes, and a number of tick species. A vaccine againstthe cattle tick, Boophilus microplus (Canestrini), using a recombinant antigen, has beentested under field conditions. Ticks feeding on vaccinated hosts are damaged by an immuneresponse directed against their gut cells. Some die on the host, others engorge but theirfecundity is reduced. The C ommonw ealth Scientific Industrial R esearch O rganization-B iotechnology Australia tick vaccine against B. microplus is cited as a model for the development of other vaccines. It is suggested that the weaker effects of vaccines against insectsas compared with ticks are related to the different structure and physiologies of the gutrather than being related to time spent on the vertebrate host. These differences in theeffects of vaccines on insects may favor vaccines which block the passage of pathogensinto vector insects. Vaccines against m osquitoes have been shown to reduce susceptibilityof mosquitoes to arboviruses. The potential of the different vaccines is discussed.

There are increasing problems with insecticide resistance in arthropods of medical' andveterinary importance,2 and a heightened publicawareness of the role insecticides play in chemical contamination of food and the environment.As a result, chemical companies, which are already facing higher costs for the developmentand registration of new products, may find thattheir product has a short commercial life. It ishardly surprising that new parasite control measures are being actively pursued. A vaccineagainst ectoparasites is an attractive alternativeto chemical control because of the potential longevity of control and the freedom from residues.

Bites from arthropods and inoculation of theirproducts stimulate a broad range of immune responses, many of which have not been fullycharacterized.3 Arthropods such as the housedust mite, Dermatophagoides sp. are also knownto be potent inhalant allergens.4 Most of what isknown relates to arthropods that remain in longterm contact with their hosts, although there isa growing body of knowledge relating to mosquitoes. Vaccines might be designed to stimulatereactions similar to those that occur at the bitesite, but the dangers of stimulating severe allergic reactions must be avoided.

The idea of a vaccine against arthropods is not

new and there are many references in the literature on attempts at vaccination against insectsand ticks.5'6 Trager was probably the first toshow the anti-arthropod effects of such a vaccine when he injected guinea pigs with extractsof whole larvae, salivary glands, or digestivetracts of partially fed female Dermacentor variabilis (Say) ticks.7'8 The partial resistance couldalso be transferred through serum from immuneanim als to those that w ere susceptible. H ow ever,there was considerable variability in the degreeof larval engorgement on the guinea pigs usedas recipients and controls. C urrently, the greatestsuccess has been achieved in developing a vaccine against the tick Boophilus microplus (Canestrini),9 the principal vector of tick fevers incattle throughout the tropics. Field trials of thisvaccine have begun.

Our paper considers vaccines against arthropods in the following context: direct protectionof hosts against ectoparasites such as ticks,mites, lice, and hematophagous and tissue-invading flies, and indirect protection by reducingvector numbers below the threshold required tosustain disease transmission cycles and by reducing vector competence. Such reductions inparasite numbers and competence could be realized by inducing reactions in the host to sali

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88 KAYAND KEMPvary antigens or more likely by inducing reactions in the vector that cause death,physiological disruption of tissues, and reducedfecundity.The growth of modern molecular biology hasstimulated studies on the vaccination againstparasites. It is now possible to obtain antigensin sufficient quantity to make vaccines possiblefor the above purpose and also for transmissionb loc kin g va cc in es ag ain st m ala ria g ameto cy tes.' EVOLUTION OF VACCIN ES AGAIN ST ARTHROPO DS

Vaccines against blood sucking insectsVaccine effects (Table 1) have been shownagainst the cattle grubs Hypoderma lineatum(Dc Vill.) and H. bovis (Linn.),2 Stomoxys

calcitrans (Linn.),'3' Glossina morsitans Westwood,'@'7larvaeof the sheep blowflyLuciliacuprina (Wied .) ,' 89 the human body louse Pediculus humanus de Geer,2the sucking louse Polyplax serrata (Burmeister),3 and to several mosquito species including Anopheles stephensiL iston,2' A edes aegypti (Linn.),2226 and A n. farauti Laveran27 (but not An. quadrimaculatusSay.)28 The effects have been variable, and theseinclude reductions in survival,20'24 fecundity andegg laying,'5'25 rupture of the gut,2 and paralysis.'3 Interestingly, Ramasamy and Ramasamyalso observed increased survival of An. farautiwhen hosts were vaccinated with midgut antigens.27The antigens used for vaccination have rangedfrom extracts of whole insects or of particularorgans, especially salivary glands and the midgut. Although most antigens have been derivedby dissection or maceration of whole insects, anin vitro culture of H. lineatum was used to produce significant protection of cattle.'2 Mostlylaboratory animals have been used in such trialsand the efficacy of these crude vaccines hascommonly ranged from 0% to 50%.The possibility of vaccinating hosts againstblood-sucking insects is an intriguing one. Insects such as fleas, lice, and keds spend considerably more time in intimate contact with thehost than the tick B. microplus. Others, such asm osquitoes and numerous other blood-suckingDiptera, spend only a short time on the host buttheir blood meal volume in relation to their sizeis as great as that of some ticks, e.g., argasids .29' @espite these similarities in feeding, the

effects of such vaccines against these insects inthe laboratory have nearly always been less thana 50% reduction (through increased mortality ordecreased fecundity, viability), and the site ofaction of such vaccines is largely unknown.'228The reason for this generally poor effect againstinsects compared with ticks may lie in the differences in the digestion of the blood meal. Ininsects, digestion occurs in the gut lumen, andnot intracellularly as in ticks. Thus, secreted digestive enzym es either at neutral (m osquitoes29)or acidic (S. calcitrans,31L. cuprina32) pH canpresumably destroy antibodies rapidly. In addition, the blood meal is encased by the peritrophic membrane, which separates the meal, and thusthe antibodies, from direct contact with the gutepi th eli um cell s.How these vaccines against insects work isopen to speculation. Antibodies raised againstwhole-body extracts of Ae. aegypti were foundto bind specifically to the midgut epithelium andto enter hemolymph,23 and those against mosquito abdomen were detected by immunofluorescence in the oocytes 22 hr after engorgementand may subsequently have reduced fecundityand egg laying.25 Antibodies against abdomenand muscle extracts were shown to damage theinternal tissue of S. calcitrans.'3 Specific antibodies detected in the hemolymph of An. stephensi were l0@ times less concentrated thanthose ingested in the original meal.33 On the basis of these and other studies w ith ticks,M .35 fleshflies,@ and the tsetse fly,'5'37 there seems to besufficient evidence to suggest that intact immunoglobulins can pass to the target tissue in someinsects. More information is needed however,since there is evidence of damage to one specifictissue resulting from vaccination against another. However, this could possibly be explained bythe crude nature of the antigens used, withshared antigens in different tissues.Whereas some investigators have found evidence of immunoglobulin passage across thegut, Vaughan and Asad did not.38 Thus, there isno conclusive proof that the antibodies producedare actually causing the observed damage. It isconceivable that the effects are caused throughdisruption of blood meal digestion.'7'21'23' Itseems unlikely that many of the questions canbe answered until efficacious antigens have beenpurified.Vaccination can be successful when directedagainst symbionts within G. morsitans'5 or


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Refer'Insect-hostsystem Antigen source Efficacy of vaccine Mode of action enceWhole None 28

89ACCINES AGAINST ARTHROPODSTABLE I

Summ ary of experim ental vaccinations against insects

Feeding success unchanged


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Reduc Reduct io n i nt io nntickseggengorgproducingAntigen (%)tion (%)@

90 KAY AND KEMPTABLE 2

Vaccinations with a native BM86 antigen and twoEsche richi a coli r ecombinan t Bm86 aga in st Boophi lu s mic roplus ( fr om re ftr ence 6 )

inoculation of crude extracts of sem i-engorgedfemale B. microplus, a 70% reduction in ticksurvival on vaccinated cattle was recorded.39Fractionation of the tick extracts and testingthem in cattle vaccination trials led eventuallyto the purification of a single efficacious antigen(Bm86).4 0'4 ' T he g en e co ding for n ear full-le ng thBm86 has been expressed in Escherichia coli42and in a Spodoptera frugiperda cell line (Richardson I, Biotechnology Australia, Sydney, Australia, unpublished data). The first vaccinationtrials with recombinant Bm86 used bacterial inclusion bodies containing the Bm86 gene product. The results were significantly poorer thanachieved using native Bm86. Auempts to generate an antigen with a structure closer to thenative protein by solubilizing and refolding therecombinant Bm866 gave a vaccine efficacyclose to that achieved with the native protein(Table 2).It is worthwhile understanding how the vac

cine against B. microplus works so that thechances for success of vaccines against other arthropods can be assessed. The idea that vaccination against ticks could be based on antigensfrom internal organs rather than mimicking theimmunity following infestation was suggestedby the results of Galun,43 Schlein and Lewis,13an d A lle n an d Humphre ys.@ 'n 1939, Trager hadin fact conducted such experiments without discussing the novelty of his approach, i.e., by protecting guinea pigs against D. variabilis infestation by intracutaneous injection of larvalextract.7'8 The suggestion from these investigators was that hosts might be immunized againstinternal tissues or antigens from the parasite andthat these antibodies, either in the gut or hemolymph, could cause critical damage. Developmental hormones might be neutralized,43 andbody muscles or gut might be damaged.'3 Incontrast, immunity following infestation isbrought about by immunologic reactions againstthe saliva of the tick.45It was this novel approach that first provided

effective immunity to the cattle tick.39 The vaccine developed did result in internal damage tothe tick, with breakdown of the gut and leakageof the blood meal into the hemoIymph.@'47 Thiswas quite different from the effects noted inticks feeding on anim als with immunity acquiredfollowing infestation. The term concealed antigens, although by no means new, was coined toindicate that the gut antigens used in the vaccine

Native Bm86 61 91E. c oli Bm86 inclusion body 24 77E. coli Bm86 refolded 27 89

T he overall effect of the vaccine is the reduction in egg productionfro m tick infe sta tio ns o n va ccin ate d an d co ntro l c attle . R ed uc ed eg g pr oduction results from few er ticks successfully engorging and fewer eggsbeing laid by those that do engorge.

priate antisera.25 The first and second immunizations were done using a 1:1 mixture withFreund's complete adjuvant. Control group rabbits were inoculated with PBS.In the first experiment, Ae. aegypti fed on rabbits immunized with mosquito antigens showedreduced fecundity.@ Since the antigen preparations were cross-reactive, it is not surprising thatall preparations (i.e., head/thorax, midgut, abdomen) produced a similar effect. By immunofluorescence, it was possible to detect specificantibodies in the midgut cells and in the abdomen of mosquitoes that were fed on the immunized rabbits 2 hr after blood feeding. Fluorescence in the oocytes was detected after 22 hr,suggesting that one of the ingested antibodieswas reacting to an egg antigen, possibly vitellogenin.The feeding behavior of Ae. aegypti appeared

to be similar on immunized and normal rabbits.Moreover, the survival rates of the two groupsof engorged mosquitoes were similar. As notedearlier, fewer eggs were laid by Ae. aegypti thathad engorged on immunized rabbits. Fewer ofthese developed to pupae, although developm ental times were comparable. Finally, the percentage of egg-laying adults in the F, generation wasa ls o lowe r.Development of a vaccine against the cattle tickB. microplusIn discussing the evolution of the vaccine

technology, it is only possible to use the example of a vaccine against the cattle tick B. microplus. This cattle tick is the only parasite that hasreceived the concentrated research effort necessary to lead to a commercial vaccine.6 Following


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ReferTick spp. and hostAntigen sourceVaccine efficacyMode ofctionenceDermacentorandersoni Midgut and reproductive85% reduc tion inngorgedUnknown44guineapigs, cattleorgans part-fed ticksweight andggsAmblyommaamerican Gut brush border enr iched82% reduction in femalesUnknown gu t d am0umguineapigsfractionto egg s to l ar va eageuspectedD.

variabilisratsWhole tick or m idgut cxtracts part-fed ticks50% reduc tion in engorgedweight delayed a ttachmentUnknown53Rhipicephalusappendicu Whole tick unfed extracts 50% reduc tion inngorgedUnknown54latusguineapigsweightR.appendiculatusrab Salivary gland and/or mid


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92 KAY AND KEMPlikely that B. microplus would be unique in itssusceptibility to a concealed antigen vaccine.There is a need for more effort to be directed tovaccines against other econom ically im portantticks.Salivary glands have been exploited as a potential source of vaccine antigens. In fact, thepurification of salivary antigens has proceededmore rapidly than for other tissues and severalinvestigators59@3 have purified or partially purified salivary antigens, all of which give somehost protection in a vaccine. However, as yet,the protection has not been strong.It is clear from immunoblotting and otherstudies that cross-reactivity occurs between antibodies raised against salivary antigens whenthese antibodies are used to probe antigen extracts from gut tissues.@ -65 Furthermore, a purified salivary antigen from ixodes ricinus (Linn).that is partially protective in vaccination is imm unologically cross-reactive with a purified antigen from Rhipicephalus appendiculatus (Neuman).62 This has led to speculation that a singlevaccine antigen might serve as a valuable toolin control of the several species of ticks that canbe found together on one host, particularly inA frica.@ However, this seem s overly optim isticbecause W illadsen and M cKenna65 have pointedout that most or all of this cross-reactivity intheir experiments was probably due to sharedcarbohydrate antigenic determ inants. M oreover,there is evidence that antibodies to the carbohydrate part of the Bm86 antigen from B. micro plu s are n ot p rotec tiv e.6 5

VECTO R VA CCINE POTENTIAL TO AFFECTPATHOGEN TRANSMISSION

Gordon and Crewe suggested that host responses to vectors might create a less amenableenvironment for both pathogens and their vecto rs.6 7 C attle resistan t to in festa tio n o f Boo ph ilu sand Rhipicephalus ticks were less susceptible todisease caused by Babesia@ and Theileria.@ W ikel reported that rabbits immunized against thetick D. andersoni (Stiles) were significantly protected (approxim ately 65% ) against subsequentexposure to ticks infected with the highly virulent tick-borne bacterium Francisella tularensis.t is interesting to note that the survivingrabbits had no evidence of antibody or of thebacterium itself. For arboviruses, infection ratesof Thogoto in R. appendiculatus were 67% less

when the ticks were fed on tick-sensitized ratherthan on naive guinea pigs.7' Partial virus neutralization reactions extended to sera from guinea pig hosts that had been repetitively exposedto bites of Ae. aegypti. Sindbis virus was neutralized by antisera to antigens of Ae. aegyptimosquitoes.72 However, antisera from rabbitsimmunized with various tissues of Ae. aegyptifailed to neutralize Murray Valley encephalitisvirus.26Vector vaccines can have an impact on theiroverall susceptibility to pathogens. T he infectionrates with Ross River virus were reduced by 3249% in Ae. aegypti fed on virus diluted in bloodfrom rabbits vaccinated w ith Ae. aegypti m idgutantigens compared with normal blood.26 ForM urray V alley encephalitis virus, Ae. aegypti infection rates from three midgut-inoculated rabbits averaged 34% compared with 80% for controls, and in a second experiment with thisflavivirus, antibodies from head/thorax and m idgut antigens produced a 20% reduction in infection.26 In all cases, the reductions in infectionrate to these arboviruses were at least equal orhigher when midgut rather than head/thorax- orabdom en-derived antigens w ere used. Statisticalanalysis indicated that the viral titers developedin both the vaccinated and the control mosquitoes were the same and that the effect was oninfection rather than transmission. Similarly,with An. farauti and Plasmodium berghei, significantly fewer oocysts developed in mosquitoes feeding on mice immunized with mosquitomidgut antigens.27 As with the previous arbovirusstudies,idgut antigensseemed more effective than those from the head and thorax. However, with these experiments, the investigatorsclaimed that midgut antigens derived from sugar-fed rather than blood-fed mosquitoes weremore effec tive .

OUTLOOK FOR THE FUTUREAt this stage, we believe that there is sufficient evidence to indicate that vaccinationagainst ticks has considerable potential for control. For blood-feeding insects with peritrophicm embranes and extracellular proteolytic digestion, vaccines may have potential but anti-fly effects have yet to be demonstrated with singlepurified antigens and their recom binant forms.Vaccines are certainly attractive because oftheir specificity, potential longevity of control,


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93ACC IN ES AGA IN ST ART hRO PODSand environmental acceptability. Resistance toinsecticides will worsen and the search for efficacious vaccines is likely to continue. The question of resistance to vaccines will not be a problem until such time as a commercial vaccine hasbeen used in the field for some time. Experiencewith commercial vaccines against viruses, bacteria, and protozoa suggests that breakdowns canoccur.73 Such a breakdown has occurred againstBabesia sp., but there is little evidence to suggest that a resistant strain was selectively induced. It seems more probable that a variant ofthe organism , less susceptible to the vaccine, hasappeared in the field through natural causes. Theproblem was resolved simply by redesigning thevaccine by incorporation of a new attenuatedstrain.It is more likely that vaccines against arthropods will be directed towards veterinary pestssuch as the cattle tick B. microplus, which isregarded as the most important tick parasite ofcattle in the world.9 Based solely on annual production losses, it w as estim ated that in A ustralia,Brazil, Argentina, Uruguay, and Paraguay alone,the economic losses due to the tick were $130.4billion (U.S.) dollars, not accounting for expenditures on acarides used in chemical control.Thus, for a veterinary pest such as B. microplus,it would seem that cost-effectiveness is assured.For medically important vectors of malaria,filaria, or arboviruses, the path is less clear.First, there is a dearth of information about theeconomic cost of these human pathogens but onhumanitarian grounds, a mosquito vaccine, if effective, would be desirable. Second, since mosquitoes are usually less host-specific than ticks,even a vaccination program that uses several ofthe major vertebrate host species would be lessefficient or impossible. This also supposes thatthose vaccinated will develop an immune reaction of sufficient titer and longevity to impact onblood-feeding arthropods. It has been suggestedthat domestic livestock such as pigs, cattle, andbuffalo could be vaccinated against Japanese encephalitis vectors for their control.26 AlthoughCulex tritaeniorhynchus Giles is considered tobe the major vector, Japanese encephalitis virusis also transmitted by several other species.Would antibodies developed to the midgut antigen(s) of Cx. tritaeniorhynchus be effectiveag ain st C x. ge lid us Theo bald , C x. fu sc oce pha lu sTheobald, or Cx. pseudovishnui Colless, not tomention species from four other genera? This

seem s unlikely because of the specificity of suchvaccines. Such an approach against Japanese encephalitis would not be universally applicablebecause the relative importance of vector speciesmay be different from region to region.74 Thus,it would be more economical and logical to continue with vaccination of humans against thepathogen as has been done for the past 20 years.In China and Japan, the economics and logisticsof large-scale pig immunization programs werefo und to b e impra ctica l.7 4Thus it would seem that a potential target foran anti-mosquito vaccine would be the ubiquitous Ae. aegypti and Cx. quinquefasciatus (Say)or a major malaria vector such as An. gambiaeGiles because of their well-defined vector statusw ith respect to dengue/yellow fever, B ancroftianfilariasis,nd malaria,respectively.ll are anthropophagic and it is suggested that humanscould be the potential recipients of such vaccines. Because humans are involved, development and clearance would be protracted.Vaccines against mosquitoes will not protectthe host against infection,27 and thus we believethat gaining commercial support w ill be difficult.Kaslow indicated such difficulties facing thetransmission blocking vaccine for malaria, butcommented that the Rubella vaccine program isprimarily directed at protecting the unborn.'H ow ever, residual insecticide spraying program salso offer indirect protection from malariathrough reduction of vector numbers and thesewere considered to be most effective and acceptable for many years. We would suggest,therefore, that vector vaccines and transm issionblocking vaccines be viewed in the same light.A uth ors' ad dress es: B rian H . K ay , Que en slan d In stitu te o f Med ic al Res ea rch, P0 Royal B ris bane Hospi ta l,Brisbane 4029, Australia. David H. Kemp, Commonwealth Scien ti fic Indus tr ia l Research Organ izat ion, Division of T ropical A nim al P roduction, Long PocketL aboratories, PMB 3, Indooroopilly 4068, A ustralia.

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15. Nogge C, 1978. Aposymbiotic tsetse flies, Glossin a morsita ns morsitan s, o btain ed b y fe ed in go n ra bb its immuniz ed s pe cific ally w ith symb ionts. J Insect Physiol 24: 299304.16. Nogge G, Giannetti M , 1980. Specific antibodies:a potential insecticide. Science 209: 10281029.17. Otieno LH, Vundla RMW, Mongi A, 1984. Observations on G lossina morsitans m orsitansm aintained on rabbits immunized w ith crudet se ts e midgu t p ro te as es . In sect Sci App l 5 : 297302.18. B ow les WM, C arnegie PR , Sandem an RM, 1987.Immuniz atio n o f sh ee p ag ain st in fec tio n w ithlarv ae of th e blowfly Lucilia cu prin a. In t J P ar

asitol17: 753758.19. Johnston LAY, Eisemann CH, D onaldson RA,Pea rson RD, Vuoco lo T , 1992. Reta rded g rowtho f Luc ilia c uprin a la rv ae o n sh eep an d th eir se rafo llowin g p rod uction o f a n immune res po nse .Int J Parasitol 22: 187193.

20. B en-Y akir D , Mumcuoglu YK, 1988. H ost resistance to the human body louse (Pediculus humanus ) i nduced by immun izat ion with lou se ext ra ct s. P roceed ings o f t he XVI II I nt erna tiona lCongress of Entomology. Vancouver, BritishColumbia,anada,282.21. A lger NE, C abrera E J, 1972. A n increase in deathrate of A nopheles stephensi fed on rabbits immunized w ith m osquito antigen. J Econ E ntomol65: 165168.

22. Sutherland GB, Ewen AB, 1974. Fecundity dec rea se in mos qu ito es ing estin g blo od from sp ec ifica lly sen sitiz ed mammals. J In se ct P hy sio l20: 655 660.23. Hatfie ld PR, 19 88 . Anti-mos qu ito a ntib od ies an dthe ir e ff ec t on f eeding , f ecundit y and mort ali tyof Aedes aegypti. Med Vet Entomol 2: 331338.24. H atfield PR , 1988. D etection and localization ofa ntib od y ing este d w ith a mosquito b lo od mea l.Med Vet Entomol 2: 339345.

25. Ramasamy MS. Ramasamy 5, Kay BH, Kidson C,1988. Anti -mosqui to ant ibodies decrease the repro du ctiv e c ap ac ity o f Aed es ae gyp ti. Med VetEntomol 2: 8793.26. Ramasamy MS. Sands M, Kay BH, Fanning ID,L aw ren ce GW, Ramasamy R , 19 90 . Anti-mosqui to ant ibod ie s r educe the suscept ib il ity o f Acd es a eg yp ti to arb ov iru s in fec tio n. Med Vet Entomol 4: 4955.27. Ramasamy MS. Ramasamy R, 1990. Effect ofan ti-mosq uito a ntibo dies o n th e in fec tiv ity o fthe roden t mala ria par as ite P la smod ium berghe ito Anophe le s fa rau ti. Med Vet Entomo l 4: 1 61166.28. Dubin IN, Reese JD, Seamans LA, 1948. Attemptto p roduce p ro te ct ion aga in st mosqu it oe s by activ e immun iza tio n. J Immunol 5 8: 2 93 297.

29. Clements AN, 1992. The Biology of Mosquitoes.Volume 1. Deve lo pmen t, Nutritio n an d Rep roduction. London: Chapman and Hall.30. Balashov Yu 5, 1972. Bloodsucking ticks (Ixodoidea ), v ec to rs o f d is ea se s o f man and animal s.Misc Publ Entomol Soc Am 8: 161376.31. L ehane M J, 1991. Biology of B lood-Sucking lnsects.ondon:HarperCollinscademic.

32. Waterhouse DF, 1940. Studies of Physiology andToxicology of Blowflies. Melbourne: Council ofScien ti fic and Independent Research (Aust ra lia)P amph le t No 102 .33. Lackie AM, Gavin 5, 1989. Uptake and persistence of ingested antibody in the mosquitoAnophelesstephensi.ed VetEntomol3:225230.34. B ro ssa rd M , Rais 0 , 1 98 4. P ass ag e o f h emolys in st hrough the midgu t epi th eli um of f emal e Ixodesricin us L . fe d o n rab bits in fe ste d o r re in fes te dw ith tick s. E xpe rie ntia 4 0: 56 1 563.

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