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Page 1: and typhoid-paratyphoid fevers WALLY VELLA · paratyphoid A and B components to typhoid vaccine was the observation that inclusion ofthese components resulted in the appearance of

Postgraduate Medical Journal (February 1972) 48, 98-106.

CURRENT SURVEY

On vaccines and vaccination: typhoid-paratyphoid fevers

WALLY VELLAM.D., F.R.C.Path., M.I.Biol.

Colonel, Army Medical Services

Assistant Professor of Pathology, Royal Army Medical College, Millbank, London, S. W.1

SummaryThe various preparations of TAB vaccines proposedin the past and/or available for use at present, togetherwith the methods suggested for the vaccination pro-cedures, are described.The difficulties of interpreting the serologic diag-

nostic tests (Widal Test) and the possible dangers ofvaccination during an epidemic (provocation typhoid)are discussed.

IntroductionThe first attempts in this direction were made

independently by Sir Almroth Wright (Lancet, 19Sept. 1896) and by Pfeiffer & Kolle (DeutscheMedicinische Wochenschrift, 12 Nov. 1896) both ofwhom inoculated dead cultures of typhoid bacteriainto man with no ill-effects and with the result thatspecific agglutinins and bactericidins made theirappearance in the blood of the inoculated men.

In the years following these first attempts at activeimmunization of man against enteric fever, theprogress which was made in connection with thesubject is unquestionably due to Sir AlmrothWright, who in addition to his unremitting researchesin the laboratory carried out a large number ofinoculations with the vaccine which had been devisedby him (Report 1912).Vaccines(a) Heat-killed andphenol preserved (HKB)The currently used TAB vaccine of the British

Armed Forces is a suspension of carefully chosen'smooth' (Grinnell, 1930; Perry, Findlay & Bensted,1933, 1934) strains of Salmonella organisms.The strains in the vaccine constitute a balanced

mixture of old 'classical strains' judiciously comple-mented by 'wild' strains obtained from variouscorners of the world. I am indebted to the OfficerCommanding, The David Bruce (Army Vaccine)Laboratory for the following information on theserotypes and strains used in the current TABvaccine (Clifford, 1971); the Salmonella typhi com-

ponent consists of three strains (Ty2, T15, T18),while the S. paratyphi components consist of twostrains each (HA6 and Al; HB3 and B1).

S. typhi Ty2 is the best known of these strains,and it is used on a world-wide scale in the prepara-tion of typhoid vaccines everywhere-it was isolatedoriginally from an epidemic of typhoid fever inRussia.Each strain is cultured on solid trypsinized meat

broth agar contained in special flasks (Roux bottles),and the resultant harvest of bacteria is killed byheating at 54°C for 1 hr and preserved in 1 0% phenolsaline as a concentrated suspension until requiredfor the production of the whole vaccine.

Vaccines are dispensed for use either in 0.5-mlampoules or in 5-ml vials containing the followingconcentration of bacilli/ml: S. typhi (three strainsx660 millions); S. paratyphi A (two strains x 750millions); S. paratyphi B (two strains x 750 millions);thus giving a total of 5000 million bacilli/ml pre-served in 0-5% phenol saline.

Users of this Forces' vaccine should note that thisvaccine is meant for intradermal inoculation, andcontains twice as many bacilli as the ordinary TABvaccine issued by commercial manufacturers.

(b) Alcohol-killed and alcohol-preserved'Towards the end of the 1939-45 war Leishman's

phenolized vaccine was replaced by an alcoholizedvaccine with supposedly superior immunizing pro-perties. Whether post hoc or propter hoc remains anarguable point, but in fact the incidence of typhoidthereafter rose sharply to decline to its previous levelonly when phenolized vaccine was re-introduced.'(Lancet, 1967.)

In the 1940s an alcoholized vaccine was for aperiod much in vogue. This was based mostly on thework of Felix who found that the Vi antigen ofS. typhi was responsible for the virulence of newly-isolated typhoid bacilli, and that vaccines containingthe virulence Vi factor were highly active in protect-ing animals against challenge by virulent bacilli.

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Vaccinies anid vaccination: typhoid-paratyphoidfevers

Morevwer, it was shown that the heat-phenoltrcatmenrt of the classical HKP vaccine almostwholly inactivated the Vi content of this popularvaccine, while tle Vi antigen was stableto alcoholtreatm.ent.

Accordingly a TAB vaccine was produced withmuch enthusiasm and great expectations, made up ofbacilli killed by 75°4 alcohol, and preserved in 25%alcohol (Felix & Pitt, 1941; Felix, 1941; Felix,Rainsford & Stokes, 1941; Climic, 1942; Edsall etal.,1959).Unfortunately under field conditions tle alco-

lholized vaccine did not fulfil its promisc, and thevaccine was withdrawn. En passant, it is worthnoting that the war-time HKP vaccine preparedwith so much care and attention from smoothvirulent strains by the Royal Army Medical Corpsworkers did prove its efficacy under field conditionsin World War II. Thus, from the classic paper byBoyd, then Dcputy Director of Pathology, MiddleEast Forces, it can be seen how the British prisoners-of-war were safeguarded from the ravages of entericfever which reigned in the camps of their captors,and how better off the Italian prisoners-of-war wercwhen the Italian vaccines wcre replaced by theBritish Army vaccine, as soon as sufficient suppliesof the latter became available for victor and van-quished alike (Boyd, 1943).

(c) Acetone-inactivated antd acetone-preser ved (AKD)The latest vaccine being now advocated, and

FIG. I. Sir William Boog Leishman, K.B.C., K.C.M.G..F.R.S., K.H.P., Professor of Army Pathology, 1903-14;Director of Army Pathology, 1919-23. A great advocateof TAB vaccine. Photograh 'by courtesy of the Comr-andant, Royal Army Medjca Cpliege.

availablc commercially is an acetone-inactivatedvaccinc; acetone, likc alcohol, also preserves the Viantigen (Landy, 1953; Landy et al., 1954).The bactcria are grown on solid vcal infusion agar

nmedium, the growth is harvested and treated withacetone; inactivation is completed by hcating at37°C for 24 hr. The bacterial suspension is vacuum-dried and therefore this vaccine necds reconstitutionwith buffered saline before use.The AKD vaccincs appear to give a fairly good

immunity and to be better than the HKP vaccine;thus in a 7-year field trial of thesc vaccines inGuyana, Ashcroft et al. (1967) report, 'In 1960about 72,000 Guyanc3e school childrcn, aged 5-15years, were divided into threc similar groups, onc ofwhich acted as a control and was given tetanustoxoid, the second was given an acetone-killedtyphoid vaccine, and the third a heat-killed phcno-lized typhoid vaccine. Two subcutaneous doses of0-5 ml of reconstituted vaccines were given 5 weeksapart. An additional 10,000 children received onedose only. The incidence of typhoid fever, diag-nosed by the bacteriological isolation of S. typhi,was followed for 7 years after vaccination. In thosegiven two doses, 146 cases of typhoid occurred in thecontrol group, and sixteen and forty-nine in theacetone and heat-phenol typhoid vaccine groups,showing protection rates of 88 and 65%4 respectively.

In those given one dose of vaccine the protectionwas somewhat greater: twenty-two cases occurredin thc control group, and one and four in the groupsgiven the acetone and heat-phenol vaccines, respec-tively. Protection showed little diminution until thefifth year after vaccination.'

In more than one country even a single dose ofvaccine has given quite good results, which primnafacie is surprising considering that these, after all,are inactivated and non-adjuvanted whole-cellbacterial vaccine; so muclh so that Ashcroft ct al.quoted above, observed that. 'It is important thatpublic health authoritics should Lc aware that onedose of a suitable typhoid vaccine can give substan-tial protection'. There is no doubt that this fact hasarouscd considerable public intere3t for example inits possible application to protect holiday makers,tourists and other short-term visitors (Ashcroft,1969; British Medical Joutrnal, 1 970a; Vella, 1970).The comparative efficacy of these tlhree vaccines

descrited in detail above can Lbe briefly stated to beas follows:

(i) Tle AKD vaccinc hias been shown to begenerally superior to the other vaccines.

(ii) The HKP vaccine is next in ecSctiveness to theAKD vaccine.

(iii) The Alc vaccine is inferior to both the aboxevaccines and is therqfore not recommended,

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These were the findings of Cvjetanovic & Uemura(1965) who examined 'the results yielded by a numberof collaborative field and laboratory studies oftyphoid vaccines conducted under the auspices ofthe World Health Organization, comparing in par-ticular the results of various controlled field trialscarried out in British Guyana, Poland, the U.S.S.R.,and Yugoslavia, and attempting to evaluate theeffectiveness of the vaccine in man'.And so finally, more than half a century after their

first introduction, the protective value of theseenteric fever vaccines has been fully vindicated,certainly as far as the typhoid component of thepolyvalent TAB vaccine is involved.The same conclusions cannot be made with con-

fidence for the other two components (or threecomponents, if S. paratyphi C is included as inTABC vaccine), that is to say for S. paratyphi Aand S. paratyphi B antigens, which were introducedduring World War I (1916) and have been incor-porated in vaccines more or less traditionally bymanufacturers of enteric fever vaccines.

'The entire justification for the addition of theparatyphoid A and B components to typhoidvaccine was the observation that inclusion of thesecomponents resulted in the appearance of specificantibodies' (Davison, 1918).

Possibly due to the milder form of enteric feverinduced by paratyphoid bacilli as compared withthe disease evoked by S. typhi, Very little workcomparatively speaking appears to have been donein the past to investigate under full field conditionsthe respective value of the paratyphoid bacilli com-ponents and so as to justify their inclusion in thepopular TAB vaccine.

It is true that work in the U.S.S.R. has shown thatit is possible to achieve protection against para-typhoid B by a suitable vaccine, and the conclusionwas reached in the trials conducted in that countrythat 'the data obtained provide a basis for theeffective use of immunization against paratyphoid Bas part of a set of measures for the prevention ofthe disease where this is called for by the epidemio-logical situation' (Hejfec et al., 1968).

Nevertheless, one supposes that the ready availa-bility of antibiotics, to which these organisms aresusceptible, in most countries militates against time,money and effort being expended by investigators togauge their efficacy, hence the tendency nowadays istowards the production of a potent monovalenttyphoid vaccine. This is the opinion, for example,held in the U.S.A., 'the effectiveness of paratyphoidA vaccine has never been established, and recent fieldtrials have shown that available paratyphoid Bvaccines are not effective, in the usually smallamounts contained in TAB vaccines. Knowing thisand recognizing that combining paratyphoid A and

FIG. 2. Arthur Felix (1887-1956), D.SC., F.R.S. Hisnumerous studies on the Vi antigen of typhoid bacilliled to a replacement of the old classical vaccines byVi-containing vaccines. Photograph by courtesy of theWellcome Trustees.

B antigens with typhoid vaccines increases the risk ofvaccine reaction, paratyphoid A and B vaccinesshould not be used' (Advisory Committee onImmunization Practices, 1969).The same advice is reiterated from Australia,

'whilst it has been clearly shown beyond questionthat typhoid vaccines protect well against typhoid,there is no evidence that paratyphoid A and para-typhoid B vaccine are effective against paratyphoidA or B infections. Furthermore, there is every reasonto believe that the paratyphoid A and B componentscontribute in no small measure to the undue re-activity of TAB vaccine. For these reasons typhoidvaccine is to be preferred to TAB vaccine' (CSL,1970).An editorial annotation in the British Medical

Journal (28 Feb. 1970) suggests, 'this is perhaps achallenge to the pharmaceutical industry in theUnited Kingdom to make a potent monovalentvaccine'.

(d) The othersBesides the bacterial vaccines discussed above

there have been numerous other preparations pro-posed for protection against the enteric fevers (seeVella, 1963) such as:

(i) 'Endotoxoid' vaccine prepared by alternatefreezing and thawing of the bacilli and used withsuccess in South Africa.

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(ii) Various antigenic extracts from the bacillihave been prepared both in France and Britain.

(iii) Aluminium hydroxide adjuvanted vaccines inHungary.

(iv) Formal-chrome preparations in Japan.Route of administration(a) Intradermal vs subcutaneousAs stated above the TAB vaccine produced by the

British Army Vaccine Laboratory is intended to begiven intradermally (ID); a separate vaccine, to begiven subcutaneously (SCI) is also issued forchildren under the age of 12.

Civilian doctors who are used to doing diagnosticskin tests (tuberculin tests, Schick tests, allergy tests)in the skin of the volar surface of the mid-forearmshould note that TAB-ID vaccine should not beinoculated in this site, or too many of their patientswill complain bitterly about increased local reactionafter vaccinations. The skin over the shoulder regioxiis most commonly used, though I have given TAB(and other vaccines) intradermally in the inter-scapular area on occasions.Also medical officers should note that AKD is

meant to be inoculated SCI or intramuscularly (IM)and not ID.The British Army changed over from SCI to the

ID route of administration in 1958-59 (HomeCommands in 1958, Sayers, 1961).There had been reports published some years

previous to this change-over reporting that antibodyresponses after vaccine administered ID wereefficacious and indeed slightly better than when givenby SCI or IMI, even when the total dose given wassmaller; thus, Tuft (1931a) stated, 'These are allevidences of the fact that in addition to providingmechanical function, the skin also seems to have aspecific biological function, designed to protect theinternal organs from disease agents possibly by theformation of immune antibodies excited by strongspecific skin stimulation'.Some authors added the rider, though, that the ID

method of inoculating the vaccines should be usedonly in re-inoculation programmes (booster doses)and not in basic primary immunization. It is thoughtthat the efficacy of the intradermal site is due to aslower adsorption of the inoculated antigen and/orabundance of the reticulo-endothelial cells in thedermis (Tuft, 1931b; Tuft et al., 1932; Siler &Dunham, 1939; Tuft, 1940; Longfellow & Luippold,1940; Leibowitz, 1943; Luippold, 1944).The advantages claimed for the ID method by its

protagonists may be listed as follows:(i) It produces an antibody response equal to that

following SCI-one should be very wary, however,of correlating too strictly serum antibodies with theimmunity status of an individual.

(ii) It evokes fewer reactions than SCI-workers atthe Research Laboratories of the U.S.A. ArmyMedical School, Washington, D.C. commented, 'thereactions that follow re-immunization intracutane-ously with 0 1 cc of vaccine are mild in character andof but short duration' (Siler et al., 1941). This obser-vation was noted with great interest by Britishworkers since 'Systemic and local reactions toinoculation against enteric fever have been a causeof much concern in the services for years' (Barr,Sayers & Stamm, 1959), and the gratifying andsatisfactory results following ID route were fullycorroborated (Noble, 1963).

(iii) A smaller dose (and therefore more economi-cal) is needed. The ID dose of 0-1 ml (500 millionbacilli) is usually reckoned to be one-fifth or two-fifths that of the equivalent SCI dose (2500 millionor 1250 million bacilli) in 1 ml and 0-5 ml respec-tively. This is fortunate as bigger volumes or greaterconcentrations of bacilli may give rise to skinnecrosis and ulceration (Miles, 1958).The disadvantages may be stated as:(i) The more time-consuming technique of ID as

against the SCI. In the bad old days when one loadeda syringe with multi-doses of vaccine, the small doseof the ID route was naturally regarded as time-saving and thus logically put forward as an advan-tage in favour of this method; now, of course, weknow better and advise one syringe (disposable)/dose/individual. We can possibly overcome thistime-element disadvantage, in this day and age, bythe adoption of the Jet (needleless) VaccinationMethod.

(ii) Some authors also point out that if due tofaulty technique the inoculation is not madeproperly, 'these doses will fail to protect!' (Davey& Wilson, 1965).These points of view are succinctly summed up as

follows, 'Primary vaccination with killed vaccinesusing intradermal jet injection cannot be recom-mended because all vaccinators may not always beable to implant the entire 0-1-ml dose of vaccine inthe skin. The intradermal jet may, however, be suit-able for vaccination ifa satisfactory immune responseoccurs when most but not necessarily all of the0-1-ml dose of vaccine is deposited in the skin.'Hence, jet injection is satisfactory for booster dosesof killed vaccines (British Medical Journal, 1970a, b).

(b) Oral vaccines: local tissue vs systemic protectionOral killed typhoid vaccine being tested in a

controlled field trial contains 1011 organisms ineach dose and three doses are given to each volun-teer. The serological studies carried out with thisvaccine have shown that it gives rise to circulatingantibodies 0, H, Vi but preliminary results in afield trial in India, as well as in volunteers, in the

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United States of America, did not show significantprotection.

... . Field trials and laboratory studics on animalsare under way to elucidatc Iccal intestinal immunityin enteric infcotions and possitle applications of oralvaccines in immunization against typhoid' (WorldHealth Organization, 1964-68).Newcomers to this field of immunology may tnink

that oral typhoid vaccines are something recent, oreven avant garde. It is true that the recent spurt ofimmunology, which is now a discipline in its fullrights, had focused attention on gut immunity inentcro-bacterial discases and entero-viral infections,and nasal mucosa immunity in the casc of respiratoryinfections, nc;ertheless possibly because of the caseof administration and general convenience whichwould accompany the introduction of a successfuloral vaccine, from a comparativelv early date in thehistory of entcric fever vaccines, research workershavc expei-imented and tried their best to produce anefficacious oral vaccine, which may be callcd theimmunological equivalent of the contraccptivc pill!Other advantages which would ensue from this

technique of administration arc freedom frominoculation hepatitis and post-vaccination reaction.Thus, we find an oral inactivated vaccine popu-

larized in France fully 50 years ago; Besredka(1919-1921) conducted the preliminary experimentalwork in animals, 'in experimental typhoid, para-typhoid or dysentery infection in rabbits, he effc-tively immunized the animals by the oral route withliving cultures, or with dead cultures given witlh adose of bile sufficiently mild to damage the mucosa.From observations that, during repeated oral im-munization, agglutinins appeared only transiently inthe blood, though the animal continued to bc resis-tant to oral challenge, he postulated not only thata local immunity had been cstablished independentlyof a general response, but that, since the intestinewas the chief susceptible tissue in these diseases, thelocal immunity was the determinant of the generalimmunity of the animal.'As can be seen from the WHO Research Pro-

gramme, 50 years later investigations are still pro-ceeding today under field conditions. As regardsdead oral vaccines it has been shown by a group ofRoumanian workers that 'oral administration of aTAB vaccine cad afford a considerable degree ofprotection to young chil,dren'. These workers addedthe rider that antityphoid paratyphoid vaccine by theoFal route could be combined with subcutaneousirioculatioh-the combined ol mixed method. Thisis based on the reasoning that 'after the creatioft ofthe local immunity of the intestine6 arty further in-crease in general immunity can be obtained only bythe intioduction of the antigen after a suitableinterval by parenteral route' (Vladtianu et al., 1965).

But oral imm1Lniz.tion vith live Xntityphoidvaccines lhas bcen considered promising by somic;I assume that if one could but colonizc the humangut with non-pathogcnic coliform crganisms carryingthe varied assortment of antigens found in S. typhiand S. paratyphi A and B then one could per'lapsmake the gut protect itself against invasion by thcenteric feier organisms, and in so doing protect thewhole body against bactcrial invasion which is theprerogativc of those dangerous organisms.One would havc to investigate, of course, the

phenomr.cna resulting from such intervention, indepth and at length; as in many other activities inthe field of medicine, so also in vaccine prophylaxisthere may be more than one facet to this problc.m.Thus, while onc is apt primarily to think of protec-tive immunity as the end result of giving a vaccinc,it must not be forgotten that the vaccince is sensi-tized (allergized) by such an intervention, and maymount a disastrous allergic reaction, 'against anti-genic products of infecting micro-organisms whichotherwise are quite non-toxic and only c omepathogenic by virtue of initiating allergic reactionsresulting in tissuc damagc'. This is the opinion ofProfessor Gell and Professor Coombs who cite intera/ia the cxperimental wiork of Matsumura whosucCc.dcd in producing a shigellosis infcction nlaboratory animals, normally refractory to Shigel iorganisms, by first sensitizing them by colonicinfusion with Escherichia coli, serotypc 0-13, whichlhas a common antigen with Shigella flexneri, and theobservations of Buxton and hiis colleagues whoattributed the pathog,e.nesis and symptomatology ofSalmonella gallinarum infections in birds not somuch to toxaemia. as to manifestations of anallergic nature. Similar factors are suggested as beingoperative in other salmonella infections includingS. typhi infections in man (Gcll & Coombs, 1968).

In experimental work carried out in the U.S.A.,Cvjetanovic, Mel & Felse;Ifeld (1970) conclude that'live orally administered vaccine prepared from astreptomycin dependent strain of S. typhi, especiallywhen administered with small doses of streptomyciri,may protect chimpanzees to a certain degree againstchallenge with live wild-type S. typhi'.For the benefit of the uninitiated it must be re-

marked that it has been found impossible, unfortu-nately, to produce in ordinary laboratory animalssuch as mice, rats, rabbits etc. a typhoid fever corre-sponding to the human infection; chimpanzees,though expensive, have been found to be the mostsuitable animals, for experimental work with typhoidorganisms, and other micro-otganisni§ causinghdman infectidng.

The Widai test (serologic tests after vaccination)'It is almost impossible to assign positive of

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negative values to arbitrary titres in any agglutinationtest because of a group of variable factors, such aspast history of infection, vaccination, time at whichspecimen was taken, and naturally occurring agglu-tinins, .. . only a rise in titre over a period of time isdefinitely significant' (Bailey & Scott, 1970).TAB vaccination is followed by a rise of serum

antibodies in the vaccine. If the HKP vaccine hasbeen used both H and Oantibodies will appear inblood, and ifAKD vaccine has been inoculated thenVi antibodies will appear in addition to H and Oantibodies; this is in consonance with what has beensaid in previous paragraphs about the characteristicsof these two vaccines.

It follows therefore that a successful vaccinationand revaccination programme in a community or anorganization, though highly advantageous from thepreventive medicine point of view, may result indifficulties as regards the interpretation by thebacteriologist of the results obtained in the serologictests for enteric fever, i.e. the Widal test. Fortunatelymodern bacteriological methods for the isolation ofthese organisms are highly successful; neverthelessthe Widal test remains a valuable weapon in theserologist's armamentarium (Felix, 1950).

In the Widal test, to a series of doubling dilutionsprepared from the patient's serum, various suspen-sions of bacilli containing H antigens or O anti-gens or Vi antigens are added, mixed and incubated,and observed for agglutination reactions.

(a) H antibodiesAfter vaccination these can be detected for many

years and hence these are not much in favour as adiagnostic index for salmonellosis, besides once thebody has been sensitized a rise of H agglutinins mayalso occur in response to any irritation of theimmunological mechanism even by non-entericorganisms-hence the anamnestic phenomenonwhich is a trap for the unwary and causes confusionand misdiagnosis.

'The residual TH antibodies resulting from TABinoculation interfere seriously with the serologicaldiagnosis of the acute disease. Moreover, thepresence of TH antibody in the serum of febrilepatients who have been inoculated with TAB vaccinehas sometimes resulted in a false diagnosis of typhoidfever' (Anderson & Gunnell, 1964).These authors, in a stimulating and thought-

provoking paper, very ingeniously suggested that apossible way out of these diagnostic difficulties is to(i) produce a vaccine from non-motile strains oftyphoid and paratyphoid bacilli-thus eliminatingthe H antigens int he vaccine. 'The general adop-tion of a non-motile vaccine strain will ultimatelyresult in the emergence of a population, immunizedagainst typhoid fever, but unencumbered with post-

inoculation TH antibodies.' (ii) Because somepatients may never be quite certain of their immunitystates, the incorporation of a rare 'exotic' flagellarantigen. 'The corresponding H suspension could beincluded in the routine Widal test, and the presenceof homologous agglutinins would indicate withcertainty that the patient had been inoculated againsttyphoid fever with the "non-motile" vaccine. Thiswould be detectable even if the patient had previouslybeen inoculated with the vaccines in current use'.

(b) O antibodiesThese disappear moderately rapidly after vaccina-

tion, so that the presence in a patient's blood of Oantibodies in any notable amount (say over 1/160)even in a vaccinated person is significant and woulddenote a recent infection. The test for O antibodiesbecomes progressively and directly more valuable thelonger the period of time that elapses after vaccina-tion or revaccination.

'Rarely have O titres as high as 1:160 beenfound in serum of vaccinated individuals unlessvaccination against typhoid has been very recent(within 7 months). Agglutination titres with the Oantigen in normal uninoculated persons have usuallybeen low. Occasional high titres may have been dueto such persons being carriers' (Hac, Flynn & Perry,1939).

(c) Vi antibodiesHKP vaccines do not compromise to any meaning-

ful extent the diagnostic value of the Widal test sinceas we have seen the preparation of vaccine by thismethod damages or denatures almost entirely theantigens of the S. typhi; exactly the opposite holdsgood for the AKD vaccine whose 'Vi' factors arepreserved by the acetone treatment.

Therefore, so far as the British Forces are con-cerned, even though all personnel are inoculated atregular intervals, the use of a 'Vi' agglutinationsuspension in the serological diagnostic tests hasmuch to recommend it; in an uninoculated popula-tion this is even more so. If a relatively high titre ofVi antibodies is detected (and Vi antibodies are notfound to the same numerically high figures as thosefound in H and O antibodies) then the patient canbe regarded with great probability as having beeninfected with a Vi-carrying S. typhi at the time hisserum was taken.The attention of the reader is drawn to the fact

that Vi antigens are not the sole and unique propertyof S. typhi; other Salmonellae and Enterobacteriaceaemay carry this surface (?capsular) antigen: 'manycoliform bacilli contain more Vi antigen than theaverage strain of the typhoid bacillus' (Wilson &Miles, 1964).

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The same applies more or less to H and 0 anti-genic factors. These antigenic cross-affinities haveposed difficulties in the application of diagnosticfluorescent microscopy to the study of enteric infec-tions (Thomason, Cherry & Edwards, 1959).

It is my rule of thumb in army bacteriologypractice to place great diagnostic value on Vi titresover 1/30; to regard as of doubtful and little sig-nificance titres below 1/10, and to consider all factorsand retest sera from patients showing a titre betweenthese values.To summarize, as far as inoculated persons are

concerned.(a) H antibodies-often a trap for the unwary.(b) 0 antibodies-useful for diagnosis, titre above

1/160.(c) Vi antibodies-useful for diagnosis, titres 1/30

and above.(d) Above all the golden rule of all serologic

diagnostic tests should be followed, that is to say, totest under exactly the same conditions, paired speci-mens of sera, or possibly a series of sera taken atappropriate intervals, and watch for difference intitre, either a significant (four-fold) rise in titre, orless usually a dramatic fall.

Provocation typhoid (vaccination during epidemics)'Provocation' typhoid refers to what has been

called also the 'negative' phase after vaccination,when for a period the resistance of the body may belowered as the result of an immunological toxaemicinsult consequent upon the administration of theforeign antigens.To vaccinate or not to vaccinate? This is the

question that sooner or later the specialist in pre-ventive medicine has to answer when confronted byan epidemic of enteric fever: '. . . in dealing with alargely unprotected civilian population because ofthe delay in building up any significant immunity,and possible interference with the diagnostic valueof the Widal test, TAB vaccine is not recommended'(Department of Health and Social Security, 1968).

Fortunately the armed forces with their attentionto and supervision of TAB vaccination programmesof personnel under their care are in a happier posi-tion than most civilian communities and organiza-tions, the advice proferred is that a reinforcing doseof TAB vaccine is to be given to personnel andfamilies. However, in cases of primary vaccination,exception is made in the case of unprotected closecontacts with known cases of enteric fever, whenvaccination is withheld as the 'vaccine would beunlikely to establish a useful degree of immunity intime to combat the risk of infection and its adminis-tration might be a cause of added danger to anindividual already incubating the disease' (Ministryof Defence, 1968). This, in my opinion, is sound

advice in accordance with that fundamental principleof medical ethics on which we all have been nur-tured-Primum non nocere, above all see that youdo no harm! I feel that this advice is to be preferredto that held by another school of thought whicheither does not accept the initial depression ofimmunity following vaccination or does not regardthis negative phase as a contra-indication to vac-cinating persons who may be incubating the disease.As a matter of fact, much can be said, and has

been said on both sides of this dilemma.In favour of vaccination the 1965 Control of

Communicable Disease Handbook, tenth edition,issued by the American Public Health Association,and used extensively as a reference handbook bymany doctors in diverse fields of medicine, advisedsuccinctly: 'Immunization of contacts: administra-tion of typhoid vaccine to family, household andnursing contacts who have been or may be exposedto cases or carriers'; whereas this handbook in its1970 (eleventh) edition is not so dogmatic and leavesthe question begging, stating that 'administration oftyphoid vaccine in these cases is of dubious value'!And that veritable Bible of British bacteriologists,

Topley & Wilson's Principles (1964), warns 'Thereis reason to believe that vaccination during the latterpart of the incubation period of the disease may,instead of protecting, induce the opposite result,namely the so-called provocation typhoid. Thisdanger is often decried but there is reason to believethat it is substantial. When typhoid fever beginswithin 2 days of an injection of TAB vaccine,the onset tends to be sudden and the course in mostcases severe'.The reader who is interested to learn what are the

expert pros and cons of this particular facet of TABvaccination is referred to Sir Graham Wilson'sproscriptive compendium on the hazards of immu-nization from which treatise one can appropriatelyquote in concluding this paragraph, 'For the presentwe must leave the question unanswered, at least asfar as typhoid fever is concerned' (Wilson, 1967).

Conclusion(a) The acetone-inactivated typhoid vaccine

(AKD) is the best preparation at present available;it is not possible to say whether or not in the futureit will or it will not be supplemented or supplantedby an oral inactivated/attenuated vaccine.

(b) More laboratory experimental work and fieldstudies are necessary as regards the paratyphoidcomponents of the TABC vaccines; on the currentopinion these should be:

(i) eliminated from the presently used polyvalentTAB (TABC) vaccine, to lessen undue post-vaccina-tion reactions or

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(ii) specially prepared for organizations, such asthe armed forces, members of the diplomatic corps,and individuals belonging to missionary or com-mercial organizations with world-wide commit-ments, where a need for these polyvalent vaccinesexists; or

(iii) tailor-made for localities where paratyphoidfevers are endemic, or the possibility of an epidemicexists.

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