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Hazards of Immunisation

SINCE immunisation has done so much to curbdiseases such as smallpox, diphtheria, and poliomyelitis,anyone who questions its use or points to its possiblehazards may get a hostile reception. One fear is thatdiscussion of the risks may impair the public’s confi-dence in these protective measures and lead to a fall inacceptance-rates and a return to epidemic prevalenceof the diseases. Sir GRAHAM WILSON is well aware ofthese dangers: in his Heath Clark lectures (now pub-lished 1 in expanded form) he says " the book will becriticized on the grounds that digging up of so manyunsavoury facts is neither necessary nor expedient andthat it will merely strengthen the case of antivaccina-tionists ...". Since immunisation is offered to healthypeople to protect them against some future and remote(though serious) illness, a very high standard of safetyshould certainly be demanded; and Sir GRAHAM’S bookis welcome as a valuable historical record illustratinglessons that should be well and truly learned and suggest-ing the need for better methods of surveillance.The hazards of faulty production of vaccine fall into

four groups: return to virulence of an attenuated livingvaccine (nowadays overcome by the use of a seed lotsystem); faulty inactivation, because of failure to attendto the detailed conditions of inactivation that are vital tosuccess or failure in safeguarding the inactivated productfrom contact with the active agent; faults in testing,where large-scale tests at all stages of manufacture areestablished as necessary; and contamination withextraneous agents or toxins. Progress is being madetowards the use of defined substrates for bacterialvaccines and of quarantined animals as a source of cellsfor viral vaccines. In future the use of human diploidcell strains may enable virus vaccines to be prepared in acell population maintained constant by a cell seed systemsimilar to that used for the virus seed. In all these

matters, the lessons of the past have surely now beenlearned; and in this country the licensing authority,through the immunological products control division ofthe Medical Research Council, requires detailed recordsof tests, samples for duplicate testing, approval of methodsof tests, samples for duplicate testing, approval ofmethods of manufacture and control, inspection of

premises, and approval of the experts responsible formanufacture and control. Faults in production shouldbe largely preventable by constant vigilance, especiallyin keeping testing methods up to date, and contaminationof vaccine due to the use of multidose containers orunsterile syringes should also be avoidable now that thedangers are so well known.The second big group of dangers are less tractable,

since they arise from the inherent toxicity of the vaccinesor the special susceptibility of the host. Toxicity is ofthree main types. Firstly, reactions may be due to theexcessive multiplication of a living agent-for example,B.c.G., vaccinia, measles, or poliomyelitis virus. Properlymanufactured and controlled B.c.G. vaccine seems to

1. The Hazards of Immunization. By Sir GRAHAM WILSON, M.D., LL.D.,F.R.C.P. London: Athlone Press. New York and Toronto: OxfordUniversity Press. 1967. Pp. 324. 45s.

produce very few serious reactions, although WILSONbelieves that continued surveillance is required to assessthe risk in previously tuberculin-positive persons, whoare often given B.C.G. during mass campaigns. Measlesvaccines give rise to mild measles and sometimes febrileconvulsions, but the reaction-rate is very much less thanthe complication-rate in the natural disease. The size ofthe risk of measles encephalitis and of subacute sclerosingencephalitis 2 after measles vaccination is not known, butall available evidence shows the frequency of reactions tomeasles vaccine to be insignificant compared with thosedue to natural measles. Not everyone will agree, butWILSON thinks there is no evidence that Sabin strains ofattenuated poliovirus can cause paralysis, although theCox strains have been associated with paralysis. WILSONobserved that the incidence of poliomyelitis within 30days of killed poliovaccine was similar to that within30 days of attenuated poliovaccine. Failures of inactiva-tion of killed poliovirus are equally likely to be of type 1,2, or 3, but the majority of cases associated with theattenuated poliovaccine are due to type 3. Casesassociated with attenuated poliovaccine have beenobserved in almost every country where adequate num-bers of susceptibles have been carefully followed. Theincidence is usually expressed in millions of doses percase, but evidence from Hungary suggests that theincidence is about 1.5 cases per 100,000 susceptibles 3-a small price to pay for the conquest of poliomyelitis,though it does point to the need to improve the type-3component of attenuated poliovaccine. As poliomyelitiswanes, this risk may become unacceptable and lead toreassessment of the use of killed vaccine. Similar prob-lems arise with smallpox vaccination in parts of the worldwhere smallpox is no longer endemic. Many expertsnow believe that smallpox vaccination should no longerbe applied generally because the risks of complicationsof all kinds are so much greater than the risks of contract-

ing smallpox, and because, it is contended, the com-munity can be adequately protected by case-finding andring vaccination. This matter has been discussed latelyby DICK,4 DOWNIE,5 and others. The argument forselective use of vaccinia is strong, provided measures

’ to control outbreaks do not include mass campaigns. because, as WILSON emphasises, it is under these

conditions that the dangers of any immunisation

procedure are greatest. Indeed, experience suggests thatseveral generations of smallpox may go unnoticed before

,

the first case is diagnosed, and that widespread vaccina-tion is then hard to avoid.

: The second group of reactions due to inherent toxicityare those associated with killed bacterial vaccines such as

, T.A.B. and pertussis. WILSON points out that there is

; strong suggestive evidence that the rare neurologicalF complications of pertussis vaccination are related to a

bacterial toxin rather than to the usual post-infectious2. Connolly, J. H., Allen, I., Hurwitz, L. J., Millar, J. H. D. Lancet, 1967,

i, 542.3. Katay, A. Tenth Symposium of European Association against Polio-

myelitis and Allied Diseases. Warsaw, 1964.4. Dick, G. W. A. Progr. med. Virol. 1966, 8, 1.5. Downie, A. W. First International Conference on Vaccines against Viral

and Rickettsial Diseases of Man; p. 475. P.A.H.O./W.H.O. Washing-ton, 1967.

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encephalitis with a presumed neuroallergic basis. Effortsto identify the protective antigens and to reduce toxicityare urgently required for both these vaccines. For

pertussis, most of the signs are that potency and localtoxicity go hand in hand.6The third kind of reaction, arising when the normal

properties of the vaccine operate in susceptible hosts,is due to hypersensitivity. It varies from the cysts whichare associated with alum-containing vaccines, and whichare usually of little importance if the vaccine is givenintramuscularly, to the usually very rare, except withimpure materials, but serious " cold " abscesses arisingafter the use of oily adjuvants. Another type of hyper-sensitivity reaction may follow natural exposure to

measles or the administration of living measles vaccineto children who have had killed vaccine. 7 These

reactions, which may be of the delayed hypersensitivityor Arthus type, are often severe, and they are associatedwith the prior use of killed whole-virus measles antigenwith an adjuvant. They seem to arise when humoralimmunity has waned but sensitivity remains. In a letteron p. 468 Dr. FULGINITI and Professor KEMPE describesevere local reactions of this type; and they have alsoseen " atypical measles " in children who had hadkilled-measles-virus vaccine five or six years before.

Hypersensitivity reactions have also been described forkilled mycoplasma vaccine 8 off low potency; and it hasbeen suggested that they are part of the mechanism ofbronchiolitis due to respiratory syncytial virus. McNEIL 9observed severe reactions in rabbits exposed to vacciniaafter they had been given killed vaccines, and thesereactions were most severe after the use of the least

potent vaccines. These difficulties might be overcomeby more potent and purer antigens. One suggestion isthat the component causing hypersensitivity reactions inmeasles vaccine is removed by the ether treatment 10used in preparing the haemagglutinin vaccine developedby NoRRBY. The most serious of the manifestations ofhypersensitivity are postvaccinal neuritis and encephalitisparticularly associated with smallpox vaccination.As WILSON says, we need more information about

reactions to vaccines and improved methods of sur-veillance both of efficacy and untoward reactions.Doctors in this country must respond to the appeal ofthe Dunlop Committee for reports about reactions tovaccines, although, as the M.R.C. measles vaccine trial 12showed clearly, control observations on unvaccinatedchildren are necessary to achieve the most meaningfulresults about complications of vaccination. All immunisa-tion procedures are a balance between benefits and

risks, and the exact point of balance will be a matter forargument between experts; and it will differ in differentcountries and at different times. In Britain the present6. Muggleton, P. W. Publ. Hlth, Lond. 1967, 81, 252.7. Katz, S. First International Conference on Vaccines against Viral and

Rickettsial Diseases of Man; p. 343. P.A.H.O./W.H.O. Washington,1967.

8. Chanock, R. M. et al. ibid. p. 132.9. McNeil, T. A. J. Hyg., Camb. 1965, 63, 525.10. Hennessen, W., Mauler, R. Lancet, 1967, i, 902.11. Norrby, E., Lagercrantz, R., Gard, S., Carlström, G. Acta pœdiat.

Stockh. 1965, 54, 581.12. Br. med. J. 1966, i, 441.

balance seems about right, though some may disagreeabout the routine use of vaccinia or pertussis vaccines.The balance is under constant review, and changes inthe recommended programmes are to be expected in thefuture 13: they will be a sign of progress, not of officialvacillation.

Alcoholic CardiomyopathyHEART-FAILURE in patients other than the elderly

usually has a well-recognised cause. When raised blood-pressure is responsible, the electrocardiogram and theretinal vessels undergo characteristic changes. Coronary-artery disease is usually accompanied by chest pain andrecognisable electrocardiographic patterns. Congenitaland rheumatic heart-disease give little difficulty; andendocrine causes can now be established with fair

certainty. There remains a small group of patients inwhom no recognisable cause is found. Postmortem

study then usually fails to clarify the reason for themyocardial failure. The descriptive term " cardio-myopathy " is applied in this situation. In this country,BRIGDEN 14 described 50 patients placed in this groupclinically or post mortem, Goodwin et al. 15 a further 56;and Barritt and AL-SHAMMA’A 16 added 13 cases whichcome to necropsy. ALEXANDER

17 calculates that heart-disease of obscure origin made up 2-4% of the populationwith heart-disease in the United States. In a highproportion of the patients, the causes remained quiteunknown. In some a strong family history suggested agenetic background, but BARRITT and AL-SHAMMA’Afound little in the clinical factors or prognosis of thosewith a family history to distinguish them from others.Some patients had evidence of amyloidosis or systemiclupus erythematosus, and in others an association withFriedreich’s ataxia or generalised amyotrophy gave alead. Myocarditis is hard to prove in life.

BRIGDEN and ROBINSON 18 underlined the importanceof alcohol as a possible cause of obscure heart-failure inthis country: they reported 50 patients, of whom 25 died.In the United States, ALEXANDER 17 now analyses a seriesof 100 patients with cardiomyopathy, of whom no fewerthan 83 were judged to be alcoholics. All of BRIGDEN andROBINSON’S patients were heavy drinkers (a continuousdaily consumption for at least ten years of either fifteenpints of beer or one bottle of spirits): 17 of their patientswere in the liquor trade. ALEXANDER defines alcoholismin his patients as the daily consumption of at least fourpints of beer or two shots of whisky. On this basis, 28%of his ordinary hospital admissions were present orreformed alcoholics. This suggestion-that amounts ofalcohol which may perhaps not be regarded as excep-tional may damage the heart-demands carefulassessment.

13. Annual Report of the Chief Medical Officer of Ministry of Health;p. 170. H.M. Stationery Office, 1963.

14. Brigden, W. Lancet, 1957, ii, 1179, 1243.15. Goodwin, J., Gordon, H., Hollman, A., Bishop, M. B. Br. med. J.

1961, i, 69.16. Barritt, D. W., Al-Shamma’a, M. Br. Heart J. 1966, 28, 674.17. Alexander, C. S. Am. J. Med. 1966, 41, 213.18. Brigden, W., Robinson, J. Br. med. J. 1964, ii, 1283.