Immunization Against Diphtheria, Pertussis (Whooping Cough) and Tetanus in Canada: The Benefits from the Use of Adsorbed Vaccine

Immunization Against Diphtheria, Pertussis (Whooping Cough) and Tetanus in Canada: TheBenefits from the Use of Adsorbed VaccineAuthor(s): JACK CAMERONSource: Canadian Journal of Public Health / Revue Canadienne de Sante'e Publique, Vol. 73, No.6 (NOVEMBER/DECEMBER 1982), pp. 404-409Published by: Canadian Public Health AssociationStable URL: http://www.jstor.org/stable/41987879 .

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Immunization Against Diphtheria, Pertussis

(Whooping Cough) and Tetanus in Canada: The

Benefits from the Use of Adsorbed Vaccine

JACK CAMERON

The Stackiw report in

and this

Drewniak1 journal by Sekla,

draws Stackiw and Drewniak1 draws attention to the fact that in Manitoba about 3 1 % of children aged 2 to 3 years do not have the recognized protective level of at least 0.01 I.U. (International Units) of diphtheria antibody in spite of receiving four doses of DPT vaccine and that about 31 % of children similarly vaccinated may be inadequately protected against whooping cough (pertussis). These findings, particularly in the case of diphtheria, confirm earlier reports from Ontario2 and Quebec.34 Sekla et al. 1 suggest two possible remedies: further injections of fluid (plain, non-adsorbed DPT) vaccine or the use

of adsorbed vaccine. The latter is the correct choice and indeed is recommended by the National Advisory Committee on Immunization.5 Ad- sorbed DPT vaccine is used worldwide and it is difficult to understand why its use has not evolved more quickly in Canada. The U.K. was slower than most countries to accept it because of concern that the use of adsorbed vaccines in general might induce paralytic poliomyelitis - provocation poliomyelitis.6 The risk was felt to be minimized when fluid diphtheria toxoid or plain pertussis vaccine i.e. non-adsorbed preparations, were used singly. These findings were not generally accepted7 but in 1 957 the Ministry of Health in the U.K. recommended that non-alum- precipitated (non-adsorbed) antigens be used to immunize against diphtheria and that they not be combined with other antigens.8 That concern now seems to be no longer valid, probably because such a high proportion of the community is protected against poliomyelitis; adsorbed vaccine has now been in use in the U.K. since 1968. 9

The most obvious benefit from adsorbed toxoids is that, for the same amount of antigen, they give antibody- responses far exceeding those possible with plain or non-adsorbed toxoids. ,0'n Adsorbed toxoids usually give responses 10 to 50 times greater than non- adsorbed. Another suggested benefit is that the level of immunological memory induced by a first injection may deter-

mine the ability of the host to react there- after to subsequent injections.12 Par- ish13 suggested that a first injection should be large, referring to its content of toxoid rather than to its volume.

The present report reviews the development of adsorbed diphtheria and tetanus toxoids and the advantages of their routine use. Pertussis vaccine is also discussed, particularly the role of agglutinins.

Diphtheria Toxoid Sekla et al. found that 136 of 205

children (66%) in Manitoba aged 2 to 3 years given three doses of fluid (non- adsorbed, plain) DPT vaccine had less than 0.01 I.U .of diphtheria antitoxin per ml of serum, the minimum accepted protective level. Of 1044 children of the same age, given four doses of vaccine, 571 (55%) had less than 0.01 I.U. In a similar survey in Ontario, MacLeod et al.,2 found that 37 of 186 children (20%) aged 4 to 6 years given three doses of fluid DPT vaccine had less than 0.01 I.U. as had 89 of 526 (17%) given four doses, 19 of 274 or 7% given five doses and 3 of 66 or 5% given six or more doses. In older age groups, 76 of 1262 (6%) aged 11 to 13 had less than 0.01 I.U., 79 of 131 1 (6%) aged 15 to 17, and in adults aged 23 to 45, 553 of 1229 (45%): in these groups the number of doses of vaccine given was not known. In a Quebec survey Frappier-Davignon, Quevillon and St-Pierre3 found that, of 41 children aged 3 to 4xh years who had

Institut Armand-Frappier, Université du Québec, 531 Boulevard des Prairies, Case Postale 100, Laval-des- Rapides, Québec, Canada, H7N 4Z3.

404 Canadian Journal of Public Health Vol. 73, November/December 1982

A brief review is given of the development of adsorbed diphtheria and tetanus toxoids and of their use as components of adsorbed DPT ( diphtheria , pertussis , tetanus) vaccine . The value of agglutinin - reponses to the pertussis component in assessing immunity to whooping cough is also discussed . It is suggested that adsorbed DPT vaccine be the vaccine of choice for use in childhood immunization programmes and adsorbed diphtheria and tetanus toxoids , separately or combined , when pertussis vaccine is contraindi - cated.



received three or four doses of DPT vaccine, 5 out of 41 (12%) given three doses and 8 out of 175 (5%) given four doses had less than 0.01 I.U. of diphtheria antibody. Lavergne et al.4 found that 186 of 616 teenagers (30.2%) had less than 0.01 I.U.; however, it was not clear how many doses of vaccine had been given.

These figures show that in Manitoba, Ontario and Quebec, protection against diphtheria is incomplete in all age groups, being least in pre-school children and young adults. All the subjects in these surveys had received vaccine containing 30 to 50 Lf of diphtheria toxoid per dose.

On the other hand, Bousfield14 found in England that 57 children aged one year given one dose of adsorbed diphtheria toxoid containing 3 Lf were Schick-negative15 - another accepted method of determining immunity - one month after injection; given a second injection of adsorbed toxoid when Schick-tested, they were still Schick-negative two years later. The results from other studies were essentially the same and the superiority of adsorbed toxoid seemed clear.1617 Schick-testing, however, requires the intradermal injection of diphtheria toxin. Diphtheria toxin, moreover, is a powerful immunizing agent in its own right and Bousfielďs results141617 are open to the objection that the injection of diphtheria toxin in Schick-testing almost certainly gives a further boost to the immune-response in addition to that given by the second dose of adsorbed toxoid. Acknowledging this objection, the Diphtheria Committee of the Medi- cal Research Council in 1962 carried out a trial in 93 infants aged 6 to 12 months in which two or three doses of fluid toxoid were injected, each dose containing 60 or 300 Lf of toxoid, and in which immunity was assessed by antibody-tit re rather than by Schick- conversion. Serum samples from the children 4 to 14 weeks after the second injection showed 31 (33%) to have less than 0.01 units of antibody. The committee expressed its concern by stating that "the highly purified material pre-

pared at the present time is not suitable for primary immunization against diphtheria."18 The use of adsorbed vaccine containing not less than 25 Lf of toxoid is now officially recommended for primary immunization in the U.K.19 As in Canada today, concern over poor immune-responses and poorly maintained immunity prompted the well documented studies which showed clearly the superiority of adsorbed toxoid. 14'16>17'20'21 The fact that the work was carried out more than 30 years ago makes one wonder why the relative merits of the two toxoids, non-adsorbed (plain, fluid) and adsorbed are still being discussed.

It is perhaps true to say that the history of adsorbed diphtheria toxoid is the history of the development of adsorbed vaccines, beginning with the studies of Glenny and Barr on the adjuvant effect of aluminium salts22,23, of Pope and his colleagues on the preparation of highly purified diptheria toxoid24 30 and of Holt20 on the preparation of adsorbed toxoid. These groups provided data from laboratory studies in guinea pigs and subsequently in infants which helped to determine the antigen content, aluminum-content and dosage-schedule for adsorbed toxoid which today is largely used as originally formulated.

Similarly improved responses to adsorbed toxoid occur in man. The comparison between the performance of adsorbed and non-adsorbed diphtheria toxoid is well documented.141617

Apart from aluminum, as hydroxide or phosphate, Bordetella pertussis is also believed to act as an adjuvant for both diphtheria and tetanus toxoids so that in non-adsorbed DPT vaccine there is thought to be this further activ- ity to enhance responses to the toxoids. This is accepted in the 1962 M.R.C. report18 which, while stating that fluid diphtheria toxoid was unacceptable by itself, said that it was acceptable if combined with pertussis vaccine. The role of B. pertussis as an adjuvant for diphtheria and tetanus toxoids, is in my view questionable.31 When diphtheria toxoid is adsorbed on an aluminum salt, how-

ever, its potency is so increased that it cannot be measured in the same system as non-absorbed toxoid.10 Such is not the case with diphtheria toxoid in the presence of pertussis vaccine: the potency of the toxoid by itself, and as a component of DPT vaccine, is measured in the same system10 so that if there is any adjuvant effect from pertussis vaccine it is probably rather little. The question of adjuvant action in general was recently reinvestigated32 and though the value of aluminum salts was confirmed the effect of endotoxin (lipopolysaccharide) as an adjuvant was at best minimal. Since the adjuvant effect of B. pertussis is believed to be mediated through its endotoxin or lipopolysaccharide component, perhaps the adjuvant effect of endotoxin on diphtheria and tetanus toxoids should be reinvestigated especially as to possible differences between endotoxins and their efficacy as adjuvants.

Is there an explanation for the appar- ent loss of efficacy of a prophylactic which in the 1920s so effectively brought diphtheria under control in Canada?32 33 34

One possibility lies in the design of the potency-test itself.10 This requires that a group of healthy guinea pigs of standard weight and injected with one sixth of the total human immunizing dose, usually 1 5 to 25 Lf, shall survive a challenge of 10 MLD (minimum lethal doses) of toxin, six weeks after immunization. In my experience few, if any, lots of diphtheria toxoid fail to pass this test. The test, however, is not quantitative and cannot discriminate between lots of toxoid which may be barely acceptable and lots which may pass the test by a wide margin. In a recent review of the performance of one toxoid over a number of years, I found that its potency, as measured by the standard assay, fell from being able to protect against a challenge of 100 MLD of toxin to being able to protect against 12 MLD. Thus it remained acceptable but of reduced potency. This variation in the antigenicity of diphtheria toxoid is well documented36-39 and will not be discussed further but it must be borne in

November/December 1982 405



mind when discussing the standardization of diphtheria toxoid and certainly before less tangible explanations for failure to protect such as a change in the nature of the disease, changes in the population at risk, use of a too highly purified toxoid, all of which have been suggested at different times. The early history of the standardization of diphtheria prophylactics is well described by Parish.40

Immunization against diphtheria carries with it the risk of sensitization to the antigen itself, more often encoun- tered with diphtheria toxoid than with tetanus toxoid, rarely with pertussis vaccine. When a series of injections is given, as with the five injections of DPT vaccine recommended in Canada for children before school-entry and, more particularly, for booster-injections in adults, there is always the risk of sensitization. This can be detected by a Schick-test which should always be carried out when the injection of diphtheria toxoid into adults is being considered. The risk of sensitization also increases with the number of injections of toxoid: by minimizing the number of injections necessary to ensure an adequate level of circulating antibody, the use of adsorbed toxoid largely obviates the need for Schick-testing. As a further consequence, it also reduces the demand on medical and paramedical services. The sero-conversion rate from Schick-negative to Schick-positive can be related to the quantity of aluminum phosphate (adjuvant) on which the toxoid is adsorbed.14 Conversion-rates exceeding 90% were recorded with a vaccine containing 5 Lf of toxoid and 5 to 7.5 mg of aluminum phospate (adjuvant) 1 . 1 1 to 1 .66 mg of aluminum). The maximum level of aluminum allowed today, whether its source be alum, aluminum hydroxide or aluminum phosphate is 0.82 (U.S.) and 1.25 (W.H.O.) mg per dose of vaccine.1011 41

Another approach to the question of sensitization is that followed in the U.S. where an adsorbed product containing 10 Lf of tetanus toxoid and only 2 Lf of diphtheria toxoid is available for use in adults.42 The low content of diphtheria

toxoid avoids the risk of provoking a hypersensitivity-reaction and also obviates, to a large extent, the need for Schick-testing. The diphtheria toxoid of this product has to be of a specified purity, a requirement not made for the diphtheria toxoid component in DPT vaccine: presumably this, in addition to the low content of toxoid, is to reduce the risk of hypersensitivity reactions.

Tetanus Toxoid Tetanus toxoid is regarded as a good

antigen and three doses of 10 Lf of a fluid toxoid give an acceptable antibody response in most subjects.12'3'4 Like the response to fluid diphtheria toxoid, however, it is not maintained for long at a high level although in most subjects immunological memory is usually well enough established to enable a subject to respond within days to a second injection. Adsorbed toxoid has the advantage that it gives both better memory and better and longer lasting protection for the injection of the same or even less toxoid, 5 to 10 Lf per dose compared with 8 to 10 Lf for fluid toxoids.

As with diphtheria toxoid, the primary immune response i.e. the response to the first injection, is a function of the concentration of antigen, of adjuvant and of their interaction.43 Hence, again, the importance of the nature of the first injection.12 Comparative data on plain and adsorbed tetanus toxoid for the immunization of pregnant women to prevent tetanus of the newborn ( teta - num neonatorum ), showed that two injections of 20 Lf of fluid toxoid gave antibody titres of less than 0.01 units in 24 of 37 subjects 74 days after injection, whereas two injections of 20 Lf of adsorbed toxoid gave titres ranging from 0.01 to 100 units in 35 of 46 subjects 68 days after the second injection. Only three subjects in the group pro- duced less than 0.01 units. In discussing neonatal tetanus a comment such as "80 to 90% protection" means that the other 10 to 20% of infants may die! The phe- nomenon of herd-immunity does not exist in tetanus. Every subject at risk must be protected individually. For the

assured prevention of neo-natal tetanus in developing countries every pregnant woman must have at least 0.01 I.U. of antibody, the minimum accepted protective level. This ensures the same level in the newborn child as in the cord- blood and thus a protected infant. Fol- lowing two injections of an adsorbed toxoid, given at least six weeks apart, a protective titre in about 90% of subjects was expected to be maintained for as long as five years after vaccination.46 The vaccine in this study contained 10 Lf of toxoid per dose of 1 ml.

Four adsorbed toxoids containing different amounts of toxoid and adjuvant were then examined to study the interplay of these two components.43 In the "virgin" group of 58 subjects, tested 4 weeks after two injections of adsorbed toxoid, 57 had antibody titres greater than 0.01 I.U. per ml. Ten months later the picture was essentially the same: one "non-responder" who had 0.02 I.U. before her second injection had 0.0025 I.U. when bled 10 months after this second injection. Thus the advantage of adsorbed toxoid is clear although perhaps not so striking as in the case of diphtheria toxoid.

As in the case of diphtheria toxoid, the use of tetanus toxoid carries with it a slight risk of sensitization and in this situation there is no agent corresponding to Schick toxin for detecting immune subjects. The risk is common- est in hospital emergency departments where toxoid may be injected without knowledge of the subjects immune- status, and also in subjects offered vaccination in industries where tetanus is regarded as an occupational hazard. These subjects are usually adults and may already have had at least five injections of tetanus toxoid. Edsall, Elliot, Peebles, Levine and Eldred47 have drawn attention to the possible dangers of over-immunization against tetanus. For practical purposes, a course of three injections of absorbed toxoid containing 5 to 10 Lf per dose, a primary course, followed by a further two injections before school-entry should guarantee protection in the majority of cases until subjects are well into their teens.

406 Canadian Journal of Public Health Vol. 73



Edsall48 observed antibody-levels 40 to 2500 times above 0.01 I.U. in children aged 4-17, and posed the valid question whether there may be an excessive use of tetanus booster injections. As a commentary on the efficacy, or perhaps over-efficacy, of adsorbed toxoids, Peebles, Levine, Eldred and Edsall59 calculated that four or more injections of adsorbed toxoid will give a level of antibody which will not fall below 0.01 units for 30 years. Thus the dilemma with tetanus is not so much an inability to immunize as a risk of over- immunizing.

A possible benefit from such a situation is the likely presence in a group of blood donors of some with high tetanus-antibody titres. Given that there is no ethical objection, such donors, once identified, could perhaps be regarded as a source of plasma for the isolation therefrom of tetanus immune globulin (T.I.G.) This might, in turn, even obviate the need to immunize subjects solely for the provision of T.I.G.

As to the age group most likely to contract tetanus, according to a survey carried out in the U.K. in 197750 it is 50 years and older.

Pertussis Vaccine The situation with pertussis vaccines

is less straightforward. Sekla et al. 1 refer to the failure by 31% of infants given four doses of DPT vaccine to produce agglutinins against B. pertussis and consider this to show that the infants are inadequately protected. Absence, or even presence of agglutinins, however, is not necessarily a reliable indicator of immunity. Perhaps the classical situation is to be found in salmonella infection where, for many years, remarkably high-titre antisera against the group, type, flagellar and phase antigens have been used for identifying salmonella types. At no time was it ever shown that the animals in which such antisera were raised were immune to salmonellosis.

In the case of pertussis infection, clinical trials in the United Kingdom5153, raised doubts about the significance of agglutinin-production. Towards the

end of these trials Evans and Perkins54,55 felt that this data warranted a recom- mendation that agglutinin-production in mice be regarded as a measure of the potency of pertussis vaccines and, by inference, the immune-state (Perkins, personal communication). However, the extract-vaccine developed by Pille- mer56 and used in the trial was one of the most potent vaccines in the trial and was also non-agglutinogenic.52 Fortunately, a correlation was established during the trial between protection in mice - the mouse-protection test57 58 - and protection in infants52»53 and this led to the adoption of the mouse-protection test as the accepted method of measuring the potency of pertussis vaccines. This is the situation today: the ability of a pertussis vaccine to protect mice is the only accepted measure of its potency. Subse- quently however, adsorbed vaccine was found to give much better agglutinin- responses in both hosts than non- adsorbed vaccine59 and it seems to be from this point that the agglutinin- response was taken to indicate a measure of protection. Adsorbed vaccines, however, do not protect better in the mouse-protection test than non- adsorbed vaccines60 and so agglutinin- production cannot be accepted as a measure of immunity. The reason for not accepting agglutinin-production as an indicator of protection against pertussis following the injection of adsorbed DPT vaccine is different from that given for not accepting it as an indicator of protection in the M.R.C, trials. In the latter case a non- agglutinogenic vaccine, the Pillemer antigen56, protected thus invalidating any suggestion of correlation between agglutinin-production and protection. In the present situation adsorbed vaccine gives better agglutinin-responses but not better protection in mice, so again, agglutinin-production has to be rejected as an indicator of protection.

Nevertheless, the agglutinin-response is better to adsorbed vaccine. This makes it important when commenting on such responses to know if the data relate to the use of adsorbed or non- adsorbed vaccine. In the U.S. adsorbed

vaccine is widely used. Experience in such a large population will clearly make it possible in time to suggest a minimum agglutinin-titre as represent- ing exposure to vaccine and also possi- bly protection. It is important to realize that the work referred to by Sekla et al. regarding the interpretation of agglutinin-titres61 refers simply to U.S. experience with adsorbed vaccine. While no such corresponding data exist on such a scale for non-adsorbed vaccine, 8 out of 1 8 infants failed to develop agglutinins to pertussis after three injections of non-adsorbed vaccine.62

All vaccines contain, within narrow limits, the same number of bacteria per dose:41,58 thus, whether a vaccine be protective or not, the agglutinin-responses are likely to be the same since they arise essentially from the bacterial content of lipopolysaccharide and to a lesser extent from the more labile capsular antigens, none of which are involved in inducing protection.63

Is there any real benefit in using adsorbed pertussis vaccine? On balance the answer is probably "Yes". Whenever non-adsorbed and adsorbed pertussis vaccines have been compared in children it has been found that by localizing the bacteria at the site of injection, adsorbed vaccine reduces the incidence of a number of sequelae - fretfulness, crying, fever, anorexia, sore arm - which cause distress both to infants and to parents.64 Less important, but still to be considered, is that from a practical point of view the logistics of using one vaccine consisting of adsorbed diphtheria and tetanus toxoids and a second non-adsorbed pertussis vaccine, where the number of injections is doubled, can hardly be contemplated.

DISCUSSION In Manitoba, Ontario and Quebec, up

to 3 1 % of children up to the age of three years have less than 0.01 I.U. of diphtheria antitoxin or antibody per ml of serum, the recognized minimum level needed to guarantee protection.12'3*4 This arises from the use of fluid or non- adsorbed diphtheria toxoid. Were adsorbed toxoid to be used much higher levels would be achieved. Antibody levels




to tetanus are acceptable although, again, the use of adsorbed toxoid will give yet higher levels. The report from Manitoba1 also interprets poor or non- existent agglutin-titres to B. pertussis as evidence of lack of immunity against whooping cough (pertussis). This is not necessarily so but again, the use of adsorbed vaccine will give agglutinin- responses in the great majority of children and will make it possible to grade the present 31% of non-agglutinin- producers.

Adsorbed vaccines, particularly DPT vaccines, are widely used throughout the world, both in developed and in developing countries and it is difficult to understand why they are not more widely used in Canada. It is all the more difficult to understand in the case of diphtheria when it is realized that diphtheria was first successfully controlled with toxoid in Canada.34 This was in the 1920s and 1930s and since then diphtheria has simply not received the attention it merits. Nevertheless, even in populations where adsorbed vaccine is used diphtheria still occurs, usually in people with questionable vaccination histories or where several unvaccinated families live in proximity.65,66 It is an ever present danger and increased antibody-levels through the use of adsorbed toxoid should be aimed at it.

There is the view that if sufficient injections of fluid toxoid are given, acceptable antibody-levels will be achieved. 1 Whilst true in some cases this is not a valid generalization. Moreover, it introduces the possibility of sensitization, well recognized in the case of diphtheria toxoid, less so in the case of tetanus toxoid. Again, the use of adsorbed toxoid achieves the double objective of enhancing antibody-responses for fewer injections of less toxoid and at the same time largly obviates the risk of sensitization. Moreover, if Trinca's studies with tetanus toxoid are validated12 not only will the merits of adsorbed vaccine be demonstrated but by the same token what might even be called the disservice done to the patient by the use of non- adsorbed vaccine: if the baseline from which the response to second and subsequent injections is low, subsequent injections, whether they be of adsorbed

or non-adsorbed vaccine, may be rela- tively ineffective.

Changes in the nature of the disease, changes in the population at risk (proportion of immigrants, genetic?) the use of too highly purified toxoids leading to loss of potency of both diphtheria and tetanus, have from time to time been suggested to explain what some consider to be a lack of efficacy of these two toxoids. The most tangible of these points, the question of loss of potency, cannot be resolved using the statutory test-systems10'11 because the assays are not quantitative: they are single level, pass-or-fail assays. In my view, much better quantitative assays are needed for both fluid and adsorbed toxoids.

Tetanus toxoid needs little comment. As a non-adsorbed toxoid it is excellent and when adsorbed is even better. The risk of sensitization is less than with diphtheria but its use should nevertheless be well controlled so as to avoid unnecessary sensitization.

Occasionally concern is expressed about the possibility of local reactions caused by the adjuvant in adsorbed vaccine. The amount of adjuvant in a dose of vaccine, usually aluminum hydroxide or aluminum phosphate, is care- fully controlled and the aluminum- content per dose of vaccine must not exceed 0.82 mg in North America. Where a reaction occurs and assuming it is neither idiosyncratic, nor a hypersensitivity-reaction, it is usually because the vaccine has been injected subcutaneously rather than intramuscu- larly. The millions of doses of adsorbed vaccines injected annually throughout the world attest to their acceptability.

Whooping cough vaccine presents quite different considerations. The lack of agglutinins commented on by Sekla et al 1 need not necessarily be regarded as lack of protection. On the other hand, if the observation is made in a population given the same vaccine, non-adsorbed or adsorbed, it is obvious that all other things being equal, those subjects with agglutinin-titres have responded better than those without. Adsorbed vaccine, while not necessarily giving better protection, will certainly give better agglutinin-responses. Most of the present non-responders will become

responders and comparisons will then be possible not only locally but with populations outside Canada, e.g. the U.S. where adsorbed vaccine is in general use.

Although the potency of pertussis vaccine as measured by the mouse- potency test is not enhanced by the presence of adjuvant, the adsorbed vaccine has other advantages which commend it. By localizing the B. pertussis component at the site of injection the adjuvant reduces, to a considerable extent, a number of reactions which upset infants and also parents who see the reactions but can do little to alle- viate them.64

Overall, it will clearly be of benefit to public health programmes in Canada if adsorbed DPT vaccine becomes the vaccine of choice for childhood immunization. While there is not perhaps the same agreement on the use of adsorbed prophylactics in older subjects67, the fact that they contain less antigen and ensure a longer lasting response would seem to commend their use in prefer- ence to non-adsorbed preparations.

REFERENCES 1. Sekla L, Stackiw W. Drewniak M. An Eva-

luation of the Immune Status of Manitobans to Diphtheria, Pertussis and Tetanus. Can. J. Public Health, 1980; 71: 227-280.

2. MacLeod DRE, Ing WK, Belcourt RJ-P, Pearson EW, Bell JS. Antibody Status to Poliomyelitis, Measles, Rubella, Diphtheria and Tetanus, Ontario, 1969-1970. Deficien- cies Discovered and Remedies Required. Can Med Assoc J. 1975; 113:619-623.

3. Frappier-Davignon L, Quevillon M. St- Pierre J. Étude de l'immunité des enfants de trois ans dans la Province de Québec. Union Med Can, 1975; 104: 1386-1392.

4. Lavergne B, Frappier-Davignon L, Burr- Paxton M. Etude de l'Immunité à la Diph-

408 Canadian Journal of Public Health Vol. 73

On présente une brève revue du développement des anatoxines diph- térique et tétanique et de leur usage en tant que composantes du vaccin DCT adsorbé (diphtérie, coqueluche et tétanos). On discute de la valeur des réponses des agglutinines à la composante pertussis pour estimer l'immunité à la coqueluche . On sug- gère que le vaccin D CT adsorbé soit le vaccin de choix pour usage dans les programmes d'immunisation de l'en- fance ou les anatoxines diphtérique et tétanique adsorbées, séparément ou en combinaison , quand le vaccin pertussis est contre-indiqué.



térie, au Tétanos et à la Poliomyélite des Ado- lescents de la Province de Québec, 1976-1977. Union Med Can, 1979; 108: 1-7.

5. A Guide to Immunization for Canadians. Minister of National Health and Welfare, Ottawa. 1980.

6. Poliomyelitis and Prophylactic Inoculation against Diphtheria, Whooping-Cough and Smallpox. Report of the Medical Research Council Committee on Inoculation Proce- dures and Neurological Lesions. Lancet, 1956; 2: 1223-1231.

7. Holt LB. A Re-assessment of the Risk of Provoking Paralytic Poliomyelitis by Mak- ing Prophylactic Inoculations Against Diph- theria and Pertussia. J Hyg, 1959; 57: 150-161.

8. Diphtheria and Whooping-cough Immunisa- tion. Br Med J, 1957; 2: 167.

9. Burland WL, Sutcliffe M, Voyce A, Hilton ML, Muggleton P. Reactions to Combined Diphtheria, Tetanus and Pertussis Vaccine: a Comparison between Plain Vaccine and Vac- cine Adsorbed on Aluminium Hydroxide. The Medical Officer, 12 January P 17-19. 1968.

10. Minimum Requirements. Diphtheria Tox- oid. U.S. Department of Health, Education and Welfare. 1947.

11. Minimum Requirements. Tetanus Toxoid. U.S. Department of Health, Education and Welfare. 1952.

12. Trinka JC. Antibody Response to Successive Booster Doses of Tetanus Toxoid in Adults. Infection and Immunity. 1974; 10: 1-5.

13. Parish H.J. The Future of Preventive Inocu- lations. Lancet, 947; 2: 413-417.

14. Bousfield, G. "Holt's Diphtheria Toxoid (P.T.A.P.): AIPO4 Content, Purity, Ageing and Durability of Immunity. Lancet, 1947; 2: 867-870.

15. Parish H J, Cannon DA. Antisera, Toxoids, Vaccines and Tuberculins in Prophylaxis and Treatment. Fifth Edition, 93-98. E.S. Living- stone, Edinburgh and London. 1961.

16. Bousfield G. Clinical Trials of Diphtheria Toxoid Aluminium-phosphate Precipitated: to Determine optimal Aluminium-phosphate Content. Lancet, 1947; 1: 286-288.

17. Bousfield G. Diphtheria Prophylaxis in Very Young Infants. Lancet, 1949; 1: 1100-1101.

18. Inefficiency of Purified Diphtheria Formal Toxoid in Primary Immunisation against Diphtheria: A Report to the Medical Research Council by its Committee on Diph- theria Toxoid. Lancet, 1962; 2: 149-151.

19. British Pharmacopoeia. Her Majesty's Sta- tionary Office. London. 1980; 2: 870.

20. Holt LB. Purified Precipitated Diphtheria Toxoid of Constant Composition (P.T. A. P.). Lancet, 1947; 1: 282-285.

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Received: April 9, 1981 Accepted: May 26, 1981




Documents

Immunization Against Diphtheria, Pertussis (Whooping Cough) and Tetanus in Canada: The Benefits from the Use of Adsorbed Vaccine