ACTIVE
IMMUNIZATION:
CURRENT
CONSIDERATIONS
Margaret H. D. Smith, M.D.
Department of Pediatrks and Epidemiokgy, Tulane University School of Medicine, an(i
The Charity Hospital of Louisana at New Orleans
Aided in part by Grant 2E-207 of the National Institute of Allergy and Infectious Diseases.
Based upon a talk entitled “Current Status of Old Vaccines,” presented in a Symposium at the 1962 Annual Meeting of the American Academy of Pediatrics, Chicago, Illinois, October 31, 1962. Dr. Geoffrey
Edsall’s talk on “Passive Immunization” to the same Symposium is the basis of his Review, which will
appear in PEDIATRICS for October.
ADDRESS: (M.H.D.S.) Department of Pediatrics, Tulane University School of Medicine, 14:30 Tulane
Avenue, New Orleans 12, Louisiana.
PEDIATRICS, Septemiwr 1963
REVIEW
ARTICLE
444
T
HE PRAC1’ICAL ASPECTS of immunization have changed in the last few years, and are inevitably destined to changecontinu-ously. Not only does modern science keep
producing newer and more potent vaccines, but the vaccines themselves alter the dis-tnibution of disease agents and thereby the epidemiologic pattern of disease. As Batson and Christie’ have expressed it: “Immuni-zation procedure is a dynamic subject in
need of constant evaluation.”
DIPHTHERIA
Nowhere does this phenomenon seem
more clearcut than in the case of diphtheria.
Whereas 25 years ago a basic course of
im-munization against diphtheria was essential,
repeated natural exposure could be relied upon to boost that immunity throughout later childhood and adolescence. Nowadays the disease itself has become so relatively
uncommon in many areas that we need to
be reminded by articles like that of Doege, Heath, and Sherman2 in a recent issue of
PEDIATRICS that 900 cases of diphtheria do
occur annually in the United States, and that these cases tend to be grouped in states where immunization programs lag. Because of the very scarcity, in most places, of
op-pontunity for natural exposure, there is an
appreciable number of adolescents and adults who, even though immunized in
childhood, has again become fully
sus-ceptible to infection with Corynebacterium diphtheriae. This falling off of immunity with increasing age must account for small
outbreaks of diphtheria among olden people in institutions,3 and for cases in recent years among certain “skid row” groups.4 It is tile reason behind the long schedule of diph-thenia toxoid inoculations recommended in the so-called Red Book of the Academy of Pediatnics. That the Red Book schedule
may, in a future edition, require
modifica-tion with respect to the need for repeated diphtheria booster stimuli is suggested by a recent article by Volk and co-workers, who
reinoculated with DT toxoid a group of
young subjects inoculated 7 to 13 years previously.6 The booster inoculation
con-tamed 2 Lf units of each toxoid; not only were good antitoxin levels achieved im-mediately but they had, 2 years later, not fallen to prebooster levels.
Exposure to live diphtheria bacilli, and perhaps also repeated injections of diph-thenia toxoid, bring on hypersensitivity to the diphtheria bacillus protein contained in subsequent doses of diphtheria toxoid.
Hence the advisability of a special toxoid to be used in adolescents and adults, which would contain only very small amounts of
diphtheria toxoid, to obviate tile necessity,
otherwise present, for performing a
Mo-loney or Zoeller skin test for
hypersensitiv-ity.7 Edsall and his collaborators, following
the pioneer observations of Canadian and
Danish workers, have been largely respon-sible for the development of the preparation labelled “TD”, i.e., tetanus-diphtheria toxoid
REVIEW ARTICLE 445
in preparation recommended for basic im-munization of children. Whether one should
start employing this type of toxoid for booster doses in children of 8 years, or 10
years, or 12 years, is difficult to say. It
de-pends really on the amount of experience which a particular child is likely to have had with diphtheria; if he has been brought up in South Louisiana, where diphtheria is endemic, or in most parts of Latin Amen-ica, or in the Middle East, then 8 years
would almost surely be the upper age limit for the safe routine use of the more con-centrated type of diphtheria toxoid. If, on
the other hand, the youngster in question
lives in one of the areas of the United States
where clinical diphtheria has not been seen for many years, than the age of 12 would
seem a logical time to start employing the
dilute type of toxoid.
Again in recent years the question of fluid toxoid versus toxoid with some form
of aluminum adjuvant has been raised,
either with regard to a higher incidence
of unpleasant side reactions to aluminum
adjuvant in adolescents and adults, or
be-cause the alum toxoids seemed to provoke
paralytic poliomyelitis more readily than
tile fluid toxoids. Studies from the Massa-chusetts Public Health Laboratories have attempted to answer this question and have, I think, answered it for adolescents and
Young adults, the answer being that alum adjuvant does not show any striking effect
on the primary response at least to tetanus toxoid. On the other hand, the findings in a recent British Report to the Medical
Re-search Council by its Committee on Diph-thena Toxoid seem to have demonstrated that very large doses of even the present
(l;IV purified preparations of formol on “fluid” diphtheria toxoid are not as effective for basic immunization of children as toxoid
vith a mineral adjuvant.b0
TETANUS
Turning now to the tetanus component of
DPT we learn from the most recent (1959) volume on the Vital Statistics of the United States, that in that year 283 (leatlls were
re-ported due to tetanus of which 99 occurred in children who had not yet reached their
fifth birthday and 32 more in young people of 5 to 19 years of age.11 Most of these lived in the southern and southeastern part of the
country. This situation exists in the face of
our having, in tetanus toxoid, maybe the most nearly perfect of all immunizing agents, whether one considers the low in-cidence of side reactions, or the long duna-tion of immunity. Several groups of in-vestigators have been interested in recent
years in learning how long after basic
im-munization previously immunized individ-uals would display a “recall” or anamnestic
type of response. If one tests adults after 10 years, as did Stafford’2 and also Looney and associates13 one finds an excellent re-sponse; if one tests children after 13 years, as did Peterson and his associates,14 one finds an equally excellent response; and if one waits 14 to 18 years, as did Goldsmith
and his associates,” and also McCarnoll and associates’6 the response is still splendid. Indeed, the findings mentioned above
sug-gest that the interval between tetanus toxoid booster injections could well be greatly lengthened.
This being the case, it does not seem
necessary, once the basic immunization against tetanus has been carried out, to administer a booster dose of tetanus toxoid at the time of each injury, provided the pa-tient has received a toxoid injection within the past year. If, however, tetanus toxoid
is administered for a fresh laceration, the
rapidity of the anamnestic response is such that one can use either fluid toxoid or alum toxoid with equal effectiveness.
For some years it was thought that
prac-tically no untoward reaction occurred with
booster doses of tetanus toxoid, even in adults. However, further experience has shown that individuals repeatedly injected
with tetanus toxoid do have a higher
in-cidence of unpleasant reactions. In a study of this phenomenon, Levine, Ipsen, and MeComb concluded “that these reactions occurred in previously immunized persons,
mark-edly after the twenty-fifth year but prac-tically insignificant below 20 years of age.”8 Their data may well lead to further obser-vations, and, at some future time, to a
lowering of the amount of toxoid contained
in the TD, or tetanus diphtheria toxoid “adult type.”
Intradermal administration of tetanus toxoid has been recommended, especially for booster doses, in order to avoid reac-tions.’7 It undoubtedly must produce a rise in antibody in the majority of individuals, but unfortunately there are few thoroughly
satisfactory data on which to base a formal
recommendation for the use of toxoid in this
fashion. (The same comment applies to sev-eral other vaccines such as typhoid and
in-fluenza vaccines, where the intradermal
route of administration has from time to time been recommended: it “must be” effec-tive, but precise data are wanting.)
To give a clear cut outline for the han-dling of tetanus-prone wounds is not p05-sible. Several recent articles give a good discussion of the problems involved.1820 The tendency at present is to try to avoid using tetanus antitoxin whenever possible. Proper cleansing of the wound, together with administration of tetanus toxoid, is
recommended for all individuals with even trivial tetanus-prone wounds; where the
wound has been present several days, is more severe, or obviously infected, suitable
antimicrobial drugs should be added to the
above treatment and continued for at least a week. Only in the previously unimmu-nized, and only where the wound is serious,
is tetanus antitoxin recommended in addi-tion to the above regime. Opinions vary as to whether the time-honored dose of 1,500
units is optimal (despite numerous recorded
instances where tetanus developed subse-quent to such a dose); or whether doses of
10,000 to 40,000 units should be preferred (despite the possibility that this may
‘blanket” the booster effect of the toxoid
ad-ministered simultaneously). Probably every-one would agree that, whenever human
antitetanus globulin is available, it should
be preferred to the animal antisera, and
that far smaller doses should suffice.
PERTUSSIS
Concerning pertussis vaccine there is at the moment no startling development. Al-though we may not recently have read much about convulsions and encephalopathy fol-lowing pertussis vaccine, an informal poll conducted a year or two ago by one of the manufacturers of pentussis vaccine showed
that this type of reaction is still occurring.21 Apparently the public is more or less
re-signed to paying a rather high price for
im-munity against whooping cough. One can
only hope that current laboratory investiga-tion will lead to a type of immunizing agent against pertussis fundamentally different from any now available.
QUADRUPLE ANTIGEN VACCINES
Nor is there any startling new develop-ment with regard to quadruple antigen vac-cines. As all of us know by now, the
Massa-chusetts Department of Health came out in August 1960 with a statement to the
ef-feet that the pertussis component of the
quadruple vaccine suffered a rapid decrease
in potency upon standing.22 This was later shown to be due in part, at least, to the pre-servative used in the quadruple vaccine, where benzethonium chloride had been substituted for merthiolate, the latter being deleterious to the poliovirus component. The Division of Biologic Standards has now set a higher standard for the initial anti-pertussis potency of the vaccine, namely
14
instead of 12 units, to offset the 6% or more monthly deterioration in potency; and has shortened the expiration date to four months from the date of issue from the manufacturer’s cold storage.23 Unfortu-nately, these rigorous standards, necessaryfor the protection of the public, render the
vaccine economically unsound. To this prob-lem add the increasing use of tile oral type of polio vaccine, and it is clear that several
REVIEW ARTICLE 447
SITE OF DPI INJECTION
Diphtheria, tetanus, and pertussis
anti-gens, singly or in combination, all have in
common that they are administered intra-muscularly. Tile optimal site for intramus-cular inoculations has recently been the sub-ject of considerable debate. There seems to be little question that the recommendation
of 40 years ago is still valid: “. . . the region
of the outer side of the thigh, where lies
tile great vastus externus muscle, is as nearly as possible tile ideal place for all
types of intramuscular injection.”21 At least
15 articles have appeared in medical
jour-nals in recent years reporting serious nerve damage following intragluteal injections,
es-peciallv in infants. 2. 2; The anterior aspect
of the thigil and tile deltoid areas are also to be preferred to the gluteal region. The
bacterial contamination of the skin is apt
to be less at these sites, and they are
tra-versed by no major nerve or blood vessel.
SMALLPOX
The more recent developments in the
field of smallpox vaccination are probably
widely known. Kravitz has reported on an ingenious plastic gadget, called by the manufacturer “Mono-Vacc” (manufactured
by
Lincoln Laboratories, Inc., only) tosim-)lify vaccination by tile multiple puncture
method.27 It is presterilized and disposable,
so tllat it would seem to deserve widespread
use. If, at some future time, the smallpox
vaccine could satisfactorily be lyophilized
(lirectly onto the points of the apparattis, it
would indeed be convenient.
The optimal age for primary vaccination
is still tinder discussion. It seems clear that eczema vaccinatum and unduly severe
“takes,” progressive vaccinia, etc., are all inure common under the age of one year; and that vaccinial encephalitis is more corn-mon after tile age of two years; therefore the optimal time for primary vaccination
would seem to lie between the ages of one
and two years.’8
Whether calf lymph vaccine should be
used, or chick embryo vaccine, is hard to
state with assurance. Because chick em-bryo-denived vaccine is theoretically less
subject to contamination by bacteria or un-desirable viruses, it is perhaps to be
preferred 2O,
Vaccine preserved by lyophilization would certainly seem preferable to liquid
vaccine, which must be so carefully kept at freezer temperature to preserve its
po-tency.” This is particularly true, of course,
in warm climates.
Vaccinia immune globulin, its
potentiali-ties and the indications for its use were
described in 1959 by Kempe on the
occa-sion of ins receiving tile Mead Johnson
Award of the Academy of Pediatnics.’ An-otiler matter discussed in ilis address is tile duration of immunity following
vaccina-tion: while an attack of smallpox confers long-lasting protection,” vaccination also confers protection, but probably for a much shorten time. Current practice in the U.S. Armed Forces is to revaccinate at least every
3
years, which probably suffices to maintaina reasonably solid level of herd immunity.
However, for personnel proceeding to con-tinental Europe, Asia, Africa, Indonesia,
New Guinea, annual revaccination is
ne-quired. For civilians a similar plan would appear wise.
It is well for pediatricians to he aware
that smallpox vaccine, wilen administered
to a pregnant woman, may produce gen-enalized vaccinia in the fetus, followed by abortion, as attested by a recent article in the British Medical Journal.’ Blood dys-crasias, particularly leukemia and
agam-maglobulinemia, and therapy with
corti-costeroid hormones, constitute absolute con-traindications to vaccination.
CLINICAL EFFECTIVENESS VERSUS
LABORATORY TESTING
All of the immunizing agents which have been discussed up to this point have in common that they have been tested in the field, so to speak, and found to be effective;
but even more important, we ilave some
measure effectiveness, and we know that
this other test (skin reaction after
diph-thenia and smallpox vaccination, serologic
tests, flocculation test in the case of diph-thenia and tetanus, intracerebral mouse challenge for pentussis), truly mirrors the effectiveness of tile vaccine on toxoid in
pre-venting illness from infection.
In the case of the next three immunizing agents, no such test exists, and I refer to
rabies and typhoid vaccines, and to BCG.
RABIES
The brain tissue containing type of rabies
vaccine, the so-called Semple vaccine, is rapidly being supplanted by a vaccine made from duck embryos’ “ (Eli Lilly and Company only). From tests of effectiveness in other mammals, we have reason to
be-lieve that this is, in general, an effective vaccine, although a recent report is
dis-turbing in tilat it does describe
consider-able antigenic variability between batches.”
The elegant demonstration by Gibbs and
Ilis coworkensb6 that none of the 22
mdi-viduals immunized with duck vaccine de-veloped electroencephalographic changes, whereas 10/69 vaccinated with brain tissue
vaccine did, should prove extremely reassur-ing to physicians who find it necessary to
administer the 7 or 14 doses of rabies vac-cine recommended for persons exposed to
a rabid animal. So far there is on record only one report of transverse myelitis
fol-lowing duck embryo rabies vaccine (an adult who ultimately recovered).’7
We must all perforce be aware of the
ap-parently increasing role played by bats in the epidemiology of rabies in almost every
state of the union.’8 Particularly disturbing
is the fact that a bat bite is not necessary
for infection : aerosol transmission of rabies has been proven in bat-inhabited caves.”
Now that a relatively safe, albeit somewhat painful, rabies vaccine is available, we
should consider its prophylactic use in Youngsters who explore caves, trap live
wild animals, or go to live in parts of the
world where rabies is endemic. Under such
circumstances a basic course of three, or
preferably four injections at intervals of 7 to 10 days should be followed by a booster dose 1 to 5 months later, as recom-mended for veterinarians, animal handlers, dogcatchers, with subsequent boosters every
few years on on the occasion of possible ex-posune.
While on the subject of rabies, we would like to mention that the antinabies horse
serum for passive immunization (made by Lederle Laboratories only) is now
stand-ardized by comparison with a reference
serum furnished by the Division of Biologic
Standands,41 that the dosage is expressed in terms of units rather than milliters, as previously.
BCG
The effectiveness of BCG in lowering the
incidence of severe forms of tuberculosis has been proven in many studies,42
includ-ing a recent one conducted in Great Britain under the auspices of the Medical Research Council.’ However most authorities are agreed that, in countries like ours with a
relatively low incidence of the disease,
BCG (available in the U.S. only from the Research Foundation, Chicago, Illinois) should be reserved for those individuals at greater than usual risk.4’ This would in-elude all children who live in households with adults wilose tubenculous disease has been arrested for no more than 5 years: also
North American children going to live in
areas of the world where tuberculosis is
endemic.
Various authorities have in tile past
sug-gested tilat BCG vaccine not be used in
newborn infants, because of a relatively higher incidence of prolonged vaccination lesions, because of presumed poor antigenic
response and because the vaccine might be discredited if a true tuberculous infection were superimposed. Recent reports’5’
show tilat untoward incidents are rare and
tilat the conversion rate is good; there seems
then ilO further reason to fear intradermal
inoculation of newborns with BCG, where
tile risk of tuberculous infection is high.
RE\TIEW ARTICLE 449
tul)ercle i)acilh fronl wiiicii 13CC is made \‘(‘re all, until recciltlv, sensitive to iSOilidZid.
Thus it was necessary, 1I1(l still is in this
country, to choose between a(llllinistening
prophylactic isoniazid to an exposed child,
thus giving him instant protection of limited
duration;’ or giving Ilim BCG, where protection is longlasting but starts only after
an interval of 2 to 4 months. With the de-velopment of a strain of bovine tubencle bacilli resistant to isoniazid, this agonizing
cilOice is 110 longer necessary. Unger,
Thomas and Muggleton reported in 1961 on the laboratory investigations On INH
sistant BCG,’’ and Gaisford and Gniffiths in
tile same issue of the British Medical Jour-ivil on a successful clinical trial involving several ilundred newborns.#{176} While this type
of BCG is iiot available in the United States,
tilOse pediatricians who travel abroad to teach and observe need to be acquainted with it: it presents great promise for large
areas of tile world where tuberculosis is the leading infectious disease.
TYPHOID
Last of all we come to a consideration of typhoid vaccine. Here, as in the case of ral)ies and BCG vaccines, there is no lab-oratory measure of its effectiveness.
Argu-ments have raged for decades-even since it was developed by Sir Almroth Wright at the time of the Boen War-as to Viletiler it
was any good or not. Review of many sepa-rate incidents left this reviewer with tile
feeling that maybe it was 75% effective at
best. The field studies carried out in the
British Army in India in the early years of this century were considered convincing at that time, but Cockburn’ showed in 1955 that they are not acceptable by modern standards. It is this general uncertainty which led W.H.O. to co-operate with the Yugoslavian health authorities in a field
trial of typhoid vaccines, in an area wilere typhoid fever is endemic. Tile trial was designed to test two types of vaccine, namely tile alcohol-killed and preserved
vaccine on the one hand; and on the other
a heat-killed and phenol preserved vaccine.
Fronl tile start it was importailt riot only to test thC efficacy of the vaccine in an
en-(ICifliC area, i)tlt 11s() to fiuid lai)oratory tests for vaccine potency which would reflect
clinical effectiveness. Laboratories in many countries co-operated in the evaluation, in-eluding tile Listen Insitute of Medical Re-search in London and the Walter Reed
Army Institute of Research in Washington. The results of the field study showed that the heat-killed phenol-preserved vaccine
gave protection in about 70% of those ac cinated, wilereas tile alcohol vaccine was not effective.5 Particularly disturbing was the fact that none of the presently used laboratory tests was found consistently to reflect the degree of effectiveness of the
vac-cine in tile Nor was tile presence
of the so-called Vi antigen in the vaccine demonstrated to be of any importance
what-soever.
In tile absence of adequate laboratory
tests for potency, it becomes impossible to
test different batches of vaccine for potency, or to work out the optimal schedule for basic immunization, on to make any
recom-mendation for booster doses. Moreover, some of the typhoid vaccines contain
para-typhoid
A
antigen, although, for someob-scure reason, Salmonella panatyphi A has dis-appeared completely from this country. My own feeling is that in the United States only cilildren wilo live in the household with a typhoid carrier should be immunized, and then with a heat-killed, phenol-preserved plain typhoid vaccine given subcutaneously.
To those vho live or travel where Sal-monelia infections are hyperendemic, I
would recommend the triple vaccine,
lleat-killed and phenol-preserved. In either case
the family should be told that the vaccine
is not very potent, and that they had best not challenge its effectiveness.
INFLUENZA
As a sort of postscript, because it is
neither a very old vaccine, nor a very new
one, comes influenza virus vaccine.
450
virus vaccines, and the laboratory tests do
seem to correlate with clinical results.’0
The
range of effective protection seems to lie between 40 and 96% with anaver-age around 78 to 80%. Unfortunately the polyvalent vaccine ordinarily employed has several serious 37 such as the high incidence of untoward reactions in
young children, which has been estimated at 8 to 40%, the short duration of tile immunity conferred by this vaccine with the need for booster doses each autumn, the ongoing
mutation of influenza viruses with the possi-bility that existing vaccines may confer less-than-usual immunity against the strains of virus yet to appear on the scene. Finally
the number of studies showing that the
ef-fective clinical protection conferred upon preschool children by anti-influenza vac-cination is very limited.
This being the situation it seems wise to reserve immunization with polyvalent in-fluenza vaccine for those children suffering
from chronic debilitating disease, such as rheumatic heart disease, congenital or hy-pentensive heart disease (particularly those with frank or incipient cardiac
insuffi-ciency); chronic bronchopulmonary, meta-bolic, renal disease; or neurological dis-orders.
Ideally, a dose of polyvalent vaccine
should be administered subcutaneously, in
early autumn, followed by a second
injec-tion about 2 months later.
GENERAL COMMENTS
It seems worthwhile to point out that the
recommendations of the Red Book are by no means always applicable to conditions in parts of the world other than Canada and the United States, and that they must also be interpreted with special care when the patient under consideration has lived abroad, or in preparing to travel abroad. In
particular, booster doses of diphtheria
tox-oid are superfluous for older children in many places and, when they do seem mdi-cated, the TD “adult type” should be
em-ployed for children of 8 years and above. Tetanus immunity should be carefully
main-tamed, and, in countries where ofle is likely to be in contact with smallpox, e.g. . Congo,
India, Indonesia, Nigeria, Pakistan, small-pox revaccination should be practiced at
intervals of 1 to 3 years. Routine
ty-phoid immunization, despite its imperfec-tions, is indicated in many parts of the world, as is BCG. \Vhere rabies is prevalent,
I personally would seriously consider pro-phylactic (i.e. “preexposure”) vaccination
against rabies, using duck embryo vaccine with three-or-four-dose-and-booster type of schedule. Special inoculations against yel-low fever, cholera, plague, etc., may also be indicated, or even required by law.
It is well to remember, Ilowever, and to warn patients, that no immunization is 100%
effective 100% of the time. Our very best vaccines are only perhaps 90% effective. The immunity which they confer falls grad-ually along a curve which varies from per-son to person; persons already suffering from another disease, or in surgical shock, or pregnant, may be physiologically more
susceptible to infection. Moreover tile size of the infective dose at tile time of
ex-posure is tremendously important. In short, even when “fully immunized” against every-thing, one still should not play with patho-genie viruses and bacteria the counterpart of the children’s game “Rover, Red Rover,
I dare you come over.”
REFERENCES
1. Batson, R., and Christie, A.: Immunization
methods and matetrials. J. Pediat., 53:51,
1958.
2. Doege, T. C., Heath, C. W., Jr., and Sherman, I. L. : Diphtheria in the United States,
1959-1960. PEDlAnucs, 30: 194, 1962.
3. Brainerd, H. D., et a!.: Susceptibility to
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REVIEW ARTICLE
451
iflOClllltiOn of noninstitutionalized children.
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22. Massachusetts Department of Public Health;
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component in quadruple antigen vaccine. l)iphthenia and tetanus toxoids and
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24. Turner, G. G. : The site for intramuscular
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26. Curtiss, P. H., Jr., and Tucker, H. J.: Sciatic palsy in premature infants: a report and
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27. Kravitz, H. : A simplied technique for
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28. Kempe, C. H. : Studies on smallpox and corn-plications of smallpox vaccination.
PEn!-ATRICS, 28: 176, 1960.
29. Cabasso, V. J., et a!.: Primary response of children to glyceninated or dried smallpox
vaccines of calf vaccine. Amer. J. Pubi. Health, 44:194, 1954.
30. Weichsel, M., and Herrera, E. G. : Vaccination
with avianized smallpox vaccine. J. Pediat., 50:1, 1957.
31. Kempe, C. H., et al.: Comparison of dried
smallpox vaccine with fresh Indian buffalo
calf lymph in revaccinations against
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Acknowledgment
The author is indebted to Dr. Geoffrey Edsall for his constructive criticism, also to Drs. John
Fox and David Karzon, and to Dr. Jorge Esco-bar Melguizo for assistance in the preparation of
