POLIOMYELITIS VACCINE

(1)

EDITORIAL

POLIOMYELITIS

VACCINE

P

FIYSICIANS, and particularly pediatricians,

throughout the United States and

Can-ada, have been deeply disturbed by

cer-tam circumstances and events surrounding

and following the wide-s1iread introduction

in April of antipohiomyelitic prophyhaxis with what is generally known as the Salk

vaccine. As a result of past experience, some

of it bitter, with new prophylactic and

therapeutic measures, a tacit or explicit

policy has long been in force among

mcdi-cal men of cautious prehimimiary exploration, with first publication of results in medical journals, gradual accumulation of data bear-ing on both the efficacy and safety of the

product concerned. before its more general

adoption is accepted. It is for this purpose

that the Councii of Pharniacy and

Chem-istry of the A.\I.A. was feunded. Examples

of the wisdom of such an approach and of

the danger of its neglect can readily be

cited. The development of diphtheria

tox-Oi(1, for instance, in its present safe and satis-factory forni, followed years of trial and error. On the other hand, the premature

introduction of yellow fever vaccine on a

mass scale, hastened by the exigencies of

World War II, was followed l)y the totally

lmnexI)ected complication of homologous

seruni ilel)atitis involving 28,585 of 2,500,000 (1 in 87 individuals).1 This unfortunate

event led to the revision of the method of vaccine I)rePttratiomi aild to its present safety. In the case of poliomyelitis, 2 supposedly

safe vaccines2’ 3 were put to fairly wide use

in human beings in the middle 1930’s. The

Kolmer vaccine, attenuated’ by sodium

ricinoleate was a(lrninistered to about 11,000 children, and the Brodie vaccine,

macti-vated with 1 : 1000 formalin, to about 9,000.

In both instances, tests for safety included

intracerebral inoculation into monkeys with

negative results. %Vith these vaccines,

para-lytic poliomyelitis occurred in a ratio of

approximately 1 case to each 1500

chil-dren inoculated, usually first in the

inocu-hated extremity or extremities, and there

were 5 deaths.4 While the claim of prior infection was made for these cases, as it has been today,

J.

P. Leake, then head of the Public Health Services, among others, dis-agreed after reviewing the evidence, and

both vaccines were promptly abandoned. In the present instance, the National Foundation for Infantile Paralysis decided

to bypass a prolonged period of trial and

error by making a single very large-scale field trial in 1954, and having the results studied by the best known methods of pro-curement of data and their statistical ap-praisal, by experts using fully objective

tecll-niques. The study culminated in the Report

of the Vaccine Evaluation Center,5 headed by Dr. Thomas Francis, Jr., the results of which, together with a scientific paper by

Dr. Salk, were dramatically announced on the morning of April 12, 1955, at Ann Arbor,

Michigan and simultaneously broadcast by television and radio, with a second “closed” telecast the same afternoon in some 65 theaters and other places of congregation throughout the country previously reserved for the purpose. There was no prior or simultaneous publication of results in any scientific journal.

The magnitude and accuracy of the

col-lected data and their analysis leave little if

any room for adverse criticism. Extensive

preliminary work had been done by Dr.

J

onas E. Salk#{176}and his collaborators in de-veloping the vaccine and studying its effects in respect to antigenicity and safety, some of which was published in IA7

Certain features of the program are, how-ever, open to criticism, and have led to serious and unforeseen difficulties, which have already interfered to a considerable

degree with conduct of the program.

The complete details of the Report were unfortunately available only to the relatively

(2)

Hall and to tile still smaller ilumber of

mcdi-cal men who received the printed Report.

The charts containing the compilations and

analyses of the basic data were illegible on

the television screen, and the speaker was at times inaudible. Lack of full knowledge

was particularly unfortunate for the many health officers throughout the country who

were to be responsible for the conduct of

the vaccination program, and also for

pedi-atricians at large who were entirely

de-l)’iileIit on lay iiiedia of communication

for infoririation and particularly for an

ap-1)raiSal of their medico-legal responsibilities. The first report to the American general

nie(lical public was a 1-page synopsis of

tile Francis Report published in the Jovrnal

of the American Medical Association on April 30/i

The almost immediate start of the mass

inlmliunization program, as planned by the

Foundation and at once demanded by an

aroused lay public was somewhat

unfortu-nate for other reasons. Scrutiny of the

pre-liminary publications by Salk and his

associ-dtCS 1S well as Dr. Salk’s own statements at

.ki#{236}nArbor revealed the fact that the corn-1)Ositiofl of the vaccine in respect to the a(ldlitiveS usedi for antiseptic, preservative aDd enhancing, as well as the time schedule

for its administration, had not yet been fully standardized, and were at the time of public

announcement still undergoing changes.

Tile use of adjuvant oil to enhance its

im-munogenic properties had been abandoned

before the 1954 field trials, probably

be-cause of its tendency to produce local

re-actions and after-effects. The addition of

MerthiolateR was shown to hasten the

de-terioratioll of antigenicity, and the value of

\Tersene to offset this effect was only

an-nounced by Salk at the Ann Arbor meeting.

Which if either of these substances was present in all or any of the products of

in-dividual manufacturers released for use in 1955 was not announced or known to the

general medical public, although later it is

understood that one of the manufacturers

had used neither. Finally, the dosage schedule was radically changed at the last

moment before general release, from 1

week and 4 weeks to 4 weeks and 7 to 10 months between the first and second and second and third injections, respectively. These various progressive and confusing changes showed most importantly perhaps,

that at the time of its general release, the vaccine and the optimal methods of the ad-ministration were still in a state of flux.

The question of safety had supposedly been answered with complete assurance by the preliminary laboratory tests which failed to show any residual viral activity by animal

inoculation and by tissue culture in tests

performed independently by 3 separate

laboratories. Safety was apparently

con-firmed by the field trials themselves. Here,

90 cases of pohiomyehitis developed during

the vaccination period and 39 others within

2 weeks after its termination, but these

were distributed about equally between the

vaccinated and unvaccinated. It is to he noted that all field trial vaccine was to

con-tam Merthiolate#{174} in a final concentration of 1 : 10,000#{176} It was stated at the April 12th meeting that all future preparations would

be approved and released by the National Institutes of Health only after certain

en-teria of safety had been met. However, the

tests, except for spot checks, would be made

by only 1 laboratory instead of 3 amid in some instances, at least, these appear to have been left to the individual

manufac-tuner, the protocols being submitted to the

N. I. H. for approval. It also appears that the addition of Merthiolate#{174} was not among the required specifications, since it may have been omitted by at least 1

manu-facturer whose vaccine

(

here designated as

Vaccine C) was officially released. It was to

this vaccine that nearly all the subsequent

trouble was traced. At last reports (May 9),

some 44 cases of pohiomychitis, nearly all

paralytic, had occurred following its use in a total of about 400,000 children receiving 1 injection each,’#{176}a ratio of about 1:9,000. The incidence from other preparations was so low as to be practically negligible.

(3)

in-jection, the distribution by days having not

as yet been published. However, 2 to 3 new

cases have been reported in the newspapers

each day since April 27, when Vaccine C was withdrawn. The ordinary range of the

incubation period after non-traumatic

cx-posures is about 5 to 27 days, with a median

of about 12 days.h1 The median incubation period in 80 cases of pohiomychitis following injections of antigens, etc., was about 13

days, with a range of 4 to 26 days (similar figures also applied to post-tonsillectomy

cases);12 and in the small series reported by

Leake in 1936, following the use of the Kolmer and Brodie vaccines, the median

was about 1 1 days, with a range of 4 to 23 days.

Since all Salk vaccine lots excepting C are

believed to contain an antiseptic and these appear to have given little if any trouble, attention is called to a report’2 published in

PEDIATRICS in December, 1953, on the

viruci-dal effect on pohiomychitis virus of several common antiseptics. Of these, Merthiolate#{174}

was found to inactivate the virus promptly

(within about 10 seconds) in dilutions up to

about 1 : 1500. Higher dilutions, such as

1 : 10,000, would probably have been effec-tive over longer periods.

Two important inferences may be drawn

from these various data. First, the standard procedures for determining the presence

or absence of viable virus in absolute terms before the addition of Merthiolate#{174} appear to be inadequate and unreliable. Second, Merthiolatc#{174} even in low concentrations can probably destroy small remaining

amounts of viable virus and make the

vaccine safe, although at the same time

re-ducing its antigenic value to a certain

cx-tent and promoting its deterioration. Whether or to what extent the addition of Versene#{174} lessens the virucidal value of the

latter it at present unknown.

In view of the extreme difficulty, if not impossibility, of detecting minute quantities of living virus in vaccine, inactivated by formalin alone, by practical laboratory

methods, the danger of omitting an effective antiseptic could probably not have been

predicted from the data at hand before the

vaccine was put to human use and we are

now in better position to avoid similar

ac-cidents in the future. Regrettably, the very

measure which lessens the danger reduces

immunogenic value. The margin between

inactivation and loss of antigenicity must be

very narrow.

That the same doubts we have expressed are now felt by those in authority is evident from the official withdrawal of present stocks of vaccine on May 8, pending review of safety standards.’#{176}

Certain curious and somewhat disturbing

features in the vaccination results that

ap-pear in the Francis Report deserve further comment. The incidence of non-paralytic

(

symptomatic) infections was essentially the same in the vaccinated children and in the controls. Protection against Type I virus

(

the most common cause of epidemics) was decidedly less than against the other 2 ty pes. Protection appears to have been mdc-pendent of the antigenicity of the different lots of vaccine used, when graded as

“Good,” “Moderate,” “Low Moderate” and “Poor” according to the antibody responses of the vaccinated children.

For the various reasons above discussed, the search for potentially better methods of

prophylaxis should continue. Important steps in this direction have already been made by Koprowski13 and by &415 who

.have isolated and tested non-paralytigenic strains which can be given orally and which

arc highly immunogenic. The persistence of satisfactory levels of antibody in human

beings for 3 years or more, as recently reported in PEDIAmICS,13’ with one of the Koprowski strains, is encouraging, and in

line with the general principle that attenu-ated living virus produces a more durable and adequate immunity than fully macti-vated viral vaccines.

REFERENCES

(4)

the Director of the California State Board of Health, among others, were cited. Notes were used, taken under difficult conditions, from the television broadcast at Rackham Hall,

Univer-sity of Michigan, April 12, 1955, at which Dr.

Francis discussed the Evaluation Center Report

and Dr. Salk read a paper on the vaccine. The Francis Report was received about 2 weeks later.

1. Editorial : Jaundice following yellow fever

vaccine. J.A.M.A., I 19:1110, 1942.

2. Kolmer,

J.

A. : Vaccination against acute anterior poliomyehitis. Am.

J.

Pub. Health, 26:126, 1936.

3. Brodie, M., and Park, W. H. : Active

im-munization against poliomyelitis. Am.

J.

Pub. Health, 26:119, 1936.

4. Leake,

J.

P. : (a) Discussion of references 2. and 3. : ibid., p. 148. (b) Poliomyelitis following vaccination against this

dis-ease. J.A.M.A., 105:2152, 1935.

5. Evaluation of the 1954 Field Trial:

Sum-mary Report. The Poliomyelitis Vaccine

Evaluation Center, Thomas Francis, Jr.,

Director, University of Michigan, Ann Arbor, Mich., April 12, 1955.

6. Salk,

J.

E., and associates: (a) Studies in

human subjects on active vaccination

against poliomyelitis. I. A preliminary

report on experiments in progress.

J.

A.M.A., 151:1081, 1953. (b)

Formalde-hyde treatment and safety testing of

experimental poliomyelitis vaccine. Am.

1.

Pub. Health, 44:563, 1954. (c) Studies

on active immunization in human

sub-jects against poliomyehitis. II. A practical means for inducing and maintaining anti-body formation. Am.

J.

Pub. Health, 44: 994, 1954. (d) Antigenic activity of poliomyelitis vaccines undergoing field test. Am.

J.

Pub. Health, 45:151, 1955.

(

e) Present status of the problem of

vac-cination against poliomyelitis. Am.

J.

Pub. Health, 45:285, 1955. 7. Salk,

J.

E. : Recent studies on immunization

against pohiomyelitis. PEDIATRICS, 12: 471, 1953.

8. Miscellany: Vaccine for pohiomyehitis.

J.

A.M.A., 157:1642, 1955.

9. Specifications and minimal requirements for poliomyelitis vaccine aqueous (poly-valent) as developed by Dr. Jonas E. Salk, Virus Research Laboratory,

Uni-vensity of Pittsburgh, Pennsylvania (to

be used during field studies to be con-ducted during 1954, under the auspices of the National Foundation for Infantile Paralysis). Issued by the N.F.I.P., Feb. 1, 1954.

10. Daily newspapers, May 9, 1955.

1 1. Sartwell, P. E. : The incubation period of poliomyeitis. Am.

J.

Pub. Health, 42:

1403, 1952.

12. Faber, H. K., and Dong, L. : Poliocidal

ac-tivity of some common antiseptics with special reference to localized paralysis.

PEDIATRICS, 12:657, 1953.

13. Koprowski, H., Jervis, C. A., and Norton, T. W. : (a) Immune responses in human volunteers upon oral administration of a rodent-adapted strain of poliomyelitis

virus. Am.

J.

Hyg., 55: 108, 1952. (b)

Further studies on oral administration of living pohiomychitis virus to human sub-jects. Proc. Soc. Exp. Bioi. & Med., 82: 277, 1953. (c) Persistence of neutralizing antibodies in human subjects three years after oral administration of poliomyehitis virus. PEDIATRICS, 13:203, 1954. 14. Sabin, A. B., Hennessen, W. A., and

Wins-ser,

J.

: Studies on variants of poliomye-hitis virus. I. Experimental segregation and properties of avirulent variants of three immunologic types.

J.

Exper. Med., 99:551, 1954.

(5)

1955;15;788

Pediatrics