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⏐ PUBLIC HEALTH THEN AND NOW ⏐

MEASLES
VACCINATION
Before the Measles-Mumps-Rubella Vaccine

| Jan Hendriks, MSc, and Stuart Blume, PhD, MA

At the beginning of the 1960s, it was clear that a vaccine against measles would soon be available.
Although measles was (and remains) a killer disease in the developing world, in the United States
and Western Europe this was no longer so. Many parents and many medical practitioners considered
measles an inevitable stage of a child’s development. Debating the desirability of measles immuniza-
tion, public health experts reasoned differently. In the United States, introduction of the vaccine fit
well with Kennedy’s and Johnson’s administrations’ political commitments. European policymakers
proceeded cautiously, concerned about the acceptability of existing vaccination programs. In Sweden
and the Netherlands, recent experience in controlling polio led researchers to prefer an inactivated
virus vaccine. Although in the early 1970s attempts to develop a sufficiently potent inactivated vaccine
were abandoned, we have argued that the debates and initiatives of the time during the vaccine’s
early history merit reflection in today’s era of standardization and global markets. (Am J Public Health.
2013;103:1393–1401. doi:10.2105/AJPH.2012.301075)

EXAMINING THE INTRODUCTION clinical trial had gained in Britain. just a few years previously, which
of four pediatric vaccines (diph- We have looked in detail at the differed in these four countries;
theria antitoxin and the pertussis, introduction of the measles vac- the other was the European pub-
polio, and measles vaccines), cine, focusing not only on the lic health authorities’ concern
Baker has argued that the middle United States and Britain but on with the implications of introduc-
years of the 20th century dis- two other European countries (the ing a new vaccine for the national
played distinctive national styles Netherlands and Sweden) as well. immunization program, as a
of vaccine innovation1: whereas Responses to the development whole, and for popular confi-
US vaccine development and im- of the first measles vaccines con- dence in it, in particular.
plementation were marked by a firm Baker’s contrast between
“current of urgency,” the more American and British styles, the THE SEARCH FOR A
cautious British set much higher one marked by a sense of MEASLES VACCINE
standards for the evidence re- urgency, the other by a cautious
quired to prove the safety and ef- insistence on randomized trial By the early 1960s the epide-
fectiveness of a new vaccine be- data. But our analysis suggests miology of measles was well
fore deciding on its introduction. that, in addition, two other con- understood. It was known that the
This, in turn, could be attributed siderations influenced policymak- disease occurred throughout the
to the influence that the statisti- ers: one was the national world, generally in regular peri-
cal pioneers of the randomized experience with polio vaccination odic cycles. With the exception of

August 2013, Vol 103, No. 8 | American Journal of Public Health Hendriks and Blume | Peer Reviewed | Public Health Then and Now | 1393
⏐ PUBLIC HEALTH THEN AND NOW ⏐

some isolated population groups, encourage other investigators and γ globulin. The inactivated vac-
almost all children contracted made the strain freely available. cine was generally administered,
measles before they reached ado- Very soon numerous other in field trials, on a three-dose
lescence. No nonhuman sources researchers (including Anton monthly schedule. Although this
of infection were known.2 By Schwarz at American Home Prod- produced no side effects, anti-
1960, thanks to the use of antibi- ucts and Maurice Hilleman at body levels were lower than
otics and improvements in living Merck) were also working at with the live vaccine, and it was
conditions, measles mortality was attenuating it further.5 In addition, not known whether they per-
declining steadily in industrialized inspired by Salk’s earlier develop- sisted beyond six months.9 A
countries (although not in the ment of an inactivated polio vac- combined schedule had also
developing world). For example, cine, other laboratories were been tried. If a dose of inacti-
developing inactivated (killed vated vaccine was given a month


virus) vaccines. One or more safe or so before the live vaccine,
The situation in the early 1960s was thus that
and effective vaccines seemed reactions caused by the live vac-
live attenuated vaccines appeared to offer within reach. But were they cine were greatly reduced. The
long-term protection against measles. Their needed and would they be used? surgeon general recommended
Although measles claimed the that children without a history
side effects, however, were a matter of
lives of 1 to 2 million children of measles be immunized at
concern, and attempts to develop further


annually in developing countries, approximately aged nine
attenuated, less reactogenic strains continued. few of these countries had ade- months.10 There seemed to be
quately organized immunization no reason to begin a mass immu-
programs at this time.6 In the nization program; the decision
in the United Kingdom deaths United States and Western to immunize could be left to
from measles had fallen from 307 Europe, which did, measles mor- individual medical practitioners
in 1949 to 98 in 1959.3 Parents tality was low and declining and and parents.
largely came to see measles as an parents seemingly accepted it as The situation in the early
unpleasant, although more or less an unpleasant part of childhood. 1960s was thus that live attenu-
inevitable, part of childhood. What reasons could there be for ated vaccines appeared to offer
Many primary care physicians introducing a measles vaccine? long-term protection against
shared this view. In March 1963 the first two measles. Their side effects, how-
In the early 1960s researchers measles vaccines were approved ever, were a matter of concern,
in numerous US and European for use in the United States: a and attempts to develop further
laboratories were, nevertheless, live vaccine produced by Merck attenuated, less reactogenic
trying to develop a measles vac- (Rubeovax) and a formalin-inacti- strains continued. (The Schwarz
cine. Building on their earlier vated one produced by Pfizer strain would be licensed in 1965,
success with the poliovirus, in (Pfizer-Vax Measles–K).7 In Sep- and Merck’s more attenuated
1954 John Enders and his Har- tember 1963 the US Surgeon “Moraten” strain in 1968.) Inacti-
vard colleagues succeeded in cul- General Luther Terry published vated vaccine produced no side
turing the measles virus. Because a statement on the status of mea- effects, but it was unclear
their initial sample was taken sles vaccines.8 The live vaccine whether it could provide protec-
from a boy named David had by this time been given to tion of adequate duration. If pro-
Edmonston, the strain became some 25 000 people in the tection was of too short duration,
known as the Edmonston strain. United States. A single dose pro- there was a risk of measles infec-
By 1960, Katz, Enders, and Hol- duced an effective antibody tion being postponed to an older
loway had shown that their response in more than 95% of age, when its effects could be
Edmonston strain, suitably atten- susceptible children—a response more serious.
uated, stimulated production of that trials had shown persisted
measles antibodies in susceptible for at least three years. Although US AND UK IMMUNIZATION
children.4 30% to 40% of these children POLICY, 1963–1968
Because it was found to be too showed signs of temporary high
reactogenic, Enders and his col- fever and a rash after vaccina- Any decision to begin mass
leagues set about attenuating it tion, side effects could be measles vaccination in the early
further. Enders wanted to reduced by coadministration of 1960s thus involved numerous

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⏐ PUBLIC HEALTH THEN AND NOW ⏐

uncertainties. Was the disease Approximately 15 million chil- community-based immunization


serious enough? Would parents dren were given one of the new programs, the expectation that
feel it worth having their chil- measles vaccines starting with measles would soon be eradicated
dren vaccinated? And if mass their licensing in 1963 and con- was to prove wildly
vaccination did seem justified, tinuing until mid-1966, and the overoptimistic.19
should the live or the killed vac- reported incidence of the disease In the United Kingdom it took
cine (or a combination of both) fell by half.15 On the basis of this longer for a consensus regarding
be used? In the United States, success, with material and finan- the desirability of measles vacci-
experience with the polio vac- cial support from the Centers for nation to emerge. As the editor
cines played a major role in Disease Control and Prevention, of the British Medical Journal
shaping the consensus that grad- and inspired by the social and warned in 1962,
ually emerged. political climate of the time, in
There is a real danger that the
Colgrove has explained how, 1967 a campaign was launched general public may become
after an initially euphoric to eliminate measles from the weary of the ever-increasing
response to the Salk vaccine, United States. “To those who ask number of immunizing injec-
tions which are being urged
demand in the United States for me ‘Why do you wish to eradicate upon their children. The admin-
the polio vaccine fell rapidly.11 By measles?’” wrote Alexander Lang- istration of this [inactivated]
the late 1950s polio was again muir, chief epidemiologist at the vaccine would require three fur-
ther injections. Measles is often
on the rise, with cases now con- Centers for Disease Control and regarded as a normal part of
centrated in socially deprived Prevention from 1949 to 1970, childhood development, and
areas with large numbers of though this view is misguided
parents may not easily be per-
unvaccinated people.12 Overcom- I reply with the same answer
suaded to depart from it.20
that Hillary used when asked
ing this problem seemed more why he wished to climb Mt.
feasible with the live Sabin vac- Everest. He said “Because it is D. L. Miller of the UK Central
cine, which required just one there.” To this may be added, Public Health Laboratory Ser-
“. . . and it can be done.”16
drop in place of the three Salk vice’s epidemiological section21
vaccine shots. It also fitted well was among those arguing most
Some were skeptical, notably forcefully for mass measles immu-
with the priorities of the adminis-
the eminent bacteriologist René nization. A large-scale survey of
tration of President John F. Ken-
Dubos, but President Lyndon B. general practitioners and hospitals
nedy, who took office in 1961.
Johnson gave the program his had shown that “serious complica-
In 1962 Congress passed the
support.17 Rapid success was tions of measles are commoner
Vaccine Assistance Act, which
anticipated: than is generally supposed.”22 In
authorized financial assistance to
states specifically for vaccination an average epidemic year, more
The availability of potent and
programs against polio, diphthe- effective measles vaccines, than half a million notified cases
ria, whooping cough, and teta- which have been tested exten- of measles could be expected in
sively over the past 4 years,
nus.13 In 1965, when this act provides the basis for the eradi-
England and Wales. Extrapolating
came up for renewal, officials cation of measles in any com- on the basis of the survey, 35 000
were anxious to avoid the socio- munity that will raise its im- patients with serious complica-
mune thresholds to readily
economic disparities in coverage tions could be expected, of whom
attainable levels. Effective use
that had emerged with polio and of these vaccines during the 6000 would be hospitalized.23 As
that were now appearing with coming winter and spring a percentage, this was small, but
should insure the eradication of
measles vaccine coverage. An the numbers were considerable
measles from the United States
amendment to the act added in 1967.18 and represented a significant bur-
measles to the diseases for which den to families and to the state. It
federal subsidies were available. Some 11.7 million doses of seemed unlikely that further
measles vaccine were distributed reductions in measles morbidity
As the problem of infectious in 1967–1968, and the estimated could be expected from improve-
disease became increasingly co-
terminous with the issue of so- number of cases of measles fell ments in hygiene, nutrition, or
cioeconomic disadvantage, the from 900 000 to 250 000. housing.
federal war on poverty provided However, because budgetary
an ideal conceptual framework Further advance is likely to
for the fight that would soon be politics subsequently led to come only from prevention of
launched against measles.14 fluctuating federal support for the disease by immunization,

August 2013, Vol 103, No. 8 | American Journal of Public Health Hendriks and Blume | Peer Reviewed | Public Health Then and Now | 1395
⏐ PUBLIC HEALTH THEN AND NOW ⏐

and on the available evidence a more powerful inactivated the United States,32 and it
this would seem to be well
vaccine would be developed appeared that this could also
worth doing.24
occur when live vaccine was
and work along these lines
The editor of the BMJ, com- as is being done in Sweden, administered after inactivated vac-
menting on the survey, was not where success has clearly been cine. There was a growing sense,
achieved in eliminating polio-
convinced: “Does this present internationally, that the inacti-
myelitis by the use of killed
survey . . . add up to a strong polio vaccine.28 vated virus vaccine should be
argument for mass vaccination as avoided.33 In August 1967 a let-
Miller argues?”25 There were British experience with the ter from Vincent Fulginiti, a spe-
other factors that would have to polio vaccines had led to a clear cialist in pediatric infectious
be considered, such as the reac- preference for the live (Sabin) diseases at the University of Colo-
tions the child might suffer from vaccine by 1964.29 But because rado, appeared in The Lancet.34
currently available vaccines. How hard evidence relating to measles He and his colleagues had started
often would the doctor have to specifically was felt to be needed, trials using three doses of killed
see vaccinated children when in early 1964 the Medical vaccine (KKK schedule) and two
they had a severe reaction? Research Council (MRC) started a doses of killed plus one live atten-
What if immunity was short study of measles vaccines. A pre- uated vaccine (KKL schedule)
lived? According to the editorial, liminary study among children some years earlier. Results
aged 10 to 18 months involved showed that in some of the chil-
[it] would be tragic if its action the comparison of four schedules. dren on the KKK schedule, immu-
was merely to postpone an attack Two groups of children received nity waned after six months:
of measles into the age-group
when complications such as en- a highly attenuated strain pro-
cephalitis would be common.26 duced either by Glaxo or by We are receiving increasing re-
ports of natural disease in both
Wellcome Research Laboratories, the KKK and KKL vaccinees. In
The editorial ended, and two groups were given the addition, 10 of these vaccinees,
Pfizer killed vaccine before one all of whom have required ad-
In Great Britain at the moment mission to hospital, have had a
of the live vaccines.30 The study new disease which we have
it is not necessarily logical to
say, “We can produce a vaccine; focused only on short-term clini- termed “atypical measles.”35
let us therefore use it.”26 cal and serological responses. It
was found that although all four How this came about was not
The editor of the The Lancet, schedules were “acceptable and understood.
however, reviewing the evidence practical,” children on the single- In May 1968 a second report
reported by Miller, was con- dose schedule seemed on average of the MRC measles vaccine trial
vinced that measles should be to have higher antibody titers. was published.36 This trial
prevented, Why this should be was involved more than 36 000 chil-
unclear and needed to be studied dren, aged from 10 months to 2
not only as Langmuir has said further, especially because other years, across Great Britain. Some
“because it is there and it can
investigators had reached the children were assigned to a con-
be done,” but also because
of the toll it takes in human opposite conclusion. A large-scale trol group and received no vac-
misery.27 trial began later in 1964. Mean- cine, whereas others in the trial
while, although the various vac- received either a single dose of
Still, even if it was agreed that cines were available for doctors Glaxo’s live attenuated (Schwarz
measles vaccination was desir- to use at their discretion, there strain) vaccine or a single dose of
able, the question of how it was as yet no national policy. In the Pfizer killed vaccine followed
should be done remained open. a letter to doctors dated Febru- one month later by a single dose
On this the editors of the two ary 21, 1966, the Ministry of of the live vaccine.37 Both sched-
journals agreed. The live vaccine Health left the choice of vaccine ules were found to give good
was problematic by virtue of the to the individual physician.31 protection in the first nine
side effects it often produced, In 1965 the first reports of a months. With time, however, dif-
whereas protection provided by strange measles-like illness in chil- ferences appeared. After two
the inactivated vaccine was of dren exposed to natural years the single-dose schedule
questionable duration. However, measles after receiving the produced a higher degree of
there was the possibility that inactivated vaccine appeared in protection (95%) than did the

1396 | Public Health Then and Now | Peer Reviewed | Hendriks and Blume American Journal of Public Health | August 2013, Vol 103, No. 8
⏐ PUBLIC HEALTH THEN AND NOW ⏐

double-dose schedule (89%). The MRC trials using the Schwarz the axiom was that this goal
would not be obtained with
MRC concluded that “there is a strain suggested that immunity
dead virus alone. In Sweden
strong case for the use of live lasted for at least two years. This however, it appears that 7
measles vaccine alone.” Not only was likely to be true also of the years after application of IPV
neither the diseases nor the
did this give a higher degree of other attenuated vaccine then
virus seem to occur. Hopefully
protection, but it also had the available in Britain, Wellcome’s we shall see the same develop-
additional advantage that only a Beckenham-31. The editor of ment with the use of inacti-
vated measles vaccine.43
single injection was required. The Lancet agreed that the killed
vaccine then available offered
It is desirable, however, that par- Gard’s research assistant and
protection that was too short
ents should be informed that live later successor Erling Norrby
vaccine alone sometimes induces
lived to be of value, and when
had started research on inacti-
a febrile disturbance or a mild used before an attenuated vac-
measles-like illness which is non- vated measles vaccines in 1959.
cine there was the possibility of
infectious, to avoid undue concern Whereas the Pfizer vaccine was
if such reactions should occur.
unusual reactions. Although it
grown in a culture of monkey
was possible that a more satisfac-
kidney cells, Norrby used dog
No case of the atypical mea- tory killed vaccine would be pro-
kidney cells and, crucially, a dif-
sles Fulginiti reported was found. duced, “killed measles vaccine of
ferent inactivation method.
the type made so far is clearly
Such reactions, which have been Rather than using formalin as
unsatisfactory and it is no longer
reported entirely from the USA, researchers in the United States
available in Britain.”42
have so far occurred only in were doing, Norrby inactivated
children who have had repeated
doses of killed vaccine. They the virus with an organic sol-
have not been observed in any
THE SEARCH FOR AN vent, Tween 80 and diethyl
of the children in the British trial IMPROVED INACTIVATED ether (TE). This treatment
in which only one dose of killed VACCINE
vaccine was given and was fol- caused disintegration of the
lowed after a relatively short pe- virus, and the Swedish research-
riod of a month by live vaccine. Unlike Britain, the United ers’ objective was a measles vac-
Nevertheless, it would be wise States, and virtually all other
not to use killed vaccine at all cine consisting only of a purified
countries, the Netherlands and hemagglutinin (a surface protein
until more information is avail-
able about the mechanism of Sweden had successfully con- of the virus).44 The expectation
such reactions and how they can trolled polio with Salk’s inacti-
be avoided.38 was that this process would
vated vaccine (IPV) and had not remove the sensibilizing agents
switched to the Sabin vaccine. responsible for the strange reac-
Meanwhile, in November Influenced by this experience, tions observed in the United
1967, the Joint Committee on vaccinologists in both countries States. Tests in guinea pigs
Vaccination and Immunisation, had a clear initial preference for showed that vaccines inactivated
the British government’s princi- an inactivated measles vaccine. As in this way were three to four
pal expert advisory body on vac- Sven Gard, professor of virology at times more potent than were
cination policy, recommended the Karolinska Institute in Stock- those inactivated with formalin.
that all children aged one year holm, told an international confer- A series of studies designed to
and older who had not had mea- ence on measles vaccine in 1964, analyze the possible usefulness
sles and had not been vaccinated
of a killed measles vaccine for
should be offered live attenuated In my opinion the use of live
vaccines should be avoided if elimination of measles began in
vaccine.39 The recommendation
possible. By introducing an au- Sweden.
was accepted, and in February tonomous organism in the indi- In 1965 Norrby justified work-
1968 local health authorities vidual a reaction-chain is initi-
ated which we probably are ing on inactivated virus vaccine
were informed. In 1968, by
unable to control in all condi- by referring to earlier experi-
which time the inactivated vac- tions. The immediate conse- ences with polio vaccines:
cine had been withdrawn in quences may seem harmless,
the United States,40 the mass but a cytopathogenic agent
does not disappear without The killed measles vaccines are
vaccination campaign using live leaving traces. . . . generally supposed to give im-
vaccine began in Britain.41 munity quantitatively and quali-
tatively inferior to that after
Although the duration of pro- In the controversy between liv- natural measles. For this reason
tection was still uncertain, the ing and inactivated poliovirus they are usually recommended

August 2013, Vol 103, No. 8 | American Journal of Public Health Hendriks and Blume | Peer Reviewed | Public Health Then and Now | 1397
⏐ PUBLIC HEALTH THEN AND NOW ⏐

for use only in combination “In the present situation inacti- Behringwerke was drafted in
with live vaccine. Similar argu-
vated measles vaccines cannot be 1969. However, Quintavirulon
ments were raised against inac-
tivated and for live poliovirus recommended for general seemed less potent and produced
vaccines. However, the excellent use.”47,48 In 1971 Sweden began more side effects than did the
results achieved in the Scandina-
mass measles immunization combination that RIV itself was
vian countries with inactivated
poliovirus vaccine appear to in- using the live vaccine. developing, and this collaboration
validate those arguments, and Like their Swedish colleagues, also ended. RIV finally decided
for this reason it would seem
Dutch investigators preferred an to use a TE-treated measles seed
unwise to discount inactivated
measles vaccines before they inactivated vaccine. In the Nether- strain obtained from Norrby
have been given a fair trial.45 lands too, polio had been success- in Sweden. They set about
fully controlled with IPV.49 This combining this with the tetrava-
In an initial study, Swedish chil- was done by adding IPV to the lent DPT-IPV combination
dren who had previously received diphtheria-pertussis-tetanus (DPT) vaccine that had become the
three monthly doses of the Pfizer vaccine already in use, thereby cornerstone of the Dutch
inactivated vaccine were revacci- avoiding disruption of the national National Immunization Program.
nated 22 to 23 months later, immunization program. The By 1967 a production process
either with a fourth dose or with country’s high immunization rate and the necessary controls had
the new TE-inactivated prepara- (more than 95%) was attributed been established.52
tion. They were then followed for to the simplicity of the immuniza- In December 1967 the health
a further 8 months and then tion schedule used. When work council published its report on
tested after 18 months and after on development of a measles vac- measles vaccines.53 The council’s
29 months. In a second study cine began at the Dutch Institute view was that although measles
children were given either three of Public Health (Rijksinstituut vaccination should eventually be
monthly doses of formalin-inacti- voor Volksgezondheid [RIV]) in included in the National Immuni-
vated vaccine plus a booster of 1964, the intention was to repli- zation Program, it was not yet
TE vaccine 17 months later, or cate the earlier strategy.50 the time to do so. It was still
they were given three monthly In 1965 Merck’s subsidiary in unclear which vaccine was to be
doses of TE vaccine and, again, a the Netherlands (MSD) requested used, how it was to be used, or
TE booster after 17 months.46 permission to import the compa- how disruption of the National
These children were followed for ny’s live measles vaccine. Obliged Immunization Program could
three years after the final booster. to respond to this request, in best be avoided. The council
Initial results with the TE-inac- October 1965 the minister of therefore recommended that fur-
tivated vaccine were promising: health turned to the health coun- ther studies, particularly of the
The mean haemagglutination-
cil (Gezondheidsraad) for advice. inactivated vaccine, be carried
inhibition titer eight months Meanwhile, RIV intensified its out before any definitive decision
after revaccination was 600 in contacts with two European man- was made. Meanwhile, import of
the group of children given for-
malin-killed vaccine, and 7800
ufacturers working on Tween- both live and inactivated vac-
in the group given Tween-ether ether inactivated vaccines: first cines should be permitted and
vaccine.47 Glaxo in the United Kingdom the decision to use one or the
(where John Beale was working other left to the individual medi-
However by 1969 despite on a TE-inactivated vaccine in cal practitioner.
“theoretical advantages,” earlier parallel with the company’s work As measles vaccines then
promise seemed not to be borne on attenuated vaccine)51 and became available, medical practi-
out. The antibodies induced by subsequently Behringwerke in tioners needed guidance on
the killed virus vaccine seemed Germany. This company had their use. Unlike in the United
to be of low protective value, and developed a pentavalent combi- Kingdom, there had been rela-
it was becoming clear that intact nation vaccine (Quintavirulon), tively little discussion of measles
surface antigens other than including an inactivated measles vaccination in the Dutch medical
hemagglutinin would have to be strain (Marburg) that it claimed press, and (also unlike in the
included in a killed virus vaccine. was less reactogenic. In the late United Kingdom) physicians at
It was not known what these 1960s RIV considered using this this time were not obliged to
were or how they should be iso- Marburg virus strain, and a provi- report cases of measles. The
lated. Norrby et al. concluded, sional licensing agreement with principal source of information

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⏐ PUBLIC HEALTH THEN AND NOW ⏐

was a national survey of general formalin-)inactivated vaccine was Development and production of CONCLUSIONS
an inactivated measles vaccine
practitioners conducted under the not advisable. It remained to be
will increase the chance that
auspices of the Dutch Association seen whether a different inactivated the number of injections in the Our comparison of the begin-
of Family Doctors (Nederlands vaccine might eventually prove of program remains limited or nings of mass measles vaccina-
more spread.56,57
Huisartsen Genootschap). Between value. Individual use of the vaccine tion in the United States and in
October 1965 and April 1966, was advisable: the consequences Great Britain bears out Baker’s
the 247 physicians who responded of vaccination were far less than In August 1970, the RIV allusion to two distinctive styles
had seen 10 700 cases of mea- of the disease itself. But introduc- was ready to begin a clinical of vaccine innovation. Pursuing
sles.54 The authors of the study ing measles vaccination into the trial. Permission was sought its war on poverty and con-
estimated that approximately National Immunization Program from the Dutch regulatory cerned by socioeconomic dispari-
16.1% of children contracting raised additional questions. From authority. “We think this is justi- ties in infectious disease
measles were likely to show some this viewpoint, combining measles fied,” wrote the new director incidence, the Johnson adminis-
complications. Extrapolating, vaccine with existing combinations general, “despite the adverse tration in the United States made
some 2700 children would be had major organizational advan- events as reported in the litera- federal funds for measles vacci-
seen by a specialist and 900 tages. The overall success of the ture after administration of a nation available starting in 1965
admitted to a hospital. National Immunization Program killed measles vaccine from an and embarked on a measles
In October 1968 the head of was crucial. American firm.”58 Using killed eradication campaign in 1967.
the RIV’s epidemiology depart- One must consider whether vaccine from another supplier The British, more cautiously,
ment published a long article in those caring for the child will (Behringwerke), these side established a large-scale clinical
the main Dutch medical journal.55 readily accept prevention of what effects did not appear. In 1971 trial to establish the relative ben-
Polak explained to doctors that is generally an unproblematic ill- the trial began, with 1207 chil- efits of the different available
whereas the application of a safe ness and/or whether this could dren enrolled. vaccines and possible immuniza-
and effective vaccine would yield lead to resistance against vacci- Children placed in one arm of tion schedules. Parents, it was
considerable benefit, the relative nation and attendance at the the trial were given Merck’s live hoped, would gradually come to
advantages of the attenuated and children’s clinic.55 Attenuvax at 12 months, whereas accept the desirability of vacci-
killed vaccines were still unclear. As experience with the use of those in the other arms received nating against what was widely
The Schwarz vaccine had been the vaccine accumulated, parents either four doses of one of the seen as an unpleasant, although
shown effective elsewhere and as well as doctors would be able inactivated (pentavalent DKTP- inevitable, childhood illness.
with few side effects, and its use to form an opinion regarding the M) vaccines at 3, 4, 5, and 12 Maintaining popular confi-
certainly merited consideration in burden associated with the effects months or three doses of one of dence in the country’s immuni-
the Netherlands. There were also of the vaccine. This would aid the DKTP-M vaccines followed zation program had to be given
inactivated vaccines that were pro- preparation for large-scale applica- by one dose of live vaccine at 12 due weight when introduction
duced by inactivation either with tion in the framework of the exist- months.59 Clinical data were col- of a new vaccine was under
formalin or Tween 80 and ether. ing national vaccination program. lected till about two years after consideration. Mass measles
The director general of RIV the fourth injection. No case of immunization began in Britain
Inactivated vaccines can pro-
vide good protection against
wrote to the state secretary for atypical measles was found, there in 1968. In Sweden it began in
measles, in any event in the health explaining the progress of was no interference between the 1971 and in the Netherlands not
short term and after repeated the pentavalent combination vac- component antigens, and there until 1976. These delays reflect
application.
cine project. Particular attention were no side effects. However, not only the greater British cau-
was being paid to the risk of the results clearly showed that tion to which Baker refers but
A mixed schedule was also a
adverse effects of the kind antibody titers declined rapidly also a concern in all three coun-
possibility, although (for unknown
reported in the United States, in children given either of the tries about the implications for a
reasons) this had sometimes led to
although no such reactions had preparations containing an inacti- national immunization program
serious reactions.
been observed in Europe when vated vaccine. The conclusion as a whole. There was a fear
It is conceivable that these com-
(purified) TE vaccines had been was now inescapable, and the that introducing a vaccine most
plications, associated with use used. Live attenuated vaccines fate of the inactivated measles parents did not see as needed
of inactivated vaccine, can be were being used effectively else- vaccine approach in the Nether- could undermine popular
avoided by the correct choice
both of vaccine and of mode of
where, and side effects were now lands sealed.60 In 1973 the deci- confidence.61
delivery.55 far less a problem than they had sion was taken to stop the The Dutch and Swedish cases
been, but their inclusion in the program. In 1974 live Attenuvax show something else as well.
Because at the time these National Immunization Program was purchased from Merck, and Both countries, unlike the United
conditions were not known, use would be more challenging than in 1976 mass measles immuniza- States and Britain, succeeded in
of the (commercially available would an inactivated vaccine. tion began in the Netherlands. controlling polio using Salk’s

August 2013, Vol 103, No. 8 | American Journal of Public Health Hendriks and Blume | Peer Reviewed | Public Health Then and Now | 1399
⏐ PUBLIC HEALTH THEN AND NOW ⏐

inactivated virus vaccine despite ensuring adequate vaccine sup- Measles: History and Basic Biology, ed. United States, Office of Technology
D. E. Griffin and M. B. A. Oldstone (Heidel- Assessment, September 1979), http://
almost universal skepticism else- plies,62 the wider relevance of
berg, Germany: Springer, 2009), 3–11. www.fas.org/ota (accessed February
where. This very recent experi- the few remaining public sector 6. As Morley’s work in Nigeria, in par- 10, 2012).
ence led virologists in both vaccinology institutes’ (e.g., in ticular, was beginning to demonstrate, 14. Colgrove, State of Immunity, 156.
countries to prefer, and to con- Brazil and in Cuba) distinctive e.g., D. C. Morley, “Measles in Nigeria,”
15. Office of Technology Assessment, A
American Journal of Diseases of Children
tinue to develop, inactivated mea- approach to innovation is rarely Review of Selected Federal Vaccine and
103 (1962): 230–233; D. Morley, M.
Immunization Policies, 182.
sles vaccines long after their US acknowledged.63 Q Woodland, and W. J. Martin, “Measles
in Nigerian Children: A Study of the 16. A. D. Langmuir, D. A. Henderson,
and British counterparts had R. E. Serfling, et al., “The Importance of
Disease in West Africa, and Its
rejected them. Unlike in the Manifestations in England and Other Measles as a Health Problem,” American
About the Authors Journal of Public Health 52, no. 2
United States and the United Jan Hendriks is with International Sup-
Countries During Different Epochs,” Jour-
nal of Hygiene 61, no. 1 (1963): 115– (1962): 1–3.
Kingdom, the issue in the Nether- port, Vaccinology Unit, National Institute
134. In 1960, responding to a request 17. Colgrove, State of Immunity, 159.
lands was not choosing between of Public Health and the Environment,
from Morley, Samuel Katz had taken 18. Sencer, Dull, and Langmuir, “Epide-
Bilthoven, the Netherlands. Stuart Blume is
commercially available alterna- with the Department of Sociology and An-
measles vaccine prepared by Merck to miological Basis,” 256.
tives. As a public sector institu- the Nigerian village in which Morley was
thropology, University of Amsterdam, Am- 19. For fiscal years 1969 and 1970,
working and a trial was conducted suc-
tion, RIV was responsible for sterdam, the Netherlands. Congress authorized no federal funding
cessfully (Katz, “John F. Enders,” 8).
Correspondence should be sent to for community immunization programs.
providing the vaccines to be used Stuart Blume, University of Amsterdam, 7. Merck’s development of the measles The number of doses distributed fell to
in the National Immunization Pro- o.z. Achterburgwal 185, 1012 DK vaccine is discussed in L. Galambos 9.4 million, and the estimated cases of
gram. It could do this by develop- Amsterdam, The Netherlands (e-mail: with J. E. Sewell, Networks of Innovation: measles rose to 533 000 in 1970 and to
s.s.blume@uva.nl). Reprints can be ordered Vaccine Development at Merck, Sharp & 847 000 in 1971. Thereafter, federal fund-
ing and producing them itself or, at http://www.ajph.org by clicking the Dohme, and Mulford, 1895–1995 (Cam- ing was restored, and measles cases fell
when appropriate, by purchasing “Reprints” link. bridge, UK: Cambridge University Press, to 400 000 in 1972. The Office of Tech-
them from a commercial supplier. This article was accepted September 6, 1995), 86–98. nology Assessment suggests a direct con-
2012. 8. L.L. Terry, “The Status of Measles nection (A Review of Selected Federal Vac-
In its work on a measles vac-
Vaccines,” Journal of the National Medical cine and Immunization Policies, 182–183).
cine, conducted from 1964 to Contributors Association 55, no. 5 (1963): 453–455. 20. “Editorial: Inactivated Measles Virus
1972, RIV was trying to develop J. Hendriks was responsible for 9. The Centers for Disease Control and Vaccine,” British Medical Journal 1, no.
the vaccine that could best— archival research in the Netherlands Prevention, in collaboration with the Colo- 5294 (1962): 1746–1747.
and participated in collection and rado State Department of Public Health, 21. The 1946 act setting up the United
effectively and safely but also review of secondary sources. S. Blume carried out a placebo-controlled trial of Kingdom’s National Health Service es-
with minimal disruption—be participated in collection and review the inactivated vaccine in 1961–1962. tablished the Public Health Laboratory
accommodated in the National of secondary sources and in drafting An outbreak of measles two to six months Service, which the MRC administered
the article. later showed the vaccine to be “82% ef- until 1960. In that year it acquired a
Immunization Program. Follow-
fective in preventing any evidence of new status under, but somewhat inde-
ing the strategy that had been so Acknowledgments measles and 93% effective in preventing pendent of, the Ministry of Health. See
successful in the case of the The authors would like to thank Suzette regular measles” (p. 64). The authors of Linda Bryder, “Public Health Research
polio vaccine, this was attempted Westling for research assistance, Hans the report were, nevertheless, skeptical re- and the MRC,” in Historical Perspectives
Cohen and Rob van Binnendijk for ad- garding the possibility of longer protec- on the Role of the MRC, ed. J. Austoker
by combining an inactivated vice, and Christoph Gradmann and Wil- tion. W. H. Foege, O. S. Leland, C. S. Mollo- and L. Bryder (Oxford, UK: Oxford Uni-
measles vaccine with the existing liam Muraskin for comments on an ear- han, V. A. Fulginiti, D. A. Henderson, and versity Press, 1989), 59–81.
DPT-P. The significance of these lier version of this article. C. H. Kempe, “Inactivated Measles-Virus
22. D. L. Miller, “Frequency of Compli-
Vaccine. A Field Evaluation,” Public
efforts, we suggest, is not that cations of Measles, 1963. Report on a
Health Reports 80, no. 1 (1965): 60–64.
they ultimately failed; it is to Endnotes On the other hand, a study in Buffalo,
National Inquiry,” British Medical Jour-
1. J. P. Baker, “Immunization and the nal 2, no. 5401 (1964), 75–78.
remind us of an approach to vac- NY, found inactivated vaccine promising
American Way: 4 Childhood Vaccines,” 23. Of these, 2000 would be expected
enough to merit further study. W. Winkel-
cine development, taking the American Journal of Public Health 90,
stein, D. T. Karzon, D. Rush, and W. E. to have a neurological condition, 13 000
no. 2 (2000): 199–207. a middle ear infection, and 20 000 a re-
needs of a national immuniza- Mosher, “A Field Trial of Inactivated Mea-
2. D. J. Sencer, H. B. Dull, and A. D. sles Virus Vaccine in Young School Chil- spiratory problem. Miller, “Frequency of
tion program as its starting point, Complications of Measles, 1963.”
Langmuir, “Epidemiological Basis for dren,” Journal of the American Medical
which in the past three decades Eradication of Measles in 1967,” Public Association 194, no. 5 (1965): 106–110. 24. D. L. Miller, “The Public Health Im-
has all but vanished. Vaccine Health Reports 82, no. 3 (1967): 253– portance of Measles in Britain Today,”
10. Younger children would be unre-
256. Proceedings of the Royal Society of Medi-
development and production in sponsive because of residual maternal
3. “Editorial: Vaccination Against Mea- antibodies. cine 57 (1964): 843–846.
public sector institutions such as sles,” British Medical Journal 2, no. 25. “Editorial: Measles and Measles
RIV, tailored in the first instance 11. J. Colgrove, State of Immunity. The
5262 (1961): 1274–1275. Vaccination,” British Medical Journal 2,
Politics of Vaccination in Twentieth-Cen-
to national health care needs 4. S. L. Katz, J. F. Enders, and A. Hollo- no. 5401 (1964): 72–74.
tury America (Berkeley, CA: University
way, “Studies on an Attenuated Mea-
and only in the second instance sles-Virus Vaccine. Clinical, Virologic
of California Press, 2006). 26. Ibid., 72.
to market opportunity, has come and Immunologic Effects of Vaccine in 12. Ibid., 132. 27. J. F. Bourdillon, “Immunisation
Institutionalized Children,” The New Against Measles,” The Lancet 284, no.
to seem an anachronism. 13. Office of Technology Assessment,
England Journal of Medicine 263, no. 4 7353 (1964): 239–240.
Although local vaccine produc- A Review of Selected Federal Vaccine
(1960): 159–161. and Immunization Policies Based on 28. “Editorial: Vaccination Against Mea-
ers are now accepted as having 5. S. L. Katz, “John F. Enders and Measles Case Studies of Pneumococcal Vaccine sles,” British Medical Journal 1, no.
an important role to play in Virus Vaccine—A Reminiscence,” in (Washington, DC: Congress of the 5485 (1966): 435–436.

1400 | Public Health Then and Now | Peer Reviewed | Hendriks and Blume American Journal of Public Health | August 2013, Vol 103, No. 8
⏐ PUBLIC HEALTH THEN AND NOW ⏐

29. George Dick, a leading member of antigen antibody reaction may occur as 45. Norrby, Lagercrantz, and Gard, 53. Gezondheidsraad, Rapport Inzake de
the British government’s vaccine advi- the effect of the inactivated vaccine “Measles Vaccination IV,” 816. Vaccinatie tegen Mazelen. Report 68-
sory committee, had carried out a trial of wears off” and that “the climate of opin- 46. E. Norrby, R. Lagercrantz, and S. 430-6 (The Hague, the Netherlands,
Koprowski’s live polio vaccine in Belfast. ion is for the present veering away from Gard, “Measles Vaccination VII. Follow 1968).
Its failure led him to oppose the use of the killed measles vaccine” (World Up Studies in Children Immunized With 54. Quoted by M. F. Polak, “Mazelenvacci-
live vaccines. However, a government Health Organization Archives; Geneva, Four Doses of Inactivated Vaccine,” natie,” Nederlands Tijdschrift voor Genees-
campaign to encourage Salk vaccine up- Switzerland; file M11/445/2). Acta Paediatrica Scandinavica 58, no. 3 kunde 112, no. 42 (1968): 1905–1906.
take in 1958 made little headway until a (1969): 261–267.
34. V. A. Fulginiti and C. H. Kempe,
famous soccer player died of polio in 55. Ibid., 1905–1909.
“Killed-Measles-Virus Vaccine,” The Lan-
spring 1959. That stimulated huge num- 47. Norrby, Lagercrantz, and Gard,
cet 290, no. 7513 (1967): 468. 56. J. Spaander, Letter dated April 26,
bers to seek vaccination, and incidence “Measles Vaccination IV,” 817.
1968 (U222/68 Dir Sp/mp) to the Dutch
fell sharply. Nevertheless, in September 35. Characteristics of atypical measles
48. “H-protein (causing hemagglutination) secretary of state regarding the develop-
1961 a polio outbreak occurred in the were high fever, coughing, and myalgia,
and F (fusion) protein (causing hemolysis) ment of a pentavalent vaccine (in Dutch;
city of Hull. The city’s health officials followed by a distinctive rash and accom-
are surface proteins on the envelope of The Hague, the Netherlands: Dutch Na-
sought permission from the Ministry of panied by pneumonia-like symptoms.
the virion needed to penetrate host cells. tional Archives, 1968). Box No. 3937.
Health to use the live (Sabin) vaccine for 36. Medical Research Council, “Vaccina- The H-protein reacts with a specific recep-
the first time in Britain. The ministry tion Against Measles: Clinical Trial 57. At Merck, Maurice Hilleman was by
tor on the host cells. After adsorption of
agreed, and vaccine was supplied by the of Live Measles Vaccine Given Alone and this time also investigating the possibilities
the virion, the F protein is involved in the
British subsidiary of Pfizer. Within two Live Vaccine Preceded by Killed Vaccine. of combining (live) measles vaccine with
fusion of the viral and the plasma mem-
weeks the epidemic was over. In early Second Report to the MRC by the Mea- other antigens. But Merck did not produce
brane. The existence of the F protein was
1962 the ministry gave local health au- sles Vaccines Committee,” British Medical DPT, and Hilleman eventually decided to
not known at this time” (S. Westling, In-
thorities permission to change to the Journal 2, no. 5603 (1968): 449–452. combine measles vaccine with mumps
terview with E. Norrby, Stockholm, No-
Sabin vaccine, and by 1963 medical and rubella. Merck’s measles-mumps-ru-
37. Vaccines for these children were of- vember 2011). Only later were Norrby
opinion had swung in favor of its exclu- bella vaccine was licensed in 1971.
fered after nine months and, if accepted, and Gollmar able to show that both for-
sive use. See T. Gould, A Summer Plague. malin and TE inactivation destroyed the 58. H. Cohen, Letter dated August 7,
the children were then excluded from
Polio and Its Survivors (New Haven, CT: F-protein, i.e., the surface component of 1970 (U234/70 Dir Co/ms) to the
the remainder of the trial.
Yale University Press, 1995). the virus that produced these so-called head of the National Control Laboratory
30. E. Norrby, R. Lagercrantz, and S. 38. Medical Research Council, “Vacci- non-HI hemolyzing-inhibiting antibodies. H. P. Lansberg (in Dutch; The Hague,
Gard, “Vaccination Against Measles: A nation Against Measles,” 452. E. Norrby and Y. Gollmar, “Identification the Netherlands: Dutch National
Study of Clinical Reactions and Serolog- 39. Joint Committee on Vaccination and of Measles Virus-Specific Hemolysis Inhib- Archives, 1970). Box No. 3937.
ical Responses of Young Children. A Re- Immunisation, “Minutes of Meeting Held iting Antibodies Separate From Hemag- 59. R. Brouwer, “Vaccination of Infants
port to the Medical Research Council by on Monday November 13, 1967. Docu- glutinating-Inhibiting Antibodies,” Infection in Their First Year of Life With Split In-
the Measles Vaccination Committee,” ment CHSC(VI) 1967 Second Meeting,” and Immunity 11, no. 2 (1975): 231–239. activated Measles Vaccine Incorporated
British Medical Journal 1, no. 5438 http://www.dh.gov.uk/ab/JCVI/ in a Diphtheria-Pertussis-Tetanus-Polio
49. U. Lindner and S. Blume, “Vaccine
(1965): 817–823. DH_095054 (accessed June 30, 2012). (Inactivated) Vaccine (DPTP-M), Com-
Innovation and Adoption. Polio Vaccines
31. “Editorial: Measles Vaccination,” The 40. Also, in 1968, Merck’s Moraten in the UK, the Netherlands and West pared With Live Measles Vaccination,”
Lancet 1, no. 7435 (1966): 473–474. strain had been licensed, and the earlier Germany, 1955–1965,” Medical History Journal of Biological Standardization 4,
32. L. W. Rauh and R. Schmidt, “Mea- Rubeovax was replaced by Attenuvax. See 50, no. 4 (2006): 425–446. no. 1 (1976): 13–23.
sles Immunization With Killed Virus Galambos, Networks of Innovation, 97–98. 60. Subsequent support for this decision
50. It has not been possible to establish
Vaccine. Serum Antibody Titers and Ex- 41. However, supplies initially available how far the needs of developing coun- came from Norrby’s discovery that inacti-
perience With Exposure to Measles Epi- were insufficient, so between May and tries, where an inactivated vaccine vated vaccine fails to generate antibodies
demic,” American Journal of Diseases of July only susceptible children aged be- could have certain advantages, also in- against the fusion protein, which later
Children 109 (1965): 232–237. tween four and seven years, plus chil- fluenced the decision to work on an in- turned out to be critical for protection.
33. In August 1966, C. Cockburn of the dren aged between one and seven years activated measles vaccine. Hans Cohen, The special feature of this deficiency is
World Health Organization wrote to who attended nursery schools or lived head of the RIV’s vaccine division and that it can provide a basis for immune
Pfizer saying, “My epidemiological col- in residential establishments, would be later its director general, was an active pathological effects that may aggravate
leagues in Czechoslovakia are rather un- vaccinated. Joint Committee on Vaccina- member of the World Health Organiza- the situation of vaccinated individuals.
willing to proceed with these studies be- tion and Immunisation, “Minutes of tion’s Expert Committee for Biological 61. As subsequent developments have
cause of the reports of rather severe Meeting of July 23, 1968. Document Standardization, which established vac- illustrated all too well. See H. J. Larson,
reactions when live vaccine is given after CHSC (VI)(68). First Meeting,” http:// cine requirements. In the 1980s, new L. Z. Cooper, J. Eskola, S. L. Katz, and
killed vaccine.” Cockburn initiated a www.dh.gov.uk/ab/JCVI/DH_095054 attempts to develop a (subunit) inacti- S. Ratzan, “Addressing the Vaccine Con-
study of this reaction. “So far there is (accessed June 30, 2012). vated measles vaccine began at the RIV. fidence Gap,” The Lancet 378, no.
very little evidence of untoward reac- 9790 (2011): 526–535.
42. “Vaccination Against Measles,” The 51. Beale had previously worked on in-
tions except from Dr Fulginiti who has
Lancet 292, no. 7568 (1968): 616– activated polio vaccine as well at Con- 62. e.g., S. Jadhav, M. Datla,
not answered my letter but whose report
618. The Beckenham-31 vaccine was naught in Canada. At Glaxo, he tested a H. Kreeftenberg, and J. Hendriks, “The
to a recent meeting was made available
withdrawn by its manufacturer in 1969. measles vaccine inactivated using Nor- Developing Countries Vaccine Manufac-
to me.” On August 15, Pfizer’s assistant
43. R. Brouwer, “Internal Report,” In- rby’s process in a small trial in Ireland. turers’ Network (DCVMN) Is a Critical
medical director replied, “We have had a
ternational Symposium on Standardiza- The conclusion, that a single dose of in- Constituency to Ensure Access to Vac-
few isolated reports of reactions follow-
tion of Measles Vaccine and the Serol- activated vaccine given one month be- cines in Developing Countries,” Vaccine
ing live vaccine, but Dr Fulginiti is the
ogy of Measles and Rubella, Institut fore live vaccine does not interfere with 26, no. 13 (2008): 1611–1615.
only investigator to report its occurrence
Mérieux, Lyon, France, June 18–20, antibody response and may even en-
in a number of cases.” In December 63. H. Thorsteinsdottir, “The Role of
1964 (in Dutch), n.p. hance it, was different from what MRC
1966 Cockburn wrote to M. Sharif at the Health System in Health Biotechnol-
found. They attributed the difference to
the United Nations Relief and Works 44. E. Norrby, R. Lagercrantz, and ogy in Developing Countries,” Technol-
the different inactivated vaccines used.
Agency (which had been offered the in- S. Gard, “Measles Vaccination IV. ogy Analysis & Strategic Management 19,
activated vaccine for use in Palestinian Response to Two Different Types of 52. R. Brouwer, “De productie en con- no. 5 (2007): 659–675; A. Lage, “Con-
refugee camps), saying that although in- Preparations Given as a Fourth Dose of trole van een geinactiveerd en ge- necting Immunology to Public Health:
formation was still rather fragmentary, Vaccine,” British Medical Journal 1, no. zuiverd mazelenvaccin.” Unpublished Cuban Biotechnology,” Nature Immunol-
it seemed possible that an “unexpected 5438 (1965): 813–817. internal report (in Dutch; 1967). ogy 9, no. 2 (2008): 109–112.

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