Use in Polio
PUBLIC HEALTH THEN AND NOW
Passive Immunization Against Poliomyelitis The Hammon Gamma Globulin Field Trials, 1951–1953
| Charles R. Rinaldo Jr, PhD
POLIOMYELITIS, OR POLIO, IS Western Europe in the late 19th particularly William McDowall Poliomyelitis has gone from being a modern saga. The poliovirus century. In the summer of 1916, Hammon, also of the University one of the worst scourges of the 20th has likely been in the human North America underwent a hor- of Pittsburgh. Here I present a century to nearing eradication in the population for thousands of rifying polio epidemic reportedly historical review of Hammon’s 21st. This success is well known to years. However, before the late claiming more than 7000 lives in development of passive immu- be attributable to the Salk inacti- 18 00s, paralytic disease attribut- 20 states.1 The peak of the US nization in the prevention of vated and Sabin attenuated polio- able to poliovirus was sporadic epidemic occurred in 1952: al- poliomyelitis, which was one of virus vaccines. and endemic, not epidemic. As most 57000 cases, more than the key advances leading to the However, before introduction of an enterovirus, it is predomi- 21 000 of them paralytic. Similar Salk vaccine.2–5 these vaccines, William McDowall nantly spread via the fecal–oral epidemic trends were occurring Hammon of the University of Pitts- route and is stable in the envi- all over the Western world. HAMMON’S BASIS FOR POLIO PREVENTION BY burgh Graduate School of Public Health ronment. Thus, conditions of Clearly there was a desperate poor sanitation and crowding need for a way to prevent polio- PASSIVE IMMUNIZATION led the first major breakthrough in common before the 20th century myelitis, preferably through a prevention of the disease by using pas- led to widespread infection at vaccine such as that developed Pittsburgh was the Steel City sive immunization in one of the earli- early ages. Improved hygienic for childhood whooping cough in 1949, covered with smoke est double-blind, placebo-controlled standards opened the portal for (pertussis) and diphtheria early in and soot, with a postwar, civic clinical trials. This study provided the poliovirus to cause more serious the 20th century. Thus, the best push to rid the city of its dirty first evidence that antibodies to polio- disease in an epidemic form. scientific and medical minds of image. It was “a city on the rise,” virus could prevent the disease in hu- Children lost their passive mater- the 1930s, 1940s, and 1950s fo- according to the Pittsburgh Press. mans. (Am J Public Health. 2005;95: nal antibody as they aged, leav- cused on polio. We all know of At the University of Pittsburgh in 790–799. doi:10.2105/AJPH.2004. ing them vulnerable to infection Jonas Salk of the University of the city’s historic Oakland sec- 040790) and, for reasons still unclear, to Pittsburgh and Albert Sabin of tion, there was an unremarkable the more severe, paralytic mani- the University of Cincinnati for School of Medicine and a brand festations of polio. their polio vaccines. However, new Graduate School of Public Annual, seasonal polio epi- many other prominent figures Health, both endowed by demics first became common- were involved in the develop- wealthy Pittsburgh families, the place in the United States and ment of the poliovirus vaccine, Scaifes and Mellons. The first
790 | Public Health Then and Now | Peer Reviewed | Rinaldo American Journal of Public Health | May 2005, Vol 95, No. 5 PUBLIC HEALTH THEN AND NOW
dean of the Graduate School of nor.9 This private organization data, although from poorly con- Public Health was Thomas Par- depended on public donations. trolled human trials conducted in ran, a world-renowned physician Its well-known publicity theme the 1920s and 1930s, suggesting and former US surgeon general. was small contributions, or the that paralysis could be prevented He recruited the cream of public “March of Dimes,” which became by passive administration of health leaders to head 6 new de- the organization’s formal name whole blood or convalescent partments. Among these individ- in 1979. NFIP funded the re- serum.4 There was also evidence uals was the eminent 45-year-old search that eventually led to the that mass immunization with William Hammon, tapped to prevention of polio. plasma could prevent the spread chair the Department of Epide- Hammon laid out his future ap- of measles virus.11 Hammon miology and Microbiology. Ham- proach to preventing poliomyelitis based much of his reasoning that mon was born in Ohio in 1904, in an address delivered at the an- antibody was protective against and his family settled in Con- nual meeting of the American polio on his postwar research in neautville, 60 miles (96 km) Academy of Pediatrics in Novem- Guam.10 He noted that the last north of Pittsburgh, so this ap- ber 1949.10 It revealed the reported polio outbreak in Guam pointment meant a return to his strengths and flaws in his reason- was in 1899. An outbreak in roots. Salk later professed his ing, based on his scientific ortho- 1948 was restricted to Ameri- strong desire for this chairman- doxy, that would lead him and cans. He found that serum from ship, having been appointed to most others in the field to reject indigenous Guamanians had neu- the School of Medicine 2 years Salk’s views on an inactivated tralizing antibodies to poliovirus, earlier, and expressed his disap- pointment that Parran recruited Hammon instead.5,6 Hammon was married with 2 Hammon believed that gamma globulin obtained from children by the time he graduated pooled plasma with known neutralizing activity for 7 from medical school. He was an neurotropic strains of poliovirus held the best promise ordained Methodist minister who, “ for protecting against natural infection. after completing undergraduate work at Allegheny College in 1931, served as a missionary in the Belgian Congo. Upon return- polio vaccine. He stressed the use probably as a result of the natu- ” ing, he was admitted to Harvard of passive immunization to pre- ral infection with the virus that Medical School and joined the vent the infection temporarily dur- persisted on the island. laboratory of Hans Zinsser, the ing the polio season. Passive im- Hammon emphasized that the famous bacteriologist and epi- munization refers to injection of role of antibody in immunity to demiologist. He received his med- blood gamma globulins that trans- poliovirus was still uncertain. ical degree in 1936, a master’s fer specific antibodies to the virus, It was only 2 years earlier of public health degree in 1938, in contrast to active immunization, that Isabel Morgan and David and a doctor of philosophy de- in which an antigenic substance is Bodian of Johns Hopkins Uni- gree in 1939. He excelled under injected that induces specific anti- versity had shown that neutraliz- Zinsser’s guidance, developing the bodies to the virus. Hammon be- ing antibody protected against first vaccine for feline panleuko- lieved that gamma globulin ob- virus challenge in monkeys.12 penia in collaboration with John tained from pooled plasma with How long neutralizing antibod- Enders.8 In 1940, Hammon was known neutralizing activity for ies endured in the blood was recruited by the University of neurotropic strains of poliovirus still unknown. Morgan and California at Berkeley. held the best promise for protect- Bodian also showed that there About the time Hammon was ing against natural infection. were 3 poliovirus serotypes,13 a learning virology at Harvard, the Hammon did not necessarily number later confirmed by the National Foundation for Infantile hope to prevent infection with NFIP Virus Typing Committee, Paralysis (NFIP) was established this approach; the goal was to of which Hammon was a mem- by President Franklin Roosevelt, prevent the virus’s pathogenic ef- ber.14 This “problem of multiple a famous polio victim, and his fects on the nervous system. immunologic types”10(p700) was former law partner Basil O’Con- There were already tantalizing one of Hammon’s arguments
May 2005, Vol 95, No. 5 | American Journal of Public Health Rinaldo | Peer Reviewed | Public Health Then and Now | 791 PUBLIC HEALTH THEN AND NOW
against the use of active vaccina- vaccines, respectively.17 ,18 These antibodies to infectious agents, tion for polio prevention. vaccines proved ineffective, with particularly measles and polio. Another barrier was making the killed vaccine causing aller- Clinical trials had shown that commercial-scale virus prepara- gic reactions and the live vaccine gamma globulin was effective tions. Work on polio was greatly resulting in several cases of against measles virus,11 and Blox- hampered by the fact that the paralysis and death. It was som22 had reported a decrease in virus could not be grown effi- unclear how much poliovirus the expected number of paralytic ciently in tissue culture. Wild- “inactivation” would be enough polio cases in an uncontrolled type virus grew preferentially in to prevent its replication yet re- gamma globulin trial involving primates and had to be adapted tain immunogenicity. Even if a more than 800 cases in Texas in to nonprimate species through superior killed vaccine became 1949. Finally, much of the impe- passage in cells or animals. available, Hammon was adamant tus for Hammon’s gamma globu- Sabin and colleagues had tried that multiple, annual inoculations lin trials came from his collabora- unsuccessfully to grow the virus would be necessary to maintain tor, Joseph Stokes Jr, a renowned in different tissue types, being immunity. In support of this pediatrician at Children’s Hospi- able to replicate their monkey view, Morgan had shown that re- tal of Philadelphia. Stokes, an brain–passaged strain only in peated, large doses of formalin- early proponent of passive immu- nervous system tissue.15 They did inactivated virus induced only nization, had conducted human not realize that this strain had temporary immunity in mon- prophylaxis trials with whole adapted to the tissue, making it keys.19 It was apparent then, and blood for poliomyelitis in the less virulent for cells derived is now well established,20 that 193 0s 23 and, with the prominent from other tissues. In his presen- these different forms of vaccines virologist Werner Henle, had tation, Hammon acknowledged involve several advantages and proposed a large trial of gamma only in passing the recent find- disadvantages. globulin immunization to the ings of Enders, Weller, and Rob- These risks led Hammon to NFIP in the mid-1940s. The pro- bins on the growth of poliovirus an ultimately incorrect supposi- posal was rejected as a result of in human extraneural cell cul- tion based on the relatively low the cost and lack of sufficient tures.16 This achievement was in morbidity and mortality of polio- supply of gamma globulin. fact of such magnitude that it virus infections: he questioned Hammon stated the basic ra- would result in their receiving the effort, expense, and “risk for tionale for his passive immuniza- the Nobel Prize in 1954. Ham- accident” to thousands of chil- tion approach: “gamma globulin mon maintained that brain tissue dren involved in developing a would only be given at times of was still “the only present source vaccine to protect a relatively probable unusual exposure, ordi- of even moderately large supplies few individuals from paralysis narily during the early phase of of virus.”10(p700) The dangers of caused by poliomyelitis relative the epidemic.”10(p702) Interest- such multiple inoculations of to efforts to prevent other impor- ingly, he was critical of the likely brain tissue had been well docu- tant diseases.10 Hammon also requirement of multiple injec- mented4 and had hampered the cited the availability of gamma tions for primary, active immu- development of a poliovirus vac- globulin as a plus for its use, not nization: “Its [gamma globulin] cine for years. recognizing that his future clini- effect would be immediate and Hammon cautioned about cal trial alone would seriously would represent no danger to using either killed or live virus deplete the nation’s reserves of any child.”10(p702) He did not ac- as a vaccine, given the failures of gamma globulin. High-quality knowledge that passive immu- earlier, relatively crude clinical gamma globulin had been avail- nization would require up to trials. Such fear was a common able in sufficient quantity for 10 cc of gamma globulin given theme voiced by Sabin and most such treatment only since the in the buttocks, a painful and leaders in the field. In the mid- late 1940s. Cohn and Oncley of involved undertaking. Moreover, 193 0s, Maurice Brodie of New Harvard had perfected multistep there was concern, based on ac- York University, William Park of fractionation processing of blood counts of such problems after the New York City Health Labo- during World War II.21 parenteral inoculations, that “lo- ratory, and John Kolmer of Tem- Soon after this accomplish- calized irritation” at the injection ple University, tested inactivated ment, Enders and others proved site could promote paralysis at- and live attenuated poliovirus that gamma globulin contained tributable to poliovirus.4,9,24
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Hammon noted that passive rus strains.27 This was enough ev- at the time that reflected both in- immunization might not prevent idence to convince the panel, terest and desperation. infection but would be expected now formally established as the Hammon and the committee to prevent clinical disease.10 This Committee on Immunization, to addressed other factors,28 includ- could lead to permanent immu- unanimously recommend that ing how to blind the injection nity through inapparent infection NFIP fund a pilot study of 5000 vials, type of control inoculum with wild-type strains. Hammon children. Notably, panel members (autoclaved Knox gelatin), source called for a controlled trial of realized that a trial of this size and dosage of gamma globulin gamma globulin to address his would not yield statistically signif- (0.14 cc per pound of body hypothesis. icant results. Rather, the study’s weight of Red Cross pooled purpose was to gain experience gamma globulin, as Bodian had THE HAMMON GAMMA in organization and administra- shown it to have neutralizing an- GLOBULIN CLINICAL tion, as well as to evaluate the tibodies to polioviruses), types of TRIALS public’s and medical profession’s syringes (disposable syringes reaction to such a trial. were not yet widely available After arriving in Pittsburgh, Hammon worked rapidly to and thus were not used), venue Hammon proceeded with his mount the trial. Most important, (public schools, to allow for large plans for a massive field trial of he finally convinced the commit- numbers of participants), injec- immune globulin in the preven- tee to use a 1-to-1 match of vac- tion administration site (right but- tion of polio. This was not a sim- cine to placebo control. In Ham- tock), legal aspects such as writ- ple process. In February 1950, mon’s words, “Only this type of ten informed consent (a half-page he failed to gain support for the test would withstand critical sci- document!), selection of geo- trial from a group of his peers entific scrutiny and be accepted graphical area undergoing a polio that included Sabin, Enders, and universally as a final evalua- epidemic of a suitable magni- Salk, under the auspices of NFIP. tion.”28(p741) This reflected an tude, approval by the local popu- They wanted to see more animal evolving appreciation since the lation (including medical groups), and human data before embark- 193 0s that clinical trials must in- publicity and preparation of clin- ing on an expensive, compli- clude control participants who do ics, and follow-up studies (includ- cated, and potentially harmful not receive the experimental ing gathering of stool and blood clinical trial. Much of the opposi- drug.29 Investigators were also samples from incident case pa- tion came from Thomas Rivers, a coming to realize that the control tients and their close contacts). prominent virologist and director group should receive a placebo, a Most critical was the definition of of the Rockefeller Institute (now substance with no therapeutic the severity of the paralytic dis- Rockefeller University). He and benefit that mimicked the test ease, for which they used a care- others were concerned about drug in size, shape, color, and fully graded scale of muscle func- Hammon’s insistence on using taste, to control for potential bias tion loss. placebo controls, based on their introduced by the “placebo ef- Hammon chose to conduct the fear of the injections provoking fect,” wherein such mock treat- initial pilot trial in Provo, Utah, paralysis, and negative reactions ment nonspecifically relieves a and the surrounding Utah from the parents of trial control disease symptom.30 The most County south of Salt Lake City.28 participants who did not receive powerful “double-blind,” placebo- This choice was based on the gamma globulin. controlled clinical trials, those need for an epidemic area pre- More than a year later, in July wherein neither the participant dicted to involve a morbidity rate 1951, studies conducted by nor the clinician was aware of of 100 per 100000, with 70% Dorothy Horstmann of Yale and whether drug or placebo was to 80% of paralytic cases occur- Bodian provided critical proof being administered, were almost ring among children in the 1- to that passively transferred antibod- unheard of at that time. Ham- 12-year age range. The team of ies protected against lethal polio- mon’s study on passive immunity investigators calculated that at virus infections in monkeys.25,26 to poliovirus would be one of the least 36 cases (24 in the control Bodian also reported that human first major double-blind, placebo- group and 12 in the treatment gamma globulin protected mon- controlled clinical trials. The trial group) were required within the keys against immediate intramus- ultimately would cost NFIP $1 study population of 5000 to cular challenge with all 3 poliovi- million, an extraordinary amount allow determination of whether
May 2005, Vol 95, No. 5 | American Journal of Public Health Rinaldo | Peer Reviewed | Public Health Then and Now | 793 PUBLIC HEALTH THEN AND NOW
the gamma globulin was protec- ever, the amount of public sup- pressed great hope that “polio- tive (i.e., whether it resulted in at port was incredible. Within 3 myelitis could eventually be as least a 50% reduction of cases in days, the team had enrolled and readily controlled as measles or the treated group). By the end of inoculated 5768 children (aged smallpox.”33(p20) August 1951, they had recorded 2–8 years) at 5 locations. The in- In the span of 10 days during vestigators stopped enrollment July 1952, the team inoculated after the gamma globulin supply 33137 children in 8 clinics. This had been exhausted, turning was still not a large enough sam- hundreds away on day 4. ple to achieve the most accurate, The results were encourag- statistically significant results pos- ing.31,32 In the 84 days following sible. As the trial was closing, an the trial, there was 1 case of advance team found 2 other suit- paralytic polio in the gamma able locations: Sioux City and globulin group (n = 2871), along surrounding Woodbury County, with 5 cases in the placebo Iowa, and nearby Dakota group (n = 2860) and 12 in County, Nebraska. By mid-July the remainder of the sample 1952, the incidence of poliomye- (n = 6800). As anticipated by litis in this area was 100 per Hammon and the committee, 100 000 population, much given the small number of cases, higher than the rate at the Texas this result was not statistically sig- location. Hammon’s team quickly nificant. The team did, however, established its trial at this site achieve the study’s primary goal and inoculated 15868 children of gaining experience in adminis- aged 1 to 11 years in 6 days. tering gamma globulin to chil- Thus, in 3 clinical trials held dren in a large clinical trial, with in less than a year, the team had no major adverse outcomes. inoculated 54 772 children. The Moreover, there was tantalizing procedure was safe, with very if not conclusive evidence that few adverse outcomes (e.g., gamma globulin modified the hyperreactivity to the inoculum) severity of paralysis, even if ad- and no associated paralysis. After ministered late in the incubation the epidemics had waned and period. the cases had been tabulated, This positive experience led to data from the combined 3 trials rapid approval of a larger trial revealed 26 cases of paralytic that required a similar poliomye- polio in the group receiving litis rate in an area of greater gamma globulin compared with FIGURE 1—Injection of 10 cc of 38 cases of paralytic poliomyeli- population density. Hammon 64 cases in the controls by 10 gamma globulin was a painful tis in Utah County for the year, and colleagues found such a set- weeks after injection.31,32 No sta- experience, as shown here in an with most occurring that month. ting in Houston and the sur- tistical analysis was available at Associated Press photograph that 31 appeared with the October 23, The epidemic was taking off. On rounding Harris County, Texas. that time, but the results were 1952, New York Times article August 30, the study plans were By late June 1952, the rate of considered “conclusive evidence describing the Hammon clinical presented to the Utah Medical poliomyelitis cases in the area of a very significant reduction in trials in Houston. Society and unanimously ac- was 27 per 100 000, and half of the total number of cases of par- cepted with “unexpected enthusi- the patients were in the 1- to alytic poliomyelitis”32(p758) owing asm.” Hammon started the trial 6-year age range. The double- to the gamma globulin. on September 4, 1951. blind trial was put into action, Hammon presented the trial Problems included such issues with enough gamma globulin results at the American Public as lack of large autoclaves to available from the Red Cross to Health Association’s annual sterilize the syringes and needles, inoculate about 28% of the chil- meeting in Cleveland on October the investigators driving 50 miles dren in this age group (Figure 1). 22, 1952. The work was hailed to Salt Lake City each night to A New York Times editorial pub- in the news media across the use hospital autoclaves.28 How- lished on the eve of the trial ex- country as the first time polio
794 | Public Health Then and Now | Peer Reviewed | Rinaldo American Journal of Public Health | May 2005, Vol 95, No. 5 PUBLIC HEALTH THEN AND NOW
could be checked, albeit tem- voluntary blood donations. The munity was of short duration, porarily (Figure 2). In his report, product also contained antibod- reinjection was required during Hammon stated: “If it is found ies to measles and infectious hep- each epidemic outbreak, the opti- that gamma globulin has not in- atitis and was needed to prevent mal time for administration was terfered with inapparent infec- these infections as well. The unknown, the study lacked con- tion and the development of ac- Korean War and routine hospital trol for preexisting immunity, tive immunity during the period needs were another major drain and the protection offered was of protection against clinical dis- on the gamma globulin supply. incomplete. ease, this will have a wide field Finally, until 1955, the lots were Hammon gave a balanced re- usefulness.”32(p759) not standardized as to amount of port of his data in an address de- The study results were pub- antibody to poliovirus, so it was livered to the American Associa- lished in 3 back-to-back articles unclear which lots were more po- tion of Physicians in May 1953 in the October 25, 1952, issue of tent against poliomyelitis. in which he summarized his con- FIGURE 2—October 23, 1952, New the Journal of the American Med- Despite these caveats, this was cerns about the misinterpretation York Times article on the report pre- ical Association (JAMA).28,31,32 the only protection people had and misuse of the results of his sented at the annual meeting of the The accompanying editorial against the disease. On the basis clinical trials.40 He opened with a American Public Health Association praised the work for the “philoso- of small studies22 and anecdotal bold statement: “we find our- in Cleveland on the effectiveness of gamma globulin in the 1952 phy of the experiment” as well as information,4 many physicians selves for the first time with an Hammon clinical trials. The photo- the “encouraging” evidence for were already using gamma glob- agent capable of preventing the graph of Hammon is modified from protection from paralytic polio.34 ulin to prevent poliomyelitis. On paralytic disease.” However, he an October 23 Pittsburgh Post- The authors cautioned, however, December 9, 1952, the Red immediately warned that “the Gazette article. that longer follow-up and final Cross announced plans to greatly evaluation of the trial were increase the production of needed before more definitive gamma globulin and distribute conclusions could be drawn. The it to 150 areas around the coun- “first successful prevention of try.36 This project would cost paralytic poliomyelitis” was $7 million but would protect lauded by Basil O’Connor as about 1 million children in the NFIP’s scientific highlight of 1953 poliovirus season. 1952 and the greatest step yet Follow-up information on the taken toward ultimate control of Hammon study was presented in the disease.35 Hammon had im- the April 11, 1953, issue of pressed upon the medical com- JAMA.37 The analysis proved munity that something could fi- that Red Cross gamma globulin nally be done to prevent the offered “highly significant protec- dreaded disease, although the so- tion against paralytic poliomyeli- lution was not perfect. tis.”37(p1284) In summary, it was As anticipated, the limited about 80% effective for 5 weeks availability of gamma globulin re- if given under these controlled stricted its use. O’Connor warned circumstances. Later analysis by that there was not enough to pro- Hammon would prove that vide “even temporary protection gamma globulin had not inter- to the 46,000,000 children and fered with acquisition of the in- adolescents most susceptible to fection or development of active poliomyelitis.”35(p32) Each lot of immunity.38 In the 1953 arti- gamma globulin was obtained cle,37 Hammon and coauthors from fractionation of a pool of at Stokes, Lewis Coriell of the Uni- least 1000 units of blood plasma versity of Pennsylvania, and Paul or serum, an expensive and time- Wehrle of Pittsburgh were cau- consuming process. In the case of tious, as was the accompanying the largest supplier, the Red editorial,39 listing several disad- Cross, the amount of gamma vantages of passive immunization globulin produced depended on and limitations of the study: im-
May 2005, Vol 95, No. 5 | American Journal of Public Health Rinaldo | Peer Reviewed | Public Health Then and Now | 795 PUBLIC HEALTH THEN AND NOW
circumstances under which it bodies against the various types including any of Salk’s detractors [gamma globulin] is effective are of poliovirus could be increased recommended that Salk conduct definitely limited and not yet to relatively high titers in previ- a limited clinical trial of his vac- completely defined, and further- ously infected children. This ap- cine in Pittsburgh and that these more the agent is in short sup- peared to be the breakthrough investigations take place on an ply.” He argued strongly against toward which the scientific field “ever increasing scale” in addi- the use of gamma globulin for had been working. tional communities through the mass, communitywide applica- In his April 1953 article, Ham- summer of 1954. tion in polio prevention, contend- mon alluded to Salk’s work by While these plans were being ing that it was a wasteful en- stating that “[i]t must be obvious made, the epidemic raged deavor: “There is not enough that a vaccine that can be given throughout the summer of 1953. gamma globulin for all children to small infants in a methodical However, now there was some- in all epidemic communities.” He way during nonepidemic seasons thing that could be done. In stressed that gamma globulin and confer more or less perma- Montgomery, Ala, the outbreak should instead be used in “a few nent immunity is much to be de- was so severe that 30000 chil- small groups,” particularly family sired, and that when such a vac- dren were given gamma globulin. contacts of individuals known to cine is available, it will largely The attempts to use gamma glob- have the disease (a process la- replace gamma globulin.”37(p1283) ulin in multiple locations re- beled contact prophylaxis). He then offered what turned out vealed the procedure’s basic to be the most significant reason shortcoming: there was not HOPE FOR THE SALK his work should be considered enough gamma globulin to go VACCINE, NO FAITH IN important to the field of polio around. The national supply was GAMMA GLOBULIN prevention: “Perhaps the greatest protected by the Office of De- contribution of the gamma glob- fense Mobilization, with a third Hammon undoubtedly knew ulin field trials is the impact [they being reserved for the polio epi- that gamma globulin’s fate in have] on the status of active im- demic expected that year. Thus, polio prevention was taking a munization through the use of a supplies were clearly insufficient. downward turn by April 1953. vaccine. In these gamma globu- In total, only 235000 children The previous month, JAMA had lin studies it has been demon- received injections in 1953. published Salk’s landmark article strated that a very low concen- By December 1953, NFIP was describing the first clinical immu- tration of antibodies will protect preparing to triple the amount of nization trial with inactivated man.”37(p1283) This was almost a gamma globulin available for polio vaccine, performed in mid- verbatim version of what Salk polio prevention during the fol- 1952.41 These results were first had stated a month earlier in lowing season. They had spent FIGURE 3—February 23, 1954, presented at a meeting of the Im- his JAMA article in reference to $5.5 million that year and would New York Times article on the 41 report by the review committee munization Committee in Her- Hammon’s trials. need to spend $19 million in the 5,6,42 of the “failure” of prevention of shey, Pa, in January 1953. The polio story was rapidly next. NFIP was being stretched poliomyelitis by widespread Ayear earlier, Bodian and changing even as Hammon’s beyond its financial capacity use of gamma globulin in the Horstmann had described 1953 article was published. while having to fulfill the great summer of 1953. viremia caused by poliovirus in- Aweek earlier, in the April 4, public hopes it had created for a fection of primates prior to devel- 1953, issue of JAMA, an editorial cure for polio. However, 2 fac- opment of paralysis, implying stated that Salk’s work implied tors were about to change this that the virus traveled to the cen- that injection of the new vaccine situation dramatically. tral nervous system via the “should be adequate to provide NFIP convened a panel of 17 blood.43,44 Until then, it was un- significant protection against the polio experts in January 1954 to clear that a bloodborne phase paralytic consequences of a natu- review the results of the first was required for infection of the ral infection with poliomyelitis widespread use of gamma globu- nervous system. virus.”45(p1198) A letter in the same lin the previous year. In addition Salk’s 1953 study showed issue written by Rivers described to Hammon, the panel included that different types of poliovi- a meeting set up by NFIP to public health epidemiologists, cli- rus, including a highly virulent advise Salk on future clinical nicians, and experts such as strain, could be inactivated by trials.46 A new Vaccine Advisory Sabin, John Paul of Yale Univer- formaldehyde.41 Moreover, anti- Committee led by Rivers and not sity, Thomas Francis of the Uni-
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versity of Michigan, Alex Lang- Committee insisted that this large muir of the Centers for Disease trial include placebo controls, in Control, and Abraham Lilienfeld contrast to Salk’s preference for of Johns Hopkins. The panel’s re- observed controls.5,9 Half a mil- port, released on February 22, lion children would receive the 1954, and published in March,47 Salk vaccine, and an additional was devastating for Hammon 300000 would receive a and his work. The committee placebo. The cost was estimated concluded that mass inoculations to be $7.5 million. As a means of of 185000 children in 23 areas avoiding potential complications the previous summer had failed in the Salk vaccine trial, use of to produce demonstrably benefi- gamma globulin for polio preven- cial results (Figure 3). Actually, tion was restricted in the 1954 the committee stated that, in season to geographical areas not most cities, the gamma globulin included in the trial.48 was given after the epidemic had These large field trials of the peaked; thus, there was little Salk vaccine were carried out chance to demonstrate an effect against the protests of Sabin and of gamma globulin in modifying others, who feared that the inacti- the epidemic. vated vaccine was unsafe and of Hammon strongly protested, low immunogenicity. The Salk filing a minority report.47 O’Con- vaccine, however, proved highly nor tried to clear up the public fi- successful. The rate of poliomyeli- asco the report created. He stated tis in the vaccinated group was 7 that the committee’s report did cases per 100000, compared not indicate that gamma globulin with 35 among placebo con- was either effective or ineffective. trols.48 The vaccine was only Moreover, NFIP was still plan- 60% to 70% protective against significantly decreased its sever- FIGURE 4—September 9, 1954, ning on tripling the gamma glob- paralysis caused by the more ity. Laboratory studies of blood New York Times article on the Rome poliovirus conference, describing ulin supply for the upcoming sea- prevalent type 1 strain, but it was obtained in the Hammon trial Hammon’s report that gamma globu- son to 3 million doses. 90% effective against paralysis also proved his theory that lin was effective in the 1953 epidemic Medical and public opinion caused by the type 2 and type 3 gamma globulin did not interfere and Salk’s report that the inactivated were clearly marshaling against strains. This did not represent with the natural development of vaccine was proving effective in his gamma globulin and in support total protection, but it was at least antibodies to poliovirus.38 Fi- 1954 trials. The article stressed that “[i]n contrast with gamma globulin, of the Salk vaccine. Just 2 days as good as passive immunization. nally, he gave a highly learned which gives temporary immunity . . . after the 1954 report on the In September 1954, Hammon yet scathing rebuttal of the 1954 the Salk vaccine is designed as a Hammon trial was issued, the be- presented his final analysis of the committee report, insisting that permanent protection.” ginning of Salk’s new clinical trial 1952–1953 controlled trial at the data from the uncontrolled was announced nationally. By the Third International Poliomye- use of gamma globulin in 1953 April, on the basis of safety re- litis Conference in Rome, along were overinterpreted. sults from use of the vaccine in with his reply to the NFIP com- The vindication of the use of 7500 children in Pittsburgh, mittee’s report on the failure of gamma globulin was not to mat- NFIP approved the larger study. the general use of gamma globu- ter. At the same Rome meeting, The resulting massive field trials lin in 1953.38 Reanalyses of his Salk offered his prediction that of the Salk vaccine in 1954, and data using isolation of virus from his vaccine would give perma- their associated controversies, feces and titration of neutralizing nent protection against poliomye- have been described else- antibodies to poliovirus proved litis (Figure 4). By the next year, where.4,5,9 While dwarfing the that gamma globulin prevented Hammon was stating that gamma Hammon trial in scope, the Salk poliomyelitis in 77% to 88% of globulin might be used too late project clearly incorporated individuals exposed to the virus to be effective in preventing dis- major aspects of the Hammon (Figure 4). He confirmed that, ease in family contacts, and its trial design and rigid scientific even when gamma globulin only practical use was in limited method. The Vaccine Advisory failed to prevent the disease, it circumstances such as quelling
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polio outbreaks in institutions eliminate the risk of vaccine- Before FDR. New Brunswick, NJ: Rut- nization against poliomyelitis. Am J Pub- and summer camps.49 associated paralytic polio.53 It gers University Press; 1992. lic Health. 193 6;2 6:119–125. was found that the type 3 strain 2. Robbins FC. Polio—historical. In: 18.Kolmer JA. Vaccination against THE WAR IS WON Plotkin SA, Mortimer ER Jr, eds. Vac- poliomyelitis. Am J Public Health. 1936; of the Sabin vaccine could revert cines. 2nd ed. Philadelphia, Pa: WB 26:126–135. on rare occasion to a virulent, Saunders Co; 1994:137–154. 19. Morgan IM. Immunization of mon- 54 The final report on the “Salk paralytic form. A new version 3. Plotkin SA, Vidor E. Poliovirus keys with formalin-inactivated poliomye- vaccine” trials was announced of the inactivated vaccine that is vaccine—inactivated. In: Plotkin SA, litis viruses. Am J Hyg. 1948;48: Orenstein WA, eds. Vaccines. 4th ed. 394–410. at the University of Michigan in more potent than the Salk ver- Philadelphia, Pa: WB Saunders Co; 20.Orenstein WA, Wharton M, Bart Ann Arbor on April 12, 1955.48 sion is now exclusively used for 2004:625–649. KJ, Hinman AR. Immunization. In: Man- According to Newsweek, “The routine vaccination in the United 4. Paul JR. A History of Poliomyelitis. dell GL, Bennett JE, Dolin R, eds. Man- Crippler has finally been de- States. New Haven, Conn: Yale University dell, Douglas and Bennett’s Principles of Infectious Diseases. 5th ed. New York, feated.” In the span of a few Since the early 1950s, the use Press; 1971. NY: Churchill Livingstone; 2000: 5. Carter R. Breakthrough: The Saga of days, 6 firms were licensed to of gamma globulin to fight infec- 3207–3234. Jonas Salk. New York, NY: Trident Press; manufacture the vaccine. By the tious diseases has steadily in- 1966. 21. Berger M. A history of immune globulin therapy, from the Harvard end of 1955, 10 million chil- creased. We now have a large 6. Smith JS. Patenting the Sun: The crash program to monoclonal antibod- dren in 5 countries had been armamentarium of licensed Polio Vaccine Controversy. New York, ies. Curr Allergy Asthma Rep. 2002;2: NY: Morrow; 1990. vaccinated. By 1956, the num- reagents that confer passive im- 368–378. 7. Reeves WC. Regional oral history. ber of polio cases in the United munity to measles, hepatitis A 22. Bloxsom A. Use of immune serum Available at: http://ark.cdlib.org/ark:/ globulin (human) as prophylaxis against States had decreased to about and B, rabies, cytomegalovirus, 13 030/kt3j49n66k. Accessed February poliomyelitis. Texas State J Med. 1949; 15 000, and by 1960 it had de- varicella zoster virus, and other 26, 2005. 75:468–470. 55,56 creased to about 3000. Still, the agents. Large double-blind, 8. Enders JF, Hammon WM. Active 23. Stokes J Jr, Wolman IJ, Carpenter and passive immunization against the inactivated vaccine was not as placebo-controlled trials are the HC, Margolis J. Prophylactic use of par- virus of malignant pan leucopenia of potent as hoped. In one 1959 norm for testing new vaccines ents’ whole blood in anterior poliomye- cats. Proc Soc Exp Biol Med. 1940;48: 57 litis: Philadelphia epidemic of 1932. Am analysis, it was shown that a and therapeutics, although 19 4–200. J Dis Child. 1935;50:581–595. number of children receiving there are strong arguments that 9. Benison S. Tom Rivers: Reflections 24.Korns RF, Albrecht RM, Locke FB. on a Life in Medicine and Science. Cam- the complete series of 3 Salk such controls are unethical when The association of parenteral injections bridge, Mass: MIT Press; 1967. vaccine injections developed known, effective therapy is avail- with poliomyelitis. Am J Public Health. paralytic poliomyelitis.50 able.58 This progress owes much 10. Hammon WM. Possibilities of spe- 1952;42:153–169. cific prevention and treatment of polio- 25. Horstmann DM. Poliomyelitis virus In 1961, the Sabin live atten- to Hammon and his scientific ex- myelitis. Pediatrics. 1950;6:696–705. in blood of orally infected monkeys and ■ uated oral vaccine was cellence and foresight. 11. Gamma globulin in prevention and chimpanzees. Proc Soc Exp Biol Med. 51 licensed. This vaccine was as attenuation of measles: report of sub- 1952;79:417–419. committee to the Blood Transfusion effective as the Salk vaccine but 26. Bodian D. Experimental studies on Committee of the Medical Research About the Author passive immunizations against poliomye- also involved several advantages Council. Lancet. 1948;2:41–44. litis: II. The prophylactic effect of human such as oral administration and Charles R. Rinaldo Jr is with the Depart- ments of Infectious Diseases and Microbi- 12. Morgan IM, Howe HA, Bodian D. gamma globulin on paralytic poliomyeli- induction of local immunity in ology and Pathology, University of Pitts- The role of antibody in experimental tis in cynomolgus monkeys after virus the gut. We now know that the burgh Graduate School of Public Health poliomyelitis: II. Production of intracere- feeding. Am J Hyg. 1952;56:78–89. bral immunity in monkeys by vaccina- and School of Medicine, Pittsburgh, Pa. 27. Bodian D. Experimental studies on attenuation of the vaccine was tion. Am J Hyg. 1947;45:379–389. Requests for reprints should be sent to passive immunization against poliomye- attributable to natural selection Charles R. Rinaldo Jr, PhD, Department of 13. Bodian D, Morgan I, Howe H. Dif- litis: I. Protection with gamma globulin of spontaneous mutations dur- Infectious Diseases and Microbiology, ferentiation of types of poliomyelitis against intramuscular inoculation and ing propagation that eliminated University of Pittsburgh Graduate School viruses: the grouping of fourteen strains combined passive and active immuniza- of Public Health, A427 Crabtree Hall, into three basic immunologic types. Am tion. Am J Hyg. 1951;54:132–143. neurovirulence while maintain- 130 DeSoto St, Pittsburgh, PA 15261 J Hyg. 1947;49:234–245. 28. Hammon WM, Coriell LL, Stokes J ing the virus’s replicative capac- (e-mail: [email protected]). 14 . Bodian D. Neutralization of three Jr. Evaluation of Red Cross gamma glob- 52 This article was accepted September ity. The number of polio cases immunological types of poliomyelitis ulin as a prophylactic agent for poliomy- 21, 2004. eventually dropped to only 72 virus by human gamma globulin. Proc elitis: 1. Plan of controlled field tests Soc Exp Biol Med. 1949;72:259–261. in 1965. Today, there are fewer and results of the 1951 pilot study in Acknowledgments Utah. JAMA. 1952;150:739–749. than 5 cases a year in the United 15. Sabin AB, Olitsky PK. Cultivation I thank Dr Margaret McDonald for of poliomyelitis virus in vitro in human 29.Shapiro AK, Shapiro E. The Power- States, all owing to vaccine strain superb editing of the article, Dr Paolo embryonic nervous tissue. Proc Soc Exp ful Placebo: From Ancient Priest to Mod- revertents and none causing Piazza for assistance in preparing the Biol Med. 1936;31:357–359. ern Physician. Baltimore, Md: Johns images, Dr Monto Ho for helpful advice, Hopkins University Press; 1997. paralysis. and Dr Kirsten St. George for review of 16. Enders JF, Weller TH, Robbins FC. Ironically, since 1999, the the article and encouragement. Cultivation of the Lansing strain of 30. Medical Research Council. The poliomyelitis virus in cultures of various prevention of whooping-cough by vacci- Centers for Disease Control human embryonic tissues. Science. nation. BMJ. 1951;1:1463–1471. References and Prevention has halted use 1949;109:85–87. 31. Hammon WM, Corriell LL, Stokes J of the live attenuated vaccine to 1. Rogers N. Dirt and Disease: Polio 17.Brodie M, Park WH. Active immu- Jr. Evaluation of Red Cross gamma glob-
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ulin as a prophylactic agent for poliomy- prophylaxis of paralytic poliomyelitis in elitis: 2. Conduct and early followup of 1953: summary of the report of the Na- 1952 Texas and Iowa-Nebraska studies. tional Advisory Committee for evalua- 2nd Edition JAMA. 1952;150:750–756. tion of gamma globulin. JAMA. 1954; 154:1086–1090. 32. Hammon WM, Coriell LL, Wehrle PF, Klimt CR, Stokes J Jr. Evaluation of 48.Francis T, Napier JA, Voight RB, et Red Cross gamma globulin as a prophy- al. Evaluation of the 1954 Field Trial of lactic agent for poliomyelitis: 3. Prelimi- Poliomyelitis Vaccine: Final Report. Ann nary report of results based on clinical Arbor, Mich: Poliomyelitis Vaccine Eval- diagnoses. JAMA. 1952;150:739–749. uation Center, University of Michigan; Community- 1957. 33. The Texas polio experiment. New York Times. July 7, 1952:20. 49. Hammon WM. Passive immuniza- Oriented Primary Care: tion against poliomyelitis. Monogr Ser 34. Gamma globulin as a prophylactic Health Care for the 21st Century World Health Organ. 1955;26: in poliomyelitis [editorial]. JAMA. 1952; 357–370. Edited by Robert Rhyne, MD, Richard 150:796. 50. Berkovich S, Pickering JE, Kibrick Bogue, PhD, Gary Kukulka, PhD, and 35. O’Connor reviews anti-polio S. Paralytic poliomyelitis in Massachu- Hugh Fulmer, MD strides. New York Times. November 11, setts, 1959: a study of the disease in a 1952:32. This book will give insight into: well vaccinated population. N Engl J • How medicine, health systems, com- 36.Red Cross polio plan to immunize Med. 19 61;264:1323–1329. young. New York Times. December 9, munity leaders, and social services 51. Sabin AB. Oral poliovirus vaccine: 1952:1. can be supportive as America’s pub- history of its development and prospects lic health practice continues to be 37. Hammon WM, Coriell LL, Wehrle for eradication of poliomyelitis. JAMA. restructured and redefined PF, Stokes J Jr. Evaluation of Red Cross 19 65;194:130–134. • New models of community-oriented gamma globulin as a prophylactic agent 52. Pallansch MA, Roos RP. Entero- primary care for poliomyelitis: 4. Final report of re- viruses: polioviruses, Coxsackieviruses, •Methods and interventions on popu- sults based on clinical diagnoses. JAMA. echoviruses, and newer enteroviruses. lation-derived health needs 1953;151:1272–1285. In: Knipe DM, Howley PM, Griffin DE, • Health promotion and disease pre- 38. Hammon WM, Coriell LL, Ludwig et al., eds. Fields Virology. 4th ed. vention as part of the overall reor- EH, et al. Evaluation of Red Cross Philadelphia, Pa: Williams & Wilkins; ganization of health services gamma globulin as a prophylactic agent 2001:723–775. • Understanding how community- for poliomyelitis: 5. Reanalysis of results oriented primary care can comple- 53. Centers for Disease Control and based on laboratory-confirmed cases. ment managed care and community Prevention. Poliomyelitis prevention in JAMA. 1954;156:21–27. benefit programs the United States: updated recommen- This book teaches skills and techniques 39. Gamma globulin in the prevention dations of the Advisory Committee on for implementing a community-oriented of poliomyelitis [editorial]. JAMA. 1953; Immunization Practices (ACIP). MMWR primary care process and topics not 151:1292–1293. Morb Mortal Wkly Rep. 2000;49(RR-5): normally taught in health professional 40. Hammon WM. Limitations on the 1–22. education. use of gamma globulin in poliomyelitis. 54. Racaniello VR. Poliovirus neuro- ISBN 0-87553-236-5 Am J Med Sci. 1953;226:125–130. virulence. Adv Virus Res. 19 8 8;34: 1998 ❚ 228 pages ❚ Softcover 41.Salk JE. Studies in human subjects 217–246. $27.00 APHA Members on active immunization against poliomy- 55. Sawyer LA. Antibodies for the pre- $39.00 Nonmembers elitis: 1. A preliminary report of experi- vention and treatment of viral diseases. plus shipping and handling ments in progress. JAMA. 1953;151: Antiviral Res. 2000;47:57–77. ORDER TODAY! 10 81–1098. 56. Keller MA, Stiehm ER. Passive im- American Public Health Association 42. Klein AE. Trial by Fury: The Polio munity in prevention and treatment of Vaccine Controversy. New York, NY: Publication Sales infectious diseases. Clin Microbiol Rev. Web: www.apha.org Doubleday; 1972. 2000;13:602–614. E-mail: [email protected] 43. Bodian D. Experimental studies on 57. Friedman LM, Furberg CD, Tel: 888-320-APHA FAX: 888-361-APHA passive immunizations against poliomye- DeMets DL. Fundamentals of Clinical litis: III. Passive-active immunization Trials. New York, NY: Springer-Verlag; COPC03J5 and pathogenesis after virus feeding in 1998. chimpanzees. Am J Hyg. 1953;58: 58. Temple R, Ellenberg SE. Placebo- 87–100. controlled trials and active-control trials 44. Horstmann DM, McCollum RW. in the evaluation of new treatments: Poliomyelitis virus in human blood dur- I. Ethical and scientific issues. Ann ing the minor illness and the asympto- Intern Med. 2000;133:455–463. matic infection. Proc Soc Exp Biol Med. 1953;82:434–437. 45. Research on a vaccine for the pre- vention of poliomyelitis [editorial]. JAMA. 1953;151:1198. 46. Rivers TM. Vaccine for poliomyeli- tis [letter]. JAMA. 1953;151:1224. 47. Evaluation of gamma globulin in
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