The United States Army Yellow Fever Commission
(1900 - 1901)

When Major Walter Reed and Acting Assistant Surgeons James Carroll, Aristides Agramonte, and Jesse Lazear gathered on the porch of the Columbia Barracks Hospital in June of 1900, they became the fourth successive board of U.S. medical officers to grapple with the appalling plague that was yellow fever. 

The persistence of this disease across the Cuban archipelago and its periodic re-emergence along the coastlines and great river drainages of the Americas was taking countless thousands of lives.  Lack of precise knowledge as to its cause and transmission had augmented yellow fever's extraordinarily high mortality rate and had given rise to quarantine regulations which constituted substantial impediments to efficient regional trade.  Endemic in the tropics, yellow fever imposed high humanitarian and economic costs upon the entire region.  Specialists regarded Cuba as one of the principal foci of the disease, and the island consequently attracted considerable attention from the medical sciences.

In 1879, one year after a devastating epidemic swept up the Mississippi valley from New Orleans, Tulane University Professor Stanford E. Chaille led the first investigatory commission to Havana, Rio de Janeiro, and the West Indies.  The Chaille Commission remained in Havana three months, and its members -- including George Miller Sternberg, who became Surgeon General of the Army, and Juan Guiteras, later Director of Public Health for Havana -- consulted with Cuban scientist Carlos J. Finlay.  They concluded that the causal agent for yellow fever was possibly a living entity in the atmosphere, an assertion which set Finlay on the path to the mosquito theory he developed in 1881.

Louis Pasteur's foundational and highly successful work in modern immunology in 1880 and 1881 gave a renewed impetus to investigations aimed at discovering the "yellow fever germ."  Over the middle years of the 1880s several scientists advanced different theories, all readily refuted by bacteriological work Sternberg undertook in Brazil and Mexico in 1887 and again in Havana in 1888 and 1889.  In 1897, Italian scientist Giuseppe Sanarelli argued that Bacillus icteroides was the culprit, and the following year a third scientific team sailed to Cuba for additional tests.  Eugene Wasdin and Henry D. Geddings appeared to confirm Sanarelli's assertion, though Sternberg, by then Surgeon General, remained skeptical.

Despite Wasdin and Geddings' insistence, the B. icteroides theory garnered significant opposition.  In fact, a few months before the third commission's report reached the public, Walter Reed and James Carroll -- Reed's assistant at the Columbian University (later George Washington University) bacteriology laboratories in Washington, D.C. -- published a thorough refutation of the icteroides proposal:  the bacteria was not a unique cause of yellow fever, but a variety of the hog cholera bacillus, "a secondary invader in yellow fever," Reed determined, unrelated to its etiology. [1]   Dispute continued, however, and when Sternberg organized the fourth investigatory board, he charged Reed and his associates to settle the B. icteroides question once and for all, then to proceed with analysis of other blood cultures and intestinal flora from yellow fever cases. 

Reed and Carroll had considerable experience in bacteriological analysis, and, Sternberg reasoned, might well be able to find the specific agent of the disease.  Aristides Agramonte, a Cuban scientist who had worked in Reed's lab at the Columbian University in 1898, was also an accomplished bacteriologist;  he had identified B. icteroides in tissue samples from cases other than yellow fever, providing further evidence opposed to Sanarelli's thesis.  Jesse Lazear, a scientist from Johns Hopkins University in Baltimore, Maryland, had joined the Army Medical Corps to study tropical diseases at their point of origin;  he received orders for Cuba in February 1900.  Lazear impressed Reed with his abilities when the two men became acquainted in March.  No doubt with Reed's advice, Sternberg assembled a crack team -- all experienced in scientific research, but each with interests as diverse as their temperaments.  The mix of talent and personalities generated spectacular results. 

What causes yellow fever?  This simple, even obvious question had dictated yellow fever research for over two decades, and so it guided Reed in organizing the work of the commission.  Bacillus icteroides and other bacteriological sampling dominated their work for the first months.  "Reed and Carroll have been at that for a long time," Lazear wrote with some impatience to his wife on August 23, ". . . I would rather try to find the germ without bothering about Sanarelli." [2]   Again and again, tests for the bacteria proved negative, and at the same time, perplexing cases of yellow fever were developing in the region.  Agramonte and Reed investigated an epidemic at Pinar del Rio, 110 miles southwest of Havana;  Lazear followed later to collect more specimens, and he also assessed the situation at Guanjay thirty miles southwest.  To "my very great surprise," Reed admitted, the specific circumstances of the appearance and development of these cases gave strong evidence against the widely-accepted notion that the excreta of patients spread the disease.  The theory of fomites --  infection from contaminated clothing and bedding -- and indeed even infection from airborne particles seemed altogether untrue.  "At this stage of our investigation," Reed concluded, ". . . the time had arrived when the plan of our work should be radically changed." [3]   The fundamental question underwent a subtle but critical transformation:  from what causes yellow fever to what transmits it.  A clear and accurate understanding of how the disease was spread would open a new avenue to its specific cause.

"Personally, I feel that only can experimentation on human beings serve to clear the field for further effective work," Reed stated to Surgeon General Sternberg, who concurred. [4]   Evidence gathering around them pointed strongly to an intermediate host, and the Commission resolved to test Carlos Finlay's mosquito theory -- then not generally accepted -- on human volunteers.  Nine times from August 11 to August 25, 1900, mosquitoes landed on the arms of volunteers and proceeded to feed.  Nine times the results were negative.  On August 27, Lazear placed a mosquito on the doubting Dr. Carroll, and four days later on William J. Dean, a soldier designated XY in the "Preliminary Note." [5]   Both promptly developed yellow fever.  Significantly, their mosquitoes had fed on cases within the initial three days of an attack and had been allowed to ripen for at least twelve days before the inoculations.  Carroll vitiated the results of his experimental sickness by traveling off the post to Havana, a contaminated zone, even as Reed, ecstatic, wrote from Washington in a confidential letter:  "Did the Mosquito do it?" [6]   Dean's case seemed to prove it, since he claimed not to have left the garrison before becoming ill.  Lazear also developed a case of yellow fever, almost certainly experimental in origin, though he never revealed the actual circumstances of his inoculation.  His severe bout of fever took a fatal turn on September 25, 1900.

Camp Lazear

On open terrain beyond the precincts of Columbia Barracks -- the American military base just west of Havana near the adjacent suburban towns of Quemados and Marianao (also called Quemados de Marianao) -- Reed established the quarantined experimental station.  Camp Lazear, as the Commission dedicated it, took form in the rolling fields of the Finca San Jose, on the farm of Dr. Ignacio Rojas, who leased the land to the Americans.  Here Reed designed two small wood-frame buildings, each 14 by 20 feet, for the experimental work, and nearby raised a group of seven tents for the accommodation and support of the volunteers.  The buildings faced each other across a small swale, about 80 yards apart, and stood 75 yards from the tent encampment.  Building Number One, called the Infected Clothing Building, was a single room tightly constructed to contain as much foul air as possible.  A small stove kept the temperature and humidity at tropical levels, and carefully attached screening secured the pair of doorways in a vestibule against intrusion by mosquitoes.  Wooden blinds on two small sealed windows shielded the room from direct sun.  Building Number Two, the Infected Mosquito Building, contained a principal room, divided into two sections by a floor-to-ceiling wire mesh screen. A door direct to the exterior let into one section, while a vestibule with a solid exterior door and pair of successive screened doors opened to the other, so configured to keep infected mosquitoes inside that section alone.  The spare furnishings in both sections -- cots with bedding -- were steam sterilized.  Windows exposed the entire room to the clean, steady ocean breezes and to sunlight.  Like the doorways, they were carefully screened.  A secondary room attached to the building but not communicating with the experimental spaces sheltered the small, heated laboratory where the Commission members raised and stored the mosquitoes to be used.

These two experimental buildings presented alternate environments -- one conspicuously clean and well ventilated, the other filthy and fetid.  Contemporary theories of disease held that yellow fever developed in unclean conditions, and consequently much time and money had been devoted to sanitation projects.  Workers steamed clothing, burned sulphur in ships' holds, and thoroughly scrubbed surfaces with disinfectant.  In cases of severe epidemic, entire buildings presumed to be infected were set afire along with their contents.  Thus the extraordinary -- and intentional -- paradox of the Commission's experimental regime:  Reed expected yellow fever to develop not in the unsanitary environment, but in the one thought to be most healthful.

Volunteers

Camp Lazear went into quarantine the day of its completion, November 20, 1900, with a command of four immune and nine non-immune individuals, all save one U.S. Army personnel.  Soon a group of recent Spanish immigrants to Cuba augmented the non-immune numbers, bringing the resident total to about twenty.  Reed strictly controlled access to the camp and ordered regular temperature recording for each volunteer to eliminate any unanticipated source of infection and to identify the onset of any case of yellow fever as early as possible.  As a result, non-immunes were barred from returning should they leave the precinct, and two of the Spaniards who developed intermittent fevers shortly after arrival were immediately transferred with their baggage to Columbia Barracks Hospital.  The immune members of the detachment oversaw medical treatments and drove the teams of mules that pulled supply wagons and the ambulance.  Experimentation did not begin until each volunteer had passed the incubation period for yellow fever in perfect health.

Reed took as much care with the design of the experimental protocol as he had with the configuration of the camp and its buildings.  Each evening, the occupants of the infected clothing building unpacked trunks and boxes of bed linens and blankets, nightshirts and other clothing recently worn and soiled by cases from the wards of Columbia Barracks Hospital and Las Animas Hospital in Havana.  These they shook out and spread around the room to permeate the atmosphere.  The stench was overpowering.  Yellow fever causes severe internal hemorrhaging, and its unfortunate victims often suffer from black vomit and other bloody discharges.  One routine delivery proved so putrid the volunteers "retreated from the house," Reed stated.  "They pluckily returned, however, within a short time, and spent the night as usual." [7]    In two succeeding trials the protocol became progressively more daring , as the volunteers then wore the clothing and slept on the mattresses used by yellow fever patients, and finally put towels on their bedding smeared with blood drawn from cases in the early stages of an attack.  Each morning, the volunteers carefully repacked the rank, encrusted materials into boxes and emerged to an adjacent tent where they spent the day quarantined from the rest of the company.  Three trials of twenty days each involved seven men altogether, lead by Robert P. Cooke, a physician in the Army Medical Corps.  None developed yellow fever.

The Commission's mosquito experiments proceeded in four series.  First, Reed sought to demonstrate that mosquitoes of the variety Culex fasciata (later called Stegomyia fasciata, and later still Aedes aegypti) could in fact transmit yellow fever, as Carlos J. Finlay had argued and the initial experiments at Camp Columbia strongly suggested.  Here the Commission members simply applied infected mosquitoes contained in test tubes or jars to the skin of the initial volunteers.  Success in these tests raised a number of questions, each one addressed in the subsequent series: 

• How could a building become infected?

• When does a mosquito develop the ability to transmit the disease?

• Over what length of time can a mosquito retain this capacity to infect?
  

The second series consequently employed the specialized "Infected Mosquito Building" to indicate how a structure could be considered infected with yellow fever.  This experiment required two groups of volunteers, one to be inoculated and another to serve as controls.  "Loaded" mosquitoes, as the men called them, were released into the screened section of Building Two -- on the side with the protected vestibule entry.  One or more non-immune men then entered the opposite section of the room through the direct exterior door, and lay down on bunks adjacent to the wire mesh screen in the center of the room.  Now the young man to be inoculated walked through the vestibule into the mosquito side of the room and proceeded to lie on a bunk adjacent to the wire screen separating him from the controls.  The inoculation volunteer remained in the building for about twenty minutes -- enough time to suffer several mosquito bites -- he then exited to a quarantine tent outside.  The controls spent the remainder of the evening and night in the uninfected side of the room, and indeed returned to sleep in the room for as many as eighteen more nights.  As Reed stated, absence of yellow fever in the controls showed "that the essential factor in the infection of a building with yellow fever is the presence therein of [infected] mosquitoes," and nothing more. [8]   The degree of sanitation, so long considered critical, was utterly irrelevant.

The third series of mosquito experiments confirmed what Henry Rose Carter, of the U.S. Public Health Service, called the "period of extrinsic incubation," [9] the length of time required for secondary cases of yellow fever to develop after an initial intrusion of the disease into a locality.  In this series, a single volunteer underwent three successive inoculations by the same mosquitoes, each group of inoculations interrupted by a period of time equal in length to the typical incubation period of the disease in humans, about five days.  In this manner, the volunteer's illness could be specifically attributed to a single inoculation group.  The use of the same mosquitoes and the same volunteer concurrently demonstrated that no peculiar personal immunity was at play, since logic dictates that a person susceptible to yellow fever on day 17 of a mosquito's contamination -- as happened in the experiment -- could not have been immune to yellow fever on day 11 or day 4.  It was thus only the mosquito's capacity to infect which changed, and that occurred no less than 11 days after contamination.

The duration of time over which these "fully ripened" mosquitoes remained infective comprised the fourth series of experiments.  For this series the Commission kept alive a group of infected mosquitoes for as long as possible, and proceeded to inoculate three volunteers -- on the 39th, 51st, and 57th day after contamination.  Each developed yellow fever. A fourth volunteer declined to be bitten on day 65, and the last two mosquitoes of the group, "deprived of further opportunity to feed on human blood" [10] expired on day 69 and day 71, clear evidence that even a sparsely populated region may retain the potential for new infections more than two months after the first appearance of the disease.

Although it went unrecorded in the published papers, Reed organized a supplemental experiment to test another species of mosquito.  Culex pungens failed to transmit yellow fever to at least one volunteer and probably to a second.  Reed's preliminary conclusions indicated that Culex fasciata was the only species capable of transmitting yellow fever. [11]

A last experimental regime involved subcutaneous injections of blood from positive cases of yellow fever to presumed non-immunes.  Reed devised these tests to confirm the presence of the yellow fever agent in the blood of a victim during the first days of an attack, and, more importantly, to settle the Bacillus icteroides question.  The same blood cultures which produced yellow fever in four volunteers also failed to grow any B. icteroides, conclusively invalidating Sanarelli's claim.

Altogether, the mosquito inoculations and the blood injections produced fourteen cases of yellow fever.  All made a full recovery.

Informed Consent

Notwithstanding the decisive medical victory -- as Reed declared, "aside from the antitoxin of Diptheria & Koch's discovery of the tubercle bacillus, it will be regarded as the most important piece of work, scientifically, during  the 19th century" [12] -- success at Camp Lazear unfolded in its own time.  Initially, Reed observed, "the results obtained at this station were not encouraging." [13]   The first inoculations of four volunteers over a period of two weeks proved disconcertingly negative each time.  Then, on December 5, 1900, private John R. Kissinger presented his arm to the mosquitoes, and late in the evening on December 8, suffered the first chills of "a well-marked attack of yellow fever." [14]   Three more men in rapid succession fell victim to the insects -- Spanish volunteers Antonio Benigno, Nicanor Fernandez, and Vicente Presedo.  The force of the conclusions was evident to everyone:

"It can readily be imagined," Reed empathetically and wryly described in his first presentation of the experiments, "that the concurrence of 4 cases of yellow fever in our small command of 12 nonimmunes within the space of 1 week, while giving rise to feelings of exultation in the hearts of the experimenters, in view of the vast importance attaching to these results, might inspire quite other sentiments in the bosoms of those who had previously consented to submit themselves to the mosquito's bite.  In fact, several of our good-natured Spanish friends who had jokingly compared our mosquitoes to 'the little flies that buzzed harmlessly about their tables,' suddenly appeared to lose all interest in the progress of science, and, forgetting for the moment even their own personal aggrandizement, incontinently severed their connection with Camp Lazear.  Personally, while lamenting to some extent their departure, I could not but feel that in placing themselves beyond our control they were exercising the soundest judgment."

"In striking contrast," Reed continued, the anxiety of the fomites volunteers began to melt into relief.  "[T]he countenances of these men, which had before borne the serious aspect of those who were bravely facing an unseen foe, suddenly took on the glad expression of 'schoolboys let out for a holiday,' and from this time their contempt for 'fomites' could not find sufficient expression.  Thus illustrating once more, gentlemen, the old adage that familiarity, even with fomites, may breed contempt." [15]

The question of human experimentation was indeed a serious one --  unavoidable, in actuality, as Reed had stated the previous summer to Surgeon General Sternberg.  When the Commission first considered a trial of Finlay's mosquito theory, Reed, Carroll, and Lazear agreed to experiment on themselves.  Agramonte, a native Cuban, had acquired immunity as a child.  Doubtless Finlay's experience of many unsuccessful inoculations communicated that positive results would not be forthcoming rapidly, so before the first series of inoculations began under Lazear's direction at Columbia Barracks, Reed left Cuba for Washington, where he completed a monumental report on typhoid fever among the army corps -- left unfinished by the sudden death of co-author Edward O. Shakespeare.  Carroll and Lazear both sickened while Reed was in Washington, and Lazear, young and strong, had no reason to anticipate that his case would be fatal.  Reed was shocked at Lazear's death, and because of his own age -- 49, a decade and a half older than Lazear and a dozen years older than Carroll -- he resolved not to inoculate himself when he returned to Cuba on October 4, 1900.  The point had already been amply demonstrated, and only a rigidly controlled experimental regime would establish the necessary proof.  Carroll, however, remained embittered about this for the remainder of his life, though he evidently never communicated his objections directly to Reed.

That initial series of mosquito inoculations was probably accomplished without formal documentation of informed consent.  Indeed, the experiments may also have been carried forward without the full knowledge of the commanding officer of Camp Columbia, and Reed consequently shielded the identity of Private William J. Dean, the second positive experimental case, behind the pseudonym "XY" in the "Preliminary Note."  No such potentially troublesome problems arose for the experimental series at Camp Lazear;  Reed obtained prior support from all of the appropriate authorities in the military and the administration, even including the Spanish Consul to Cuba.  With the advice of the Commission and others, he drafted what is now one of the oldest series of extant informed consent documents.  The surviving examples are in Spanish with English translations, and were signed by volunteers Antonio Benigno and Vicente Presedo, and a third with the mark of Nicanor Fernandez, who was illiterate.

The documents take the form of a contract between individual volunteers and the Commission, represented by Reed.  At least 25 years old, each volunteer explicitly consented to participate, and balanced the certainty of contracting yellow fever in the general population against the risks of developing an experimental case, followed by expert and timely medical care.  The volunteers agreed to remain at Camp Lazear for the duration of the experiments, and as a reward for participation would receive $100 "in American gold," with an additional hundred-dollar supplement for contracting yellow fever.  These payments could be assigned to a survivor, and the volunteers agreed to forfeit any remuneration in cases of desertion. 

For the American participants no consent documents appear to survive,  though in contemporary letters Reed assured his correspondents that the Commission obtained written consent from all the volunteers.  The record of expenses for Camp Lazear -- maintained by Reed's friend and colleague in the medical corps, Jefferson Randolph Kean -- indicates that the same schedule of payments for participation and sickness applied to the Americans as well. Volunteers who participated in the fomites tests and in addition the later series of blood injections and the single trial of an alternative species of mosquito also earned $100 each plus the $100 supplement if yellow fever developed.  Two Americans declined these gratuities, as Kean termed them, Dr. Robert P. Cooke, of the fomites tests, and John J. Moran, who had recently received an honorable discharge from the service, and was the only American civilian to participate.  His was the fourth case of yellow fever to develop from mosquito inoculation. Moran eventually settled in Cuba, where he managed the Havana offices of the Sun Oil Company, and late in life became a close friend of Philip S. Hench.  Together the two men rediscovered the site of Camp Lazear in 1940 -- Building Number One still intact -- and successfully lobbied the Cuban government to memorialize there the work of Finlay and the American Commission in the conquest of yellow fever.

Reed informally commemorated his own experiences at Camp Lazear by commissioning a group photograph, evidently taken there shortly before he left Cuba in February 1901.  A more important event occurred on the sixth of that month when Reed presented the results of the Camp Lazear yellow fever experiments to a great ovation at the Pan-American Medical Congress in Havana.  Three days later he set sail for the United States, and once landed, drafted the Congress paper as "The Etiology of Yellow Fever -- An Additional Note," published immediately in the Journal of the American Medical Association. [16]  

Though his correspondence intimates a great appreciation for Cuba, Reed never returned to the warm, sunny shores of the island freed of a dreadful plague.  Carroll stayed behind at Camp Lazear through February to complete the last experimental series officially bearing the imprimatur of the Yellow Fever Commission, and returned to Washington soon after March first. [17]   The Medical Corps retained the lease on Camp Lazear against the possibility of continuing experiments another season, and Carroll, in fact, returned to Havana in August 1901 for a final experimental series, though he did not make use of Camp Lazear.  This work involved at least three volunteers at Las Animas Hospital, Havana, who submitted to blood injections.  Carroll's assignment aimed at a greater understanding of the yellow fever agent, and he proved that blood drawn from active cases of yellow fever remained virulent even after passing through fine bacteria filters.  In addition, by heating contaminated blood which had previously caused cases of yellow fever, Carroll rendered it non-infective -- thereby establishing that this filterable entity, though sub-microscopic, was demonstrably present in the bloodstream.  Carroll wrapped up the series in October and returned home to stay. [18]   In Cuba, J. Randolph Kean made the last rental payments to Signore Rojas on October 9, 1901, and Camp Lazear, for more than a generation, slipped out of the realm of memory.