1916:
The newly established Rockefeller Foundation Yellow Fever Commission
visited suspected endemic countries in Ecuador Peru Colombia Venezuela Brazil South America was in Guayaquil , Ecuador West Africa .
The actual campaign for the
eradication of Yellow Fever from Guayaquil
was held up due to First World War. Preliminary
work however did get underway.
1918:
A special commission arrived in Guayaquil Guayaquil
The
full-scale campaign for the eradication
of Yellow Fever from Guayaquil
1919:
Dr.Hideyo Noguchi announced the discovery of leptospira that in
guinea-pigs produced lesions suggestive of yellow fever (Noguchi, 1919)
After much experimental work, Noguchi
decided (erroneously, as was proved
later) that this leptospira was the cause of yellow fever and named it Leptospira icteroides (Noguchi, 1925). He
found that the use of a potent immune serum in the treatment of experimental
infection of guinea pigs with L. icteroides
gave definite protection (Noguchi, 1920).
Experiments also showed that the injection of killed cultures of L. icteroides into susceptible animals
conferred on them a state of immunity that endured for at least 5 or 6 months
(Noguchi and Pareja, 1921). Both the serum and vaccine were put to trial in
humans without delay and some thousands of people received inoculations.
Thus the findings of Reed commission were contradicted and the etiology of Yellow Fever was again in a state
of confusion. The then lack of susceptible animals and proper tools for
diagnosis of Yellow Fever and its differentiation from spirochetal jaundice
misled Noguchi.
In June last case of Yellow Fever was
reported in Guayaquil Guayaquil
After this success Rockefeller
Foundation worked in many endemic areas. By the end of 1924 the disease had been eradicated from Mexico, Central America, and Ecuador. Other trouble areas in South America were being attacked.
1920:
The West Africa Commission recommended
that another, more fully equipped, commission be sent to carry out extensive
and prolonged investigation of the situation in West Africa, including a
laboratory study of the suspected fevers of the region.
1925:
The danger that the completion of Trans African Railways may carry the
fever to the East revived the fear, which the opening of Panama
Canal aroused.
Following the recommendations of the
Yellow Fever Commission to West Coast of Africa, in this year another
commission, under the leadership of Dr.
Henry Beeuwkes, was sent to West Africa Yellow Fever Commission established
headquarters in Lagos
During the first 2 years of the
operation the Commission failed to isolate Noguchi’s L. icteroides. In the meantime doubt as to validity of Noguchi’s
findings had also arisen in a number of other quarters in Brazil Cuba U.S.A.
Laboratory work on the disease was
very much handicapped by the lack of an experimental animal. This was so important an obstacle at this
juncture that the group in West Africa
concentrated on trying to overcome it. So, a systematic search began. The investigators tried guinea pigs, white
rats, and white mice imported from Europe, a number of species of African
monkeys, as well as pouched rats (Cricetomya
gambianus), puppies, kittens, goats, all the local fauna, but in vain
(Vincent, 1927; Stokes et. al., 1923 a).
In further effort to find such an
animal, Dr. Henry Beeuwkes, the Director of the Commission visited the firm of
Carl Hagenbeck in Hamburg and there chose animals
from parts of the world distant to West
Africa. They were Indian rhesus
and crown monkeys and Brazilian
marmosets (Stokes et. al., 1928, a).
1927:
In May during an epidemic of Yellow
Fever at Lareth, Gold Coast, West Africa ; six Indian Crown monkeys (Macacus sinicus) were inoculated with blood from patients with
Yellow Fever. Five of these developed fever and died, while one did not show any reaction, it was felt from further
studies that these animals are susceptible to Yellow Fever only to a moderate
degree (Stokes et. al., 1928, a).
On June 30 Dr. A. F. Mahaffy, a member
of the West Africa Commission stationed at Accra, obtained blood specimens from
two patients (in Kpev 100 miles of Accra) suspected of having mild infections,
one of whom was a 28 year old African
man named Asibi. Dr. Mahaffy and Bauer of the Commission’s laboratory staff
inoculated the blood into rhesus monkey
(Macacus rhesus), one marmoset and two guinea pigs.
Guinea pig and marmoset failed to show any reaction but the monkey developed
fever on the 4th day after inoculation, was found moribund and
eventually collapsed on following morning (Stokes et. al., 1928, b).
This first experimental transmission of the virus of
yellow fever to an animal other than man opened up entirely new possibilities
of laboratory and field research.
The transmission of infection from
this monkey to others was done serially (by injecting citrated blood/serum or
by bite of Aedes aegypti mosquito)
and more than 50 of the monkeys were tried without failure. The same workers confirmed definitely that
the causative agent of yellow fever was filterable virus.
Propagation of
now famous “Asibi strain” of yellow fever virus also began with this experiment (Stokes et. al., 1928, a).
In December Mathis, Sellard and
Laigret isolated another strain of yellow fever virus at Institute Pasteur at
Dakar during the yellow fever epidemic, which broke out in Senegal, 1927
(Durieux, 1959; Lloyd, Theiler & Ricci, 1936). This virus had been
transmitted to Macacus rhesus monkey
by the bite of Aedes aegypti fed 24
and 31 days earlier on the patient suffering from mild yellow fever, a Syrian man named Francois Mayali
(Monath, 2004). The virulent organs from one of the monkeys infected in this
way were transported in frozen state to Europe and America, where they were
placed at the disposal of various labs under the name of “French strain” (also known
as Dakar Virus).
Isolation of the
“Asibi” and “French” strains in 1927 enabled the development of vaccines, and
research was initiated immediately in England, the United States, West Africa
and Brazil (Monath,
2004).
Asibi, West African yellow fever survivor, who provided a blood sample from which the virus, used in extensive future research, was isolated. (Image Source)
1928:
Edward Hindle of the Wellcome
Research Laboratories, London
On
June 24, 1928 Yellow Fever Laboratory was established by International Health
Division in Rockefeller Institute New York as Dr. Wilbur A. Sawyer as Director.
1928-1930:
Different
workers reported transmission of Yellow Fever other than A.aegypti.
Dr.
J H Bauer: A.leutocephalus, A.apicoannulatus and
Eretmapodites
chrysogaster (Bauer, 1928).
Cornelious
B Philip: A.vitattus, A.africanus and
A.simpsoni
(Philip
1928).
Davis and
Shannon: Aedes (Ochlerotatus) scapularis (Davis and Shanon).
Dinger et.al: Aedes (Stegomyia) albopictus (Dinger et.al.1929).
Philip: Taeniorrhynchus (Mansonioides) africanus Theobald
(Philip, 1930 a, b, c)
1929-30:
Cross immunity tests with different
strains of viruses settled the issue, that yellow fever of West
Africa and America
1930:
Dr.
Max Theiler of the Department of
Tropical Medicine of the Harvard
Medical School, working with French strain of virus, made the important
discovery that white mice were susceptible to yellow fever if inoculated
intracerebrally and that a fixed virus
for mice with a shortened incubation period and heightened virulence, could be
produced by repeated passage through these animals (Theiler, 1930).
1931:
Theiler described the use of mice in
testing sera for protective substances against yellow fever virus (Theiler, 1931).
This mouse
protection test of Theiler’s as modified by Sawyer and Lloyd, became one of the
principal tools in yellow fever research and epidemiologic investigation
(Sawyer and Lloyd, 1931).
In the 5 years following isolation of yellow fever virus,
32 cases (5 fatal) had occurred among laboratory workers (Berry and
Kitchen, 1931).
Some form of
protective immunization was obviously in order.
Dr.
Wilbur A Sawyer and his associates, as well as other investigators,
observed that monkeys inoculated with highly virulent strains of yellow fever
virus 4 to 6 hours following an injection of immune serum possessed a solid
active immunity after passive immunity had disappeared. Sawyer using a less virulent French strain (established in
mice by Theiler) devised a vaccine
consisting of a 10 percent suspension of infected mouse brain tissue in fresh,
sterile, human immune serum. This material when used with supplementary
immune serum, gave solid immunity in monkeys without the development of
symptoms. After thorough testing in monkeys, 10 persons were vaccinated between
May 13 and June 29, 1931
(Sawyer, Kitchen, and Lloyd, 1931, 1932).
This was the
first vaccine against yellow fever and after its introduction no further cases
of disease occurred in the International Health Division Laboratories.
1932:
Sellard and Laigret tested the French
mouse brain virus without immune serum in humans (Sellard and Laigret, 1932).
Mathis and Coworkers described the field trials of this vaccine (Mathis,
Laigret, Durieux, 1934). Vaccine came to
be known as “Dakar” vaccine.
First tissue culture experiments with
yellow fever virus were reported by Haagen and Theiler (1932). They tested
various fragments of tissue, using French neurotropic strain, but inspite of
good tissue growth, the virus disappeared from the majority in a few days.
Finally the best results were obtained when chick embryo was used as tissue
component. The tissue component consisted of finally minced chick embryo, and
the fluid portion was Tyrode’s solution containing normal monkey serum.
January to April there was a wholly
rural epidemic of yellow fever in the Valle do Chanaan Espirito Santo, Brazil,
in which A.aegypti could definitely
be ruled out as vector. The epidemic was
described in details by Soper, Penna, et al (1933). Workers proposed jungle
cycle of yellow fever transmission by mosquito other than A. aegypti between monkey and accidentally from monkey to man. The
complexity of the problem was further accentuated by the repeated detection of
yellow fever of jungle origin in Brazil
During 1936 to 1950 the laboratories
and epidemiologists in Rio de Janeiro Bogota , Colombia Entebba , Uganda Lagos , Nigeria America Africa by solving the riddles like its
transmission, vectors involved, maintenance in nature, etc.
As a by product of the study of jungle yellow fever by
the Rockefeller Foundation quite a number of unknown viruses were isolated form
man and mosquitoes such as Ilheus from South America and West Nile; Uganda
S, Ntaya and Zika from Africa (Yellow
Fever Conference, 1954).
1936:
Lloyd, Theiler, and Ricci successfully
established highly virulent Asibi strain (after 53 monkey passage and more than
3 years without intervening passage through an animal host) in a culture medium
containing embryonic mouse tissue and 10 percent monkey serum in Tyrode’s
solution for 13 subcultures. Then separate batch of this was cultivated in a
medium containing minced whole chick embryo for 58 subcultures. Thereafter the
medium was modified by removing the brain and spinal cord from the chick embryo
before mincing. The virus was maintained
for 160 subcultures. The resultant
strain was designated as 17D
(Theiler & Smith, 1937 a).
The viscerotropic
and neurotropic virulence of this virus had been markedly reduced between 89th
and the 114th subculture in vitro.
1937:
Elmendorf and Smith (1937) first
reported of the successful infection of the developing chick embryo through chorio-allantoic membrane and direct
inoculation of the embryo itself with Yellow Fever Virus.
Theiler
and Smith, after prolonged and careful study in laboratory animals began human immunization (starting November, 1936) with a single
inoculation of modified 17D strain of
virus, without immune serum (Smith, Penna and Paoliello, 1938; Theiler and
Smith, 1937, b). However, normal human serum was added to vaccine as
stabilizer. Thus named as “17D serum
based’’ vaccine by Hargett, Burruss and Donovan (1943).
The
vaccine entered field trial in Brazil in June, 1937 (Smith, Penna and
Paoliello, 1938). The vaccine became
famous by name of “17-D Vaccine”.
1938:
Over 1 million Brazilians had received
the 17 D Vaccine (Monath T.P., 1996) and over 100,000 persons in French West Africa have received the French Neurotropic
Vaccine (FNV) (Durieux, 1956).
1939:
Peltier, Durieux et al., reported
application of neurotropic mouse brain vaccine to skin by mild scarification,
known as “Scratch” or topical method.
1940:
In December Fox et. al., prepared
experimental batches of 17D serum-based vaccine from which serum was eliminated
(Fox et al., 1942). Working independently Hargett et al., found that
satisfactory vaccine could be prepared using distilled water as diluent and
coined this preparation as “17D aqueous base” vaccine (Hargett et al., 1943).
1941:
Out
break of encephalitis occurred in Brazil
1942:
The technique of vaccine production was altered; so that all vaccines
to be used for immunization were
initiated from primary and secondary seed lots of known character only and
thus the difficulties associated with the properties of virus itself are
eliminated (Fox, Kossobudzles & Fonsela Da Cunha, 1943).
The successful utilization of Yellow
Fever Vaccine in the 1940 and effective antimosquito measures, and
disappearance of disease from urban areas, however, led to a loss of interest
among scientists in the disease and thus not
much work was done till 1970 i.e. till the development of molecular techniques.
1951:
Dr. Max Theiler was awarded Nobel Prize for Physiology
and Medicine in 1951 for his unparallel contribution in the research of yellow
fever.
After
he retired from the Rockefeller Foundation in 1964, Dr Theiler became professor
of epidemiology and microbiology at Yale University, where he remained until
1967. He died of lung cancer on 11 August 1972, at the age of 73. Singapore Med J 2017; 58(4): 223-224
Max Theiler receives the Nobel Prize in Physiology or Medicine from the hands of His Majesty the King Gustaf Adolf VI on December 10, 1951. Photo by the Karolinska Institutet. (Image Source)
Yellow fever vaccination certificate
References for History of Yellow Fever Series will be updated soon.
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