Thomas Francis Jr.’s Flu Review (1937)

When I originally started researching the origins of the supposed isolation of the influenza “virus,” I was not expecting to spend so much time on Thomas Francis Jr. It became evident, however, that throughout the early flu research of the 1930’s and 40’s, Francis Jr. was “Mr. Influenza.” It was also apparent that his research papers were the gifts that keep on giving so it was very hard to stop reading them.

It just so happened that while I was reading his supposed “isolation” of Influenza B in 1940, Francis Jr. referred back to his own 15-page review from 1937 as evidence for the necessary criteria/evidence needed to justify a new influenza strain. Obviously, I couldn’t pass up the opportunity to see what 1937 Francis jr. said in order to back up 1940 Francis Jr.’s own conclusions. There were quite a few interesting admissions made in his review. Highlights below:

Epidemiological Studies in Influenza

“INFLUENZA is primarily a clinical and epidemiological syndrome which appears in epidemic waves of varying proportions. In fact, Crookshank states, “the name, ‘influenza,’ stands not for an entity: not for something with objective existence in nature; but for the triple conception of a disease, an epidemic prevalence, and an epidemic constitution or period.” Crookshank represents the school which rightly or wrongly encompasses under the term influenza all forms of infectious disease occurring at a time when illness of epidemic character is widespread. Thus encephalitis, choriomeningitis, infectious mononucleosis, infectious jaundice, staphylococcus food poisoning, and acute respiratory infections occurring at the same time in a given area would represent to his notion different types of influenza.

It is doubtless true that outbreaks of certain diseases may be concomitant with, or followed by certain others, and that one may by its particular mode of attack prepare the soil for another. It is also true that the clinical aspects of a disease vary from individual to individual. But with increasing knowledge of specific causative agents, many diseases which have hitherto been grouped together under some general terminology are being removed and placed in their proper niches. In most instances the study of infectious diseases has resulted in the separation of one or more fairly concise clinical entities from what was previously an inclusive designation. Thus, pneumonias due to different types of pneumococcus, to the hemolytic streptococcus, or to psittacosis virus, have distinctive features and the etiological classification of the cases has shown that the different groups present rather characteristic disease pictures.

At the present time it seems likely that included in the term influenza are several different diseases apparently so similar from a purely clinical standpoint as to be indistinguishable. Many attempts have been made to suggest definitive criteria based upon epidemiological, clinical, or laboratory standards. Epidemiologically the terms pandemic, epidemic, and sporadic influenza have been used. Clinically the common cold, grippe, influenza-like, are terms which express the effort toward differential diagnosis. Leukopenia or the demonstration of Pfeiffer’s bacillus have been studied as diagnostic aids. But none of the criteria have been sufficiently specific to lead to an exclusive diagnosis.

What then is influenza? I must confess that it is perhaps less difficult to say what it is not. Influenza is not the ordinary head cold usually characterized by running nose and absence of fever; it is not the acute tonsillitis or sore throat of streptococcus origin; it is not the low grade fever of chronic sinusitis
with its accompanying malaise; it is not the nausea, vomiting and diarrhea of food poisoning; it is not lobar pneumonia. It is not Rift Valley fever, psittacosis, or jungle yellow fever. Influenza is rather an acute infectious respiratory disease of epidemic nature which is of variable extent and severity. It is characterized by a rapid dissemination, high morbidity, sudden onset with fever, chills, pharyngitis, cough, myalgias, leukopenia, and inconstant bronchitis or pneumonitis. The mortality is low, the immediate recovery is usually prompt after a course of 3 or 4 days, but weakness far out of proportion to the illness may persist for some time. Within the scope of this general definition lies the problem for investigation.

It is impossible within the limits of the present discussion to attempt a review of the great mass of contradictory evidence which has accumulated in the literature on influenza. I shall deal primarily with the more recent studies relating to the virus etiology of the disease.

In 1931 Shope published the first of his papers establishing the fact that swine influenza was produced by a filterable virus in symbiosis with a hemophilic bacterium, H. influenzax suis. The virus agent was found to be the essential component in the cause and dissemination of the disease, and in the immunity which followed infection. The bacterium appeared only to increase the severity of the infection induced by the virus.

In 1933 Smith, Andrewes. and Laidlaw recovered a virus from cases of human influenza following the intranasal inoculation of ferrets with the nasal washings of acutely ill patients. The disease was transmissible from sick ferrets to normal animals by suspensions of nasal turbinates or by direct contact. Recovered animals were immuine to reinfection and their serum contained antibodies capable of neutralizing the virus. The same investigators reported that ferrets were also susceptible to swine influenza virus and that the two viruses were somewhat related. Shope then found that if ferrets were anesthetized at the time of their inoculation with swine influenza virus, they developed extensive pneumonia.

In 1934, with material from human patients- suffering from influenza in Puerto Rico, we were successful in isolating a strain of virus in ferrets. It was noted in addition that the human influenza virus after a period of adaptation also produced lung lesions in infected ferrets. It was likewise found that mice were susceptible to the Puerto Rico virus, while Andrewes, Laidlaw, and Smith independently reported similar results with the WV. S. virus. In mice a fatal disease, with extensive pneumonia, occurs. To date it has not been possible to transfer the disease directly from man to mouse. Onlv after a period of passage through ferrets has the virus been found capable of producing demonstrable infection in mice. At the present time the P.R. 8 virus is infective for both mice and ferrets in a dilution of 1:1,000,000.

Subsequently we succeeded in cultivating both human and swine influenza virus in the tissue culture medium of Li and Rivers, while Burnet has reported the successful adaptation of the virus to growth on the chorioallantoic membrane of the developing egg.”

“While the strains of virus appear to be immunologically identical, certain differences in their pathogenicity have
been observed. The virus from Puerto Rico has been rather striking in the speed with which it became adapted to animals. In ferrets, Strain 5, which was subsequently lost, produced gross lung lesions after 6 passages, P.R.8 after 7-11 passages. The Philadelphia virus appeared to produce more marked nasal symptoms than the P.R.8, but lung lesions were not observed in significant extent until the 11th passage, thereafter irregularly and of much lesser extent than with the P.R. 8 strain. The Alaska virus was carried directly through 30 passages with large inocula before infected ferrets exhibited any consistent gross pulmonary consolidation. Still the febrile reaction in ferrets has been quite pronounced with all these strains since the original passage. Furthermore, after the transfer of virus to mice, the Puerto Rico virus rapidly enhanced its virulence and titer for this species of animal, whereas the
Alaska virus has been consistently weaker. The latter strain, though having approximately the same end-point in titrations, as measured by lung lesions in mice, requires a much larger dose to produce a fatal infection. It has not yet been successfully maintained in tissue culture under conditions to which the other strains become readily adapted.

It seems quite possible that these quantitative differences in the pathogenicity of various strains for experimental animals may reflect in some degree the severity of the disease which the respective strains might elicit in a human population. For instance, the P.R. 8 virus may represent a strain of severe epidemic capacity, while the Alaska strain might be extremely mild except in a highly susceptible population. From the evidence, no conclusion can be drawn except to note that the P.R.8 strain was infective in a semi-tropical country during a time when excellent weather was the rule; the Alaska strain was obtained from an isolated community in Arctic winter.”

“The P.R. 8 ferret-passage virus when administered intranasally to normal ferrets in 10 percent concentration produces a severe disease of fatal proportions, with labored breathing and extensive pulmonary involvement as well as pronounced nasal discharge. The febrile reaction is at times absent because of the severity of the illness.
When previously immune ferrets are reinoculated after a period of months
with similar material, various degrees of reaction ensue. Some show little or
no evidence of illness, others show a brisk, sharp rise of fever with or without mild nasal symptoms, but rarely exhibit significant symptoms of respiratory distress. They usually remain active and eat well. If on the 4th day after inoculation lungs and turbinates of such animals are removed, they show no significant lesions. When strong suspensions of these organs are introduced into a normal ferret, the normal animal does not become ill nor, in our experience, does it develop neutralizing antibodies. These results indicate that free virus is not present in those tissues which in the infected susceptible animal constitute a rich source and that the reinoculated animal possesses the capacity to dispose rapidly of the virus actually introduced. It still retains, therefore, a very effective immunity. The fever and mild nasal symptoms seem to represent an accelerated immune reaction. Moreover, ferrets in a waning state of immunity in which antibodies still persist can be made completely resistant again by a single vaccinating dose of active virus.

It has not been possible to infect ferrets or mice by any route other than the respiratory tract. When the virus is inoculated subcutaneously or intraperitoneally even in large amounts,
no signs of illness are observed. Ferrets so treated develop circulating antibodies but do not become completely resistant to intranasal infection. In fact, they mav exhibit fever similar in degree to the fully susceptible normal animal.”

“In mice, on the other hand, repeated
subcutaneous or intraperitoneal injec-
tions of virus elicit not only the formation of antibodies but a solid immunity
to intranasal infection with many lethal
doses of infectious agent. The results are apparently influenced to some extent by the route of injection, the source of material, and the number of injections.”

“The problem of immunity to influenza
in human individuals is beset by many difficulties, the chief of which is, perhaps, the problem of diagnosis. How is one to evaluate the history of an individual who says he has influenza each year? Is it possible that some persons develop a staunch and persistent immunity while others have only a slight and transitory resistance following infection? The epidemiological evidence is in certain ways contradictory since in most instances the conclusions have been based upon the supposition that all outbreaks were the same disease.”

“In an effort to determine the occurrence of antibodies in the population at large, sera of 136 individuals of different ages were collected along the Eastern Seaboard. They were tested by means of mouse protection tests against the P.R. 8 strain of human influenza virus. The results were classified as complete, partial, or no protection. Of these sera, 49.2 percent gave complete protection, 29.4 percent gave partial protection, and 21.3 percent gave no protection to mice. Distinct differences were observed at different ages. Including all those which exerted a complete or partial protective action, the serum of all new-born infants contains antibody. These antibodies are lost during the 1st year of life but between the 1st and 5th years, two-thirds of the children studied possessed considerable antibody. Thereafter, the curve rises so that from 20 to 40 years of age, 90 per cent of the
sera exerted a protective action; thereafter a slight but definite decline was observed. The results suggest the interpretation that approximately half the population after the 1st year of life have a rather high degree of resistance to influenza and that one-third of the same population has a moderate degree of resistance. Whether the so-called partial immunity represents individuals with a waning immunity, or individuals who never reached a high degree of immunity cannot be stated. The fact that this intermediate state increases with age up to 50 years suggests the former probability. The presence of antibodies in young children joins with the fact that the virus has been isolated in recent epidemics to indicate that this virus has been responsible for outbreaks of disease in recent years. Furthermore, the high incidence of either partially or- completely protective sera in older individuals is indicative of infection at some previous time, but since the duration of antibodies is not known it is difficult to state whether they are of recent or remote origin. Enough is known to say that antibodies persist for 1 year at least, and that recently convalescent individuals have a high incidence of antibodies.

Somewhat similar results have been obtained in England by Andrewes, Laidlaw, and Smith in a series of 64 individual sera studies. While the percentages of protective sera at different ages differ somewhat, the general trend is the same. Brown in Boston has also reported results of tests made with the sera of children and adults. The chief difference noted is that the serum of children in Brown’s series appear to have less antibody than noted in our group. This may well be attributable to variations in the distribution of the disease in the two districts.

The relation between a history of previous attack of influenza and the occurrence of neutralizing antibodies is not extremely sharp. Of 78 individuals above 12 years of age from whom fairly accurate statements were obtained, there. were 45 who gave positive histories and 25, or 55.5 per cent of them, possessed potent circulating antibody. Negative histories were obtained from 33 subjects and 39.3 per cent of these had strongly positive sera. On the other hand, the serum of only 9 of 18 individuals who had influenza in 1918 gave complete protection, while of 31 who had influenza, between 1933 and 1935, 27 or 87 percent possessed high content of circulating antibodies. These results together with those in children suggest that the strongly protective sera are most common among individuals infected in recent years.”

“It seems, however, that the characteristics of the virus agent alone are not sufficient to explain the severity of the 1918-1919 epidemic. There can be little doubt that the severe pneumonias and the increased fatality were attributable to a high incidence of secondary infections in which the hemolytic streptococcus played an outstanding role as it did in the measles epidemics. The highest age incidence of
influenza was in childhood, but the highest mortality rate was in adults, especially males, of 20-35, the age group most affected by the dislocation of population. As Jordan says, “Case fatality is doubtless greatly affected by differences in the virulence of the accessory microbes that are mainly responsible for death . . . and perhaps by difference in the virulence of the influenza virus itself. . . . In a word, the factors that determine case fatality in influenza are for the most part accidental and extraneous and are not dependent directly on the nature of the virus.”

“Furthermore, with material from cases of clinical influenza, cultures have been made which when tested in human volunteers produce symptoms of the common cold. The viruses have not been pathogenic, however, for the smaller laboratory animals.

In our laboratory, attempts to cultivate the strains of human influenza virus in the same medium and under the same conditions as those employed for the cultivation of the cold virus have been so far unsuccessful. It appears, therefore, that the viruses are different in their growth requirements and in their pathogenicity for animals.

The possibility that a virus of influenza might after a considerable period of absence from the human organism produce only symptoms of a common cold is not remote. In all epidemics varied degrees of clinical severity are noted. Referring to our observations on the antibody content of human serum, one might readily infer that different degrees of immunity might result in different degrees of illness. This is actually observed in ferrets which can be classified as not immune, partially immune, and completely im- mune. Furthermore, Smillie has recorded an epidemic of influenza in Labrador in which the illness varied from a mild common cold to severe influenza.

In any case, both the common cold and influenza are important in the incidence of the more severe disease lobar pneumonia. The greater the understanding of either of these conditions, the greater will be its application in unraveling the problem of the other respiratory diseases.”

RELATION TO OTHER RESPIRATORY DISEASES OF SIMILAR CHARACTER

While strains of virus of a fairly uniform type have been recovered repeatedly from outbreaks of human influenza in different localities, other outbreaks have occurred from which no virus was isolated. Thus Andrewes, Laidlaw, and Smith failed to recover virus from an epidemic of influenza in the garrison at Woolwich, England, in 1935. Both in England and in our laboratory similar failures have occurred in attempts to isolate influenza virus from numerous cases of influenza-like infections of sporadic nature. Moreover, completely uniform results have not been obtained in outbreaks from which influenza virus has been isolated.

During February and March, 1936, a widespread incidence of acute respiratory disease, diagnosed as influenza, occurred in the United States and Canada. It was first called to our attention by Dr. J. J. Sippy of Stockton, Calif. Through the kindness of the state and local health authorities of California, it was possible to study the disease directly. The illness as observed appeared to be typical influenza; the onset was sudden with chills and fever, headache, generalized aches and pains, nasal and pharyngeal irritation without pronounced coryza. In most instances the fever was of 3 days’ duration, although a brief secondary rise on the 5th day was not uncommon. Nausea and vomiting were not commonly observed. Hoarseness and cough not infrequently began at the time the temperature reached normal and persisted for an indefinite period. A small proportion of cases, in adults primarily, developed a mild bronchitis or bronchopneumonia with tenacious yellow sputum. Physical examination usually revealed nothing except the flushed face and a rather dry pharynx with swollen lymphoid follicles but without exudate. Muscular tenderness was frequently evident. Temperatures ranged up to 104.0 F. Convalescence was commonly associated with a protracted weakness and depression. The leukocyte counts regardless of the day of disease averaged about 6,000 per cu. mm.”

“We witnessed, therefore, an explosive outbreak of respiratory disease diagnosed as influenza which affected most severely the youngest third of the population.

Throat washings were obtained from 47 cases. These were mixed with equal parts of glycerine and shipped by air express to the laboratories of the International Health Division in New York. There ferrets and mice were inoculated with 33 samples, and filtrates of the material were introduced into tissue culture medium. In no instance was influenza virus recovered. Furthermore, serum was obtained from 32 of the patients during the acute stage, from
28 of the same individuals 2 weekis after
recovery and from 12 of them again 4 weeks after recovery.

These sera were tested against P.R. 8 virus in mouse protection tests. In all but 1 case the convalescent serum failed to show an increase in antibodies to human influenza virus. The acute and convalescent sera from 10 patients were also tested aginst swine influenza virus. No differences between neutralizing capacity of the acute and convalescent sera was detectable.

We are faced then with an epidemic of what was clinically and epidemiologically influenza in which attempts to isolate a virus were unsuccessful. The general nature of the outbreak was very suspicious of a virus disease. Several explanations may be offered for the failure. It may be that the virus was of low virulence and failed to infect ferrets. This is suggested by the facts’ that in some instances the first-passage ferret exhibited a mild elevation of temperature but on subsequent passages the temperature reactibn’ became less and less definite. On the other hand, it may be that the conditions of shipping resulted in death of the active agent. We have, however, recovered virus from similar material in other outbreaks as late as 3 weeks after its’ collection and shipment. The failure of the convalescent sera to exhibit any increase in neutralizing antibodies suggests that if the causative agent were influenza virus, it was of very low antigenic property. The most likely conclusion, on the basis of the present knowledge at least, is that the epidemic was caused by an entirely different virus.

If this be the case, it is evident that the term “influenza” embraces more than a single etiological entity and that continued efforts must be made to isolate the etiologic agents and to differentiate such clinically similar but etiologically different diseases. It may be, however, that the results can still be attributed to a peculiarity of a strain of influenza virus of extremely low pathogenicity for experimental animals, capable in humans of infecting only superficially without eliciting a demonstrable increase in circulating antibodies.”

It is clearly evident that since the isolation of a filterable virus from human influenza, a distinct progress has been made. The distribution of the virus, the problem of immunity to the disease, the relation of current influenza to the common cold, pandemic influenza, and other similar infections have all been approached through experimental methods. Moreover, fundamental aspects of prevention and therapy have been investigated. Nevertheless, the knowledge is of necessity incomplete. Diagnostic aids adaptable to general use, simple tests available for widespread immunity studies without large supplies of animals are still wanting. In short, the preliminary skirmishes have been very promising but the campaign is far from complete.”

doi: 10.2105/ajph.27.3.211

In Summary:

• Crookshank stated, “the name, ‘influenza,’ stands not for an entity: not for something with objective existence in nature; but for the triple conception of a disease, an epidemic prevalence, and an epidemic constitution or period.”
• Crookshank represented the school which rightly or wrongly encompassed under the term influenza all forms of infectious disease occurring at a time when illness of epidemic character is widespread
• This included:
  1. Encephalitis
  2. Choriomeningitis
  3. Infectious mononucleosis
  4. Infectious jaundice
  5. Staphylococcus food poisoning
  6. Acute respiratory infections
• Francis Jr. claimed it was doubtlessly true that outbreaks of certain diseases may be concomitant with, or followed by certain others
• It was also true that the clinical aspects of a disease vary from individual to individual
• Many diseases which had been grouped together under some general terminology were being removed and placed in niches (i.e. they were thought to be the same disease process but were being separated by virology)
• At that time, it seemed likely to Francis Jr. that included in the term influenza are several different diseases apparently so similar from a purely clinical standpoint as to be indistinguishable (i.e. they were the same disease)
• Clinically, they used names like the common cold, grippe, and influenza-like as terms to express the effort toward differential diagnosis (in other words, they assumed these symptoms of disease were caused by different “viruses” and needed to be separated)
• None of the criteria used was sufficiently specific to lead to an exclusive diagnosis
• Attempting to define influenza, Francis Jr. confessed that it is perhaps less difficult to say what it is not
• He defines influenza as rather an acute infectious respiratory disease of epidemic nature which is of variable extent and severity
• It is characterized by:
  1. A rapid dissemination
  2. High morbidity
  3. Sudden onset with fever
  4. Chills
  5. Pharyngitis
  6. Cough
  7. Myalgias
  8. Leukopenia
  9. Inconstant bronchitis or pneumonitis
• The mortality was low, the immediate recovery was usually prompt after a course of 3 or 4 days, but weakness far out of proportion to the illness may persist for some time
• Francis Jr. states that within the scope of this general definition lies the problem for investigation
• He admits it was impossible within the limits of his paper to attempt a review of the great mass of contradictory evidence which had accumulated in the literature on influenza so he dealt primarily with the more recent studies relating to the “virus” etiology of the disease (a little selection bias perhaps?)
• In 1931 Shope published the first of his papers establishing the “fact” that swine influenza was produced by a filterable “virus” in symbiosis with a hemophilic bacterium, H. influenzax suis
• In 1933 Smith, Andrewes. and Laidlaw recovered a “virus” from cases of human influenza following the intranasal inoculation of ferrets with the nasal washings of acutely ill patients
• In 1934, Francis Jr. credits himself with isolating a strain of “virus” in ferrets with material from human patients suffering from influenza in Puerto Rico
• He states that it was likewise found that mice were susceptible to the Puerto Rico “virus”
• It was not possible to transfer the disease directly from man to mouse
• Onlv after a period of passage through ferrets had the “virus” been found capable of producing demonstrable infection in mice

Quick Detour on Serial Passaging

The serial passaging used by Francis Jr. and others at this time was a process created by Louis Pasteur where tissues from “infected” animals are ground up, mixed with additives, and “passed” (i.e. injected) through invasive inoculations into healthy animals in an attempt to make them sick. They repeated this process (sometimes through multiple animals) until they get the desired result:

“Alternatively, an in vivo experiment can be performed where an animal is infected with a pathogen, and this pathogen allowed time to grow in that host before a sample of it is removed from the host and passed to another host. This process is repeated for a certain number of hosts; the individual experiment determines this number.”

“To solve this problem, Pasteur worked with the rabies virus in vivo.^[6][7] In particular, he took brain tissue from an infected dog and transplanted it into another dog, repeating this process multiple times, and thus performing serial passage in dogs.^[6] These attempts increased the virulence of the virus.^[6] Then, he realized that he could put dog tissue into a monkey to infect it and then perform serial passage in monkeys.^[6] After completing this process and infecting a dog with the resulting virus, Pasteur realized that the virus was less virulent.^[6] Mostly, Pasteur worked with the rabies virus in rabbits.^[7] Ultimately, to create his vaccine for rabies, Pasteur used a simple method that involved drying out tissue. As is described in his notebook:

In a series of flasks in which air is maintained in a dry state…each day one suspends a thickness of fresh rabbit spinal tissue taken from a rabbit dead of rabies. Each day as well, one inoculates under the skin of a dog 1 mL of sterilized bouillion, in which has dispersed a small fragment of one of these desiccated spinal pieces, beginning with a piece most distant in time from when it was worked upon, in order to be sure that it is not at all virulent.^[6]

Pasteur mostly used other techniques besides serial passage to create his vaccines. However, the idea of attenuating a virus through serial passage still holds.”

https://en.m.wikipedia.org/wiki/Serial_passage

It was through this disgusting practice that they claim “isolation” of a “virus” assumed but never seen in their ground up tissue soup.

End Detour

• While the strains of “virus” appeared to be immunologically identical, certain differences in their pathogenicity were observed
• In ferrets, Strain 5, which was subsequently lost, produced gross lung lesions after 6 passages, P.R.8 after 7-11 passages
• The Philadelphia “virus” appeared to produce more marked nasal symptoms than the P.R.8, but lung lesions were not observed in significant extent until the 11th passage, thereafter irregularly and of much lesser extent than with the P.R. 8 strain
• The Alaska “virus” was carried directly through 30 passages with large inocula before infected ferrets exhibited any consistent gross pulmonary consolidation
• The febrile reaction in ferrets had been quite pronounced with all these strains since the original passage (in other words, the only constant with them all was a fever)
• Francis Jr. speculated that it seemed quite possible that these quantitative differences in the pathogenicity of various strains for experimental animals may reflect in some degree the severity of the disease which the respective strains might elicit in a human population
• However, he admitted that from the evidence, no conclusion could be drawn
• When previously immune ferrets are reinoculated after a period of months with similar material, various degrees of reaction occurred:
  1. Some showed little or no evidence of illness
  2. Others showed a brisk, sharp rise of fever with or without mild nasal symptoms, but rarely exhibited significant symptoms of respiratory distress
  3. They usually remained active and ate well
  4. If on the 4th day after inoculation lungs and turbinates of such animals were removed, they showed no significant lesions
• When strong suspensions of these organs were introduced into a normal ferret, the normal animal did not become ill
• Francis Jr. claimed that these results indicated that “free virus” was not present in those tissues which in the infected susceptible animal constitute a rich source
• He felt that the fever and mild nasal symptoms in the “immune” animals seemed to represent an accelerated immune reaction
• It was not possible to infect ferrets or mice by any route other than the respiratory tract
• When the “virus” was inoculated subcutaneously or intraperitoneally even in large amounts, no signs of illness were observed
• Ferrets so treated developed circulating antibodies but did not become completely resistant to intranasal infection
• In fact, they exhibited fever similar in degree to the fully susceptible normal animal
• The results of “immunity” in mice were apparently influenced to some extent by:
  1. The route of injection
  2. The source of material
  3. The number of injections
• The problem of immunity to influenza in human individuals was beset by many difficulties, the chief of which is the problem of diagnosis
• The epidemiological evidence was contradictory since in most instances the conclusions have been based upon the supposition that all outbreaks were the same disease (now based on the supposition that all outbreaks are different diseases)
• In an effort to determine the occurrence of antibodies in the population at large, sera of 136 individuals of different ages were collected along the Eastern Seaboard
• They were tested by means of mouse protection tests against the P.R. 8 strain of human influenza “virus” (if the mouse survived “virus” injection after being injected with human blood, the human was considered to have antibodies)
• The results were classified as complete, partial, or no protection and of these sera, 49.2 percent gave complete protection, 29.4 percent gave partial protection, and 21.3 percent gave no protection to mice
• Distinct differences were observed at different ages
• The results suggested the interpretation that approximately half the population after the 1st year of life have a rather high degree of resistance to influenza and that one-third of the same population has a moderate degree of resistance
• Whether the so-called partial immunity represented individuals with a waning immunity, or individuals who never reached a high degree of immunity could not be stated
• The high incidence of either partially or- completely protective sera in older individuals was indicative of infection at some previous time, but since the duration of antibodies was not known it was difficult to state whether they were of recent or remote origin
• Enough was known to say that antibodies persist for 1 year at least
• These findings completely contradict the yearly or now every 6 month flu shot when nearly everyone had antibodies that persisted for at least one year that was assumed to provide protection
• Somewhat similar results were obtained in England by Andrewes, Laidlaw, and Smith in a series of 64 individual sera studies yet the percentages of protective sera at different ages differed
• Brown in Boston also reported results of tests made with the sera of children and adults and the chief difference noted was that the serum of children in Brown’s series appeared to have less antibody than noted in Francis Jr.’s group
• The relation between a history of previous attack of influenza and the occurrence of neutralizing antibodies was not extremely sharp
• Of 78 individuals above 12 years of age from whom fairly accurate statements were obtained, there were 45 who gave positive histories and 25, or 55.5 percent of them, possessed potent circulating antibody while negative histories were obtained from 33 subjects and 39.3 percent of these had strongly positive sera
• On the other hand, the serum of only 9 of 18 individuals who had influenza in 1918 gave complete protection
• In other words, antibody results differed by studies and even those with no history of influenza had antibodies showing it to be a meaningless measurement
• According to Francis Jr., the characteristics of the “virus” agent alone were not sufficient to explain the severity of the 1918-1919 epidemic
• He believed that there could be little doubt that the severe pneumonias and the increased fatality were attributable to a high incidence of secondary infections in which the hemolytic streptococcus played an outstanding role as it did in the measles epidemics
• He offered a quote by Jordan saying “Case fatality is doubtless greatly affected by differences in the virulence of the accessory microbes that are mainly responsible for death . . . and perhaps by difference in the virulence of the influenza virus itself. . . . In a word, the factors that determine case fatality in influenza are for the most part accidental and extraneous and are not dependent directly on the nature of the virus.”
• In other words, the influenza “virus” is not strong enough alone to cause severe disease and there were other factors which contributed to disease, thus influenza can be explained without the assumption of invisible “viruses”
• With material from cases of clinical influenza, cultures were made which when tested in human volunteers produced symptoms of the common cold
• The “viruses” were not pathogenic, however, for the smaller laboratory animals
• In his lab, attempts to cultivate the strains of human influenza “virus” in the same medium and under the same conditions as those employed for the cultivation of the cold “virus” were unsuccessful
• Francis Jr. claimed that the possibility that a “virus” of influenza might, after a considerable period of absence from the human organism, produce only symptoms of a common cold is not remote
• In all epidemics varied degrees of clinical severity are noted
• He states that one might infer that different degrees of immunity might result in different degrees of illness
• Smillie recorded an epidemic of influenza in Labrador in which the illness varied from a mild common cold to severe influenza
• Both the common cold and influenza are important in the incidence of the more severe disease lobar pneumonia (maybe because they are all part of the same diseasee process?)
• Other influenza outbreaks have occurred from which no “virus” was isolated
• Andrewes, Laidlaw, and Smith failed to recover “virus” from an epidemic of influenza in the garrison at Woolwich, England, in 1935
• Both in England and in Francis Jr.’s laboratory, similar failures have occurred in attempts to isolate influenza “virus” from numerous cases of influenza-like infections of sporadic nature
• Completely uniform results were not obtained in outbreaks from which influenza “virus” has been isolated
• During February and March, 1936, a widespread incidence of acute respiratory disease, diagnosed as influenza, occurred in the United States and Canada
• The illness as observed appeared to be typical influenza:
  1. Onset was sudden with chills and fever, headache, generalized aches and pains, nasal and pharyngeal irritation without pronounced coryza
  2. In most instances the fever was of 3 days’ duration, although a brief secondary rise on the 5th day was not uncommon
  3. Nausea and vomiting were not commonly observed
  4. Hoarseness and cough not infrequently began at the time the temperature reached normal and persisted for an indefinite period
  5. A small proportion of cases, in adults primarily, developed a mild bronchitis or bronchopneumonia with tenacious yellow sputum
  6. Physical examination usually revealed nothing except the flushed face and a rather dry pharynx with swollen lymphoid follicles but without exudate
  7. Muscular tenderness was frequently evident
  8. Temperatures ranged up to 104.0 F
• Francis Jr. stated that they had witnessed an explosive outbreak of respiratory disease diagnosed as influenza which affected most severely the youngest third of the population
• However, after using throat washings obtained from 47 cases (which were mixed with equal parts of glycerine) to “infect” ferrets, in no instance was influenza “virus” recovered
• In all but 1 case the convalescent serum failed to show an increase in antibodies to human influenza “virus”
• Francis Jt. admitted they faced an epidemic of what was clinically and epidemiologically influenza in which attempts to isolate a “virus” were unsuccessful
• He offered a few thoughts on why they failed to isolate a “virus” from a disease diagnosed as influenza:
  1. It may have been that the “virus” was of low virulence and failed to infect ferrets
  2. It may have been that the conditions of shipping resulted in death of the active agent
  3. The failure of the convalescent sera to exhibit any increase in neutralizing antibodies suggested that if the causative agent were influenza “virus,” it was of very low antigenic property
• The most likely conclusion to Francis Jr. was that the epidemic that was clinically and epidemiologically influenza was caused by an entirely different “virus”
• He decided it was evident that the term “influenza” embraced more than a single etiological entity and that continued efforts must be made to isolate the etiologic agents and to differentiate such clinically similar but etiologically different diseases
• However, Francis Jr. also added that the results could still be attributed to a peculiarity of a strain of influenza “virus” of extremely low pathogenicity for experimental animals, capable in humans of infecting only superficially without eliciting a demonstrable increase in circulating antibodies
• Francis Jr. concludes that the knowledge of influenza is of necessity incomplete and that while the preliminary skirmishes were very promising, the campaign was far from complete

It should become clear after reading this “review” that Francis Jr. was only interested in highlighting any research that somewhat supported his own assumptions/conclusions. He admitted there was a “great mass of contradictory evidence” yet for some reason (cough…Rockefeller $$$…cough) he only wanted to focus on the newer studies that did not entirely contradict his own. What proceeded through 15 pages was a devolution from a review into a sorry set of excuses for why he and others failed to find their “virus” in every case/outbreak of the same disease. However, 1937 Francis Jr. did ultimately give 1940 Francis Jr. the perfect excuse by guessing that a new strain of “virus” was to blame for the many instances of “isolation” failures, thus setting the stage for his own “discovery” of Influenza B a few years later and giving himself a nice pat on the back to boot.