“The story of the development of the vaccines for Influenza A is not … a pitched battle, but a long campaign — the slow, bit-by-bit accumulation of data in which one doctor builds upon the laboratory experience of another.”
I
BEHIND the factory smoke and the roar of machinery for national defense there is another, greater defense for humanity being worked out these days in laboratories where influenza is being studied. Patient, persistent, brilliant experiments are being made in California, Puerto Rico, England, Malta, Minnesota, Suez, Pennsylvania, South Africa, Budapest, and New York to defeat a baffling enemy that is so small it cannot be seen with a microscope.
Influenza! It was a dread word in 1918-1919. It is a dread word now to anyone who has the memory of that winter. Just what is its present threat? Will it now become rampant again? If it does, have we any better protection in February 1941 than we had in February 1919?
Six foremost influenza specialists in this country and in England say that we now have far, far better protection. Startling new weapons have emerged from the laboratory in the past few years. With these, they feel, we are equipped to put up a fight, a sufficiently stiff fight to keep a pandemic from raging and causing the havoc of the last. Another month, another week even, and some one of the many investigators at work on the subject may give us even better means of control.
Our greatest weapon is the vastly increased knowledge of the disease collected by the Rockefeller Health Foundation, the United States Public Health Service, university laboratories and bacteriologists all over this country and in the British Empire — particularly the English bacteriologists C. H. Andrewes, P. P. Laidlaw, and Wilson Smith, who should be placed foremost among the contributors of knowledge on this subject. None of that 1919 nonsense of running around with masks on this time. We know now that influenza is a virus capable of passing through filter paper. We know it attacks children and young adults in double proportion to older people. We know it particularly attacks expectant mothers, probably because of their increased hormone activity. And when we know more about hormones we’ll know the specific why of that. We know that influenza is weakening out of all proportion to the severity of the illness. In common with many of the virus diseases, it reduces white corpuscles in the blood. After the disease has run its course, it in turn produces antibodies against itself. If a high antibody content in the blood could be set up before exposure, the chances of immunity would be greatly increased.
Three vaccines which may lead to the production of antibodies — none of them expensive or difficult to prepare — are now available. A self-administered spray for the mouth is being tested to make sure that its promise of a three-day immunity is valid. How effective any of these will be in a pandemic is unknown, because they have yet to be put to a severe test.
A different sort of protection is offered by a new ultra-violet lamp, constructed to cast rays in the form of a curtain that kills all air-borne germs entering a room. Detailed research now tells us that 50 per cent of the mortality from influenza in 1918 was due to the various sorts of pneumonia which complicated the attack of the disease. If the influenza virus this year should again become associated with certain of the bacteria which cause pneumonia, we may be able to prevent the terribly high death rate. We have many of the miraculous new sulfonamide compounds to combat many types of pneumonia. But what worries us is that influenza has a striking tendency to join forces with other public enemies. It is the role played by these secondary invaders which still makes the behavior of the disease so unpredictable, still makes it impossible for health officers and doctors to prophesy even one week beyond this present one of writing whether the existing scattered local epidemics will completely subside or whether they will change their mild nature and start roaring as a pandemic.
‘Pandemic’ is not another word for ‘epidemic,’ any more than ‘hurricane’ is another word for ‘breeze.’ Influenza becomes epidemic every year in some part of the world. It creeps into a city, — sometimes in winter, sometimes in summer, — attacks the children and young adults, and burns itself out a month later. Once in three, in eleven, twenty, or even thirty years, one of these epidemics explodes into a pandemic and sweeps around the world. No medical man knows yet what it is that keeps it local, or sends it rampaging across continents, any more than meteorologists can put their fingers on the precise combination of low and high pressure areas that will turn an ordinary Caribbean gale into another 1938 New England hurricane.
The 1918 pandemic affected 500,000,000 people throughout the world and killed 20,000,000, according to the figures of the United States Public Health Bureau — nearly four times as great a mortality as that of the war itself. Here in the United States there were more than 550,000 deaths, approximately five times the number of American soldiers officially stated to have died from all causes in the war. Many of these men, too, were victims of influenza. Among children and young people between twenty and thirty the death rate soared. It was higher everywhere for men than for women, except for the appalling toll it took of expectant mothers. And all along the way, colored groups weathered the disease better than the white population.
These are bare numerical facts. Those who remember the plague describe it with horror, and dwell not upon the details of masks, of mass panic, of closed theatres and schools, but on how whole towns were stricken, schools turned into pesthouses, nurses and doctors exhausted. In many places it was simply taken for granted, for endless weeks, that anyone who could stand up would take care of those who could not.
In the past one hundred and fifty years of medical history there have been six influenza pandemics. There has been no regular spacing between them, no predictable cycle of activity. According to records of the United States Public Health Service, they occurred in 1830, 1833, 1836, 1847, 1889, and 1918. However, each pandemic — and this fact now arrests the attention of health authorities — coincided with widespread natural disaster. At the time of each pandemic, war had marched over fields and crops, or an earthquake had scattered multiple misery, or some river, like the Yangtze, had suddenly changed from a river into a sea.
The 1918 visitation followed the general wildfire pattern of previous pandemics. It fanned out from one country — Japan, in that instance. It spread eastward, westward, and southward. It crossed the Pacific in two weeks, struck at San Francisco, and in one week reached peak proportions; four weeks later it was gone. But meanwhile it had moved across the Rockies to Salt Lake City, and progressively to Kansas City and to Chicago. By the time it reached New York it met itself coming across the Atlantic, by way of Europe, from Asia.
Influenza travels exactly as fast as man. In oxcart days its progress was slow. In 1918 man could girdle the globe in eight weeks, and that is exactly the time it took influenza to complete its own encirclement. Today, by clipper planes and air transport, man moves like the wind. Influenza will move at that same speed. This modern speed makes its advent unpredictable from day to day, and means that our control over it must be in proportion swifter.
II
Ask the average young doctor what influenza is and he will say: ‘It is a symptom-complex, characterized by sudden onset, fever, headache, chills, muscular pains, and a cough.’ ‘And that,’ he will add, pounding the desk in a kind of frustration, ‘is precisely the same behavior as that of half a dozen other diseases.’
Ask the doctor who labored through the 1918-1919 visitation and he will tell you that influenza was then a prairie fire, variously diagnosed as tonsillitis, pneumonia, yellow fever, sleeping sickness, and spinal meningitis.
In other words, influenza is a sort of clinical diagnostic wastebasket, and always has been. Italians in the seventeenth century were the first to call the plaguing, recurrent disease ‘influenza,’ thereby adroitly shifting all blame on to ‘the influence of the stars.’ And that is about as accurate as the six or seven other medical explanations offered in the intervening three centuries.
Only within the past seven years have bacteriologists reached into the wastebasket, extracted scraps of knowledge, and fitted them together into a factual scientific unit. There are still many unidentified scraps in the basket: there are still an unknown number of units to be pieced together before the large and complex picture of influenza is completed.
The first important piece of the puzzle fell into place in 1933 in England, when Andrewes, Laidlaw, and Smith isolated a virus which proved to be influenza. They inoculated washings from the throats of influenza patients into ferrets (whose reactions to infection and immunization in this disease are very close to those of human beings). A mild febrile disease occurred in these animals as a result. Andrewes likewise established the fact that, during convalescence from the virus, antibodies appeared in the blood of ferrets and of man, which, mixed with the virus, would prevent its inducing an infection in a normal ferret. This identification was a tremendous step. It was obviously fundamental — a mark from which all further studies could take their departure. Doctors everywhere took heart. None of them realized at the time that the tough little virus would turn out to have more relations than a rabbit. Many strains of type A have been isolated, some showing certain differences from others, but all belonging to a group known as Influenza A.
The first photographs of Influenza A, made quite recently at the Children’s Hospital in Philadelphia and the Radio Corporation of America laboratories in Camden, New Jersey, magnify it 150,000 times until it is a ball about the size of a pea, and show it to be quite without distinguishing features. Laboratory workers have now distinguished a strain of virus quite distinct from any of those belonging to Influenza A, which they have designated as Influenza B. Highly magnified, the B virus looks to be the same purplish-red mass as type A.
Dr. Frank L. Horsfall, Jr., who has done much intensive research on influenza for more than four years in the New York laboratories of the International Health Division of the Rockefeller Foundation, says: ‘There is no reasonable basis upon which to doubt that virus A has caused many epidemics influenza in the last seven years. There is equally good evidence that this virus has not caused all of them.’
As examples, Dr. Horsfall cites the 1936 epidemic in California, the 1939 epidemic in England, and the 1940 epidemic in South Carolina. All of these cases were clinically typical of influenza, yet the attending doctors and the bacteriologists who hurried to the districts could not recover virus A. Nor did the patients have the definite antibody response to the virus following the disease.
On the other hand, the very recent December outbreak of influenza in California and other West Coast states proved to be caused by virus A. Health authorities are not sure of the source of this epidemic, but at present they are linking it to those that have successively hit Puerto Rico, Cuba, and Hawaii within the past eight months. Vaccines were rushed to California, but, as they were administered after the epidemic had gained headway, their immunizing effects were negligible.
III
The story of the development of the vaccines for Influenza A is not a dramatic one, in the sense of colorful, theatrical incidents. It has been, not a pitched battle, but a long campaign — the slow, bit-by-bit accumulation of data in which one doctor builds upon the laboratory experience of another. Yet already it ranks with any of the great stories of man’s conquest over microbes.
Laboratory work has been constant since 1918. Army doctors in the United States, England, France, and Germany have studied their scanty data and tabulated them. In England the bacteriologists Andrewes, Laidlaw, and Smith began their intensive experiments and eventually identified virus A. Since the death of Sir Patrick Laidlaw, Andrewes and Smith have continued their experiments and are still making valuable contributions.
The International Health Division of the Rockefeller Foundation has advanced hundreds of thousands of dollars to equip laboratories and put trained bacteriologists in such field stations as California, Minnesota, Pennsylvania, and Budapest, Hungary. In its New York laboratories the Health Division has maintained a corps of influenza specialists — among whom have been Dr. Thomas Francis, Jr. (who did much of the pioneer work), Dr. Frank L. Horsfall, Jr., Dr. Thomas Magill, Dr. E. R. Rickard, Dr. C. H. Stuart-Harris, Dr. T. F. Lennette, Dr. Dorothy Beck, and a score of assistants.
One of the most important studies of influenza has been conducted by Dr. Joseph Stokes, Jr., Dr. Werner Henle, and Dr. Leslie Chambers for the past five years at the Children’s Hospital in Philadelphia and at the University of Pennsylvania Medical School. Dr. Richard E. Shope of the Rockefeller Institute for Animal Diseases, Princeton, N. J., has been engaged on specialized studies of swine influenza and its relation to human beings. The New York City Public Health Laboratories, under the direction of Dr. Ralph Muckenfuss, have also been doing considerable experimental work with vaccines.
When the vaccine experiments were begun there was, of course, no trace of the 1918 strain of influenza to study. It will never be known whether it was virus A type. There have been, however, in the past twenty years, a number of epidemics which could be studied, in Puerto Rico, Alaska, California, Detroit, Philadelphia, Alabama, New York, and South Carolina.
Identifying — or failing to identify — the minute virus each time the disease appears in scattered parts of the world is a lengthy procedure, and the necessary delay is one of the major handicaps in emergency. Because the virus is so infinitesimal, identification can only be made by the injection of nose and throat washings from patients into the noses of ferrets. At least three weeks are consumed from the day throat washings are taken until positive results are obtained from these animals. If, then, an injection of vaccine is given, all of ten days must elapse before the dose can produce a high antibody content in the patient. But by this time a good month will have elapsed since the onset of influenza in the district.
Three types of vaccine have been used in the past few years. Dr. Stokes in Philadelphia has used an active tissue culture. Another type is a formaldehydeinactivated virus from mouse lungs used by Andrewes and Smith in England. The third is a formalinized complex vaccine worked out by Dr. Horsfall and Dr. Lennette of New York, containing both Influenza A virus and canine distemper virus.
The length of immunity produced by these vaccines varies with the individual. In some cases it lasts three months, in others six or eight. Dr. Horsfall found in certain experimental cases that 40 per cent of the individuals were still immune at the end of one year.
In England, where the 1939 epidemic was bad, though not nearly as bad as some exaggerated reports made it, vaccinations were given to volunteers at the Woolwich, Windsor, Shorncliffe, Aldershot, and Colchester barracks. A five to one hundred and twenty-five fold increase in the antibody content of the blood followed such vaccination.
For five years Dr. Stokes has been administering experimental vaccines intramuscularly to more than 7000 children and adults. The children’s groups were at the Children’s Hospital in Philadelphia, while the adult groups were at five large state colonies in New Jersey. In general the results have been promising. In the fairly severe 1936 epidemic in that district, of each one hundred persons vaccinated only two contracted the disease, and their attacks were mild, with temperatures never exceeding 103 degrees — relatively moderate for influenza. Immunity in these groups varied from three to eight months. Each year there have been routine vaccinations. This winter, in the face of sporadic epidemic outbreaks, two sets of vaccinations were given.
A large emergency supply of these vaccines has been made up. Following a process of freezing and drying, they are being stored at the Philadelphia hospital in case of a general outbreak. In addition, the E. R. Squibb & Sons Laboratories have been making vaccines in large volume the past year.
Meanwhile Dr. Stokes, Dr. Henle, and Dr. McGuinness at the Children’s Hospital are trying to perfect a vaccination short-cut. This would be in the form of a nasal and mouth spray made of pooled human serum obtained from some seventy-five people with high immunity to influenza. A locally protective spray, it could be administered quickly and easily by individuals at the first warning of epidemic influenza, and would become effective immediately. The spray is not expensive to produce, but it is still in the experimental stage, and its positive protection for large groups is not yet assured.
Quite recently Dr. Horsfall and Dr. Lennette have reported the use of a formalinized complex vaccine prepared from chick embryo (infected with virus A and canine distemper) which has proved very effective in stimulating antibodies by a single subcutaneous injection in man. Moreover, these antibodies did not diminish during the first three months after vaccination and gave cross immunization against several strains of virus A.
More than a million doses of these vaccines have been made up and given by the International Health Division of the Rockefeller Foundation to Dr. Andrewes in England to be used among military groups. Another batch of the vaccines is being prepared for use in the refugee child groups of continental Europe. Dr. Wilbur A. Sawyer, Director of the Health Division, who recently returned from a survey of child refugees in certain of the German-occupied countries of Europe, has expressed himself as very hopeful of the protection this vaccine may afford.
Some groups of city health officers and epidemiologists have considerable faith in the value of the new ultra-violet lamp. This curious, unwieldy-looking weapon, with its square glass shade, was developed by Professor William F. Wells and his wife, Dr. Mildred Wells, in the laboratories of the Harvard School of Public Health and the University of Pennsylvania School of Medicine. It does actually what its name implies — installed over a doorway in mess halls, classrooms, barracks, hospitals, workrooms, and theatres, it lets down a solid curtain of ultra-violet rays which instantly kill all air-borne germs.
A recent example of its power was given at the Home for Hebrew Infants in Bronxville, New York. In wards adjacent to one in which the lamp was installed, 165 children out of 168 developed chicken pox. Where the lamp was used, not one case developed.
More than five hundred lamps are already in use in various parts of the United States — schools and hospitals have installed them to protect children, not only from influenza, but from measles, chicken pox, and other infectious diseases. English and Canadian medical authorities have ordered lamps for use in troop barracks, in children’s dormitories, and in other quarters where there is abnormal crowding.
These lamps may offer a way to reduce the menace exerted by apparently well people who spread the influenza virus. In one hospital study it has been found that 30 per cent of those exposed to influenza remained perfectly well and developed their own antibodies in sufficient force to withstand the disease. But while they were doing this they were carriers of the virus, capable of infecting many others. Doctors regard such persons as a greater menace than the acutely ill, because, continuing their daily work, they may spread infection widely.
IV
No general plan of national influenza control can be worked out in advance by health authorities until doctors know which type of influenza they are fighting. Dr. Thomas Parran, Surgeon-General of the United States Public Health Service, says: ‘So little is known yet of the factors of epidemicity of influenza that no pre-devised plan of control can be recommended as having specific value. The incubation period of the disease is extremely short. Victims are perhaps most infectious before they actually become ill enough to withdraw from public circulation, and consequently the infection is rapidly and widely spread by apparently well people. It is impossible to prevent all human contact even when an epidemic threatens, which makes administrative control impracticable.’
The United States Public Health Service has no hand in planning or administering health measures in draft and in army camps. All of this is handled by army doctors, but at this writing no general program for influenza control has been agreed upon for barracks and cantonments in this country.
Lieutenant-Colonel Arthur P. Hitchens, M. C., who is Professor of Public Health at the University of Pennsylvania, gave this note of hope to a meeting of the American Public Health Association in Pittsburgh last winter.
‘Just as,’ Colonel Hitchens said, ‘the Spanish-American War gave Walter Reed the opportunity to conquer yellow fever, I feel that the conquest of influenza will come out of the present war.’
https://www.theatlantic.com/magazine/archive/1941/02/fighting-the-flu/653968/