Spanish Flu Research Paper

It’s National Influenza Vaccination Week, and we’re taking a look back to 1918, the time of the “Spanish” influenza pandemic. When the illness emerged, several useful vaccines had already been developed: smallpox, typhoid fever, and rabies, for example. Scientists and physicians tried many different approaches to develop influenza vaccines during the pandemic even though the cause of influenza was not clear. We look at several of them below.

No other epidemic has claimed as many lives as the Spanish influenza epidemic in 1918-1919. Worldwide, at least 40 million people died as this virulent illness swept through city after city (some estimates put total deaths closer to 70 million). Newspaper reports described people dying within hours of first feeling ill. The mortality rate was highest among adults under age 50, who were, for unknown reasons, particularly vulnerable to serious disease resulting from this strain of influenza.

The first reported cases of an unusual influenza appeared in U.S. Army camps in Kansas in early spring 1918. Later that spring, officials reported large numbers of cases from Europe, though this flu did not seem particularly dangerous. However, influenza became more deadly in late summer. Soon waves of infection moved through towns, nations, and continents, overwhelming hospitals and medical personnel. Because of wartime censorship, reports of influenza were not widely distributed, but news from Spain continued to flow. The name Spanish influenza came from the devastating effects of the flu in Spain in autumn 1918.

Hunting for a Culprit

German physician Richard Pfeiffer (1858-1945), once a student of Robert Koch, had isolated bacteria from the lungs and sputum of influenza patients during the influenza pandemic of 1892. Pfeiffer believed that these bacteria were the cause of influenza, and they came to be known as “Pfeiffer influenza bacillae” and later Bacillus influenzae (now Haemophilus influenzae). The scientific and medical world widely, but not universally, adopted this view. Dissenters argued that other types of bacteria could be isolated from influenza cases, and pointed to strains of streptococcal, pneumococcal, and other bacteria as potential causes. Further, they noted that B. influenzae could not be found in all cases of influenza, sometimes not even in most. Many argued that the bacterial infections were opportunistic infections arising in the wake of influenza, and that the true cause of initial infection remained unidentified.

The 1918 and 1919 volumes of the Journal of the American Medicine Association (JAMA) include many articles on the cause, prevention, and treatment of influenza. Again and again, investigators wonder at the spotty presence of B. influenzae in the ill, note its presence in healthy individuals, and observe it in other infections such as measles, scarlet fever, diphtheria, and varicella (chickenpox). In one article, the authors write, “There seems to be no justification for the belief that the epidemic was due to the influenza bacillus, which is probably a secondary invader and bears about the same relation to the influenza cases as to respiratory infections of a different sort” (Lord 1919).

In spite of the uncertainties surrounding the cause of influenza, William H. Park, MD, at the New York City Health Department (and later instrumental in diphtheria immunization) was convinced that Pfeiffer’s bacillus was the culprit, and he set about devising a vaccine and antiserum against it. It was ready on October 17, 1918. In Philadelphia, Paul Lewis worked on refining pneumococcal vaccines that had been in development for a few years, with the added challenge of adding Pfeiffer’s bacillus to the mix. On October 19, 1918, the Philadelphia municipal laboratory released thousands of doses of the vaccine (a mix of killed streptococcal, pneumococcal, and B. influenzae bacteria). Others across the globe tried to develop vaccines as well. The following accounts of vaccines developed in 1918 come from the January 4, January 18, January 25, and March 22, 1919, issues of the Journal of the American Medical Association.

Vaccine Development Across the United States

At the Naval Hospital on League Island, Pennsylvania (the Philadelphia Naval Shipyard), physicians described their approach to a vaccine: “After the nature of a drowning person grasping at a straw, a stock influenza vaccine was used as a preventive in fifty individual cases and as a curative agent in fifty other uncomplicated cases” (Dever 1919). They made the vaccine made from B. influenzae and strains of pneumococcus, streptococcus, staphylococcus, and Micrococcus catarrhalis (now Moraxella catarrhalis). Each dose contained between 100,000,000 and 200,000,000 bacteria per cubic centimeter, in a four-dose regimen. The investigators reported that no vaccinated individuals (who were hospital workers) became sick, but also noted that strict preventive measures were taken, such as the use of masks, gloves, and so on. In a group of ill patients treated therapeutically with the vaccine, none developed pneumonia but one developed pleurisy (infection of the lining of the lungs). They noted, “The course of the disease [in those treated therapeutically]…was definitely shortened, and prostration seemed less severe. The patients apparently not benefitted were those admitted from four to seven days after the onset of their illness. These were out of all proportion to the number of pneumonias that developed and the severity of the infection of the control cases. The effects were always more striking, the earlier the vaccine was administered.” Finally, they concluded that, “The number of patients treated with vaccines and the number immunized with it is entirely too small to allow of any certain deductions; but so far as no untoward results accompany their use, it would seem unquestionably safe and even advisable to recommend their employment.”

Another group of investigators described the use of vaccines at the Naval Training Station in San Francisco. They relate that Spanish influenza did not reach San Francisco until October 1, 1918, and that that staff at the training station therefore had time to prepare preventive measures (Minaker 1919). Isolation was easy, due to the location of the base on Alameda Island, reachable only by boat from San Francisco and Oakland. Naval Yard personnel were required to use an antiseptic throat spray daily. Beyond these measures, the authors noted that “steps were taken to produce a prophylactic vaccine,” even though there was a “great diversity of opinion as to the exciting cause” of the pandemic. In general pneumococcus and streptococcus were seen as the cause of the most severe complications.  Additionally, and amid dissent, they decided to obtain a culture of B. influenzae from a fatal case at the Rockefeller Institute to include in the vaccine. In all, the vaccine contained B. influenzae, 5 billion bacteria;  pneumococcus Types I and II, 3 billion each; pneumococcus Type III, 1 billion;  and Streptococcus hemolyticus (S. pyogenes), 100 million.

Guinea pigs were first injected with the vaccine to assess toxicity, and then five lab worker volunteers were inoculated. Lab tests determined that their white cell count increased and their sera agglutinated B. influenzae (meaning that they had antibodies in their blood that reacted to the bacteria). Side effects from the injection included local swelling and pain but no abscesses. Given permission to proceed, more vaccine was prepared and 11,179 military and civilians were inoculated, including some at Mare Island  (Vallejo, CA) and San Pedro as well as San Francisco civilians associated with the Naval Training station. In most experimental groups, the rate of influenza cases was lower than in the uninoculated groups (though no information is given on how the statistics for the uninoculated groups were gathered, nor is there information on how a case was defined). Moreover, people who were inoculated received the injections about three weeks after influenza appeared in California, so it’s impossible to tell whether they had already been exposed and infected. The percent of influenza cases in control groups ranged from 1.5% to 33.8% (the latter being nurses in San Francisco hospitals), whereas between 1.4% and 3.5% (the latter being hospital corpsmen on duty in an influenza ward) of those in the inoculation group became ill with influenza.

Another use of vaccine was documented in Washington State at the Puget Sound Navy Yard (Ely 1919). Investigators claim that influenza invaded the Navy Yard when a group of sailors arrived from Philadelphia (it’s unclear exactly when they arrived, but the paper states that “the period of observation was from September 17 to October 18, 1918”). In all, 4,212 people were vaccinated with a streptococcal vaccine. The investigators reported that the influenza attack rate in the vaccinated ranged from 2% to 57% and in the unvaccinated from 1.8% to 19.6%. However, they noted that no deaths occurred in the vaccinated men. They stated “We believe that the use of killed cultures as described prevented the development of the disease in many of our personnel and modified its course favorable in others.” The investigators concluded that B. influenzae played no role in the outbreak.

E. C. Rosenow (Mayo Clinic) reported on the use of a mixed bacterial vaccine in Rochester, Minnesota, where about 21,000 people received three doses of vaccine in his initial study. He concluded that “The total incidence of recognizable influenza, pneumonia, and encephalitis in the inoculated is approximately one-third as great as in the control uninoculated. The total death rate from influenza or pneumonia is only one-fourth as great in the inoculated as in the uninoculated.” He would go on to test his vaccine in nearly 100,000 people.

In an editorial entitled “Prophylactic Inoculation Against Influenza,” Journal of the American Association of Medicine editors warned that, “the data presented are simply too inadequate to permit a competent judgment” of whether the vaccines were effective. In particular, they addressed Rosenow’s paper:

“To specify only one case: The experience at a Rochester hospital—where fourteen nurses (out of how many?) developed influenza within two days (how many earlier?) prior to the first inoculation (at what period in the epidemic?), and only one case (out of how many possibilities?) developed subsequently during a period of six weeks—might be duplicated, so far as the facts given are concerned, in the experience of other observers using no vaccines whatever. In other words, unless all the cards are on the table, unless we know so far as possible all the factors that may conceivably influence the results, we cannot have a satisfactory basis for determining whether or not the results of prophylactic inoculation against influenza justify the interpretation they have received in some quarters.”

Measuring Success

Certainly none of the vaccines described above prevented viral influenza infection – we know now that influenza is caused by a virus, and none of the vaccines protected against it. But were any of them protective against the bacterial infections that developed secondary to influenza? Vaccinologist Stanley A. Plotkin, MD, thinks they were not. He told us, “The bacterial vaccines developed for Spanish influenza were probably ineffective because at the time it was not known that pneumococcal bacteria come in many, many serotypes and that of the bacterial group they called B. influenzae, only one type is a major pathogen.” In other words, the vaccine developers had little ability to identify, isolate, and produce all the potential disease-causing strains of bacteria. Indeed, today’s pneumococcal vaccine for children protects against 13 serotypes of that bacteria, and the vaccine for adults protects against 23 serotypes.

A 2010 article, however, describes a meta-analysis of bacterial vaccine studies from 1918-19 and suggests a more favorable interpretation.  Based on the 13 studies that met inclusion criteria,  the authors conclude that some of the vaccines could have reduced the attack rate of pneumonia after viral influenza infection. They suggest that, despite the limited numbers of bacteria strains in the vaccines, vaccination could have led to cross-protection from multiple related strains (Chien 2010).

It was not until the 1930s that researchers established that influenza was in fact caused by a virus, not a bacterium. Pfeiffer's influenza bacillus would eventually be named Haemophilus influenzae, the name retaining the legacy of its long-standing, though inaccurate, association with influenza. And today, influenza vaccines – as well as H. influenzae type b vaccines—are widely available to prevent illness.

See also our articles on Influenza Pandemics and Influenza, as well as this video clip of vaccine developer Maurice Hilleman discussing the emergence of the Asian influenza pandemic in 1957.

Sources

Chien Y, Klugman KP, Morens DM. Efficacy of whole-cell killed bacterial vaccines in preventing pneumonia and death during the 1918 influenza pandemic. JID 2010;202(11):1639-1648.

Dever FJ, Boles RS, Case EA. Influenza at the United States Naval Hospital, League Island, PA. JAMA 72;4: 265-267.

Ely CF, Lloyd BJ, Hitchcock CD, Nickson DH, Influenza as seen at the Puget Sound Navy Yard. JAMA 72;1: 24-28.

Lehmann KB, Neumann, R. Wood’s Medical Hand Atlases. Atlas and Essentials of Bacteriology. New York: William Wood and Company, 1897.

Lord FT, Scott AC Jr., Nye RN. Relation of influenza bacillus to the recent epidemic of influenza.  JAMA 73;3:188-190.

Minaker AJ, Irvine RS. Prophylactic use of mixed vaccine against pandemic influenza and its complications at the Naval Training  Station, San Francisco. JAMA 72;12:847-850.

Plotkin SA. Personal correspondence. November 23, 2011.

Prophylactic inoculation against influenza. JAMA 72;1:44-45.

Rosenow EC. Prophylactic inoculation against respiratory infections during the present pandemic of influenza. JAMA 72;1:31-34.

Shakman SH. On the Relation between Influenza and Post-Influenzal (VonEconomo's) Encephalitis, and Implications for the Study of the Role of Infection in Epilepsy and Schizophrenia; A Review of the Historical Works and Perspective of E.C. Rosenow (1875-1966), longtime head of Experimental Bacteriology (1915-44) for the Mayo Foundation, Rochester, Minnesota. Institute of Science. No date. http://www.instituteofscience.com/mental/Shakman-History-Rosenow.pdf.

Spanish flu research concerns scientific research regarding the causes and characteristics of the "Spanish flu", a variety of influenza that in 1918 was responsible for the worst influenza pandemic in modern history. Many theories about the origins and progress of the Spanish flu persisted in literature, but it was not until 2005, when various samples were recovered from AmericanWorld War I soldiers and an Inuit woman buried in the Alaskantundra, that significant research was made possible.

Origin of virus[edit]

One theory[who?] is that the virus strain originated at Fort Riley, Kansas, by two genetic mechanisms — genetic drift and antigenic shift — in viruses in poultry and swine which the fort bred for local consumption. Though initial data from a recent reconstruction of the virus suggested that it jumped directly from birds to humans, without traveling through swine,[1] this has since been cast into doubt. One researcher published in 2004 argued that the disease was found in Haskell County, Kansas as early as January 1918.[2] A similar and even more deadly virus had been seen earlier at British camps in France and at Aldershot.[3]

Earlier investigative work published in 2000 by a team led by British virologist, John Oxford[4] of St Bartholomew's Hospital and the Royal London Hospital, suggested that a principal British troop staging camp in Étaples, France was at the center of the 1918 flu pandemic or at least a significant precursor virus to it. There had been a mysterious respiratory infection at the military base during the winter of 1915-16.[5]

Discovery of viral genomes[edit]

In February 1997, Johan Hultin recovered samples of the 1918 influenza from the frozen corpse of a Native Alaskan woman buried for nearly eight decades in permafrost near Brevig Mission, Alaska.[6] He brought the samples to a team[where?] led by Jeffery Taubenberger of the US Armed Forces Institute of Pathology (AFIP). Brevig Mission lost approximately 85% of its population to the 1918 flu in November 1918. One of the four recovered samples contained viable genetic material of the virus. This sample provided scientists a first-hand opportunity to study the virus, which was inactivated with guanidinium thiocyanate before transport. This sample and others found in AFIP archives allowed researchers to completely analyze the critical gene structures of the 1918 virus. "We have now identified three cases: the Brevig Mission case and two archival cases that represent the only known sources of genetic material of the 1918 influenza virus", said Taubenberger, chief of AFIP's molecular pathology division and principal investigator on the project.[7][8]

The February 6, 2004 edition of Science magazine reported that two research teams, one led by Sir John Skehel, director of the National Institute for Medical Research in London, another by Professor Ian Wilson of The Scripps Research Institute in San Diego, had managed to synthesize the hemagglutininprotein responsible for the flu outbreak of 1918. They did this by piecing together DNA from a lung sample from an Inuit woman buried in the Alaskan tundra and a number of preserved samples from American soldiers of the First World War. The teams had analyzed the structure of the gene and discovered how subtle alterations to the shape of a protein molecule had allowed it to move from birds to humans with such devastating effects.

On October 5, 2005, Tumpey and other researchers at the Centers for Disease Control and Prevention (CDC) in Atlanta, GA and the Mount Sinai School of Medicine in New York announced that the (~13 kbp) genetic sequence of the 1918 flu strain, a subtype of avian strain H1N1, had been reconstructed using historic tissue samples and a small part of the RNA from a modern strain.[9][10][11]

Characteristics of virus[edit]

Influenza viruses have a relatively high mutation rate that is characteristic of RNA viruses. The H5N1 virus has mutated into a variety of types with differing pathogenic profiles; some pathogenic to one species but not others, some pathogenic to multiple species.[12] The ability of various influenza strains to show species-selectivity is largely due to variation in the hemagglutinin genes. Genetic mutations in the hemagglutinin gene that cause single amino acid substitutions can significantly alter the ability of viral hemagglutinin proteins to bind to receptors on the surface of host cells. Such mutations in avian H5N1 viruses can change virus strains from being inefficient at infecting human cells to being as efficient in causing human infections as more common human influenza virus types.[13]

In July 2004, researchers led by H. Deng of the Harbin Veterinary Research Institute, Harbin, China and Robert Webster of the St. Jude Children's Research Hospital, Memphis, Tennessee, reported results of experiments in which mice had been exposed to 21 isolates of confirmed H5N1 strains obtained from ducks in China between 1999 and 2002. They found "a clear temporal pattern of progressively increasing pathogenicity".[14] Results reported by Webster in July 2005 reveal further progression toward pathogenicity in mice and longer virus shedding by ducks.

In December, 2008, research by Yoshihiro Kawaoka of University of Wisconsin linked the presence of the three specific genes (termed PA, PB1, and PB2) and a nucleoprotein derived from the H5N1 1918 flu samples was enough to trigger similar symptoms in animal testing.[15]

Research of viral pathogenesis[edit]

Recent research of Taubenberger et al. has suggested that the 1918 virus, like H5N1, could have arisen directly from an avian influenza virus.[10] However, researchers at University of Virginia and Australian National University have suggested that there may be an alternative interpretation of the data used in the Taubenberger et al. paper.[16][17] Taubenberger et al. responded to these letters and defended their original interpretation.[18]

Other research by Tumpey and colleagues who reconstructed the H1N1 virus of 1918 came to the conclusion that it was most notably the polymerase genes and the HA and NA genes that caused the extreme virulence of this virus.[11] The sequences of the polymerase proteins (PA, PB1, and PB2) of the 1918 virus and subsequent human viruses differ by only 10 amino acids from the avian influenza viruses. Viruses with seven of the ten amino acids in the human influenza locations have already been identified in currently circulating H5N1. This has led some researchers to suggest that other mutations may surface and make the H5N1 virus capable of human-to-human transmission. Another important factor is the change of the HA protein to a binding preference for alpha 2,6 sialic acid (the major form in the human respiratory tract). In avian virus the HA protein preferentially binds to alpha 2,3 sialic acid, which is the major form in the avian enteric tract. It has been shown that only a single amino acid change can result in the change of this binding preference. Altogether, only a handful of mutations may need to take place in order for H5N1 avian flu to become a pandemic virus like the one of 1918. However it is important to note that likelihood of mutation does not indicate the likelihood for the evolution of such a strain; since some of the necessary mutations may be constrained by stabilizing selection.

On 18 January 2007, Kobasa et al. reported that infected monkeys (Macaca fascicularis) exhibited classic symptoms of the 1918 pandemic and died from a cytokine storm.[19]

Blood plasma as an effective treatment[edit]

In the event of another pandemic, US military researchers have proposed reusing a treatment from the deadly pandemic of 1918 in order to blunt the effects of the flu. Some military doctors injected severely afflicted patients with blood or blood plasma from people who had recovered from the flu. Data collected during that time indicates that the blood-injection treatment reduced mortality rates by as much as 50 percent. Navy researchers have launched a test to see if the 1918 treatment will work against deadly Asian bird flu. Results thus far have been inconclusive[citation needed]. Human H5N1 plasma may be an effective, timely, and widely available treatment for the next flu pandemic[citation needed]. A new international study using modern data collection methods, would be a difficult, slow process. But many flu experts, citing the months-long wait for a vaccine for the next pandemic, are of the opinion that the 1918 method is something to consider.[20]

In the worldwide 1918 flu pandemic, "physicians tried everything they knew, everything they had ever heard of, from the ancient art of bleeding patients, to administering oxygen, to developing new vaccines and sera (chiefly against what we now call Hemophilus influenzae—a name derived from the fact that it was originally considered the etiological agent—and several types of pneumococci). Only one therapeutic measure, transfusing blood from recovered patients to new victims, showed any hint of success."[21]

See also[edit]

Sources and notes[edit]

  1. ^Sometimes a virus contains both avian adapted genes and human adapted genes. Both the H2N2 and H3N2 pandemic strains contained avian flu virus RNA segments. "While the pandemic human influenza viruses of 1957 (H2N2) and 1968 (H3N2) clearly arose through reassortment between human and avian viruses, the influenza virus causing the 'Spanish Flu' in 1918 appears to be entirely derived from an avian source (Belshe 2005)." (from Chapter Two : Avian Influenza by Timm C. Harder and Ortrud Werner, an excellent free on-line Book called Influenza Report 2006 which is a medical textbook that provides a comprehensive overview of epidemic and pandemic influenza.)
  2. ^Barry JM (January 2004). "The site of origin of the 1918 influenza pandemic and its public health implications". J Transl Med. 2 (1): 3. doi:10.1186/1479-5876-2-3. PMC 340389. PMID 14733617. 
  3. ^Origins of the 1918 Pandemic: The Case for Francehttp://www.npr.org/templates/story/story.php?storyId=5222069
  4. ^EU Research Profile on Dr. John Oxford
  5. ^Connor, Steve, "Flu epidemic traced to Great War transit camp", The Guardian (UK), Saturday, 8 January 2000
  6. ^Brown, David (October 10, 2005). "Resurrecting 1918 Flu Virus Took Many Turns". Washington Post. 
  7. ^Lethal secrets of 1918 flu virus; BBC
  8. ^Kolata, Gina (1999). Flu: The Story of the Great Influenza Pandemic of 1918 and the Search for the Virus That Caused It. Farrar, Straus and Giroux. pp. 255–65. ISBN 978-0-374-15706-7. : Johan Hultin first attempted to recover samples from Brevig in 1951, but he was unsuccessful. In 1997, by then a seventy-two-year-old retired pathologist, he decided that science had advanced enough to make another attempt worthwhile. Taubenberger had already recovered RNA of limited quality from samples of two servicemen who had died in the pandemic, and Hultin wrote offering his services to try to get better quality samples from Brevig permafrost. Taubenberger accepted, and Hultin went alone to Brevig in August 1997, and recovered the sample from the Alaskan woman, which Taubenberger and his team then analysed.
  9. ^"The 1918 flu virus is resurrected". Nature. 437 (7060): 794–795. October 2005. doi:10.1038/437794a. PMID 16208326. 
  10. ^ abTaubenberger JK, Reid AH, Lourens RM, Wang R, Jin G, Fanning TG (October 2005). "Characterization of the 1918 influenza virus polymerase genes". Nature. 437 (7060): 889–893. doi:10.1038/nature04230. PMID 16208372. 
  11. ^ abTumpey TM, Basler CF, Aguilar PV, et al. (October 2005). "Characterization of the reconstructed 1918 Spanish influenza pandemic virus". Science. 310 (5745): 77–80. doi:10.1126/science.1119392. PMID 16210530. 
  12. ^Kou Z, Lei FM, Yu J, Fan ZJ, Yin ZH, Jia CX, Xiong KJ, Sun YH, Zhang XW, Wu XM, Gao XB, Li TX (2005). "New genotype of avian influenza H5N1 viruses isolated from tree sparrows in China". J. Virol. 79 (24): 15460–6. doi:10.1128/JVI.79.24.15460-15466.2005. PMC 1316012. PMID 16306617. 
  13. ^Gambaryan A, Tuzikov A, Pazynina G, Bovin N, Balish A, Klimov A (January 2006). "Evolution of the receptor binding phenotype of influenza A (H5) viruses". Virology. 344 (2): 432–438. doi:10.1016/j.virol.2005.08.035. PMID 16226289. 
  14. ^Chen H, Deng G, Li Z, et al. (July 2004). "The evolution of H5N1 influenza viruses in ducks in southern China". Proc. Natl. Acad. Sci. U.S.A. 101 (28): 10452–10457. doi:10.1073/pnas.0403212101. PMC 478602. PMID 15235128. 
  15. ^"Researchers unlock secrets of 1918 flu pandemic". Reuters. December 29, 2008. 
  16. ^Gibbs MJ, Gibbs AJ (April 2006). "Molecular virology: Was the 1918 pandemic caused by a bird flu?". Nature. 440 (7088): E8–E8. doi:10.1038/nature04823. PMID 16641948. 
  17. ^Antonovics J, Hood ME, Baker CH (April 2006). "Molecular virology: Was the 1918 flu avian in origin?". Nature. 440 (7088): E9–E9. doi:10.1038/nature04824. PMID 16641950. 
  18. ^Taubenberger JK, Reid AH, Lourens RM, Wang R, Jin G, Fanning TG (April 2006). "Molecular virology: Was the 1918 pandemic caused by a bird flu? Was the 1918 flu avian in origin? (Reply)". Nature. 440 (7088): E9–E10. doi:10.1038/nature04825. 
  19. ^Kobasa D, Jones SM, Shinya K, et al. (January 2007). "Aberrant innate immune response in lethal infection of macaques with the 1918 influenza virus". Nature. 445 (7125): 319–323. doi:10.1038/nature05495. PMID 17230189. 
  20. ^npr.orghistory.navy.mil
  21. ^https://www.ncbi.nlm.nih.gov/books/n/nap11150/pdf/ The Threat of Pandemic Influenza: Are We Ready? Workshop Summary (2005) (free online book)] page 62

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