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Spanish Influenza Pandemic and Vaccines
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.”
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.
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.