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A History of Influenza Prevention Through Vaccination

A History of Influenza Prevention Through Vaccination. Theodore C. Eickhoff, MD Professor Emeritus Division of Infectious Disease University of Colorado Health Sciences Center Denver, Colorado. Landmark work of Smith W, Andrewes, CH, Laidlaw, PP Published in Lancet 1933; 2: 66-68

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A History of Influenza Prevention Through Vaccination

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  1. A History of Influenza Prevention Through Vaccination Theodore C. Eickhoff, MD Professor Emeritus Division of Infectious Disease University of Colorado Health Sciences Center Denver, Colorado

  2. Landmark work of Smith W, Andrewes, CH, Laidlaw, PP Published in Lancet 1933; 2: 66-68 Isolated Influenza A virus A technological tour-de-force for it’s day History Begins with the Identification of Influenza Viruses

  3. Initial Evidence of a Filterable Agent

  4. Effect of Virus on Normal and Immune Ferret

  5. One year later, Thomas Francis, Jr., (then at the Rockefeller Institute) identified an agent from an outbreak of ILI in Puerto Rico, that proved to be transmissable from ferret to ferret to mouse, with accidental transmission to humans as well. Became a standard laboratory strain – A/Puerto Rico/8/34 (PR8) Simultaneous confirmation of transmissabilty from Smith, Andrewes and Laidlaw (Mill Hill) Confirmation of Transmissability

  6. Francis, T Jr. & Magill TP. J Exp Med 1937; 65: 251-259. Virus grown in minced chick embryo culture Not clear how it was inactivated Studied in normal healthy medical students “Available data do not enable prediction of use in preventing natural disease. Seems not unlikely that the increase in circulating antibody will be accompanied by an increased ability to combat the natural disease.” First Attempt to Vaccinate Humans

  7. Titers After Natural Infection

  8. Influenza B • Francis, T Jr. Science 1940; 92; 405-408 • February-March 1940: Epidemic of ARD at Irvington House, NY • Neutralization tests revealed no in antibody titer to PR8 strain • Isolate from a patient named Lee; strain subsequently became known as B/Lee

  9. Enter World War II • Next phase of the history of influenza vaccination was written by the Commission on Influenza of the Armed Forces Epidemiological Board (AFEB) • Thomas Francis, Jr, MD (then at the University of Michigan) chosen as first Director in 1941. • Ambitious work plan illustrative of what were considered the major unanswered scientific questions of the day.

  10. Thomas Francis, Jr., MD

  11. First year’s proposed budget:$53,200 for each of 3 units The princely sum of $159,600!!

  12. 1942-43 • There was concern that an epidemic of influenza A would occur in 1942 or 1943 • Efforts to organize a vaccine evaluation within the armed services unsuccessful • Dogma of the time was that influenza A would recur every 2-3 years; influenza B every 4-6 years • This dogma promulgated (and retracted decades later) by:

  13. Ypsilanti State Hospital • When no influenza appeared, trials carried out in mental institutions • Virus was formalin-inactivated, and a mercurial added as a preservative • Results showed clearly that vaccine exerted a protective against even a severe challenge. • Francis, Salk, Pearson, Brown: J Clin Invest. 1945; 24: 536-546 • Francis, Salk, Pearson, Brown: J Clin Invest. 1945; 24: 547-553

  14. 1943-44 • June 1943: Authorization obtained to conduct vaccine trial at several universities and army posts; total of 8 centers participated • Vaccine contained A/PR8 and an A strain isolated from a recruit in May, 1943, plus B/Lee • Epidemic obligingly appeared in the fall of 1943 • Scope of outbreak greater than in any other outbreak since 1918-19, but not particularly severe

  15. Results: • Among 6,211 controls, attack rate was 7.11% • Among 6,263 vaccines, attack rate was 2.22% • VE thus 69% • Greatest percentage of cases of illness among vaccinees in those with the lowest antibody titers • Thus, unequivocal evidence of vaccine efficacy • Virus isolated in California showed some evidence of antigenic change

  16. Other Advances in the 1940s • Adverse reactions, both local and systemic, proved to be acceptable; most studies carried out in military or ASTU’s on college campuses • Progress made in purification of vaccines by various methods of centrifugation • Dose of vaccines estimated in terms of mg, desired amount of antigen probably not more than 0.2 mg • Higher doses elicited increased local / systemic reactions

  17. Other Advances in the 1940s (2) • Quantification of hemagglutinating capacity of RBCs studied by Salk and Hirst • Led to development and standardization of HI testing, and eventually to quantification of antigen in CCA units • All previous tests done in mouse neutralization tests – highly labor intensive • Mouse world breathed a sigh of relief! • Hirst GK. J Exp Med. 1942; 75: 49-64 • Salk JE. J Immunol. 1947; 57: 301-321

  18. Other Advances in the 1940s (3)Adjuvants • Work done largely by Jonas Salk • Calcium phosphate adsorption proved not to be promising • Early 1950s, water-in-oil emulsions proved to be useful • Advantages • Ab responses increased with same amount of Ag • Ab levels persist longer, decline more slowly • Breadth of response greater • Immediate reactions greatly decreased

  19. Adjuvants-1950’s • Mineral oil in mannide monooleate (Arlacel A) studied extensively in 1950s-1960s • Eventually abandoned by the military due to 2 major concerns: • Late reactions at injection site (IM), cysts, sterile abscesses, etc. • Concern about long-term oncogensis, even though 2 follow-up studies done by the IOM showed no increased risk of oncogenesis, even after 20 years of observation

  20. Jonas E. Salk, MD

  21. Fred Davenport, MD

  22. Leadership of the Commision on Influenza • Thomas Francis, Jr. retired as Director in 1955 • Subsequently replaced by Dr. Fred Davenport, also of the Univ. Michigan School of Public Health • Served as Director from 1955-1971.

  23. Asian Influenza, 1957-58 • This was the first pandemic of the “modern” (virologic) era of influenza research • Major lesson that emerged: “pandemic” virus was really not fundamentally different from “epidemic” virus; differed only in the degree of antigenic change • Studies of H2N2 Ab levels in various age groups showed elevated levels in persons over 60; similar virus caused pandemic of 1889-90 • First substantive evidence of antigen recycling • Hennesy AV, Davenport FM, et al: Milit Med. 1964; 129: 38-50

  24. Asian Influenza Vaccine • Virus seeded around the world before pandemic started, allowing time for some vaccine production • Gordon Meiklejohn (Univ. Colorado) showed at LAFB that a single dose of 200 CCA units was immunogenic, and was 60% protective • Recommended dose for military: 400 CCA units • Meiklejohn G. J Infect Dis. 1983; 148: 775-784

  25. Asian Influenza Vaccine, 1957-58 • Effectiveness of 200 CCA unit dose also confirmed at Great Lakes Naval Training Station Gundlefinger BF, Stille WT, Bell JA. New Engl J Med. 1958; 259:1005-1009 • A few civilian studies also confirmed immunogencity and protective effect; one CDC study carried out in the Atlanta Penitentiary Dull HB, Jensen JE, et al: JAMA; 1960; 172: 1223-9 • In my recollection, relatively little vaccine was available for use in the civilian population • Personally, a very vivid event

  26. Progress in Vaccines During the 1960s • Efforts devoted to further purification; development of zonal centrifugation by Eli Lilly • Recognition of reactivity in children of whole virus vaccines; beginning of efforts to break down whole viruses by ether or gentle detergents • Split and subunit vaccines were both less immunogenic and less reactive than whole virus vaccines

  27. Hong Kong Influenza-1968 • Discovery of “Hong Kong” flu purely fortuitous; Dr. Thomas Francis “happened” to stop overnight in Hong Kong, and “happened” to read in the paper about an influenza epidemic there • A/Aichi/8/68 (H3N2) suitable for vaccine production; production delays resulted in little vaccine for either civilian or military use. • Several military studies showed evidence of heterotypic protection; about 50% at LAFb • Eickhoff TC, Meiklejohn G. Bull. World Health Organ. 1969; 41: 562-563 • In general, civilian population seemed to fare worse than miltary; effect of anti-neuraminidase Ab?

  28. The 1970s • Gordon Meiklejohn became the last Director of the Commission on Influenza in 1971. • Administrative decision made by the US Army to terminate the AFEB – in its former format – as well as the several commissions in 1973. • Seen as too much of “an old boys club” • Also, influenza as well as other ARDs were considered “conquered”

  29. Gordon Meiklejohn, MD

  30. Selected Observations from LAFB Studies

  31. Selected Observations from LAFB Studies-2

  32. Final Meeting of the Commission on Influenza13-14 November, 1972

  33. Major Accomplishments of the Commission on Influenza • Inactivated virus vaccine could protect against both influenza A and B • Immune serum via the respiratory route did not protect against aerosol challenge • The attack rate of influenza varied inversely with with the HI antibody titer • Immunity following natural infection was not very durable,- decreased as early as 4.5 months after infection • Natural influenza, both A and B, varied greatly in severity • Influenza virus was extremely unpredictable, necessitating studies over many years.

  34. Further Progress in the 1970s • Ed Kilbourne pioneered techniques for genetic reassortment, based on studies in his lab from the 1960s • Since 1971, influenza A H3N2 virus component in vaccines have generally been “high-growth” reassortant virus, combining the high growth characteristcs of the donor (PR8) strain with the H3 and N2 of the new variant strain

  35. Swine Influenza-1976 • Entire effort based on death of 1-2 recruits at Fort Dix, NJ • Multi-center sero-response studies sponsored by NIAID • Vaccination of entire US population began in September, 1976; no stop-go decision points built into the plan • Program terminated when GBS association was recognized • Widely known thereafter as “the swine flu debacle” • Heads rolled – CDC Director lost his job even though he was not in the loop • Set back vaccine use for years

  36. More recent History: 1980s and 1990s • H1N1 and H3N2 viruses have co-circulated in the world since 1977 – previously unknown • Steady antigenic drift of influenza A viruses; no major antigenic shift – yet • Global surveillance systems have improved enormously. Good global surveillance has minimized vaccine-wild virus mismatches, when high-growth reassortants are available

  37. Regulatory Issues • During the 1960s. Regulated by the Division of Biological Standards, NIH; strain selection done mostly by members of the Commission on Influenza • 1970s: switched to FDA, eventually done by Center for Biologics Evaluation and Research; strain selection done by invited consultants – mostly the same folks as above

  38. Regulatory Issues - 2 • Remained in FDA; during the1980s increasing input from civilian and CDC experts • FDA Advisory Committee: unwieldy acronym of VRBPAC • For some years in late 80s-early 90s, strain selection done jointly by VRBPAC and ACIP • During the last 10 years, strain selection has been solely a VRBPAC function, with expert consultation from CDC

  39. In Closing: • Have focused on vaccine development in the US, because that is, in fact, where most influenza vaccine development has occurred • Have developed enormous new respect for our forbears in this endeavor to prevent influenza, whose painstaking efforts have brought us to where we are today

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