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Yellow Fever

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Vaccines: A Biography

Abstract

In 1951, Max Theiler (Fig. 10.1), a Rockefeller Foundation scientist, became the only person to be awarded the Nobel Prize in Medicine and Physiology for the development of a virus vaccine (Norrby 2007). His live, attenuated 17D vaccine was not the first yellow fever vaccine to be tested in humans, but it was by far the most successful one. More than 500 million doses have been distributed since the late 1930s. Yellow fever vaccine history, told briefly in this chapter, provides numerous lessons to those interested in the science of vaccinology; it is enriched by the cast of colorful characters who were involved in vaccine discovery and introduction into routine use, and informed by the investigation of various mishaps in manufacturing and application.

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Notes

  1. 1.

    In fact the first studies showing mice to be susceptible to herpes virus were done earlier by G Blanc and J CamioPetros (Recherches experimentales sur herpes. CR Soc Biol 1921; 84: 859).

  2. 2.

     Eugen Haagen became the Chief of the Medical Department of the Luftwaffe in Nazi Germany and apparently continued studies on yellow fever. Allegedly, he made new vaccines against yellow fever and tested them on inmates of the Nazi concentration camp at Natzweiler-Struthof.

  3. 3.

     Unfortunately, Theiler and Smith’s passage series was not preserved and is not available for genetic studies, which would undoubtedly have shown which mutations were responsible for the phenotypic changes observed.

  4. 4.

    In 1976 Bio-Manguinhos (Laboratorio de Technologia em Productos Biologicos de Manguinhos) was created as the manufacturing arm of the Oswaldo Cruz Foundation.

  5. 5.

     In 1945 the monkey neurovirulence test was introduced as a requirement for the control of yellow fever 17D vaccine. The monkey test for neurovirulence itself has undergone a number of refinements over the years. The original method involved only clinical observations of the animals. In the 1960s improved methods were developed by Nathanson et al. (Am J Epidemiol 1965; 82:359–381 and 1966; 84:524–540) who identified indicator centers (nuclei) in the brain that were sensitive to differences in virulence. In 1987, the methods were further developed by Levenbook et al. (J Biol Stand 1987; 15:305–313). They described an improved clinical scoring system and more discriminatory histopathological assessment of inflammation and neuronal damage.

  6. 6.

     From 1990, when surveillance for vaccine associated adverse events was instituted in the US, through March 2006, a total of 29 additional cases of YEL-AND were reported worldwide. The cases since 1990 have been predominantly in adults (including elderly). Advanced age is now recognized as a risk factor. The incidence of YEL-AND is approximately 1 in 300,000 and the case fatality rate is probably 1–2%.

  7. 7.

     Nevertheless, vaccines manufactured in eggs, including yellow fever 17D, test positive by the product-enhanced reverse transcriptase (PERT) assay, reflecting the presence of defective particles containing endogenous avian leucosis or retrovirus sequences. No evidence has been found for infectious or inducible replication-competent retroviruses or for infection with avian leucosis or endogenous avian retrovirus in humans.

  8. 8.

     Determined in a constant serum-virus dilution test, the log10 neutralization index being the difference in log10 titer of virus with and without serum containing neutralizing antibody.

  9. 9.

    The age cut-off was later changed to 9 months, which is the age at which infants are routinely immunized in the Expanded Programme for Immunization in endemic countries.

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  1. Kleiner Perkins Caufield & Byers, 2750 Sand Hill Rd, Menlo Park, CA, 94025, USA

    Thomas P. Monath

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  1. Dept. Medicine & Community Health, Brown University, Providence, 02912, U.S.A.

    Andrew W. Artenstein

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Monath, T.P. (2010). Yellow Fever. In: Artenstein, A. (eds) Vaccines: A Biography. Springer, New York, NY. https://doi.org/10.1007/978-1-4419-1108-7_10

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