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is observed in a postvaccination human challenge trial, it can (antibodies) taken from an immune donor patient or animal,
provide additional evidence and justification to funding agencies without administering a vaccine to the patient. Early work by
for proceeding to large and expensive field trials. This is particu- Emil von Bering (1854–1917) with small-animal serum therapy
larly advantageous in the context of an epidemic, where rapid experiments led to the development of human serum therapies
vaccine development and deployment are needed for optimal for passive immunization. In 1900, von Bering used horse sera
impact on morbidity and mortality. A contemporary example from immune horses to cure and prevent diphtheria caused by
is Zika virus vaccine development—for which postvaccination Corynebacterium diphtheria. The very first Nobel Prize in Physiol-
human challenge experiments are under consideration. ogy or Medicine in 1901 was awarded to von Behring “for his
The history of vaccination entered its second phase in the work on serum therapy, especially its application against
nineteenth century. The miasma theory (which postulated that diphtheria, by which he has opened a new road in the domain
infectious diseases were caused by a noxious form of bad air) of medical science and thereby placed in the hands of the physician
was gradually replaced by the development of the germ theory a victorious weapon against illness and deaths.” 25
(according to which infectious diseases were caused by micro- During the second half of the nineteenth century, scientists
organisms too small to be seen without magnification). Animal were discovering the immune system’s defense mechanisms. The
experiments and laboratory cultivation of microbes were key Nobel Prize in Physiology or Medicine for 1908 was awarded to
advances relating to the germ theory in the second half of the Ilya Ilyich Mechnikov (1845–1916) and Paul Ehrlich (1854–1915)
nineteenth century. Robert Koch (1843–1910) and the great “in recognition of their work on immunity” and for establishing
French chemist Louis Pasteur (1822–1895) made significant the concepts of cell-mediated and humoral immunities. Mech-
contributions through their many key observations and experi- nikov described the abilities of certain white blood cells (WBCs)
ments in both agricultural and human infectious diseases and of starfish larvae to perform phagocytosis or engulfment and
vaccines. Koch’s famous four postulates laid out the requirements destruction of harmful bacteria and other microbes. Ehrlich
for establishing causality of infectious diseases by microbes and worked on serum therapy against diphtheria with von Bering
proved that Bacillus anthracis was the cause of anthrax. This and speculated that certain WBCs have receptors that bind toxins
provided the first proof of a microbial etiology of a specific formed by bacteria, and when these receptors separate from the
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disease. Pasteur’s work was credited with saving the silkworm cells, they become antibodies.
industry, reducing the spoilage of wine, stopping epidemics among In 1924, Gaston Ramon (1886–1963) developed the method
agricultural herds, and the development of vaccines against human of chemical inactivation of bacterial toxins with formaldehyde
infectious diseases, such as rabies and anthrax. Through attenu- and heat to produce toxoids of the pathogenic toxins of diphtheria
ation or inactivation of wild-type microbes, Pasteur produced and tetanus, producing safer vaccine antigens that retained their
vaccines that induced protection against a number of diseases. immunogenic potential.
He performed a number of classic vaccination and challenge The Nobel Prize in Physiology or Medicine 1951 was awarded
experiments in farm animals; these experiments were designed to Max Theiler (1899–1972) “for his discoveries concerning yellow
to show that in experimental challenges, his altered (attenuated fever and how to combat it.” Theiler, through passage of yellow
or inactivated) cultures of microbes could be delivered as vaccines fever virus in mice, developed an attenuated live yellow fever
that offered protection to susceptible animals and herds against virus variant designated 17D, which became a highly effective
organisms that could be devastating, including veterinary vaccine.
pathogens, such as chicken cholera and anthrax, and human Other innovators who exploited the potential of microbial
pathogens, such as rabies. 24 cultivation were Enders et al., who, in the 1940s, discovered
Twenty-first century vaccinology is a multitasker’s dream, methods for cultivation of poliovirus in cell culture. This removed
encompassing multiple fields, including microbiology, immunol- the obstacles in the field of poliovirus vaccine development,
ogy, medicine, epidemiology, statistics, policy, manufacturing, which then advanced relatively quickly after decades of very slow
molecular biology, public health, and ethics. But vaccinology progress. Laboratory growth of poliovirus permitted the develop-
was not always so. Certainly in the 1700s and earlier centuries, ment of both the inactivated polio vaccine (IPV; Salk, licensed
the variolators and the great Jenner knew they had created a in 1955) and the live attenuated oral polio vaccine (OPV; Sabin,
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protected condition in their patients through their intervention monovalent licensed in 1961, trivalent in 1963). As a result of
only if their patient survived that intervention. But they had no these vaccines, still in use today, poliovirus type 2 was eradicated
specific knowledge of the killed or attenuated microbe they were in 1999, and no wild-type poliovirus type 3 has been detected
administering, of the virulent microbe they were protecting since 2012. Only poliovirus type 1 is still endemic in 2016 in
against, or of the immune system changes induced in the bodies just two countries, Pakistan and Afghanistan. The progress toward
of their patients (or even of the existence of the immune system). polio eradication is impressive, as the final steps are being taken,
In the nineteenth century, Pasteur and Koch certainly knew but final eradication will require great persistence in vaccinating
that microbes were the cause of infectious diseases and that the populations in these countries and sustained attention to
weakened forms of microbes (vaccines) could create a protected surveillance. 27
state after administration to livestock or humans. But they had In their considerations of the power of vaccines and other
no specific knowledge of the changes produced in the vaccine preventive interventions to protect humans and reduce infectious
recipient’s immune system. disease incidences, public health officials have described the stages
In the early twentieth century, passive immunization was leading to the ultimate goal of ending human suffering caused
developed as a therapy for infectious diseases. Active immuniza- by infectious diseases: control, elimination, eradication, and
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tion involves administering a vaccine to trigger a subsequent extinction of infectious diseases (Table 90.1). The long road,
cascade of changes in the patient’s own immune system leading which will hopefully culminate soon in poliovirus eradication,
to a protected state (immunity), whereas passive immunization began with successful poliovirus cultivation in cells in the labora-
is direct transfer of the protective immune effector molecules tory. “For their discovery of the ability of poliomyelitis viruses