Page 1255 - Clinical Immunology_ Principles and Practice ( PDFDrive )

1216 Part ten Prevention and Therapy of Immunological Diseases

In a measles outbreak in California in 2014–2015, of the 110 yellow fever, and influenza viruses). In a few cases, attenuated
patients, 49 were unvaccinated; in that subgroup, 24% were zoonotic organisms closely related to human pathogens were
children too young to be vaccinated, and 67% were intentionally employed to produce cross-reactive protective responses in
unvaccinated (mostly children) as a result of parental beliefs. humans (e.g., vaccinia, an animal poxvirus utilized as a vaccine
Such outbreaks point out the importance of community immunity against human smallpox, and Bacille Calmette-Guérin [BCG],
to protect the vulnerable (unvaccinated) members of our com- an agent of bovine tuberculosis [TB] developed as a human TB
munities. Given that many of the recent measles outbreaks in vaccine).
the United States have been linked to imported cases, another Later, split-virus vaccines utilized partially purified protein
important lesson is that as long as a vaccine-preventable, highly antigens derived from whole killed viruses (e.g., split-virus
transmissible infectious disease exists anywhere in the world, it influenza vaccines). The polysaccharide capsules of bacteria were
remains a potential threat everywhere—and thus vaccination purified from cultures of serologically distinguishable strains,
programs will continue to be important to ensure the health of or serotypes, within single bacterial species leading to polyvalent
all community members in any part of the world. polysaccharide vaccines (e.g., the 23-valent pneumococcal
Another powerful example of vaccine-induced community polysaccharide and the quadrivalent meningococcal polysac-
immunity comes from pneumococcal vaccines. There are many charide vaccine). Bacterial toxins were purified from cultures
specific challenges associated with pneumococcal vaccines: the and made harmless by application of heat or chemical treatment
large number of circulating serotypes, the suboptimal immu- to produce toxoid vaccines (e.g., tetanus and diphtheria
nogenicity of polysaccharide only vaccines, and noninvasive vaccines).
carriage of the organism—all of which lead to significant problems During the closing years of the twentieth century and in the
in establishing community immunity. However, in spite of those early twenty-first century, the advances in genetics, molecular
challenges, introduction of the pneumococcal conjugate vaccines biology, immunology, and microbiology have led to new theory-
in infants in 2000 not only led to reduction in invasive diseases based (so-called rational) approaches to vaccine development.
among the vaccinated population of children but also produced Perhaps “informed empiricism” is an apt description of much
a significant reduction in adults, particularly among seniors, in of early twenty-first century vaccine development: experimental
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whom this bacterium frequently causes pneumonia. This result approaches that are heavily influenced by our now-imperfect,
highlights the effectiveness of community immunity produced always evolving knowledge of innate and adaptive immune
by vaccines. responses and of microbial antigens but are still dependent on
Other recently introduced vaccines have made a significant an iterative system of trial and error to discover safe, well-tolerated,
impact in relatively brief periods. The 2006 implementation of and efficacious vaccines. Vaccine developers today also benefit
routine rotavirus vaccination prevents an estimated 40 000 to from the cumulative body of knowledge and experience in
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60 000 rotavirus hospitalizations in the United States annually. vaccinology that has accumulated over the past century.
The human papillomavirus (HPV) vaccine is a recombinant There have been numerous changes in the design of vaccine
virus-like particle (VLP) vaccine for primary prevention of cancer. immunogens. The formation of links between bacterial polysac-
The CDC Advisory Committee on Immunization Practices (ACIP) charides and protein carriers (conjugation) led to dramatic
recommended routine HPV vaccination for girls in 2006 and improvements in protection against certain bacterial diseases.
for boys in 2011. Within 6 years of the introduction of vaccine Conjugation of H. influenzae, N. meningitidis, and, most recently,
for girls, there was a 64% decrease in the prevalence of the four S. pneumoniae polysaccharides to proteins improved these vaccines
types of HPV contained in the vaccine among females 14–19 by converting them from T cell–independent antigens to T
years of age and a 34% decrease among those 20–24 years of cell–dependent antigens.
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age. This example shows the power of an excellent new- Adjuvants are materials added to vaccine antigens to enhance
generation viral vaccine, even when uptake is incomplete. At the the recipient’s immune response. Recent advances in our under-
end of the first decade of the current century, cases of hepatitis standing of the innate immune system have led to an appreciation
A, hepatitis B, and varicella have been reported to be at record that adjuvants act through their effects on innate immunity.
low levels 49,50 (see Table 90.2). Adjuvant-triggered innate signals enhance the quantity and quality
of the downstream adaptive immune responses to the vaccine
RECENT CHANGES IN VACCINE antigen. Today’s vaccinologists are developing vaccines with
DEVELOPMENT STRATEGIES specific molecular adjuvants (e.g., Toll-like receptor-5 [TLR-5],
CD-40L, and interleukin-12 [IL-12]), intended to shape the
Vaccines were originally developed with no knowledge of the immune response to provide a presumed best fit for protective
immunological correlates of protection or, indeed, of the existence immunity against the targeted pathogen.
of the immune system. Similarly, the earliest vaccines were The advent of molecular biology in the mid-twentieth century
developed without an in-depth understanding of microbial resulted in many new avenues for vaccine development. Advances
antigens and epitopes, which are critical to the production of in molecular biology allowed for cloning of microbes’ genes and
protection against disease. Rather than having a theoretical or their expression in recombinant molecular systems, and vaccines
purely logical basis, for a century and a half after Jenner, vaccina- could consequently be designed on the basis of the in vitro
tion continued to be based on experience and clinical observation. expression of one or a few genes. For example, the hepatitis B
The observations and experiences led to a concept that was vaccine, originally developed by Hilleman, was purified hepatitis
evaluated by a trial-and-error approach. The desired outcomes B surface antigen (HBsAg) from the blood of humans with chronic
of the trial-and-error, or empirical, approach to vaccine develop- infection. Soon thereafter, a second licensed hepatitis B vaccine
ment were protection against disease and survival after exposure was produced in yeast cells through recombinant DNA methods
to the pathogen. Vaccines were initially attenuated or killed that inserted the HBsAg gene into yeast organisms for expression
versions of the whole wild-type human pathogens (e.g., rabies, and purification. The recombinant hepatitis B vaccine is in use