E

V

kwnaytda

twcfoidomha

bttfitof

roeipwv1as[ip

i

0h

Vaccine 30 (2012) 5299– 5301

Contents lists available at SciVerse ScienceDirect

Vaccine

jou rn al h om epa ge: www.elsev ier .com/ locate /vacc ine

ditorial

accine history: The past as prelude to the future

The concept underlying vaccines antedated the science we nownow as “vaccinology” by hundreds of years if not longer [1]. Theidely acknowledged formal history of vaccines began with Jen-er’s systematic investigations into the protective effect of cowpoxgainst smallpox in the waning years of the 18th century [2]. Eightyears later Pasteur discovered the process of microbial attenua-ion and its implications for immunization; shortly thereafter, heemonstrated protection against rabies in humans using such anpproach [3].

During the eight decades between Jenner’s landmark work andhat of Pasteur, few scientific advances in vaccines—other than theidespread implementation of smallpox vaccination—were forth-

oming. But the 19th century witnessed other “events” of moreundamental importance to the fledgling field: the germ theoryf disease was proven; the sister sciences of microbiology andmmunology were launched; technical advances by Koch and hisisciples led to the discovery of numerous specific bacterial causesf distinct infectious diseases; and, at century’s end, a new class oficrobes—viruses—were discovered [4]. These revelations would

ave the salutary effect of galvanizing vaccine science and acceler-ting the pace of its rapidly evolving history.

By the middle of the 20th century, first-generation vaccines hadeen developed to address many of the most lethal pathogens ofhe day. Toxoid vaccines brought diphtheria and tetanus under con-rol. On the heels of partially successful, killed bacterial vaccinesor cholera and typhoid, the first inactivated viral vaccines—againstnfluenza—were invented. A live, attenuated vaccine—17D—provedo be successful in preventing yellow fever in humans, earning onef its creators the only Nobel Prize in Medicine or Physiology givenor the development of a virus vaccine [5].

To a large extent, advances in vaccines were—andemain—inextricably linked to and dependent on those inther scientific disciplines. Tetanus and diphtheria toxoid vaccinesvolved directly from early discoveries in the developing field ofmmunology; the related field of adjuvant chemistry evolved inarallel. Influenza and yellow fever vaccines only became possibleith the advent of laboratory techniques for the cultivation of

iruses on the chorioallantoic membranes of chick embryos in the930s [6]. Within 15 years, a series of incremental, accumulatingdvances in tissue culture techniques culminated in the first,uccessful, ex vivo cultivation of poliovirus in non-neural tissue7]. The effect of this discovery on the science of vaccines would bemmediate and profound, leading—five years later—to an effective

olio vaccine and ushering in the “golden age” of vaccines [8].

Following the success with polio a series of vaccines target-ng important diseases of childhood—measles, mumps, rubella,

264-410X/$ – see front matter © 2012 Elsevier Ltd. All rights reserved.ttp://dx.doi.org/10.1016/j.vaccine.2012.06.060

and varicella—were developed and proven to be broadly effective.But into the 1970s, effective vaccines against some of the mostlethal bacterial pathogens—pneumococcus, meningococcus, and H.influenzae type b (Hib)—remained elusive. The key to finding thecorrelate of immune protection for these agents required a thor-ough re-examination of polysaccharide immunochemistry—workinitially done more than a half a century earlier by Avery andHeidelberger at the Rockefeller Institute [9]. Their investiga-tions into the “specific soluble substance”—pneumococcal capsularpolysaccharide—led to clinical trials of first generation pneu-mococcal vaccines, a line of vaccine research that essentiallyceased with the meteoric rise of antibacterial chemotherapy in the1940s [10].

However, as is well documented, bacterial resistance to novelantibacterial drugs occurred rapidly, reinforcing the need forpreventive vaccines [11]. The last quarter of the 20th century wit-nessed the development of effective, first-generation, multivalent,pneumococcal and meningococcal polysaccharide vaccines and aneffective Hib vaccine [12]. The development of conjugate vaccinetechnology—itself originally derived from Landsteiner’s basic workin immunochemistry at the turn of the century—led to advanced-generation polysaccharide vaccines that have since shown abetter likelihood of addressing some of the gaps in immuno-genicity and durability of response of the earlier generationvaccines.

More recent approaches based on novel platforms have engen-dered vaccines against hepatitis B, a recombinant subunit product;rotavirus, using bovine-human reassortants; and human papillo-mavirus, through virus-like particles. New, innovative strategieshave been developed to attempt to address some of the shortcom-ings of current vaccines. For example, Group B meningococcus,a major cause of sporadic and epidemic disease throughout theworld, continues to pose a dilemma to vaccinologists due to itsmolecular mimicry of certain polysialic moieties found on host tis-sues. “Reverse vaccinology,” an informatics-based approach aimedat identifying genomic sequences coding for immunologic tar-gets [13], has yielded a candidate group B meningococcal vaccinethat has been found to be safe and immunogenic against multiplestrains in children and adults and has also shown early promisein infants [14]. More recently, vaccinomics and systems biologyapproaches to understanding and developing new vaccines havebeen developed as answers to problems in discovery of new vaccinecandidates and as part of a “personalized vaccinology” approach to

vaccine discovery and use [15–17].

The history of vaccines, now entering its third full century, isstill rapidly evolving. Although much of it remains to be written,

5 e 30 (2

ttii“sdap

m“teEtptadf“ugth

tslcwmebfioodofavl

tiisvntsmttnnh

cdttoi

[

300 Editorial / Vaccin

his history informs the future of vaccine science in several, impor-ant ways. It reminds us that progress in this field, as with thatn other areas of biological and physical science, generally occursncrementally, based on past achievements. This represents thenormal science” described by Kuhn in his landmark treatise oncientific discovery [18]. However, periodically, “game-changing”iscoveries occur through the accumulation of these incrementaldvances, and it is these events that cause shifts in extant scientificaradigms, propelling the field forward.

Even in its condensed history as compared with other areas ofedical science, vaccinology has experienced a number of such

game-changing” events. Jenner’s systematic study of cowpox; Pas-eur’s serendipitous discovery of microbial attenuation and hisxperiments with anthrax and rabies vaccines; von Behring’s andhrlich’s discoveries of antitoxin and toxoids, respectively; the cul-ivation of measles and polioviruses ex vivo; the recognition ofolysaccharides as determinants of antigenic specificity for cer-ain pathogens by Avery, Heidelberger, and later by researcherst the Walter Reed Army Institute of Research [10]; and theevelopment of a subunit vaccine—hepatitis B—that prevents aorm of cancer [19] all qualify, among many others, as criticalmoments” that led to paradigm shifts in scientific thinking. Bynderstanding the kinetics of such processes, today’s vaccinolo-ists gain insight and perspective on how the field has evolved,he factors that influenced its progress, and where it may beeaded.

Vaccine history teaches that advances in vaccines are closelyied to the development of new and improved technologies, them-elves often derived from other, related fields. Vaccine science madeittle progress from Jenner’s time to the latter part of the 19thentury. It was only after Koch had defined a laboratory frame-ork within which to understand the etiologic role of specificicrobial organisms in specific disease states that rapid progress

nsued. Similarly, advances in developing vaccines against toxin-ased infections awaited technological advances in the nascentelds of immunology and adjuvant chemistry. The developmentf vaccines for some of the most important viral disease scourgesf childhood required first the discovery of viruses, in the lastecade of the 19th century, followed by another half-centuryf incremental technical advances in tissue culture—derivedrom the fields of zoology, embryology, surgery, engineering,nd pathology—before culminating in the ability to cultivateiruses in vitro. From there, the path to vaccines was a straightine.

The study of the history of vaccines provides insights into howoday’s vaccinologists might approach new and lingering problemsn infectious diseases. By understanding how the field has evolved,nnovative strategies—informed by novel technologies—can be pur-ued and applied towards the development of safe and effectiveaccines against chronic infections, highly variable pathogens, oron-infectious diseases such as cancer. Like our predecessors,oday’s vaccinologists must learn from the history of vaccinecience, sampling liberally from applicable data. However, weust also stand ready to incorporate new concepts and new

echnologies—such as vaccinomics and systems biology—towardshe discovery of new vaccines [17,20]. In order to fully realize theext “golden age” of vaccinology, we must not only embrace suchew paradigms, but also continue to reflect on how we arrivedere.

Such reflections on the past are critical as we move from “vac-inology I” to “vaccinology II” in considering how vaccines areevised and deployed [21]. Knowledge of past approaches and solu-

ions can inform new approaches, while at the same time causing uso leave currently cherished scientific notions. For example, muchf early vaccinology was characterized by an “isolate-inactivate-nject” paradigm. While considerable progress was made on this

[

[

012) 5299– 5301

level, it is a clearly insufficient approach to developing vaccinesagainst hyper-variable viruses such as HIV, HCV, and others. Impor-tantly, the history of the public’s use and acceptance of vaccines isanother historical element critical to understanding today’s anti-vaccine movement [22] and the current attempts globally to protectthe public health in terms of high levels of vaccine coverageand attempts to eliminate (measles) and eradicate (polio) currentscourges.

A very practical side to vaccine history has also become appar-ent. With the success of vaccines in controlling outbreaks of diseasehave come “success induced” and often unanticipated issues. Thewidespread use of vaccines against previously common child-hood viral illnesses, such as measles and rubella, has preventedregular epidemics of disease such that parents and the publicno longer appreciate the considerable morbidity and mortalitycaused by these diseases. This, in turn, leads to a laissez-faireattitude toward the importance and urgency in using these vac-cines to ensure high coverage rates. For similar reasons, youngphysicians and nurses are no longer familiar with the clinicalpresentation of these diseases and are often unaware of theirmorbidity and mortality and the need for high vaccine coveragerates.

While no one entity can solve these issues, we have devised apractical response. A new section, entitled “The History of Vacci-nology,” will be a regular feature of our journal. This section has anappointed Associate Editor, Dr. Andrew Artenstein, who will craft,shepherd, and build this new and important section. In combina-tion with another new section, “Visual Vaccinology,” we intend toinclude visuals (pictures, graphs, etc.) that will illustrate past andcurrent vaccine development, the diseases themselves, and appli-cations to current issues in vaccinology. We believe these newsections will provide important context as prelude to the future.We invite manuscripts, ideas, and your thoughts as we launch theseexciting sections.

Conflicts of interest

The authors have no conflicts to disclose regarding themanuscript.

References

[1] Artenstein AW. Vaccinology in context: the historical burden of infectious dis-eases. In: Artenstein AW, editor. Vaccines: a biography. New York: Springer;2009.

[2] Jenner E. An inquiry into the causes and effects of the variolae vaccine: a diseasediscovered in some of the western counties of England, particularly Gloucester-shire, and known by the name cox pox. Birmingham, AL: Classics of MedicineLibrary; 1978.

[3] Debre P. Louis Pasteur. Baltimore: The Johns Hopkins University Press; 1994.[4] Opal SM. A brief history of microbiology and immunology. In:

Artenstein AW, editor. Vaccines: a biography. New York: Springer;2009.

[5] Norrby E. Yellow fever and Max Theiler: the only Nobel Prizefor a virus vaccine. J Exp Med 2007;204(November (12)):2779–84.

[6] Goodpasture EW, Woodruff AM, Buddingh GJ. The cultivation of vaccine andother viruses in the chorioallantoic membrane of chick embryos. Science1931;74(October (1919)):371–2.

[7] Enders JF, Weller TH, Robbins FC. Cultivation of the lansing strain ofpoliomyelitis virus in cultures of various human embryonic tissues. Science1949;109(January (2822)):85–7.

[8] Poland GA, Oberg AL. Vaccinomics and bioinformatics: accelerantsfor the next golden age of vaccinology. Vaccine 2010;28(April (20)):3509–10.

[9] Heidelberger M, Avery OT. The soluble specific substance of pneumococcus. JExp Med 1923;38(June (1)):73–9.

10] Artenstein AW, LaForce FM. Critical episodes in the understanding and control

of epidemic meningococcal meningitis. Vaccine 2012;(April).

11] Finland M. Emergence of antibiotic-resistant bacteria. N Engl J Med1955;253(December (22)):969–79.

12] Artenstein AW. Polysaccharide vaccines. In: Artenstein AW, editor. Vaccines: abiography. New York: Springer; 2009.

e 30 (2

[

[

[

[

[

[

[

[

[

[

Editorial / Vaccin

13] Pizza M, Scarlato V, Masignani V, Giuliani MM, Arico B, Comanducci M, et al.Identification of vaccine candidates against serogroup B meningococcus bywhole-genome sequencing. Science 2000;287(March (5459)):1816–20.

14] Gossger N, Snape MD, Yu LM, Finn A, Bona G, Esposito S, et al. Immuno-genicity and tolerability of recombinant serogroup B meningococcal vaccineadministered with or without routine infant vaccinations according to differ-ent immunization schedules: a randomized controlled trial. J Am Med Assoc2012;307(February (6)):573–82.

15] Haralambieva IH, Poland GA. Vaccinomics, predictive vaccinology and thefuture of vaccine development. Future Microbiol 2010;5(December):1757–60.

16] Poland GA, Ovsyannikova IG, Kennedy RB, Haralambieva IH, Jacobson RM. Vac-cinomics and a new paradigm for the development of preventive vaccinesagainst viral infections. Omics 2011;15(9):625–36.

17] Poland GA, Kennedy RB, Ovsyannikova IG. Vaccinomics and personalizedvaccinology: is science leading us toward a new path of directed vaccine devel-opment and discovery? PLoS Pathogens 2011;7(12.).

18] Kuhn TS. The structure of scientific revolutions. 3rd ed. Chicago: The Universityof Chicago Press; 1996.

19] Blumberg BS. Hepatitis B. In: Artenstein AW, editor. Vaccines: a biography. NewYork: Springer; 2009.

20] Oberg AL, Kennedy RB, Li P, Ovsyannikova IG, Poland GA. Systems biol-ogy approaches to new vaccine development. Curr Opin Immunol 2011;

(May).

21] Poland GA, Hollingsworth JR. From Science II to Vaccinology II: a new episte-mology. Vaccine 2011;29(February (8)):1527–8.

22] Poland GA, Jacobson RM. The age-old struggle against the antivaccinationists.N Engl J Med 2011;364(January (2)):97–9.

012) 5299– 5301 5301

Associate EditorAndrew W. Artenstein ∗

Department of Medicine, Memorial Hospital of RhodeIsland and The Warren Alpert Medical School ofBrown University, Providence, RI, United States

Editor-in-ChiefGregory A. Poland

Mayo Vaccine Research Group and Program inTranslational Immunovirology and Biodefense, MayoClinic and Foundation, Rochester, MN, United States

∗ Corresponding author at: Department ofMedicine, Memorial Hospital of Rhode Island, 111

Brewster St., Pawtucket, RI 02860, United States.Tel.: +1 401 729 3100; fax: +1 401 729 3282.E-mail address: artenstein@brown.edu (A.W.

Artenstein)

12 June 2012