A Century of Pneumococcal Vaccination Research in Humans

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REVIEW 10.1111/j.1469-0691.2012.03943.x

A century of pneumococcal vaccination research in humans

J. D. Grabenstein1 and K. P. Klugman2,3 1) Merck Vaccines, West Point, PA USA, 2) Rollins School of Public Health and Division of Infectious Diseases, School of Medicine, Emory University, Atlanta, GA, USA and 3) Medical Research Council, National Institute for Communicable Diseases Respiratory and Meningeal Pathogens Research Unit, University of the Witwatersrand, Johannesburg, South Africa

Abstract

Sir Almroth Wright coordinated the first trial of a whole-cell pneumococcal vaccine in South Africa from 1911 to 1912. Wright started a chain of events that delivered pneumococcal vaccines of increasing clinical and public-health value, as medicine advanced from a vague understanding of the germ theory of disease to today’s rational vaccine design. Early whole-cell pneumococcal vaccines mimicked early typhoid vaccines, as early pneumococcal antisera mimicked the first diphtheria antitoxins. Pneumococcal typing systems developed by Franz Neufeld and others led to serotype-specific whole-cell vaccines. Pivotally, Alphonse Dochez and Oswald Avery isolated pneumococcal capsular polysaccharides in 1916–17. Serial refinements permitted Colin MacLeod and Michael Heidelberger to conduct a 1944– 45 clinical trial of quadrivalent pneumococcal polysaccharide vaccine (PPV), demonstrating a high degree of efficacy in soldiers against pneumococcal pneumonia. Two hexavalent PPVs were licensed in 1947, but were little used as clinicians preferred therapy with new antibiotics, rather than pneumococcal disease prevention. Robert Austrian’s recognition of high pneumococcal case-fatality rates, even with antibiotic therapy, led to additional trials in South Africa, the USA and Papua New Guinea, with 14-valent and 23-valent PPVs licensed in 1977 and 1983 for adults and older children. Conjugation of polysaccharides to proteins led to several pneumococcal conjugate vaccines licensed since 2000, enabling immunization of infants and young children and resultant herd protection for all ages. Today, emergence of disease caused by pneumococcal serotypes not included in various vaccine formulations fuels research into conserved proteins or other means to maximize protection against more than 90 known pneumococcal serotypes.

Keywords: Antiserum, history, pneumococcal vaccine, serum therapy, Streptococcus pneumoniae Original Submission: 9 January 2012; Revised Submission: 22 January 2012; Accepted: 26 January 2012 Editor: M. Paul Clin Microbiol Infect 2012; 18 (Suppl. 5): 15–24

standing of the germ theory of disease in 1911 to today’s Corresponding author: J. D. Grabenstein, Merck Vaccines, 770 rational vaccine design is remarkable. At this centennial of Sumneytown Pike, WP97-B364, West Point, PA 19426 USA E-mail: [email protected] the first human trial of pneumococcal vaccination, conducted under Wright’s direction by G.D. Maynard [2,3], this paper reviews the slow, but inexorable, progress from crude to On 4 October 1911, British physician Sir Almroth E. Wright refined vaccines (and antisera) over the last 100 years. (1861–1947) began a series of at least three studies testing whole-cell heat-killed pneumococcal vaccine among several The early years: isolation and serum thousand gold miners who had come from tropical areas to therapy the mine compounds in Johannesburg, in the Transvaal prov- ince of South Africa [1–4]. Wright did not realize at the time the remarkable serotype specificity of Streptococcus pneumo- George M. Sternberg (1838–1915), a US Army physician, and niae. He did realize the enormous burden of a sudden-onset the renowned Louis J. Pasteur (1822–1895) independently disease with a 35% case-fatality rate [4–6]. isolated S. pneumoniae by animal passage in New Orleans and Nonetheless, Wright’s evaluation of that first pneumococ- Paris, respectively, in 1880 [7–10]. During subsequent dec- cal vaccine a century ago started a chain of events that has ades, this pathogen was the focus of considerable scientific delivered pneumococcal vaccines of increasing clinical and attention, as it was recognized to be a principal cause of public-health value [1–3]. The progress from vague under- pneumonia, bacteraemia and meningitis [10,11]. This bacte-

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rium was assigned the name Diplococcus pneumoniae in 1920 rate was 28% compared with 40%. For serotype 3 the case- and was revised to Streptococcus pneumoniae in 1974; infor- fatality rate was unchanged (40% in historical controls and in mally, it has long been known as the pneumococcus [3,12]. serum-treated patients). Evaluation of pneumococcal vaccines in the early 1910s was not the beginning of attempts toward immunological From empirical vaccines to specific ones therapy of pneumococcal disease. Albert Fra¨nkel (1864– 1938) was the first to demonstrate humoral immunity following pneumococcal infection of animals (rabbits) in 1886. Before Wright administered two doses of whole cell, killed He noted that rabbits who recovered from pneumococcal pneumococcal vaccine to the miners in his randomized clini- infection were immune to re-infection [13,14]. Georg Klem- cal trial, early vaccine manufacturers had already begun mar- perer (1865–1946) and his brother Felix Klemperer (1866– keting whole-cell pneumococcal vaccines. The first specific 1932) showed in 1891 that serum from rabbits injected with record to our knowledge is the pneumococcal vaccine heat-killed pneumococci (or filtrates of broth cultures) con- (‘Pneumo-Bacterin’) licensed in the USA in 1909, with manu- ferred immunity to re-infection with the same strain, but not facturers such as H.K. Mulford Co., Eli Lilly & Company necessarily different strains [15]. On this basis, they are con- (Figs 2 and 3), and Parke, Davis & Co. sidered the discoverers of serum therapy. These early whole-cell heat-treated products empirically By 1895, anti-pneumococcal serum appeared in the H.K. mimicked whole-cell typhoid, cholera and plague vaccines that Mulford catalogue (where it remained into the 1940s) had already achieved some degree of clinical success. Distribu- (Fig. 1) [16]. Early forms of this product would have been tion continued into the 1930s; their product licences remained justified on an empirical basis, by analogy to diphtheria anti- bureaucratically (if not commercially) active until c. 1960. toxin. Early studies of antiserum therapy of pneumococcal These products took form in a variety of injectables and tab- infections came in the 1910s. Neufeld, Alphonse R. Dochez lets, combining killed pneumococci with other bacterial vac- (1882–1964) and Rufus I. Cole (1872–1966) contributed cines such as Staphylococcus aureus, Neisseria (Moraxella) information about such treatment for patients with pneumo- catarrhalis, the bacillus of Friedlander (Klebsiella), Bacillus (Hae- nia [17–19]. In 1915, Oswald T. Avery (1877–1955) fraction- mophilus) influenzae, and others. Some formulations used a ated serotype 1 antipneumococcal serum with ammonium mineral-oil or cottonseed-oil base (lipovaccines), rather than sulphate as a means of concentrating the product; others an aqueous base, to prevent autolysis, increasing the bacterial developed other means of concentration [16,20]. dose per volume, and to slow down absorption [24]. Russell L. Cecil (1881–1965) and his colleagues reported In Wright’s first study between October 1911 and April large series of patients treated with serotypes 1 and 2, or 1, 1912, 5963 vaccinees were compared with 5671 controls. 2 and 3 antiserum at Bellevue Hospital in New York City in The whole-cell vaccine doses (developed from circulating the late 1920s and 1930s [20–23]. The death rate for recipi- strains, but without regard to serotype specificity) ranged ents of serotype 1 antiserum was 13%, compared with his- from 300 million to 600 million organisms given subcutane- torical controls with serotype 1 disease who did not receive ously in two doses 8–10 days apart [1]. The results among the serum (22%). Similarly, for serotype 2 the case-fatality the vaccines and controls were imprecisely recorded, so a second study in more than 8000 miners began in August 1912. The vaccine in this second study, also produced without regard to capsular type, ranged from 40 million to >2.5 billion organisms per dose 7–12 days apart. This second vaccination study offered protection (19.5 attacks of pneumonia per 1000 vaccinees compared with 26.4 per 1000 controls over 6 months), but protection was only evident during the first 2 months. Wright also noted that respiratory diseases other than pneumonia were reduced in vaccinees during the first 2 months, but the case-fatality rate of pneumonia was not reduced. In the third trial, started in late 1912, a dose of 500 million organisms apparently reduced pneumonia incidence by 25–50% and the death rate by 40–50% [3]. Pneu- FIG. 1. Antipneumococcic serum packaging. Source: H. K. Mulford monia was also reduced in a subsequent trial of diamond Company catalogue, Philadelphia, PA, USA, May 1914:286. miners at the Premier diamond mine in 1912 [1].

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FIG. 3. Pneumococcus antigen packaging, types I, II, III and IV, 20 billion partially autolysed pneumococci per 1 c.c. Source: Hand Book of Pharmacy and Therapeutics. Eli Lilly and Company, Indianapolis, IN, USA, 1925:222.

include three serotypes and a fourth heterogeneous group yet to be categorized [10,26,27]. The contemporary ‘Danish’ classification system was developed by Edna Lund and colleagues at the Statens Seruminstitut, Copenhagen, in the 1950s [12]. Independently, Wright’s South African prote´ge´ Sir F. Spen- cer Lister (1876–1939) developed a distinct typing system based on phagocytosis and specific agglutination at the South African Institute for Medical Research in Johannesburg. He FIG. 2. Pneumococcus vaccine, prophylactic and therapeutic (pneu- found additional virulent strains in his setting that were not mococcus bacterin) packaging, ‘1000 million killed pneumococci in found in Europe or North America [3–5,24,28,29]. Lister each c.c.,’ likely Types I, II and III. Source: Hand Book of Pharmacy used his typing system in 1914 to develop the first serotype- and Therapeutics. Eli Lilly and Company, Indianapolis, IN, USA, specific whole-cell pneumococcal vaccines, containing his ser- 1919:208. otypes A, B and C [30]. Serotypes B and C corresponded to As Wright was conducting his trials, realization of the serotypes 2 and 1, respectively (although Roman numerals serotype-specificity of the pneumococcus was rising. In 1909, were used in the early twentieth century). Serotype A was at the Robert Koch Institute for Infectious Diseases in Berlin, not known in North America at that time, but is now known Franz Neufeld (1861–1945) and Ludwig Ha¨ndel (1869–1939) to be serotype 5 [24]. developed a method to distinguish serotypes of pneumococci Lister demonstrated that there were predominant sero- [10,17,24,25]. They took advantage of the quellung (‘swelling’) types of pneumococci and advocated a new approach to vac- reaction, in which antibodies bind specifically to certain sub- cine trials, arguing (probably correctly) that immunization of sets of pneumococcal capsules, such that they are more eas- half of the workers at a mine may protect those unvacci- ily viewed microscopically. The serum specificity of this nated through interruption in transmission [30]. Eventually, reaction leads to the term serotype. They also developed a Lister advocated immunizing all workers at a mine and com- mouse protection test to measure the degree of immunity paring records of pneumonia to those pre-vaccination. In his [24]. Dochez, at the Rockefeller Institute for Medical Crown Mine ‘experiment,’ c. 11 000 black South African min- Research in New York City, extended Neufeld’s groups to ers were vaccinated with three doses at 7-day intervals; 82

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cases of lobar pneumonia subsequently occurred, but none military studies was 59% for pneumonia and 70% for case- caused by pneumococcal groups A, B or C [24,29]. These fatality. Military studies showed less heterogeneity and may studies were conducted at the Crown, Premier and De provide more accurate results than civilian studies, given the Beer’s Consolidated Diamond Mines, as well as the Rand various forms of selection and information biases. The Gold Mines. authors concluded that the systematic biases in these studies Lister reported in 1917 on pneumonia incidence rates do not exclude the possibility that whole-cell inactivated among newly arrived miners immunized at three mines, com- pneumococcal vaccines conferred cross-protection to multi- paring them to rates before immunization. Critically, his ple pneumococcal serotypes or that bacterial vaccines played studies did not document the serotype distribution of pneu- a role in preventing influenza-associated pneumonia. mococcal isolates at each mine before immunization, but used a mixture of strains in his vaccines based on isolates Advances using the pneumococcal capsule generally collected over the period and representing perhaps <1% of the pneumonia cases at the mines [3]. Medical staff arranged for all miners to receive Lister’s eight-valent vaccine In 1916–17, Dochez and Avery isolated what we know today from 1918, but by 1926 it appeared that effectiveness had as capsular polysaccharides, but which they called ‘soluble waned, attributed to inadequate coverage (<40%) of circulat- specific substances of pneumococcus’ or SSS [10,19,36,37]. ing pneumococcal serotypes and other pneumonia-causing Between 1923 and 1929, Avery and Michael Heidelberger bacterial species [31]. Notably, in a serotype analysis of (1888–1991) at the Rockefeller Institute conducted a series pneumococcal pneumonia isolates from 1930 to 1934, the of studies establishing capsular antigens as the basis of the incidence of pneumococcal pneumonia cases caused by vac- serotypes of pneumococcal bacteria [37–39]. Rene´ J. Dubos cine serotypes 1, 2, 5 and 7 was halved among vaccinees (1901–1982) and Avery established the critical role of the compared with those not vaccinated, whereas the rate of pneumococcal capsule as a virulence factor in 1931 serotype 3 cases (also in the vaccine) was three-fold higher [10,40,41]. in vaccinees than in controls [3,31]. In 1927, Oscar Schiemann and Wolfgang Casper discov- As the pneumonia and other severe pulmonary manifesta- ered the immunogenicity of pneumococcal capsular polysac- tions of the 1918–19 influenza pandemic arose, amid the cli- charides working at the Koch Institute [19,42,43]. In 1930, max of World War I, research teams offered their various Thomas Francis Jr (1900–1969) and William S. Tillett (1892– heat-inactivated, whole-cell bacterial vaccines (labelled in var- 1974), working at Harvard University and the Rockefeller ious ways as ‘influenza vaccines’, and usually including S. pneu- Institute, injected pure pneumococcal polysaccharides as a moniae components [24,32]. One commentator decried the form of skin test in people recovering from pneumococcal ‘mushroom’ vaccines that rapidly sprouted up to respond to pneumonia. Their goal was to identify whether serotype-spe- that emergency, noting that many of them were ‘shotgun’ cific pneumococcal antibodies evoked by polysaccharides vaccines containing many bacterial components, but of were present. Indeed, they found that antibodies developed unclear clinical value [24]. These vaccine makers were wrong not only to the polysaccharide serotype causing infection but about a bacterial aetiology for influenza viral infection; how- also, in a group repeatedly tested, to the serotypes previ- ever, they were inadvertently on the right track in terms of ously injected [44–46]. Maxwell Finland (1902–1987) used the secondary bacterial pneumonias induced by influenza these findings to conduct studies assessing the relation of viral infection [33]. polysaccharide dose to immunological responsiveness Early tests of pneumococcal serotypes 1, 2 and 3 vaccine [11,47]. occurred at Camp Upton, New York, and Camp Wheeler, In 1929, Avery covalently coupled (i.e. conjugated) pneu- Georgia, in 1918–19, with substantial reductions in serotype- mococcal polysaccharides to proteins to improve immunoge- specific pneumonia incidence among the vaccinees compared nicity. The proteins evaluated were horse globulin and egg with those unvaccinated [21,34,35]. albumin, and the polysaccharides were presumably serotypes To apply modern epidemiological methods to the 1918– 1 and 2 [48]. It would take several decades for this develop- 19 data, Chien and colleagues reanalysed studies of bacterial ment to achieve practical clinical value. vaccine efficacy from that era and calculated vaccine efficacy Working at Harvard Medical School and Johns Hopkins of 34% in preventing pneumonia and 42% in reducing case- University in the 1920s and 1930s, Lloyd D. Felton (1885– fatality rates among six civilian studies of patients with influ- 1956) showed that pure pneumococcal polysaccharides enza, using random-effects models [33]. Based on fixed-effect induced antibody in humans [46,49,50]. He developed biva- models in their 2010 analysis, the pooled efficacy from three lent vaccines against serotypes 1 and 2 that were tested in

field trials during the 1930s among 120 000 men at Civilian Paul Kaufman extended this study by assessing older sub- Conservation Corps camps [5,19,51–53]. These trials were jects of both sexes at a residential institution in New York inconclusive, partly because bacteriological studies after vac- City [60]. Among more than 5000 vaccinees, the research cination were incomplete and partly because of the open-air team calculated a 90% reduction in pneumococcal pneumonia character of the camps. and bacteraemia due to vaccine serotypes 1, 2 and 3. It An epidemic of lobar pneumonia at the main adult psychi- would not be until the 1970s that the inadequate antibody atric hospital in Worcester, Massachusetts, provided an response to pneumococcal polysaccharides of most children opportunity to assess serotype 1 pneumococcal infections in younger than 2 years of age would be recognized [11,19,61]. 1937 [54]. After immunization of patients and staff with a In 1947, E.R. Squibb & Sons obtained a licence in the USA serotype 1 pneumococcal polysaccharide antigen (‘Felton to distribute two forms of hexavalent pneumococcal polysac- antigen’) produced by Lederle Laboratories (Pearl River, charide vaccine, based on clinical data to that point New York), the outbreak was abruptly interrupted. Curi- [46,53,56,60,62]. Squibb’s adult formulation contained poly- ously, the outbreak next arose within 2 weeks at an annex saccharides for serotypes 1, 2, 3, 5, 7 and 8. The epidemiol- facility 5 km (3 miles) away. Again, the antigen was widely ogy of serotype distribution led to different choices for the administered and the outbreak was stopped. paediatric vaccine formulation: serotypes 1, 4, 6, 14, 18 and In 1941, Felton et al. directly compared serotype-specific 19. Squibb’s vaccines were not widely adopted, because post- whole-cell pneumococcal vaccines and polysaccharide pneu- war clinicians preferred to treat pneumonias with newly mococcal vaccines in humans [55]. They tested 79 adults with introduced antibiotics, like penicillin, chlortetracycline and bivalent whole-cell serotypes 1 and 2 pneumococcal vaccine chloramphenicol [6,10,11,53]. Prevention of infection through with a dose of 225 million organisms of each serotype, fol- vaccination was disregarded. Production of the two hexava- lowed 14 days later with 450 million organisms of each sero- lent vaccines ceased in 1951 and Squibb voluntarily withdrew type. They contrasted these results with two cohorts of 92 their licences in 1954, because of lack of acceptance and and 1099 adults who received 400 lg serotype-1 polysaccha- inadequate sales. ride and 200 lg serotype-2 polysaccharide. The authors found no significant differences with respect to protective titres Randomized clinical trials of 1970s induced, individual variation in response, or the percentage of recipients without detectable serum antibody [55]. Little additional research or development on pneumococcal polysaccharide vaccines (PPVs) was conducted by pharma- Wartime urgencies revisited ceutical manufacturers until 1968, when Eli Lilly & Co. began preparing vaccines under contract from the US National From 1942 to 1945, Heidelberger and Colin M. MacLeod Institutes of Health (NIH) [63]. In turn, this NIH effort was (1909–1972) took advantage of the preceding developments motivated by a singular clinician-scientist named Robert in polysaccharide technology to develop and test a pneumo- Austrian (1916–2007). Austrian could not accept the treat- coccal polysaccharide vaccine at the US Army Air Force ment failures of a fast-incubating pathogen like S. pneumoniae Technical School, Sioux Falls, South Dakota [53,56,57]. In (17–30% mortality, despite antibiotic therapy, at Kings this institutional setting with a high incidence rate of pneu- County Hospital in Brooklyn) [6,11,19,64]. Austrian cata- mococcal infections, they tested capsular polysaccharides logued the frequency of inadequate therapy of pneumococcal against pneumococcal serotypes 1, 2, 5 and 7. diseases, organized epidemiological surveys of serotype fre- In the study over 7 months of the winter of 1944–1945, quency, and organized additional clinical trials of PPVs to four cases of vaccine-type pneumococcal pneumonia devel- determine their clinical value. Austrian’s career was based at oped among 8586 vaccine recipients, in contrast to 26 cases the Bellevue Hospital in New York City, then the Rockefel- among 8449 controls injected with saline as placebo. All four ler Institute, and later at the University of Pennsylvania. He cases among vaccinees developed within 2 weeks of vaccina- attributed the under-recognition of pneumococcal disease tion. Cases of non-vaccine-type pneumococcal pneumonia aetiology in part to insufficient attention to laboratory-based postvaccination occurred at comparable rates in each group. diagnosis (including serotyping) [11]. Interestingly, the pneumococcal carriage rate in vaccine Beginning in August 1972, Austrian coordinated clinical tri- recipients was significantly lower than in the control group als of hexavalent and 12-valent pneumococcal vaccines in in this study, similar to findings from South Africa in the c. 12 000 Witwatersrand gold miners in the Transvaal region 1970s [56–59]. of South Africa (e.g. East Rand Preparatory Mine), harkening

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back to Wright’s work a century ago [4,11,63,65]. Briefly, a Immunization Practices (ACIP) recommended the vaccine for hexavalent vaccine containing groups/types 1, 3, 4, 7, 8 and people 2 years or older with certain chronic health condi- 12 and later a 13-valent formulation of groups/types 1, 2, 3, tions that increased the risk of pneumococcal infection or as 4, 6, 7, 8, 9, 12, 14, 18, 19 and 25 (both produced by Eli an outbreak control measure in institutions [73]. In 1979, Lilly) were administered in a randomised fashion (50 lg each Lederle Laboratories also introduced a 14-valent PPV. Table 1 polysaccharide serotype per 0.5-mL dose) to newly recruited summarizes various vaccine characteristics and introductions. miners on their day of arrival at the mines in Johannesburg. The basis for licensure for both products was based on Volunteers were randomly divided into three groups, to reductions in invasive pneumococcal disease and pneumococ- receive either PPV, a meningococcal serogroup A polysac- cal pneumonia in the studies performed in the 1970s. charide vaccine (Merrell–National Laboratories), or a sterile PPV14 was indicated for people 50 years and older, or saline injection. those 2 years and older with certain underlying health condi- Meanwhile, Lilly was having difficulty developing its formu- tions. Its 14 serotypes targeted 70–80% of invasive pneumo- lation of PPV and chose in 1975 to invest its human and coccal disease (IPD) in the US [73–75]. other capital in other therapeutic areas [63]. Part of Lilly’s Pneumococcal experts recognized the need for expanded calculus included the relative rarity of documented pneumo- protection against a wider array of serotypes, so a broader coccal disease and the difficulty of confirming its diagnosis. global survey of invasive pneumococcal isolates coordinated This problem was mitigated by the self-funded pneumococcal by multiple national governments and the World Health research programme that Merck Sharp and Dohme (MSD) Organization led to a decision to recommend 23-valent vac- began in 1970, building on its expertise acquired in develop- cines. Thus PPV23 was introduced in 1983 by both Merck ing and producing a meningococcal polysaccharide vaccine and Lederle, with serotypes covering about 87% of bactere- for the US Army [19,66]. The companies developed vaccine mic pneumococcal disease in the US [74–77]. PPV23 formu- formulations of various valencies, but only after testing each lations contain 25 mcg per polysaccharide antigen, rather individual polysaccharide for safety and immunogenicity. than the 50 mcg per antigen in PPV14 (Table 1). The transi- In the early 1970s, MSD conducted clinical trials among tion was intended to better balance immunogenicity and c. 4700 gold miners at the Kloof Gold Mine and Gold Fields safety [75]. The ACIP recommendations published in May West near Johannesburg, led by Pieter Smit, demonstrating 1984 were the first to encourage routine vaccination of safety and a 76% reduction in pneumococcal pneumonia healthy adults 65 years or older [77]. cases for the hexavalent vaccine and a 92% reduction in The manufacturing complexity for any vaccine with so cases for the 12-valent vaccine [59,63]. MSD’s findings were many individual components should not be underestimated. comparable to those found for Lilly’s product used by Aus- Effectively 23 distinct vaccines within one formulation, PPV23 trian [65]. production involves 23 separate fermentations, isolation and At the same time, the National Institute for Allergy and purification of their capsular polysaccharides, and then blend- Infectious Diseases contracted with clinical investigators in ing 23 polysaccharides into one liquid solution. Each vaccine universities and private practice to conduct US clinical trials lot requires hundreds of assays for lot release, from master of pneumococcal vaccine. Austrian was principal investigator cell bank through final product. These assays include tests for the studies at the Dorothea Dix Hospital in Raleigh and for identity, concentration, purity, potency/strength, and at the Kaiser Permanente Medical Center in San Francisco safety. In the case of multivalent pneumococcal conjugate [11,19,65,67,68]. Important studies showing reductions in vaccines (PCVs, discussed below), the conjugation and adju- morbidity and mortality in children and adults were con- vant steps add more complexity. ducted in Papua New Guinea as well, coordinated by Ian Riley and colleagues [69–72]. From polysaccharides to conjugates Meanwhile, increasing reliance on antibiotic therapy was leading to antibiotic-resistant strains of pneumococci causing pneumococcal diseases [6,10,11]. This situation offered a Pneumococcal polysaccharide vaccines are poorly immuno- better reception to a fledgling pneumococcal vaccine than genic in children younger than 2 years of age, who are at was the case in the late 1940s. The results of all these trials, high risk of invasive pneumococcal disease. To improve the coupled with serotype surveillance from North America, immune response to the capsular polysaccharide in young Europe and South Africa, led MSD to submit a licence appli- children, third-generation vaccines in which capsular polysac- cation for a 14-valent PPV that was approved in November charides are conjugated to one of several different proteins 1977. In January 1978, the US Advisory Committee on were developed and tested [78].

TABLE 1. Pneumococcal vaccines distributed since 1977

Manufacturers (trade names) Valence: serotypes included Date introduced, initial region

Pneumococcal polysaccharide vaccines Merck Sharp & Dohme (MSD) (Pneumovax) 14-valent: 1, 2, 3, 4, 5, 6A, 7F, 8, 9N, 12F, 18C, 19F, 23F, 25F November 1977, USA Lederle Laboratories (Pnu-Imune) August 1979, USA Institut Me´rieux (Imovax Pneumo 14) February 1981, France

SmithKline Beecham (Moniarix) 17-valent: 1, 2, 3, 4, 6A, 7F, 8, 9N, 11A, 12F, 14, 1980s, Europe 15F, 17F, 18C, 19F, 23F, 25

Merck Sharp & Dohme (MSD) (Pneumovax 23) 23-valent: 1, 2, 3, 4, 5, 6B, 7F, 8, 9N, 9V, 10A, 11A, 12F, 14, July 1983, USA Lederle Laboratories (Pnu-Imune 23) 15B, 17F, 18C, 19F, 19A, 20, 22F, 23F, 33F July 1983, USA Institut Me´rieux (Pneumo 23) 1987, Europe Chengdu Institute of Biological Products 2005, China

Pneumococcal conjugate vaccines Wyeth Laboratories (Prevnar or Prevenar) 7-valent: 4, 6B, 9V, 14, 18C, 19F, 23F February 2000 for infants, USA and Europe GlaxoSmithKline (Synﬂorix) 10-valent: 1, 4, 5, 6B, 7F, 9V, 14, 18C, 19F, 23F March 2009 for infants: Europe Wyeth Laboratories (Prevnar 13 or Prevenar 13) 13-valent: 1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F, 23F February 2010 for infants, late 2011 for adults, Europe, Australia, USA

Around 1980, John B. Robbins and Rachel Schneerson tection of others, clinicians are now considering the relative picked up on Avery’s work [48], to develop polysaccharide– merits of PPVs and PCVs for adults. In 2012, the only avail- protein conjugation technology further. Using capsular poly- able randomized controlled trial results for preventing pneu- saccharides from Haemophilus influenzae type b (Hib) and mococcal disease in adults describe the performance of PPVs pneumococcal serotype 6A, they tested serum albumin, Limu- and evaluate clinical endpoints [85–89]. The recent licensure lus haemocyanin, diphtheria toxin, cholera toxin and tetanus of PCV13 for adults is based on non-inferiority of antibody toxoid as carrier proteins, in early studies at the Food and concentrations in relation to PPV23 serotypes in common. Drug Administration laboratories [79–82]. Unlike other PCV13 is the subject of a randomized controlled trial in the researchers they did not need complete Freund’s adjuvant Netherlands on adults that eventually will compare its clinical or administration by intravenous or intraperitoneal routes to performance to a saline placebo [90]. The two vaccine types enhance immunogenicity. Their success hinged on developing will need to be evaluated in the light of evolving serotype methods to bind the polysaccharide units to the carrier pro- distribution of pneumococcal diseases in both children and teins. adults. The first protein-conjugated polysaccharide vaccines achieved licensed status in the USA in 1987, in the form of Conclusions and future prospects for conjugated Hib vaccines. PCVs followed in 2000 (Table 1). pneumococcal vaccines Routine use of PCV7 (which does not include serotype 19A) was associated with increasing incidence of disease due to serotype 19A [83,84], often referred to as emergence or A century of development of pneumococcal vaccines in replacement disease. This phenomenon highlights the public- humans has seen first whole-cell vaccines, then polysaccha- health value of pneumococcal vaccines with broad serotype ride vaccines with valencies ranging from 1 to 23, and finally coverage. Ten-valent and 13-valent PCVs are currently mar- protein-conjugated polysaccharide vaccines with valencies keted; Merck is developing a 15-valent PCV. ranging from 5 to 15. Routine vaccination of infants and young children has led The future may include conserved pneumococcal protein to a prompt and sustained reduction among vaccinees in vaccines, currently in clinical trials [91]. Further, it may be invasive pneumococcal disease involving corresponding ‘back to the future’ to return to whole-cell vaccines to pre- vaccine serotypes. Remarkably, the burden of invasive pneu- vent replacement disease, as animal data suggest that whole- mococcal disease among older children and adults who did cell non-encapsulated pneumococcal vaccine may protect not receive PCV has also fallen markedly in the context of against a variety of serotypes [91]. routine paediatric vaccination programmes [83,84]. This herd-protection effect is most likely the result of reduced Acknowledgements transmission of vaccine-type pneumococci in the community as a result of decreased carriage. Beyond the pivotal role of PCVs in protecting infants and The research assistance of Dennis B. Worthen at the Lloyd young children, while offering the potential for indirect pro- Library of Cincinnati and Karie Youngdahl at the College of

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Physicians of Philadelphia (and its HistoryofVaccines.org Pro- 17. Neufeld F, Ha¨ndel L. Weitere Untersuchungen u¨ber Pneumokokken ¨ ject) are greatly appreciated. Heilsera. III Mitteilung Uber Vorkommen und Bedeutung atypischer Varietaten des Pneumokokkus. Arb Kaiserlichen Gesundheitsamte (Ber- lin) 1910; 34: 292–304. 18. Cole R, Dochez AR. Report of studies on pneumonia. Trans Assoc Am Conflict of interests Phys 1913; 28: 606–616. 19. Chase A. Magic shots: a human and scientific account of the long and continuing struggle to eradicate infectious diseases by vaccination. New John D. Grabenstein is an employee of Merck & Co., White- York, NY: William Morrow, 1982. house Station, NJ, manufacturer of 23-valent pneumococcal 20. Cecil R, Plummer N. Pneumococcus type I pneumonia, a study of ele- ven hundred and sixty-one cases, with especial reference to specific polysaccharide vaccine and developer of a candidate 15- therapy. JAMA 1930; 95: 1547–1553. valent pneumococcal conjugate vaccine. Keith P. Klugman 21. Cecil RL, Austin JH. Results of prophylactic inoculation against pneu- has received consultancies from Pfizer Vaccines, GSK and mococcus in 12,519 men. J Exp Med 1918; 28: 19–41. Merck, all manufacturers of pneumococcal vaccines. 22. Cecil RL, Larsen NP. Clinical and bacteriologic study of one thousand cases of lobar pneumonia. JAMA 1922; 79: 343–349. 23. Cecil RL, Plummer N. Pneumococcus type II pneumonia: a clinical and bacteriologic study of one thousand cases with special reference References to serum therapy. JAMA 1930; 98: 779–786. 24. Fennel EA. Prophylactic inoculation against pneumonia: a brief history and the present status of the procedure. JAMA 1918; 71: 2115–2130. 1. Wright AE, Morgan WP, Colebrook L, Dodgson RW. Observations 25. Neufeld F, Ha¨ndel L. 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A brief history of pneumonia at Camp Wheeler. J Exp Med 1919; 29: 457–483. the pneumococcus in biomedical research: a panoply of scientific dis- 36. Dochez AR, Avery OT. Soluble substance of pneumococcus origin in covery. Clin Infect Dis 1993; 17: 913–924. the blood and urine during lobar pneumonia. Proc Soc Exp Biol Med 11. Austrian R. Maxwell Finland lecture. Random gleanings from a life 1917; 14: 126–127. with the pneumococcus. J Infect Dis 1975; 131: 474–484. 37. Austrian R, Oswald T. Avery: the wizard of York Avenue. Am J Med 12. Kauffmann F, Lund E, Eddy BE. Proposal for a change in the nomen- 1999; 107 (suppl 1A): 7S–11S. clature of Diplococcus pneumoniae and a comparison of the Danish 38. Heidelberger M, Avery OT. The soluble specific substances of pneu- and American type designations. Int Bull Bacteriol Nomenclature Taxon- mococcus. J Exp Med 1923; 38: 73–79. omy 1960; 10: 31–40. 39. Heidelberger M. A ‘‘pure’’ organic chemists downward path. Annu 13. Fra¨nkel A. 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83. Pilishvili T, Lexau C, Farley MM et al. Sustained reductions in invasive Full text at: http://www.mrw.interscience.wiley.com/cochrane/ pneumococcal disease in the era of conjugate vaccine. J Infect Dis clsysrev/articles/CD000422/pdf_fs.html 2010; 201: 32–41. 87. Huss A, Scott P, Stuck AE, Trotter C, Egger M. Efficacy of pneumo- 84. Miller E, Andrews NJ, Waight PA, Slack MP, George RC. Herd immu- coccal vaccination in adults: a meta-analysis. CMAJ 2009; 180: 48–58. nity and serotype replacement 4 years after seven-valent pneumococ- erratum 1038. cal conjugate vaccination in England and Wales: an observational 88. Andrews R, Moberley SA. The controversy over the efficacy of pneu- cohort study. Lancet Infect Dis 2011; 11: 760–768. mococcal vaccine. CMAJ 2009; 180: 18–19. (editorial). 85. Fedson DS, Liss C. Precise answers to the wrong question: prospec- 89. Austrian R. Pneumococcal vaccine and pneumococcal pneumonia. Ann tive clinical trials and the meta-analyses of pneumococcal vaccine in Intern Med 1988; 108: 762. (letter) elderly and high-risk adults. Vaccine 2004; 22: 927–946. 90. Hak E, Grobbee DE, Sanders EAM et al. Rationale and design of 86. Moberley SA, Holden J, Tatham DP, Andrews RM. Vaccines for pre- CAPITA: a RCT of 13-valent conjugated pneumococcal vaccine effi- venting pneumococcal infection in adults. Cochrane Database Syst Rev cacy among older adults. Neth J Med 2008; 66: 378–383. 2008, Issue 1. DOI: 10.1002/14651858. http://www.mrw.inter 91. Moffitt KL, Malley R. Next generation pneumococcal vaccines. Curr science.wiley.com/cochrane/clsysrev/articles/CD000422/frame.html Opin Immunol 2011; 23: 407–413.

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