International Reviews of Immunology

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Anti-infectious human vaccination in historical perspective Enrico D'Amelio, Simonetta Salemi & Raffaele D'Amelio To cite this article: Enrico D'Amelio, Simonetta Salemi & Raffaele D'Amelio (2015): Antiinfectious human vaccination in historical perspective, International Reviews of Immunology, DOI: 10.3109/08830185.2015.1082177 To link to this article:

Published online: 25 Nov 2015.

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Date: 26 November 2015, At: 23:37

INTERNATIONAL REVIEWS OF IMMUNOLOGY./..


Anti-infectious human vaccination in historical perspective Enrico D’Amelioa,∗ , Simonetta Salemic,∗ , and Raffaele D’Ameliob,c

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a Via Felice Grossi Gondi Rome, Italy; b Sapienza University of Rome, Department of Clinical and Molecular Medicine, Via di Grottarossa Rome, Italy; c S. Andrea University Hospital, Via di Grottarossa Rome, Italy



A brief history of vaccination is presented since the Jenner’s observation, through the first golden age of vaccinology (from Pasteur’s era to 1938), the second golden age (from 1940 to 1970), until the current period. In the first golden age, live, such as Bacille Calmette Guérin (BCG), and yellow fever, inactivated, such as typhoid, cholera, plague, and influenza, and subunit vaccines, such as tetanus and diphtheria toxoids, have been developed. In the second golden age, the cell culture technology enabled polio, measles, mumps, and rubella vaccines be developed. In the era of modern vaccines, in addition to the conjugate polysaccharide, hepatitis A, oral typhoid, and varicella vaccines, the advent of molecular biology enabled to develop hepatitis B, acellular pertussis, papillomavirus, and rotavirus recombinant vaccines. Great successes have been achieved in the fight against infectious diseases, including the smallpox global eradication, the nearly disappearance of polio, the control of tetanus, diphtheria, measles, rubella, yellow fever, and rabies. However, much work should still be done for improving old vaccines, such as BCG, anthrax, smallpox, plague, or for developing effective vaccines against old or emerging infectious threats, such as human-immunodeficiency-virus, malaria, hepatitis C, dengue, respiratory-syncytial-virus, cytomegalovirus, multiresistant bacteria, Clostridium difficile, Ebola virus. In addition to search for innovative and effective vaccines and global infant coverage, even risk categories should adequately be protected. Despite patients under immunosuppressive therapy are globally increasing, their vaccine coverage is lower than recommended, even in developed and affluent countries.

Accepted  July  KEYWORDS

History; infections; vaccinations; vaccines; vaccinology

Introduction Among the possible means to control infectious diseases, clean water and vaccination are, in the order, the most effective [1]. The results obtained through vaccination are easily demonstrated by both, epidemiological data [2,3] and the consideration that, for the first time in the history of mankind, one infectious disease, such as smallpox, has been eradicated following a clear strategy of vaccination campaign [4]. Thus, a brief history of vaccination allows this practice be adequately valued in the control of infectious diseases, as accurate expression of the scientific advances in the fields of microbiology, immunology and molecular biology. Moreover,

CONTACT Raffaele D’Amelio raff[email protected] Sapienza University of Rome, Department of Clinical and Molecular Medicine, S. Andrea University Hospital, Via di Grottarossa ,  Rome, Italy ∗ These Authors contributed equally ©  Taylor & Francis Group, LLC

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the antigen changes induced by the continuous mutual interrelationship between microorganisms and immune system, which are often unknown, are witnessed by the difficulty in developing effective vaccines towards parasites [5], mycobacteria [6], and RNA viruses [7]. The brief history of vaccination will be developed since the origin (the discovery of the Variola vaccine by Jenner and the introduction of the word “vaccination” [8]), through the first golden age (the period from Pasteur’s era to 1938), the second golden age (1940–1970, characterized by the discovery of cell culture technology), until the rationally designed, modern vaccines [9]. During the first golden age of vaccinology live attenuated [rabies, tuberculosis and yellow fever], inactivated [typhoid, cholera, plague and pertussis] and subunit [tetanus and diphtheria] vaccines have been developed. During the second golden age, instead, cellculture technology has allowed polio, measles, mumps, and rubella vaccines be developed. In spite of the undeniable merits of vaccines in the fight against infectious diseases, for a long time they have been developed empirically. Only recently, in consideration of the difficulties in obtaining a protective vaccine against human immunodeficiency virus (HIV), malaria or tuberculosis, the need to identify the correlates of protection for the different microorganisms has been underscored [10]. By this knowledge, vaccines and adjuvants able to selectively stimulate the protective immune response may be developed.

The origin Since the 10th century AD, trials in China to prevent/mitigate smallpox were reported. This could be obtained by the so called “variolation,” that is the inoculation of scab material from patients suffering of smallpox to healthy people, with the hope of inducing a protective mild disease. This practice, however, was not free from the risk of provoking smallpox [3]. At the end of the 18th century, the English physician Edward Anthony Jenner tried a new strategy, by inoculating humans with the material from cowpox blister instead of the material from human scabs. The trial was successful, by achieving an effective protection with a reasonable low risk of developing disease. This strategy was based on the observation that the farmers milking the cows infected by cowpox only caught a localized mild disease, but resulted protected towards the human smallpox. These data were published in 1798 and opened the era of vaccination [11]. The general practice of inoculating attenuated/inactivated microorganism to prevent infectious diseases was, in fact, named “vaccination” after the Latin word “vacca” which means “cow” [12]. It should be underlined that the association realized by Jenner of a sort of cross-protection between cowpox and smallpox is even more brilliant considering that it happened in a period when: (1) the germ theory was not yet established; (2) the reasons for the disease-spreading phenomenon were quite unclear; (3) the awareness of the immune system existence, with its operating rules, such as cross-protection, was lacking. Today we know that smallpox is caused by the Variola virus (major or minor according to the severity of the induced disease), pertaining to the Orthopoxvirus genus of the Poxviridae family, which also includes Vaccinia, Cowpox, and Monkeypox. All of them are potentially pathogens for human species. Vaccinia virus is often confused with Cowpox virus, based on the Jenner’s report that cowpox had been used, but they represent two distinct species of the Orthopoxvirus genus. During the 20th century, it was established that all available smallpox vaccines were based on Vaccinia virus [3]. Despite the quick success of vaccination in different countries, including the Americas and Asia, in addition to Europe, Jenner was even contested, also in relation to the priority of his discovery [13]. The smallpox in the 18th century killed an estimated 400,000 Europeans each year, was responsible of over 30% of all blindness and of the death of 20–60% of all infected patients. Still

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in 1967 it was estimated to be responsible of 15 million cases and 2 million deaths [14,15]. This vaccine, although quite reactogenic, has been very effective and systematically administered in many world countries. Already in 1812, the US War Department ordered that vaccination be substituted for variolation to prevent smallpox [16]. However, the limit for the worldwide vaccination was represented by the reduced viability of the liquid vaccine lymph during the transports, mainly to tropical areas. A real advancement, in the course of the first decades of the twentieth century, was achieved, therefore, with the dehydration before and lyophilization afterwards (during the First World War) of the lymph. Nevertheless, despite in the 50s of the last century smallpox was eradicated in many areas of Europe and North America, still in 1958 its consequences were catastrophic in 63 countries, thus stimulating the World Health Assembly (WHA) to set in motion the process of worldwide eradication [4]. The aggressive eradication campaign, planned by the World Health Organization (WHO) and headed by Donald Ainslie Henderson, started in 1967 and, after a decade, in 1977 the last case of natural smallpox was discovered in Somalia. The approved budget for eradication was $ 2.4 million/year for 10 years, compared with over $ 2.5 billion for the failed malaria eradication campaign between 1957 and 1975 [4]. After the successful eradication campaign, the WHO announced the disease eradication and recommended to cease vaccination worldwide. However, following the dramatic episode in the United States in 2001 of the anthrax-contaminated letters, lack of immunization for smallpox has been considered a vulnerability towards a bioterrorism threat. A renewed interest for a safer and at least equally effective vaccine has been, therefore, observed after over two decades since smallpox eradication. Smallpox has, in fact, been included among the most dangerous, category A, possible biological weapons [17]. This new situation induced the US Department of Defense (DoD) to reinstitute large-scale vaccination for the military personnel. Over 1,500,000 in the DoD and 39,000 individuals in the Department of Health and Human Services were, therefore, vaccinated in 2002 [18]. The possible future vaccines for smallpox include attenuated strains, such as the Modified Vaccinia virus Ankara (MVA), which has been attenuated over serial (> 500) passages on chicken embryo fibroblasts, or the fourth generation vaccines, represented by subunit, recombinant antigens, expressed by proteins or DNA genes [3].

The first golden age of vaccinology Despite the success in the fight against smallpox, the observation by Edward Jenner remained isolated for nearly a century. Times too early and lack of association between birth of vaccination and knowledge of microbiology and immunology prevented the extension to other infectious diseases of the principle that inoculation of an attenuated microorganism could protect from natural infection. This happened in the second half of the nineteenth century, when the chemist Louis Pasteur approached biology with scientific method, thus opening the era of microbiology and immunology, together with the contemporaneous Robert Koch. The first golden age spans a period of time ranging from Pasteur’s era to 1938.

Pasteur’s era In 1878, Pasteur discovered the bacterial etiology of the so-called fowl cholera—the agent was later named Pasteurella multocida in his honor. In the following year, the casual observation that the old bacterial cultures resulted attenuated [19] paved the way for applying vaccination to other infectious diseases [20,21]. The next interest of Pasteur was addressed to anthrax, the

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bacterial origin of which had been discovered by Robert Koch, who failed to obtain an attenuated bacterial strain in spite of serial subcultures [19]. Pasteur succeeded by preventing spore formation, thus a vaccine was prepared and tested in 1881 on animals; all vaccinated animals survived in good health following inoculation of virulent bacteria, whereas all the nonvaccinated animals died or fell severely ill in 2–3 days [22]. During the last century, anthrax human vaccines have been developed, either live in the former Soviet Union or acellular, including the protective antigen of the anthrax toxin, in the UK and United States. Despite the demonstrated safety and efficacy, the need for an innovative anthrax vaccine is highly felt, even in consideration that Bacillus anthracis, the etiological agent of anthrax, has been included among the most dreadful category A biological agents [17]. Thus, vaccines based on recombinant protective antigen of anthrax toxin are in phase 2 clinical trials [23]. Afterwards Louis Pasteur turned to the study of rabies, an almost invariably lethal disease for humans even today. He succeeded in attenuating the virus through different methods, including either the passage from dogs to monkeys or the desiccation of rabbit spinal cord followed by air exposure for 15 days [24]. The vaccine obtained by the second method was successfully tested for the first time in July 1885 on a 9-year-old boy bitten by a rabid dog [12]. Profiting from the rabies long incubation period, vaccination resulted protective in an already infected patient. It enabled to consider the vaccination use not only for the infection prevention in healthy people, but also for the treatment of already infected patients, provided that the incubation period be long enough. In addition to rabies, in which therapeutic vaccination in case of suspected bites is still used, a post-exposure protection has also been observed for hepatitis B (HB), hepatitis A (HA), measles, and varicella vaccines [25] and this approach has been tried, even though unsuccessfully as yet, in the search of a therapeutic vaccine for HIV. Soon after Pasteur’s discovery of the possibility to attenuate the bacterial virulence, other Authors took advantage of methods able to physically or chemically completely inactivate bacteria as a new vaccine source [26]. Thus, the first typhoid [27,28], cholera [29], and plague [30] vaccines, all consisting of killed whole bacterial bodies, were developed by the end of 19th century [31]. In contrast with the live attenuated, the inactivated vaccines are frequently safer, but generally less effective. Typhoid and cholera vaccines have, in fact, been replaced by more effective new vaccines, whereas the need for a more effective innovative vaccine for plague is felt principally in the light of the bioterrorism threat, considering that even Yersinia pestis, the etiological agent of plague, has been included among the most dreadful category A agents [17]. The new typhoid and cholera vaccines will be later reported, whereas plague has been updated by adding the live and the subunit (F1 and V) vaccines. However, studies analyzing the efficacy of the single plague vaccines or comparing the different vaccines are lacking, thus information is only coming from animal models [32]. A recombinant subunit plague vaccine is in advanced development, even though efficacy will only be explored in animal models before licensing, for ethical and practical reasons [33]. The great scientific credit earned and the important school founded by Pasteur enabled the network of Pasteur Institutes in France and in overseas African and Asian French colonies be organized. It has provided a substantial contribution to the development of vaccinology, as recently named the science which deals with the study of vaccines [34]. Tuberculosis In the first decades of the 20th century two new live as well as the bacterial-derived toxoid vaccines were developed. The live bacterial anti-tubercular vaccine Bacille Calmette-Guérin (BCG), after Albert Calmette and Camille Guérin, was for the first time successfully used in

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1921, after over 25 years of studies, interrupted by the first World War. BCG was orally administered to a 3-day baby, born to a mother who had died of pulmonary tuberculosis one day after delivery [35]. Mycobacterium tuberculosis, the etiologic agent of human tuberculosis, had been discovered in 1882 by Robert Koch [36], whose efforts to develop a vaccine had been, however, unsuccessful. Tuberculosis was very feared because widespread and burdened with high mortality, of the order of 300/100,000 in 1895 in Lille (France). In the same year Calmette, as Director of the Pasteur Institute in Lille, started his studies on tuberculosis, which eventually led to vaccine development [35]. Calmette and Guérin used, for vaccine preparation, Mycobacterium bovis instead of Mycobacterium tuberculosis, attenuated by several passages in a culture medium supplemented with sterile beef bile. They took advantage, in fact, of both the Jenner’s experience on the use of a different species related pathogen and Pasteur’s experience on the attenuation of microorganisms. Since 1921, BCG has been safely administered to approximately 4 billion subjects [35,37,38] and included among the vaccines provided by the Expanded Program on Immunization (EPI) of the WHO. In spite of the Lubeck disaster in 1930 (the administration of a BCG contaminated with virulent M. tuberculosis to 250 children caused 73 deaths and 135 infections who recovered [38]), and the incomplete protection provided by the vaccine, quoted in the range 0–80%, depending on the type of disease and population [39], BCG is still largely used. In particular, BCG is very effective against miliary and meningeal tuberculosis in < 5-year-old children, especially if not previously infected with M. tuberculosis or sensitized with environmental mycobacteria [40]. Although neonatal vaccination is cost-effective in high-burden countries [41], adult vaccination only provides little protection, especially against pulmonary tuberculosis, with a possible negative influence of decreasing latitude [40]. Moreover, it cannot be used as a booster, when the immunity wanes, generally after a decade [42], does not eradicate latent tuberculosis and does not prevent subsequent tuberculosis [43]. In HIV-infected infants evidence of protection exerted by BCG is limited and the risk of disseminated BCG very high (1100–4170 per million in HIV-infected infants versus 70% [43]. Consequently, WHO stated that HIV represents a full contraindication for BCG vaccination in infants, even though at high risk for tuberculosis infection [44]. Conversely, BCG has demonstrated to be protective towards other mycobacterial diseases, such as leprosy and Buruli ulcer, and capable to improve atopic disorders, nematode infections, bladder cancer, melanoma, and immune response to other vaccines [45,46]. Although BCG is only a partial solution to the problem of tuberculosis prevention, after nearly a century since its discovery no more effective vaccines have still been developed. It underlines the complex biology of the microorganism and of its interaction with the host. New live recombinant vaccines substituting BCG, or adjuvanted recombinant proteins, or viral vector expressing antigens, able to boost the immune response induced by BCG priming [prime-boost strategy], are currently under development [9]. Lack of availability of an effective vaccine, however, has influenced the poor disease control. This has been underlined by the WHO in the last decade of last century [47], by defining tuberculosis a global emergency, with about one third of the world’s population infected, a current annual estimate of nearly 9 million new cases and 1.7 million deaths [48]. Yellow fever The yellow fever is a viral disease transmitted by infected Aedes aegypti and Haemagogus species mosquitoes, endemic in Sub-Saharan Africa and tropical South America. It is responsible for 200,000 clinical cases and 30,000 deaths annually, according to WHO estimates. The live viral vaccine against yellow fever was prepared by Theiler and Smith, by attenuating the

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virus through passages in mice and chick embryos [49]. This vaccine, derived from an African patient (Asibi was his name, thus it was denominated the Asibi strain) with a relatively mild form of the disease, was successfully inoculated in a Macacus rhesus to reproduce the disease. Thus, the first laboratory model of the disease was obtained. Afterwards, this strain was attenuated through serial passages in the mouse brain, according to the Pasteurs method of attenuating rabies virus through passages in nonhost nervous tissue [50]. Meanwhile, Andrew Watson Sellards, from the department of tropical medicine at Harvard, was in Dakar, Senegal, to study a local outbreak of yellow fever and he heard of the success with Asibi strain. He joined Constant Mathis, the Director of the local Pasteur Institute, and Jean Laigret, who was responsible of the health defense to control the outbreak. Laigret had injected the blood from a patient with mild yellow fever into a rhesus monkey, thereby producing a severe form of the disease. This strain, attenuated through serial passages on mice brain and described by Sellards, Mathis and Laigret [51], was named French strain as opposed to Asibi strain. Both have been used as vaccines. The Asibi strain was used together with serum antibodies to reduce its virulence, whereas the French strain, which could induce fever and central nervous system reactions, was used in combination with smallpox vaccine. Both, in fact, could be administered by scarification. The two vaccine strains coexisted until 1982, when the French strain ceased to be produced. During the passages for attenuation, in fact, both strains, while reducing hepatotropism, increased neurotropism. However, only the Asibi strain, after the hundredth passage in nervous tissue-deprived chick embryo, showed a markedly reduced neurovirulence, being unable to kill intracerebrally-inoculated mice. Denominated 17D strain [52], it was used by Fred L. Soper, of the Rockefeller Foundation, in 1938 in a large vaccination campaign in Brazil, on nearly one million inhabitants, thereby proving its safety and efficacy [53]. It is still used, mainly when traveling to endemic countries, for which vaccination is compulsory, according to the international health regulations [54]. Despite the search for a safe and effective yellow fever vaccine has been a joint effort of different researchers, only Theiler was awarded the Nobel Prize in Physiology and Medicine in 1951, for his discoveries on yellow fever and how to combat it. Recently, after many decades of successful use of this vaccine, some insights have been provided on how it works. It strongly stimulates, in fact, innate immunity, through the activation of different Toll-like receptors on dendritic cells. These cells release pro-inflammatory cytokines, as interleukin (IL)12p40, IL6 and interferon (IFN)α, eventually leading to a mixed T helper (Th)1/Th2 cytokine profile and antigen-specific CD8+ T cells [55]. More recently, the same group [56] and another [57], independently and successfully, applied the systems biology approach to this vaccine for the first time. Briefly, they: (1) confirmed the anti-viral response, with activation of IFN type I pathway; (2) observed the activation of genes involved in the regulation of complement and inflammasome; (3) identified the genes able to predict neutralizing antibodies and specific CD8+ T-cell response. Tetanus, diphtheria, botulinum, and toxoid vaccines The recognition in 1888 by Émile Roux and Alexandre Yersin [58] and in 1890 by Faber [59] of the relevance for virulence of the toxins, in Corynebacterium diphtheriae and Clostridium tetani [60], led to vaccine preparation. Vaccines have been performed through the toxoids, that is the formaldehyde-inactivated toxins, by Gaston Ramon in 1923 and 1926, respectively [61,62]. Toxoids maintain an acceptable antigenicity, while losing the toxin virulence. These vaccines resulted very effective, thus inducing an excellent control of diphtheria and tetanus. At the end of the second World War, a formaldehyde-induced toxoid vaccine for protection towards Clostridium botulinum toxins was even developed in the United States. The toxins are



seven, from A to G, four of which (A, B, E and F) cause naturally occurring human botulism, with the other ones causing human botulism only at high doses. Consequently, the vaccine was before developed as bivalent (A/B), afterwards as pentavalent (A-E). It was only released as investigational new drug (IND) for at-risk-workers and the military. Clostridium botulinum has, in fact, been included among the most virulent category A biological agents [17]. More recently also recombinant adjuvanted molecules, corresponding to a part of toxin or to the whole molecule devoid of its catalytic activity, have been developed and tested as possible vaccines [63].

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Pertussis In this period also whole-cell pertussis vaccine has been prepared, through Bordetella pertussis inactivation [64], usually by heating. The vaccine, mostly combined with tetanus and diphtheria toxoids (the trivalent DTP vaccine has been included in the EPI by the WHO), proved effective, but also able to induce local and systemic adverse events. The former have been especially observed in adolescents and adults, for whom it is, therefore, recommended at a reduced dose [65]. The introduction of the whole-cell inactivated vaccine in the forties of the last century in the United States has enabled annual cases, which were nearly 200,000 in the pre-vaccine era, be gradually reduced until approximately 1,000 in 1976. In the developing countries, pertussis is still a problem, with 89,000 estimated deaths in 2008 [66]. However, in the United States, starting from the eighties of the last century, a progressive increase of annual cases, even in adolescents and adults, for still unclear reasons, has been observed, with over 48,000 cases in 2012 [67]. Among the developed countries, increased case incidence seems to be observed in the United States only. In Italy, an epidemiological study performed in the 90s of the last century in the military enabled to exclude a situation like the one observed in the United States [68]. The need for a systematic administration of an additional booster vaccine dose in the USA adulthood should therefore be evaluated and in case recommended. Influenza In the first half of the 20th century, the viral nature of influenza was discovered, the influenza viruses characterized and cultivated in chick embryo tissue [69]. Thus, the first live influenza vaccines were developed and tested in the 30s of the last century [70,71]. A few years later the first killed influenza vaccine, effective although reactogenic, because poorly purified, was developed [72]. Since then, the inactivated influenza vaccine has been purified, in order to only include subunits, represented by the viral proteins necessary for host infection (haemagglutinin [HA]) and viral spread (neuraminidase [NA]). These may slightly (drift) or profoundly (shift) mutate, each year or with unpredictable periodicity, respectively. Thus, multivalent vaccines, including the subunits from circulating strains, have been developed. Recently, a live nasal influenza vaccine has been licensed in the United States and comparatively studied with the inactivated one through the systems vaccinology approach. The live vaccine, like the yellow fever vaccine, was able to stimulate the type I IFN response, but it was less effective in stimulating a systemic antibody response. Interestingly, the relevance of the gene product calcium/calmodulin-dependent kinase IV in the negative regulation of antiinfluenza antibody response, never appreciated before, has been observed [73]. The two vaccines have similar effectiveness in preventing influenza-like illness and influenza/pneumonia events in healthy adults [74]. However, they work through different mechanisms: live vaccine,



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in fact, in analogy with natural infection and live polio vaccine, stimulates immune system at mucosal level, with consequent local and systemic immune response [75], including specific cell-mediated immunity [76]. Inactivated vaccine, instead, especially works through the stimulation of circulating antibody-secreting cells [73]. Whatever the route of administration and the mechanism of action, influenza vaccines, deriving from an RNA virus, are characterized by high antigenic variability, which reduces the effectiveness and makes the annual vaccine repetition a need. However, experimental and clinical trials have recently been performed for “universal” vaccines. They may be obtained by including in the vaccine composition viral invariant proteins, such as the M2 ion channel protein and the stalk domain (HA2) of the haemagglutinin [75,77].

Cell culture technology and the second golden age of vaccinology In the middle of the 20th century, the cell culture method was adapted to grow viruses. Moreover, it was also recognized to be able to fortuitously select less virulent strains, thus fit to directly develop viral vaccines [31,78]. For their discovery of the ability of poliomyelitis viruses to grow in culture of various types of tissue John F. Enders, Frederick S. Weller and Thomas H. Robbins were awarded the Nobel Prize for Physiology and Medicine in 1954. This achievement enabled to isolate, maintain and attenuate a viral vaccine strain in the laboratory, instead of to be forced to look for an animal model, as performed before. In the second half of the 20th century different live attenuated or inactivated viral vaccines have, therefore, been developed, including polio, measles, rubella, and mumps [31]. In this period, mainly during World War II, the need to protect the military represented an important stimulus to produce large quantities of the inactivated typhus and influenza vaccines and to develop the inactivated Japanese B encephalitis vaccine [79]. The mosquitotransmitted etiologic agent of Japanese encephalitis is a flavivirus, similar to West Nile virus. More recent Japanese encephalitis virus vaccines are cell cultured, live attenuated, and highly safe and immunogenic. The annual incidence is of 50,000–175,000 cases, with a mortality of 20–30% and permanent sequelae in 30–50% of the survivors. Even a recombinant, live attenuated, vectored chimeric yellow fever-Japanese encephalitis vaccine has been developed and is commercially available in Australia and Thailand [80]. Poliomyelitis The history of the development of the polio vaccines, which are included among the most significant advances of the last century, is worth being briefly reported for their relevance in the control of this dreaded disease. Until the middle of the last century in many world countries periodical poliomyelitis outbreaks struck children, adolescents and adults, with a mortality rate of paralytic cases which was 2–5% for children and 15–30% for adults [81]. During the first half of the century, it was established that polio is caused by viruses, which may infect the host by oral route [82] and that the viral strains are three [83]. Moreover, it was also observed that oral infection was accompanied by a transient intestinal carrier state and a viremic phase. The induced specific antibodies were found to be protective. This information was crucial for designing inactivated and oral vaccines, which were thus developed [84,85,86]. First Jonas Salk developed a formaldehyde-inactivated parenteral vaccine [87], which was adopted by United States in 1955 and largely used [88]. This vaccine led to a decrease of the incidence of paralytic cases from 13.9/100,000 in 1954 to 0.8/100,000 in 1961 [89], although the accident of Cutter Laboratories, Berkeley, had caused 260 cases of poliomyelitis and 10 deaths, due

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to a failure of vaccine virus inactivation. In 1987, an inactivated polio vaccine of enhanced potency was licensed in the United States [90]. The history of oral polio vaccine, instead, consists of the independent efforts of at least three groups of researchers in the United States, led by Hilary Koprowsky at the Wistar Institute in Philadelphia, Herald Cox at the Lederle Laboratories and Albert Sabin, at the Children’s Hospital Research Foundation in Cincinnati. First Koprowsky developed a type 2 strain rodent-adapted oral vaccine [91]. A few years later, Herald Cox developed another oral polio vaccine, by using viral strains, some of which related to the strain of Koprowsky, who had originally been at Lederle Laboratories, together with Cox. Albert Sabin started his work on oral polio vaccine in 1953 and chose polio strains cultivated in cynomolgus monkey kidney, driven by the prior work of Ender’s group [92]. He obtained a live attenuated oral vaccine, which was considered less neurotropic than the other two oral vaccines, thus licensed at the beginning of the 60s of the last century [93]. The easy oral administration, which is the same route of the natural infection (polioviruses are, in fact, enteroviruses), the consequent consideration of a double level of defense, mucosal and circulatory, and the long-lasting protective immune response [92], in addition to its low cost, determined the success of the Sabin’s vaccine. It was, in fact, adopted in many world countries and inserted in the EPI by the WHO. In 1972 Sabin donated his vaccine strains to the WHO [92]. Although the live attenuated vaccine may very rarely induce paralytic polio in vaccinated subjects, generally for a reverse to virulence of attenuated viruses, particularly the type 3 (patients affected by humoral immunodeficiency are at special risk), the vaccine role in polio control has been so relevant that the current WHO plan foresees a polio eradication by 2018 [94]. Should this goal be achieved, polio would be the second eradicated infective disease, after smallpox, both as a consequence of vaccine use.

Adenoviruses In the same period, at the Walter Reed Army Institute of Research in United States, Maurice Hilleman, a scientist with a central and unprecedented role in vaccinology for the high number of developed vaccines, discovered the adenoviruses and produced a killed vaccine, which was licensed in 1958 for pediatric use [79]. A live oral bivalent adenovirus vaccine was approved for the use in the military only and administered since 1971 until 1999, when it was interrupted for more than 10 years and restored in 2011 [95].

Measles, mumps and rubella In the 50s of the last century, Enders and colleagues succeeded in preparing the attenuated Edmonston B viral strain for measles vaccine, which was licensed in the United States in 1963 [96]. Maurice Hilleman and colleagues, instead, could isolate and develop the attenuated mumps vaccine strain Jeryl Lynn, after Hilleman’s daughter [97], as well as a live attenuated rubella vaccine strain [98]. The efficacy of the trivalent live attenuated measles/mumps/rubella (MMR) vaccine in male adults was calculated to be nearly 95% for measles and rubella [99], lower for mumps, probably as a consequence of poor viral attenuation [100]. Measles vaccine has been included in the EPI by the WHO. However, measles cases are still too many and on the increase from 2010 to 2011 in Europe, Africa, South East Asia, and Eastern Mediterranean Region [101], thus inducing the WHO to revise and postpone the WHA 2010 measles eradication goal to be achieved by 2015. The Global Measles and Rubella Strategic Plan, in fact, considers measles elimination in at least five of six WHO regions by 2020. MMR coverage



has been, at least temporarily, reduced in many countries, as a consequence of a presumed association MMR/autism [102,103], later on retracted by Lancet [104].

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The modern era of vaccines—the advent of molecular biology This period corresponds to the last three decades of the last century and is principally marked by the advent of molecular biology. However, not all the vaccines produced in those years have been obtained by molecular biology. Some vaccines have, in fact, been performed according to traditional methods. Sometimes both, recombinant and traditional vaccines have been developed towards the same microorganism (this is the case for HB virus, rotavirus and cholera) and may coexist (rotavirus and cholera only). Moreover, an increasing attention to the study of vaccine immune response has also been provided, as demonstrated by the conjugate polysaccharide vaccines. HB vaccines and recombinant vaccines The HB virus was first identified by Baruch S. Blumberg in 1964 in an Australian Aborigenal person and called Australia antigen, later identified as the viral envelope protein [105]. In 1968, Alfred Prince associated this antigen with the serum hepatitis[106]. Baruch Blumberg in 1976 was awarded, together with D. Carleton Gajdusek, the Nobel Prize in Physiology and Medicine for their discoveries concerning the replication mechanism and the genetic structure of the viruses. HB virus is transmitted from mother to son, through infected blood or blood products and through sexual intercourse. More than 90% of infected people recover spontaneously, whereas approximately 10% proceed to chronic state. This especially happens in infants, who cannot clear the virus for the immune system immaturity. HB virus is responsible for an estimated 240 million subjects chronically infected in the world, about 780,000 of whom are estimated to yearly die as a consequence of acute infection, cirrhosis or hepatocellular carcinoma [107]. Thus vaccine prevention is pivotal. The first vaccine was obtained by Maurice Hilleman in Merck from seropositive plasma, chemically treated to inactivate any possible virulence [110]. However, the contemporaneous advances in molecular biology led to the development of the first recombinant vaccine represented by the engineered HB surface antigen, the gene of which had been inserted in a yeast, which was licensed in 1986 [108,109]. This innovative vaccine replaced the plasma-derived [110], which had been licensed in 1981 and proven to be safe and effective [79]. Currently, at least 183/194 WHO Member States vaccinate their infants for HB, thus it is predictable that HB virus infection will be largely controlled within the next few decades [107]. After a few years, the recombinant acellular pertussis vaccine was developed [111]. It replaced the much more reactogenic former whole-cell pertussis vaccine. Although safer, acellular pertussis seems to be less protective than the other. This may be due to the different immunological components stimulated by the 2 vaccines. The former, alum-adjuvanted, able to preferentially stimulate Th2 (poorly effective in defense) and Th17, but scarcely Th1, and the latter able to strongly stimulate Th1 and Th17, both effective in protection [112]. Two recombinant vaccines were developed for Lyme disease, both composed of the Borrelia burgdorferi outer surface protein A. The first was licensed in 1998, whereas the other was never licensed. As a consequence, in fact, of public concern about adverse events (fear of a never demonstrated vaccine-induced arthritis) and other considerations, including efficacy of approximately 80%, lack of available safety and immunogenicity data for 50-year-old people, and safety comparable to placebo, excepting the solicited local and systemic adverse reactions, which were higher in the vaccine group [141]. In 1994, a very effective, killed HA vaccine, based on the pioneering studies of Hilleman et al. [76], was developed and licensed. This vaccine has demonstrated its usefulness mainly in travelers, to whom, isolated or combined with HB vaccine, may be offered [142]. The possibility to move from an animal model to cell culture methods to grow viruses has enabled to develop effective inactivated vaccines for rabies virus from human diploid or chick embryo cells [143], which may be used in both, pre- and postexposure prophylaxis.

Polysaccharide and conjugate vaccines In the seventies of the last century, following a long interval since the pioneering studies on Streptococcus pneumoniae [144], the plain polysaccharide vaccines for Hib [145], Neisseria meningitidis [146] and Salmonella typhi [147] were developed. Capsular polysaccharides, in fact, may directly stimulate B cells to synthesize protective antibodies, without Tcell intervention. T-independence, however, involves: (1) less effective and short-lasting antibody response, principally oligoclonal [148]; (2) poorly protective immune response in < 2year-old infants for limited switching to IgG2 [149], the main defensive IgG subclass against polysaccharide antigens; (3) lack of memory cell induction. Despite undeniable merits in controlling the diseases induced by the above reported microorganisms in the adults, a series of considerations led to the replacement of plain polysaccharide by conjugate vaccines. These include the poor response in infants, who are preferential targets for the majority of the considered diseases, the less effective and short-lasting immune response, but principally the recently demonstrated responsibility in the progressive reduction of the immune repertoire for lack of memory effect. Conjugate vaccines were obtained according to the method set up by Amery already in 1929 [150], examined in depth by Jennings [151] and realized by Hilleman’s group [152] and others [153,154,155,156], since the 80s of the last century until more recently [157,158]. Conjugation, in fact, with a largely known protein antigen, such as diphtheria and tetanus toxoids, not only transforms T-independent into T-dependent antigens, but also stimulates the immune response, through the recruitment of bystander helper T cells [159]. However, the technical problems of conjugation are also related to the right protein/polysaccharide ratio and the number of polysaccharides to be conjugated to protein. This may be a special problem for Streptococcus pneumoniae, which includes more than 90 different serotypes. Recently, a 13-valent conjugate pneumococcal vaccine has been developed and licensed [160]. The high cost due to technical problems of conjugation and the limited protection, especially in the geographical areas characterized by high prevalence of serotypes not included in the vaccine, prompted some researchers to explore alternative routes for developing cheaper and universally protective vaccines. Trials have been done with the surface pneumococcal proteins A and C, but recently the whole cell vaccine, already tried nearly a century ago, has proved cheap, successful and able to mediate protection through specific antibodies and Th17 cells [161,162].



Table . Main human vaccine characteristics with the approximate year of availability and the main vaccine developer(s).

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Variola Rabies Typhoid

Live attenuated Live attenuated Inactivated

  

Cholera Plague Tuberculosis Diphtheria Tetanus Whole-cell Pertussis

Inactivated Inactivated Live attenuated Subunits (toxoid) Subunits (toxoid) Inactivated

     

Yellow Fever Influenza Polio Streptococcus pneumoniae Polio Measles Mumps Rubella Neisseria meningitidis Adenoviruses Haemophilus influenzae type b Typhoid Hepatitis B

Live attenuated Inactivated Inactivated Subunits (polysaccharides) Live attenuated Live attenuated Live attenuated Live attenuated Subunits (polysaccharides) Live attenuated Subunits (polysaccharides)

          

E Jenner [] L Pasteur [] R Pfeiffer, W Kolle [], AE Wright [] J Ferrán [] W Haffkine [] A Calmette, C Guérin [] G Ramon [] G Ramon [] AH Mayer, M Kristensen, E Sörensen [] M Theiler∗, HH Smith [] JE Salk [] JE Salk [] CM McLeod [] AB Sabin [] JF Enders∗ [] MR Hilleman [] MR Hilleman [] EC Gotschlich et al. [] MR Hilleman [] JB Robbins, R Schneerson []

Live attenuated Subunits (s antigen) plasma-derived Subunits (s antigen) recombinant Live attenuated Conjugated protein/polysaccharide Conjugated protein/polysaccharide Conjugated protein/polysaccharide Subunits (toxin) recombinant Subunits recombinant Inactivated Conjugated protein/polysaccharide Live attenuated reassortant Subunits (OspA) recombinant

 

R Germanier, E Füer [] MR Hilleman []

  

P. Valenzuela et al. [], WJ McAleer [] M Takahashi [] R Schneerson et al. []


R Schneerson et al. []


SC Szou et al. []

   

R Rappuoli et al. [] R Kirnebauer et al. [] MR Hilleman [] CK Fairley et al. []

 

HF Clark, et al. [] SmithKline Beecham []

Hepatitis B Varicella Haemophilus influenzae type b Streptococcus pneumoniae Salmonella typhi Vi Acellular Pertussis Papillomavirus Hepatitis A Neisseria meningitidis Rotavirus Lyme disease

∗ Nobel prize winners (JF Enders not for developing measles vaccine, but for the ability to grow polioviruses in cultures).

A list in chronological order of the main developed vaccines is reported in Table 1, whereas the classification of vaccines with the corresponding types of immune response is summarized in Figure 1.

The biological weapons threat In 1999, the Centers for Disease Control and Prevention (CDC) in the United States, prompted by the fear that microorganisms could be used as weapons, convened a meeting in Atlanta, in order to classify the biological agents according to the level of danger [17,163,164]. The agents were classified into three categories, the most dangerous category A, followed by B and C. In the category A, the included microorganisms were represented by Variola major, the etiologic agent of smallpox, Bacillus anthracis, the etiological agent of anthrax, Yersinia

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Figure . Vaccine classification and corresponding types of immune response.

pestis, the etiological agent of plague, Clostridium botulinum (botulinum toxins), the etiological agent of botulism, Francisella tularensis, the etiological agent of tularemia, Filoviruses and Arenaviruses (e.g., Ebola virus, Lassa virus), the etiological agents of viral hemorrhagic fevers. For all these agents, vaccines are either unsatisfactory or lacking, thus further justifying their inclusion among the dreadful category A agents. Considering that the diseases caused by these microorganisms are either eradicated or relatively uncommon, the stimulus to develop safer and more effective vaccines is weak and principally driven by the fear that they could be used in bioterrorism context. However, the progress towards new vaccines have been already reported for smallpox, anthrax, botulinum toxins and plague, whereas for Francisella tularensis and Ebola are reported below. Francisella tularensis is a Gram-negative bacterium with the potential to induce lifethreatening human diseases, including the glandular form, pneumonia and septicemia, and it results infectious for even low inhalant doses. Killed vaccines have been proven ineffective and a live vaccine strain (LVS) exists as investigational new drug (IND) offered to at-risk laboratory personnel. Recently recombinant attenuated derivatives from a virulent category A strain, SCHU S4, were tested in rabbits. Two out of these derivatives showed partial protection (27–36%) against death, a result better than with LSV, thus providing the first demonstration of protection in an animal species other than a rodent [165].

The twenty-first century and future prospects The current century shows the increasing trend to move from an empirical vaccine development to a rational design [166]. Genetic engineering allows the development of a number of applications [31]. They consist of the vectored vaccines, that is the inclusion of genes coding for

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the protein antigens in live attenuated viral or bacterial vectors [167], such as poxviruses, adenoviruses, BCG [31], Salmonella or Listeria. These latter vectors enable to immunize through the mucosal route [9]. Another possible application is represented by the reverse genetics, that is the preparation of DNA complementary (cDNA) to viral negative RNA strands and reconstitution of the viruses through co-infection of cells with those cDNA plasmids [168,169]. Finally, the reverse vaccinology, that is the inclusion of a microbial gene in Escherichia coli, in order to evaluate the possible interest of the coded proteins for vaccine development [170], thus moving the focus of attention from the microorganism to its genome [171]. By this last approach an effective vaccine against Neisseria meningitidis serogroup B has been recently developed [172]. Its capsular polysaccharide is, in fact, poorly recognized by the immune system. This vaccine includes three proteins present in the majority of meningococcal B strains able to stimulate protective response. By comparative genome analysis an effective vaccine against Streptococcus agalactiae, one of the leading causes of childhood invasive infections in USA and Europe and also an emerging threat in the elderly, has been designed [170]. By reverse vaccinology, the acellular pertussis vaccine has also been realized, and vaccines able to replace the conjugate ones, mainly those with several polysaccharides, may perhaps be developed in the future [173]. Synthetic DNA vaccines appear very promising, but they have not yet been licensed in humans, due to their low potency. However, recent technological advances have generated renewed interest for this new type of vaccines also in humans [174]. Systems vaccinology is a modern approach to the study of vaccine immunity, adopted from systems biology, which describes, in an interdisciplinary and systematic way, the complex mutual interactions among the different components in a biological system, thus analyzing it as a whole. Systems vaccinology has already demonstrated its capacity to predict the response to a vaccine even at individual level and to deepen the scientific knowledge of the immune response to vaccine [175]. Systems vaccinology implies different technologies, including modern mass spectrometry and different microarrays (DNA, antibody and pathogen proteome) [176]. Moreover, identifying molecular signatures which are early expression of different immune functions may help to discover new correlates of protection [175]. Thus, systems vaccinology is a very promising study approach, which has already provided convincing evidence of its extreme potential. In the approximately 130 years since Pasteur’s time, although the principle of attenuation/inactivation has generally been successfully applied, the difficulty in developing effective vaccines in different diseases enabled to realize that it does not always work. BCG, lack of effective vaccines for malaria and HIV, the difficulty in developing effective vaccines for RNA viruses, due to their high variability, witness that a deep knowledge of the microorganism biology and the relative correlates of protection are required in order to design effective vaccines [177]. In particular, the need for yearly influenza vaccine administration, as a consequence of drifted annual antigenic modifications, and the lack of vaccines for hepatitis C virus (HCV) and HIV are examples for such complexity. Moreover, the best vaccines are those addressed towards microorganisms which are completely and permanently cleared by the immune response. Conversely, no effective vaccines have been developed towards microorganisms which are barely challenged by the immune system, such as HCV, HIV, respiratory syncytial virus (RSV), cytomegalovirus, Pseudomonas aeruginosa, Staphylococcus aureus and malaria [9]. Furthermore, in some viral infections, the presence of specific antibodies may not result in protection, but, as in the case of dengue, in infection enhancement [178]. However, despite this possible enhancement, very recently a recombinant, vectored (attenuated 17D yellow fever vector), live, tetravalent dengue vaccine has been used in phase 3 clinical trials in Latin America and Asia in 9- to 16-year-old children. It has been demonstrated to be

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safe and effective. Vaccine efficacy versus placebo, after a three-dose immunization schedule, against virologically confirmed dengue cases of 60.8%, hospitalization for dengue of 80.3% and severe dengue of 95.5%, has been demonstrated [179].Dengue is a mosquito-transmitted viral disease, caused by four different subtypes, responsible for an estimated annual 390 million infected subjects, approximately one quarter of whom are symptomatic [180]. HCV is a flavivirus responsible for an estimated chronic infection of 130–150 million patients and annual death of 350,000–500,000 people worldwide [181]. The current efforts for an HCV vaccine are addressed towards the prime-boost model. Priming with a chimpanzee adenovirus and boost with the MVA as vector, expressing a non structural region from a genotype 1b virus with genetically inactivated RNA-dependent RNA-polymerase activity (NS5b), in order to induce specific T-cell response, is under study [182]. Hepatitis E virus induces a generally self-limiting disease transmitted through fecal-oral route, with a mortality of 1–3%, which may even reach 25% in pregnant women. It is responsible for an estimated worldwide annual 20 million infections, over 3 million of which acute, and an estimated over 56,000 deaths [183]. A recombinant vaccine has been developed and licensed in China and recently it has been demonstrated to induce specific antibodies and protection lasting up to 4.5 years [184]. The history of the efforts spent in the search for an effective HIV vaccine is very instructive as expression of the difficulties encountered in case of a very variable microorganism, able to escape the immune system reaction. In particular, the first trials to develop vaccines including the gp 120 Env protein have been unsuccessful [185,186], as well as the adenovirus vectored vaccine containing clade B Gag, Pol and Nef, without Env, with the intent to activate cellular immune response. Actually, despite the appearance of specific anti-Pol and Nef CD8+ T-cell response in the majority of vaccinees, viral levels were not decreased [187,188,189]. More recently, a phase III study in Thailand of 2 HIV vaccines in combination, one canarypox vector encoding Gag, Env and protease for priming and one recombinant subunit Env gp 120 for boosting (prime-boost strategy), has achieved 31.2% of protection. Although low, it is the first demonstration that protection from HIV may be vaccine-induced. Furthermore, the correlates of protection have been identified in antibodies specific for V1 and V2 variable regions of gp 120 [190,191]. Currently, biotechnological approaches may help identifying invariant relevant epitopes even in RNA hyper-variable viruses, such as HIV and influenza, through the use of broadly neutralizing monoclonal antibodies [192,193,194,195]. The rational design of universal influenza and HIV vaccines may, therefore, be facilitated. Moreover, the conceptual design of innovative vaccines may also take advantage of and be driven by deep sequencing. That is the capacity to generate millions of sequence of the immunoglobulin genes, to identify intermediates to maturation of the broadly neutralizing antibodies [195,196,197]. RSV is responsible for the induction of low respiratory infections in approximately 30 million children annually, 10% of whom require hospitalization, and of approximately 200,000 deaths, generally in < 5-year-old children. RSV may interfere with the host immune system, by stimulating inflammation and a Th2 cell population able to dampen cytotoxic T cell activity and viral clearance. Despite efforts for developing a vaccine date back to the sixties of the last century, no vaccine has been approved and licensed yet. This may at least partly be linked to the unsuccessful formalin-inactivated RSV (FI-RSV) vaccine, which was able to stimulate a florid, non-protective, antibody response. Rather, the disease with wild-type RSV was more severe than in non-vaccinated subjects, and two vaccinated children died with a clinical picture of lower respiratory infection and the presence of RSV in the lungs [198]. The reasons for such behavior are not completely understood; it has been hypothesized that formalin was

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able to inactivate protective epitopes, thus stimulating the synthesis of non-protective, nonneutralizing, antibodies, and even failing to induce protective CD8+, RSV-specific, cytotoxic T-lymphocytes [199]. FI-RSV vaccine failure witnesses the difficulty of vaccine development, if the virus biology is not completely known and the approach to vaccine preparation is largely empirical. The majority of vaccines currently under study are at preclinical phase and only two attenuated vaccines have been successfully tested in infants through intranasal route [200]. Cytomegalovirus is a herpesvirus, which represents the most frequent cause of congenital birth defect, with an estimated 0.6% annual incidence. Moreover it may cause severe diseases in immune- compromised individuals, such as transplant recipients. The search for a safe and effective vaccine is, therefore, of pivotal relevance. Recently, by a method denominated “analytic vaccinology”, consisting in the careful analysis of the specific anti-cytomegalovirus antibodies, in order to identify the neutralizing epitope(s), it has been possible to identify a highly immunogenic pentamer. It was capable, in fact, to elicit, when administered to mice in Chinese hamster ovary (CHO) cells, powerful neutralizing antibody response, at a titer 1,000-fold higher than those found in the sera of convalescent donors [201]. Pseudomonas aeruginosa is a gram-negative bacterium, particularly resistant to antibiotics, able to induce life-threatening infections in immune-compromised patients, thus making the search for an effective vaccine urgent. Several P. aeruginosa antigens have been tested as candidate vaccines, including lipopolysaccharide O antigens, flagella, outer membrane proteins, and antigens of the type III secretion system, but they, although protective and promising, have not yet provided conclusive results [202]. Staphylococcus aureus is a gram-positive microorganism, causing life-threatening infections in humans, equipped with several virulence factors and able to evade the defensive activity of the immune system. Moreover, it is resistant to the majority of the antibiotics. This makes the search for a vaccine necessary but difficult, for a series of reasons, including the need for vaccine to contain different virulence factors, which are often poorly known, and the lack of knowledge of the correlates for protection. However, very recently a candidate combination vaccine, including five different virulence factors in its composition, mixed with a new alum adjuvant linked to a Toll-like receptor 7 agonist, was able to protect nearly 100% of mice challenged with four different staphylococcal strains. Protection was associated to high specific antibody titers and Th1 skewed immune response. Moreover, low frequencies of Th17 cells were also present [203]. Malaria presents a global annual incidence of approximately 200 million people and 1.2 million deaths [204]. Recently, after decades of unsuccessful trials, a phase III trial of a recombinant vaccine containing 2 antigens, one circumsporozoite protein and the surface antigen of HB virus, with the adjuvant AS01, showed 55% of protection in 5- to 17-month age group, but lower (34.8%) in 6- to 12-week-old infants [205]. Despite incomplete protection, this vaccine seems to be the first reliable malaria vaccine candidate to move forward. Ebola hemorrhagic fever is a high mortality, dreadful disease, induced by one filovirus, first described in 1976 in Africa, in a border area between south of Sudan and north of the former Zaire, and episodically reappearing in self-limiting outbreaks. Ebola virus, together with other filoviruses and arenaviruses, like Marbourg and Lassa, has been included among the dreadful category A biological agents. The last Ebola epidemic in West Africa, which has started in the first half of 2014 and is still ongoing, at the end of May 2015 has registered over 27,000 infected patients, over 11,000 (41%) of whom died. A candidate vaccine, formed by the vesicular stomatitis virus (rVSV) as vector, genetically modified to express Zaire strain Ebola virus glycoproteins (rVSV-ZEBOV), developed by NewLink Genetics and Merck Vaccines

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USA in collaboration with the Canadian Public Health Agency, after having successfully concluded a Phase I clinical trial last January [205], is currently in phase II and phase III clinical trials in Guinea and Sierra Leone. The strategy will be ring vaccination, that is the vaccination of contacts of confirmed, probable and suspected cases, the same strategy used for the successful smallpox eradication. Moreover, the vaccine will be offered to frontline health care workers. The interim analysis has shown that rVSV-ZEBOV might be highly effective and safe in preventing Ebola [206]. Another vaccine, the chimpanzee adenovirus vectored recombinant vaccine (chAd3-ZEBOV), developed by GlaxoSmithKline in collaboration with the US National Institute of Allergy and Infectious Diseases, has successfully completed phase I clinical trial last January, is performing phase II clinical trial and planning phase III. Johnson & Johnson, in association with Bavarian Nordic, has developed a heterologous prime-boost vaccine, known as Ad26-EBOV and MVA-EBOV, currently in phase I clinical trial. Novavax, a biotech company in the USA, is developing a recombinant Ebola vaccine based on Guinea 2014 Ebola strain. Finally, Russian Federation is developing different Ebola candidate vaccines, some of which vectored with influenza virus (phase I trial will start in the second half of 2015), or adenovirus or VSV or recombinant rabies virus [207]. Clostridium difficile is annually responsible in the USA alone of an estimated 500,000 infections and 15,000–20,000 deaths with an annual cost of approximately $ 3.2 billion [208]. Considering that this infection is on the increase and that hyper-virulent strains are emerging, the problem to develop protective vaccines has been faced since a few years. Despite many candidates have been identified, some perplexity still remains on the optimal vaccine composition, in order to completely detoxify the toxins and act not only for improving symptoms but also for avoiding colonization [209].

The adjuvants The more the antigens are purified the less they are immunogenic, thus they need to be associated with an adjuvant, that is a substance capable of increasing the immune response. The term “adjuvant” comes from the latin adjuvare, which means “to help.” It was used for the first time by Ramon to denominate the substances (tapioca, saponin, agar, etc.) used to increase the immune response to diphtheria and tetanus toxoids [210]. For more than 70 years, the only approved adjuvant for human use was represented by aluminum phosphate or hydroxide (alum), which works by stimulating inflammasome, Th2 and humoral immune response, but poorly Th1 [211]. More recently, other adjuvants, single or alum-associated, have been approved, able to more strongly stimulate antibody response and induce a shift from Th2 to Th1 [212]. Among the different candidates for alum substitution, phospholipid bilayer vesicles (liposomes) are very promising. Virosomes (liposomes composed by influenza membrane lipids and glycoproteins, supplemented with phosphatidylcholine [PC]) are included in licensed influenza and hepatitis A vaccines since 1997 [213]. Moreover, MF59, an oil-in-water emulsion, including a low percentage (4.3%) of biodegradable squalene oil, stabilized with Tween 80 and Span 85 in citrate buffer from Novartis, incorporated in influenza vaccine, has been licensed and safely employed in million subjects. Even AS04, 3–0-desacyl-4 -monophosphoryl lipid A (MPL) derivative from lipopolysaccharide (LPS) of Salmonella Minnesota detoxified and linked with alum, from GSK Biologics, has been licensed and incorporated in HB and papillomavirus vaccines [214]. MF59 works very well, by increasing level, diversity and affinity of antibody response to influenza pandemic vaccine [215,216]. Despite the reported lack of effectiveness

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Figure . Chronology of licensed adjuvants, adjuvanted vaccines and their main mechanisms of action.

of MF59 if simultaneously, but separately, administered with vaccine [217], actually it was able to stimulate the antibody response to a non-adjuvanted, seasonal influenza vaccine, when the adjuvanted pandemic vaccine was simultaneously, but separately, administered [218]. AS03 is an adjuvant very similar to MF59, licensed for influenza vaccines by GSK Biologics. The AS03adjuvanted pandemic influenza vaccine has been associated with the appearance of cases of narcolepsy after vaccination in some North European Countries [219], whereas this has not been observed with the MF59-adjuvanted pandemic flu vaccine [220]. This enables to infer that such differential behavior may be linked to the α-tocopherol, which is included in the AS03, but not in the MF59, composition [221]. Quite different, instead, is AS04, which works as an agonist of Toll-like receptor 4, thus stimulating Th1 cells and complement-fixing antibodies [222]. The chronology of these licensed adjuvants, the adjuvanted vaccines and their main mechanisms of action [223.224,225,226,227,228,229] are summarized in Figure 2. Finally, AS02, which is used in the attempts to develop vaccines against HIV, tuberculosis and malaria, is an oil-in-water emulsion including QS21 (an extract of the bark of the South American tree Quillaja saponaria) and MPL, whereas AS01 contains also liposomes [214]. However, all the approved adjuvants, including alum, the newer emulsions and LPS derivative with alum, act by primarily stimulating innate immunity, which in turn activates specific immune response. This behavior mimics the response to natural infections and live viral



Table . Global infant EPI vaccine coverage in . Vaccine

Global coverage

DTP BCG Measles HBV Polio

% % % >% %

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DTP = Diphtheria,/Tetanus/Pertussis, third dose; BCG = Bacille Calmette-Guérin; HBV = Hepatitis B virus.

vaccines, such as yellow fever and influenza, where the gene signatures of innate anti-viral activation are precociously evident, as explored by systems vaccinology [56,230].

Special people categories needing tailored vaccination programs In order to take full advantage of the vaccine potential, the highest possible global vaccine coverage should be promoted. Routine infant immunization should be further expanded. Regarding the EPI-included vaccines, in fact, the global 2013 coverage may be estimated in 84% for the third dose of the trivalent DTP, 90% for BCG, 84% for measles, > 94% for HB and 84% for polio, with only 3 remaining wild poliovirus endemic countries (Table 2), thus allowing to register approximately 13% of children not yet covered [231]. Moreover, the promotion of systematic vaccination of selected people categories according to the specific risk profile should be actively pursued. Regarding the travelers, WHO and CDC recommend to be up-to-dated with routine immunization, including MMR, DTP, and polio, varicella and influenza (CDC only). Moreover, yellow fever (compulsory for travels to some endemic countries), HA (strongly recommended even though administered the same day of departure [232]), HB, meningococcal meningitis, Japanese encephalitis, rabies, typhoid, and cholera vaccines, depending on destination and in special circumstances, are even recommended. Regarding the military, vaccination programs are indeed already present in 90% of countries [233], frequently introduced well before, even decades, and exceeding, the vaccination programs for civilian population [234] and generally rightly implemented [233]. This underlines the role of the military in vaccinology, with military researchers having invented, developed or improved at least 20 vaccinations [234]. Moreover, especially in the countries where military service is compulsory, screening for infectious diseases and vaccination programs substantially contribute to the fight against infectious diseases, thus complementing the activity of the civilian health services [233]. In the pregnant women living vaccines should be avoided during pregnancy, whereas no limitation is considered with inactivated or subunit vaccines [235], as influenza, tetanus and pertussis, which are recommended and result protective for the fetus and newborn too [9]. Healthcare workers, who may become source of vaccine-preventable infections [236], should at least be immunized with influenza and HB vaccines. Moreover, they should maintain updated high coverage for all the vaccine-preventable diseases endemic for the country and according to the occupational risk [237]. The food handlers should receive typhoid [238] and HA [239] vaccines. Patients with chronic diseases on immunosuppressive therapy, who are particularly exposed to infections [240] and generally not adequately covered [241,242], and their household and close contacts should at least receive influenza and pneumococcal vaccinations. They



Table . Special people categories needing tailored vaccination programs.

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• Travelers • Military • Pregnant women • Healthcare workers • Food handlers • Patients with chronic diseases on immunosuppressive therapy and their household & close contacts • Elderly • Potential targets of bioterrorism threats

are, in fact, strongly recommended by the European League against Rheumatism (EULAR) [243], but scarcely administered worldwide [244]. Moreover HB vaccine should be offered to seronegative patients [245,246], whereas vaccines for papillomavirus and for shingles (which is currently a live attenuated vaccine) should be evaluated according to the specific risk of infection. The elderly should receive influenza, conjugate pneumococcal and shingles vaccines [247]. The potential targets of bioterrorism threats should receive vaccines for unusual pathogens, such as CDC category A, [17,248], or prophylaxis according to the specific threats (Table 3).

Conclusions The history of vaccination is strictly and reciprocally interwoven with the development of microbiology, immunology and molecular biology. Effective vaccines have been developed by applying advances in these fields, and, conversely, the study of successful vaccines may promote advances in immunology [149]. It has been estimated that vaccines annually prevent almost 6 million deaths worldwide [249] and that in the United States a 99% reduction of the nine diseases for which specific vaccinations were recommended for decades has been registered [2]. Moreover, the annual return of investment for vaccination has been calculated to be in the range of 12–18%, even though there may be a large underestimation [1]. Finally, the vaccine effect is also addressed to the prevention of consequences of infectious diseases, including cancer, as in the case of HB and papillomavirus vaccines. Much work should still be done for improving old, but unsatisfactory, vaccines, such as BCG [250], anthrax [23], smallpox [251], plague [252], or for developing effective vaccines for HIV [253], malaria [205], HCV [182], dengue [254], RSV [255], cytomegalovirus [256], multi-resistant bacteria [203], Clostridium difficile [208,209] and Ebola virus [257] (Table 4). Moreover, many efforts are also addressed to find more and more immunogenic, safe, and easy to use (in relation to route of administration and number of contemporaneously administered antigens) vaccine preparations. Recently, an aerosolized measles vaccine has demonstrated to be immunogenic, but inferior to the subcutaneous vaccine with respect to the rate of seropositivity [258]. The continuous reduction of companies able to produce vaccines, that may cause concern on the capacity to respond, should an outbreak occur, and the high cost for developing a vaccine, which may be calculated in $ 500–1,000 million [259], make the research for innovative vaccines difficult. Moreover, these conditions may also make the regular vaccine supply to developing countries not sure, despite the international efforts, through WHO, United Nations Children’s Fund (UNICEF) and the Foundations, such as the Bill and Melinda Gates Foundation [31]. Economic and organizational reasons (cold chain maintenance, need for the presence of healthcare workers for parenteral administration, etc.) are the main constraints for global full vaccine coverage in developing countries. However, vaccines are even underused in affluent



Table . Prospects for future vaccines.

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Infectious disease/microorganism Tuberculosis Anthrax Smallpox Plague HIV Malaria Hepatitis C virus Dengue Respiratory syncytial virus Cytomegalovirus Multiresistant bacteria (Staphylococcal) Clostridium difficile Ebola virus

Vaccine has to be

Type of vaccine references

Improved Improved Improved Improved Developed Developed Developed Developed Developed Developed Developed

Live Recombinant/Vectored vaccine [] Recombinant [] Attenuated/Subunit/Recombinant [] Live/Recombinant subunit [] Vectored + Recombinant subunit [] Recombinant [] Vectored prime-boost (adenoviral+MVA) [] Recombinant live vectored (YF) [] Attenuated/Mucosal [] Recombinant Pentamer [] Recombinant Combined Virulence Factors []

Developed Developed

Recombinant Toxin Subunits [,] Vectored recombinant (VSV-chAD) []

HIV: human immunodeficiency virus; MVA: Modified Vaccine Ankara; YF: yellow fever; VSV: vesicular stomatitis virus; chAD: chimpanzee adenovirus .

countries, frequently for concern on safety, despite the successes in controlling infectious diseases and the documented safety. A Medline search for “vaccine risks” largely overcome (approximately five-fold) the search for “vaccine benefits” [1]. Recently, the legal and ethical issues linked to the need to protect voluntarily unvaccinated children during outbreaks through social distancing measures has been discussed [260]. Vaccines are administered to healthy people, who are scarcely prone to undergo medical treatment, thus a continual education program should be performed, to make people aware that vaccines represent a precious resource, in order to promote voluntary adhesion. Only a great and coordinated global effort among different societal components (university, research centers, pharmaceutical industry, ministry of health), joined to a continual education addressed to both, healthcare personnel and general population, will allow people be broadly covered.

Declaration of interest The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the article.

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Anti-Infectious Human Vaccination in Historical Perspective.

A brief history of vaccination is presented since the Jenner's observation, through the first golden age of vaccinology (from Pasteur's era to 1938), ...
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