Vaccines Have Serious Side Effects

The Revised Authoritative Guide To Vaccine Legal Exemptions

Comprehensive, authoritative information about vaccine exemptions you can trust, from Alan Phillips, J.D., a leading vaccine rights attorney with years of experience helping clients throughout the U.S. legally avoid vaccines in a wide variety of vaccine-refusal settings. Critical details for parents, students, immigrants, healthcare employees, military personnel and contractors, agencies, attorneys and clientsvirtually anyone concerned with legally avoiding vaccines in the United States. This Guide provides and explains: Important background information about the legal system; How state and federal statutes, regulations, constitutions and legal precedent interact to define the boundaries of your legal exemption rights; How to deal with local authorities and to avoid mistakes that cost others their exemption; Where legal technicalities and practical reality differand what to do about it; More here...

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Variolation and Vaccination in Late Imperial China Ca 15701911

Variolation using human pox against smallpox in China was one of the ancient popular inoculation practices existing in different parts of the world before Jennerian vaccination 2 , This chapter deals with its historical development and its importance in the introduction of Jennerian vaccination in the country during the early nineteenth century,

Introduction of Jennerian Vaccination

In the Spring of 1805, the vaccine was carried on live subjects from Manila to Macau by a Portuguese merchant, Hewit. From Macau, Jennerian vaccination was introduced to China in Canton 21 . In this same place, a cowpox vaccination bureau was immediately established - under auspices of Alexander Pearson, surgeon of the East-India Company's factory at Canton - by some Cantonese merchants and medical experts who began to study and apply the technique. Pearson also wrote a tract on the subject, which was translated into Chinese as Zhongdou qishu (Wonder book on inoculation), and published to popularize vaccination8 22 . Pearson noticed that this technique had been met with fewer obstacles from prejudice than could be anticipated, especially in a Chinese community. In the first 12 months of the introduction of vaccination in Canton, thousands were inoculated and Chinese doctors or merchants who were associated with the Company soon became vaccinators 23 . One of the technical difficulties...

A vaccine against HIV

Improved knowledge and understanding of the pathophysiological mechanisms during the course of HIV-1 infection have not only contributed to the development of antiretroviral treatment strategies, but have given rise to new therapeutic approaches, such as cytokine therapies, e.g., IL-2 and therapeutic vaccination. However, the most important challenge and thus, the demand for a better understanding of the immunopathogenesis of HIV-1 infection, remains the development of a protective vaccine, which is urgently needed to interrupt the epidemic especially in countries of the Sub-Sahara and Southeast Asia. The spectrum of vaccine strategies against HIV includes HIV-derived peptides or proteins, the use of viral or bacterial vectors, naked DNA, pseudovirions or the use of live attenuated HIV strains. The discussion about whether a vaccine should primarily aim at inducing a humoral or a cellular based protective immune response The discussion about how to best monitor the induction of...

Vaccination in the Intensified Smallpox Eradication Programme

It takes over 100 pages of the book Smallpox and its Eradication to describe just the planning of the programme 8 . For this conference, the focus is on vaccination, details of which are set out in another chapter of the book 9 . An early priority was that none of the WHO regular budget of 2.4 million a year should be spent on procurement of vaccine, since the cost of the vaccine required would have substantially exceeded the total budget. Hence, it was decided that the vaccine would have to be provided by donation or by local production in the smallpox-endemic countries. This was not an easy task. Disillusioned with eradication by its experiences in the malaria eradication campaign, UNICEF (United Nations Children's Fund) provided minimal help, and Henderson himself had to spend a substantial part of his time persuading industrialised countries to make a donation of the vaccine. Although by the mid-1960s, tissue culture production of vaccines was a well-established procedure,...

New Methods of Vaccination

Before 1967, vaccination was carried out either by a scratch method, or by a multiple pressure technique. Two new methods of vaccination were developed during the Intensified Programme. A high-tech method, the jet injector 13 , was used by the United States CDC staff in the campaign in west and central Africa and later in Brazil. However, it could not be used effectively in sparsely settled rural areas, and in developing countries maintenance was a problem. Far more effective was an invention by Ben Rubin of Wyeth Laboratories that was donated by them to the smallpox programme - the bifurcated needle 14 . Dipped into a vial of reconstituted vaccine, it held a dose between its prongs. After this had been deposited on the skin, 15 vertical pricks with the bifurcated needle through the droplet resulted in successful vaccination. A reusable plastic container was designed by Ehsan Shafa, and produced in Pakistan, which could be filled with sterile needles each morning, used throughout the...

Role Of Carbohydrate In Vaccine Strategies To

Cells with pseudotypes could be blocked with anti-HTLV-I serum, but failed to be significantly inhibited with anti-HIV serum or a V3-neutralizing anti-gp120 monoclonal antibody. This may represent a possibility for pseudotypes to escape neutralization by the immune system in vivo. Importantly, the neutralizing capacity of lectins and anticarbohydrate monoclonal antibodies was found to block infection by cell-free pseudotypes in CD4 negative cells. These data suggest that although viral cofactors might expand the tropism of HIV in vivo, HIV and HTLV-I seem to induce common carbohydrate neutralization epitopes which might be conserved targets in a vaccine design strategy. Targeting carbohydrates which are not structurally encoded by the viral genome as targets for neutralizing antibodies could present a new possibility for group-specific vaccine development because they are not sensitive to viral genetic variabilities present on a broader range of isolates. Early studies on consecutive...

The Diffusion of the First Generation of Vaccines and

First, one must define the distinction between variolation and Pastorian vaccination, both being founded on the specific protection given to a person by a first attack of a contagious disease or by a first contact with its agent. Variolation consisted of inoculating a normal pathogenic agent in order to give the host immunity against this agent. The only trick used to avoid a purely natural disease with all the sometimes disastrous consequences, was to inoculate at a very young age, to diminish the dose of pathogen injected (for example, variolation with cutaneous punctures) or to choose an abnormal route of administration (for example, the end of the tail for the bovine peripneumonia). In occidental countries, variolation was used during a period of approximately 80 years for many diseases but mostly for smallpox, sheep pox, and bovine peripneumonia. In contrast, Pastorian vaccination induced immunity by using a pathogenic agent diminished in its virulence by an artificial technique...

Alphavirus Used In Cancer Vaccines

Alphavirus vectors have frequently been applied for vaccine production. In this context, recombinant particles as well as naked nucleic acids have been applied. The proof of concept was originally demonstrated for viral surface proteins known for their potential immunogenicity and capability to induce cytotoxic T-cell (CTL) responses and protection against challenges with lethal viruses (20). Moreover, immunization against tumor challenges has resulted in some promising observations (Table 1). For instance, injection of RNA from an SFV vector expressing bacterial -galactosidase into mice provided protection against tumor challenges (21). Administration of recombinant SFV particles expressing the P1A gene resulted in protection against P185 tumor challenges in mice (22). The human papilloma virus (HPV) E6 and E7 oncoproteins have been

BCG Vaccine Manufacture

The tiglet and sticky growth of mycobacteria was of great concern to Calmette. Attempts to improve homogenization contributed to the discovery of BCG. The growth characteristics remain a concern for vaccine preparation and standardization. Since Guerin, some laboratories have continued to grow BCG as veils on Sauton's medium. The bacillary mass is obtained by filtration, dispersed by ball milling, and resuspended in protective solutions in order to stabilize the vaccine. The bacillary content in colony-forming units largely differs because of the variability in water content, the degree of dispersion, the killing of bacteria by ball milling homogenization, and the differences in manufacturing processes. Dispersed grown cultures were first used by Dubos and Fenner, and subsequently by others 25 . At present, many BCG vaccine producers use dispersed grown BCG. These cultures permit obtention of a high ratio of live to dead bacilli per dose and offer better resistance to stabilization by...

VSV Gene Therapy and Vaccines

The generally low seroprevalence of VSV antibodies in the general population and genetic malleability indicated that VSV could be an attractive vector to develop new vaccines (26). VSV elicits strong humoral and cellular immune responses in vivo and naturally infects at mucosal surfaces (89-91). As mentioned, a major observation also included that VSV were found to accommodate large gene inserts and multiple genes in their genomes (88). Thus, it wasn't long before a variety of foreign viral glycoproteins were cloned into VSV vectors for the purpose of developing novel vaccines (89,92,93). Early studies involved placing the hemagglutinin (HA) or neuraminidase (NA) of influenza virus into VSV as extra genes. High-level expression of the heterologous products were obtained and animals inoculated with these VSV vectors were protected against lethal doses of influenza virus (88,89). Substitution of the VSV G protein with influenza virus HA was also found to function well and to exhibit...

Vaccine Approaches Relevant To Htlvi

In designing a vaccine for any infectious agent, it is necessary to define the antigens, the method of delivery capable of inducing protective immunity, and any safety concerns. We will first consider several vaccine approaches relevant to HTLV-I and will then assess the HTLV-I antigens most appropriate for use in one of the vaccine strategies. Finally, a review of the HTLV-I vaccine animal studies will be presented and the future directions of HTLV-I vaccine research will be discussed. Two vaccine approaches that have been successful in combating other virus infections are the use of inactivated and live attenuated vaccines. For several reasons, however, neither the inactivated nor the live attenuated vaccine approaches are appropriate for an HTLV-I vaccine. With HTLV-I clearly being a human oncogenic virus, it is problematic to ensure that a viral preparation is entirely inactivated. Although inactivated HTLV-I vaccines have been tested in animal models,113,119 the problems of...

Toward a Significant Improvement Vi Polysaccharide Vaccines

To improve the tolerance of whole-cell killed typhoid vaccines, numerous attempts were made over the years to prepare more or less purified extracts. Among these, the Vl antigen seems to be the most promising and best chemically defined candidate. The Vi polysaccharide of S. typhi is composed of a homopolymer of N-acetylgalacturonic acid expressed as a capsule around the bacterial body. This capsular polysaccharide was recognized as a virulence factor and as a possible immunogen as early as 1932 by Felix and Pitt 13 . In 1954, Landy proposed to study the Vi antigen as a vaccine formulation by injecting it in a highly purified form 14 . Unfortunately, the technique they employed was denaturing for the polysaccharide and the vaccine did not provide significant protection for volunteers 15 . Subsequently, in 1972, Wong and Feeley were able to purify the Vi antigen in nondenaturing conditions with hexadecyltrimethylammonium bromide 16 . This work opened the way to further development,...

Htlvi Vaccine Candidates

HTLV-I proteins are currently being assessed for their ability to induce protective immune responses. Several HTLV-I proteins are being tested individually and or in various combinations in a polyvalent vaccine ap proach. These include the envelope gp46 (surface protein) associated with gp21 (transmembrane anchor protein), the gp46 surface envelope protein alone, the major core protein p24, and the matrix protein p19. It appears that the envelope proteins represent the major targets of the immune system during HTLV-I infection,28 as is observed with other retroviruses, where immune responses to retroviral envelope proteins can be protec-tive.76 While any HTLV-I-based envelope vaccine would probably require gp46 to play a role, the inclusion of all or part of gp21 requires some consideration as gp21 is known to contain an immunosuppressive region.133134 However, other retroviral proteins may provide additional protection. For instance, the HIV-1 matrix protein p17 is capable of...

Vaccination Past Present and Future

In 1300, vaccines were not available, and Siena did not have the choice of preventing the plague. Only recently has mankind managed to partially control infectious diseases thanks to the discovery and development of antibiotics and vaccines. The new technologies to develop vaccines available today have the power to achieve even much more spectacular results in the fight against infectious diseases. Genomics, Proteomics and Vaccines edited by Guido Grandi 2004 John Wiley & Sons, Ltd ISBN 0 470 85616 5 1.2 Vaccination the past A more successful approach came in 1796 with Edward Jenner, an English physician. During his practice in the countryside, he had noticed that farmers exposed to infected materials from cows did not develop the disease but acquired immunity to smallpox. Jenner decided to use the less dangerous material derived from the bovine (vaccinus) lesions to 'vaccinate' a boy (James Phipps) and showed that he was immune to a subsequent challenge with smallpox. The...

The Efficacy of Whole Cell Vaccines

A review of all studies and trials cannot be made in this context, but two sources are recommended, i.e., Whooping cough by Joseph E. Lapin 1 and a review by Fine and Clarkson 2 . In the early years of the twentieth century, attempts were made to develop whole-cell vaccines, but for these early studies, the current definition of vaccination may not be valid since many workers have considered prophylaxis to include preventive treatment in the incubation period of the disease, as noted by Lapin. An example of the problem - and the value of checking original sources - is the 1933 report of Thorvald Madsen, Director of the Danish State Serum Institute, describing the use of whole-cell vaccine during the 1923-1924 and 1929 epidemics in the Faroe Islands 3 . The paper is often quoted as an important contribution for the acceptance of the notion of prevention of whooping cough by vaccination, as it represented the first pertussis vaccine prepared in a standardized fashion and submitted to...

The Adverse Effects of Whole Cell Vaccines

The history of the risks of whole-cell pertussis vaccine is as old as the history of its protective efficacy, since two deaths in newborns were reported by Madsen 3 . The whole issue of the risk versus benefit debate of whole-cell pertussis vaccines cannot be presented here, but an extensive review of the risk for permanent damage was done by Griffith 11 , and by Wardlaw and Parton 12 . The current status of the issue is that whole-cell vaccine has not been shown to cause permanent brain damage or death. The vaccine does give rise to reversible, neurological reactions, causes fever with febrile convulsions, and induces local reactions at a rate approaching 100 13 . The high rate of adverse effects and the fear of serious damage have resulted in many countries in a low vaccine uptake - and a concomitant increase in the disease incidence - and stimulated a renewed interest in basic research, greatly neglected after the successful introduction of whole-cell vaccine in general vaccination...

Development of Subunit Vaccines

Again, a full review of the subject cannot be made, but the textbook of Wardlaw and Parton 12 provides background information about today's acellular and subunit vaccines. To summarize the current status of protective antigens in pertussis, A key paper for our current understanding of pertussis was a review 14 by Margaret Pittman, published in 1979, in which she hypothesized that pertussis was a toxin-mediated disease - by analogy with diphtheria and tetanus - and that pertussis toxin (PT) was the major cause of the harmful effects of the disease. She therefore thought that a PT toxoid should be sufficient for protection. Margaret Pittman, who died in 1995, made important contributions to the pertussis field for 50 years. She maintained to the end of her days the firm belief that additional antigens in subunit pertussis vaccines - if not shown to be absolutely necessary -or impurities in the case of the other toxoid vaccines - should be avoided as they had the potential to cause...

Heat Shock Proteins As Vaccine Vehicles

In the killing, in an antigen-specific manner, of tumor cells and virus-infected cells. This dichotomy in antigen presentation theoretically excluded the presentation of an exogenous antigen in the MHC I molecules. However, in some conditions, APC are able to present exogenous antigen in the context of the MHC I molecules to CD8+ T cells, a process called antigen cross-presentation (Heath and Carbone, 2001 Yewdell et al., 1999). It is thought that antigens have to be taken up via endocytic receptors to be efficiently cross-presented in vivo (Arnold-Schild et al., 1999 Castellino et al., 2000 Singh-Jasuja et al., 2000 Wassenberg et al., 1999). This process allowed to propose new vaccine strategies based on the targeting of endocytic receptors selectively expressed by DC. Several studies were focused on identifying vector proteins exhibiting DC-targeting properties and able to mediate cross-presentation of vaccine antigens associated or coupled to the vehicle. The outer membrane protein...

The Efficacy of Subunit and Acellular Pertussis Vaccines

Table 1 summarizes the vaccines tested in clinical trials, their composition, the efficacy estimates and a personal best opinion about the likelihood of the vaccine's protective efficacy. The first efficacy trial of the Japanese vaccines, JNIH-6 and JNIH-7, employed a novel approach to case definition - based on positive culture or positive serology -for VE calculation. It was claimed that this method would be the most specific for pertussis 17 . However, if B. pertussis were replaced by S. pneumoniae and if it was claimed that bacterial culture from a nasopharyngeal aspirate is specific for pneumococcal pneumonia in child, then the source of the problem encountered in this trial, i.e. colonization, would be evident. Table 1 Reported vaccine efficacy (VE) estimates for acellular subunit and whole-cell pertussis vaccines in recent (1986-1995) trials and a likely estimate of the protective efficacy after correction for major biases introduced by laboratory methods, use of laboratory...

Laboratory Correlates with Protection for Subunit Vaccines

The issue has not been settled since the intracerebral challenge test is not applicable to subunit vaccines. Immunogenicity assays could be used, but no minimal requirements have, as yet, been formulated. The value of immunogenicity data has also been questioned, due to the lack of a serological correlate which could not be shown in the first Swedish efficacy trial 17 . Other data have been presented which confirm that a correlation must exist, e.g. specific immune globulin with antibodies against PT alone modified the clinical disease in children 18, 20 . A study in adults also found a correlation with antibody levels against both PT and FHA, although the correlation was stronger for the antibodies against PT 21 . The failure to show a correlation in the first trial can have several causes, but the most likely one seems to be the dilution of the cases by a large proportion non-cases (of colonization with B. pertussis). In trial 2, a preliminary trend analysis of the postvaccination...

Nonhuman Primate Vaccine Studies

A few HTLV-I vaccine studies have been conducted in different species of monkeys.54,94,118,119 The number of monkeys employed in these studies by necessity is usually small, rendering the assessment of efficacy difficult. The challenge virus inoculum consists of either xenogeneic HTLV-I-infected T-cells or allogeneic STLV-I-infected T-cells. In one vaccine study,54 cynomol-gus monkeys were immunized with an E. coli-derived HTLV-I envelope-P-galactosidase fusion protein mixed with complete Freund's adjuvant. High doses (100-250 g) of the purified fusion protein were administered intradermally twice, followed by further boosting either intravenously or intradermally. The monkeys were then challenged with the human HTLV-I-infected T-cell line MT-2. Two of the six vaccinated monkeys appeared to be transiently infected by the challenge virus. The remaining four monkeys that exhibited the highest levels of neutralizing antibody were protected from HTLV-I infection. In contrast, all four...

The Future of Polysaccharide Protein Conjugate Vaccines

There are many reasons to predict that conjugates serve as vaccines for inducing protective levels of antibodies to both the polysaccharide and protein components of these new vaccines. Furthermore, it seems likely that there is a limit to the number of conjugates that use the same carrier protein. We tentatively suggest the following components of conjugate vaccines for routine infant vaccination modified by the epidemiology of the country (1) capsular polysaccharides of H. influenzae types b and a Groups A, B, C, Y, and W135 of meningococci, types 1, 3, 6, 9N, 14, 18C, 19F, 19A, and 23F of pneumococci types 1, 2, and 3 of GBS types 1, 2, 5, 12, and 13 of E. coli Vi of S. typhi and Vibrio cholerae O139 ( 2) O-SPs of S. typhimurium, S. choleraesuis, S. enteritidis, S. paratyphi A, Shigella dysenteriae type 1, S. flexneri type 2a, S. sonnei, and V. cholerae O1 (3) genetically toxoided proteins from Corynebacterium diphtheriae, Clostridium tetani, C. difficile, C. welchii, Bordetella...

Yellow Fever Vaccines The Success of Empiricism Pitfalls of Application and Transition to Molecular Vaccinology

In 1951, Max Theiler was awarded the Nobel Prize in Medicine and Physiology for the development of yellow fever vaccine. The discovery phase of Theiler's research preceded the prize by only about 20 years, during which time his vaccine against yellow fever had been put into wide-scale use in Africa and South America, and tens of thousands of yellow fever deaths had been averted. After smallpox vaccine, which had been discovered some 135 years before, yellow fever was the first human vaccine to be used at a population level for control of a major epidemic disease. Yellow fever vaccines were developed during an early stage in the history of virology, using empirical methods. Approximately 50 years later, research was initiated on the molecular basis of attenuation progress is briefly reviewed here. The history of yellow fever vaccines provided a number of important paradigms for vaccine development in general (Table 1). Table 1 Yellow fever vaccine as a paradigm for vaccine development...

Isolation of Yellow Fever Virus a Requisite Step Towards a Defined Vaccine

The development of a defined vaccine against yellow fever obviously depended upon the isolation, characterization, and ability to grow the etiologic agent. In 1925, the Rockefeller Foundation established the West Africa Yellow Fever Commission, with headquarters at Yaba (near Lagos), Nigeria. An important objective of the Commission was to isolate and characterize the etiologic agent 7 . As luck would have it, a widespread epidemic of yellow fever occurred along the West African coast in 1926-1927. In July 1927, blood obtained from a nonfatal case named Asibi yielded a pathogenic agent when inoculated into Indian crown monkeys. The agent was subsequently passed to rhesus monkeys, shown to be a filterable virus 8 , maintained in the laboratory by continuous passage in monkeys or mosquitoes, and ultimately stabilized by lyophilization 9 . The Asibi strain became the focus of attempts to develop a vaccine at the Rockefeller Institute laboratories in New York. Contemporary efforts to...

Early Attempts at Vaccination

The earliest attempt to use the newly isolated yellow fever virus for immunization was made by Edward Hindle at the Wellcome Research Laboratories in London 11 . Hindle was aware of the recent reports of inactivated vaccine preparations against veterinary pathogens, including foot-and-mouth disease, fowl plague, and canine distemper viruses. Since yellow fever virus could, at the time, be propagated only by passage in monkeys, he used liver and spleen tissue from a monkey infected with the French strain as a vaccine substrate. The tissue emulsion was inactivated with formalin or phenol. Rhesus monkeys inoculated subcutaneously with putatively inactivated virus survived when challenged a week later with a large dose of infected liver suspension, whereas unvaccinated animals succumbed. Hindle's work was followed by other attempts to produce chemically inactivated vaccines. For example, Petit and Stefanopoulo reported protection of monkeys after two injections of inactivated vaccine...

Partially Attenuated Live Vaccines and Sero Immunization

Theiler knew that Pasteur had modified the virulence of rabies virus by serial passage in rabbit brains, and he believed that smallpox virus had been attenuated naturally, probably by passage through an unusual (bovine) host. He therefore undertook a series of sequential brain-to-brain passages of yellow fever virus in mice in an attempt to attenuate its pathogenicity. At the 29th and 42nd passage levels, the monkeys inoculated with the mouse brain material survived infection without developing yellow fever hepatitis. Moreover, they had developed immunity, as illustrated by resistance to challenge with virulent virus 20 . Theiler also noted that sequential passage of the virus in mice led to an increase in its neurotropism, suggesting that, with further passage, the virus might eventually become fixed in its neurovirulence for mice, in the same way that rabies virus had after sequential passage in rabbit brain. The implications for preparation of a vaccine were clear The French virus...

Mucosal Hiv Vaccine Needed

Systemic humoral and cell-mediated immune responses is thought to be important for vaccine-induced protection against HIV infection. The hallmark of a mucosal immune response is the detection of antigen-specific secretory-IgA (S-IgA) in mucosal secretions and the presence of antigen-specific T and B cells in mucosal effector tissues.4243 Systemic immunization rarely if ever induces mucosal immune responses, while mucosal immunization has the advantage of inducing both systemic and mucosal immune responses.30-31'37'40'44 Therefore, if mucosal immune responses are required for prevention of mucosal HIV infection, HIV vaccines will need to be administered via a mucosal route. The following sections will briefly review the organization of the mucosal immune system and discuss the protective mechanisms employed by the humoral and cellular arms of the mucosal immune system.

Development and Initial Field Trials of Yellow Fever 17D Vaccine

Research efforts at the Rockefeller Institute in New York were directed towards the development of an attenuated vaccine that had no neurovirulence properties. The French strain fixed by passage in mouse brain was considered too dangerous for use in humans, since it was capable of producing yellow fever encephalitis in monkeys and was associated with neurological accidents in humans. There was also a concern that the virus had residual viscerotropism, since Findlay and Clarke had shown reversion on repeated direct liver passage in monkeys 42 . 17E) was deemed too virulent for human inoculation without coadminstration of immune serum. The 17E virus replaced the mouse brain virus for sero-immunization of laboratory workers 48 . In November, 1935, speaking at the Annual Meeting of the American Society of Tropical Medicine in Baltimore, Sawyer noted that a safer strain has supplanted the original neurotropic strain for use with immune serum in vaccination and it is confidently expected...

Problems with Vaccine Manufacturing and Control Neurological Accidents Caused by 17D Virus

By 1941, approximately two million persons had received 17D vaccine in Brazil, Colombia, Bolivia, the United States, England, and West Africa, without reports of serious vaccine-related adverse events. However, in July of that year, a Brazilian physician in Minas Gerais noted more than 20 cases of encephalitis occurring after yellow fever immunization. Investigations were undertaken by the Yellow Fever Research Service (jointly maintained by the Brazilian Ministry of Health at the Rockefeller Foundation), resulting in a published report by John Fox and his colleagues the following year 54 . The epidemiological investigation which ultimately encompassed 55,073 vaccines, revealed the occurrence of 273 (0.5 ) unusually severe reactions, 199 (0.36 ) with central nervous system disease signs, and 1 death with encephalitis. Similar disease in the unvaccinated population was significantly less frequent. The highest incidence of encephalitis occurred in individuals who had received vaccine...

Prevention of Yellow Fever in French West Africa Using the French Neurotropic Vaccine

The initial success of field trials with the French neurotropic vaccine between 1937 and 1940 was followed by a massive campaign to immunize the entire population of francophone colonial West Africa. Yellow fever vaccination was made compulsory in 1941, and over the next six years, nearly all inhabitants of the vast territory - approximately 14 million persons - received the vaccine 61 . By 1953, 56 million vaccinations had been performed, a number twice that of the population of the region 62 . This remarkable feat was accomplishable because of the simplicity and low cost of manufacturing the mouse brain vaccine, its relative stability under field conditions without refrigeration, and its simple method of administrations via scarification. The vaccine was prepared in Dakar by the intracerebral inoculation of weaned mice. When the mice showed signs of paralysis (day 4-5), brains were aseptically removed, frozen, and desiccated, and a powder prepared by grinding a mortar and pestle...

Adventitious Agents Hepatitis B and Avian Leucosis Viruses in 17D Chick Embryo Vaccine

Early manufacturing procedures for yellow fever 17D vaccine included the addition of nonimmune human serum to the tissue culture fluid and to the final vaccine as a stabilizer. As early as 1937, Findlay and McCallum noted the occurrence of acute hepatitis occurring 2-7 months after 17D yellow fever vaccination 72 . Similar cases were reported in Brazil by Soper and Smith 73 . There were lessons from history transmission of hepatitis by human blood had been described as early as 1885, caused by smallpox vaccine prepared from human lymph 74 , and in the 1930s, there was an outbreak of jaundice among recipients of human measles and mumps-convalescent plasma 75 . The occurrence of jaundice associated with specific lots of 17D vaccine were investigated in Brazil in 1939 and 1940 76 . At first it was suspected that such cases could be due to reversion of yellow fever virus, but this was excluded based on the occurrence of cases in vaccines known to be immune to yellow fever prior to...

The need for a rotavirus vaccine

Since the golden age of viral gastroenteritis commenced in the early 1970s, many viruses have been implicated as etiological agents of diarrhoeal illnesses. However, rotaviruses reign as the number one cause of severe diarrhoeal disease worldwide, surpassing the enteric adenoviruses, astroviruses, caliciviruses and bacterial agents. Thus, the need for a rotavirus vaccine is clear and compelling, with the goal being the prevention of severe rotavirus diarrhoea during the first two years of life when the consequences of such illnesses are most serious.

Rotavirus features relevant to vaccine development

Rotaviruses are 70 nm in diameter, non-enveloped and possess a distinctive double-shelled outer capsid. Within the inner shell is a third layer, the core, which contains the viral genome comprised of 11 segments of double-stranded (ds)RNA. During coinfection with different rotavirus strains, the segmented genomes readily undergo genetic reassortment. With regard to vaccine development, the two outer capsid proteins, VP4 and VP7, deserve special attention (Kapikian & Chanock 1996). VP7, a glycoprotein, comprises one of two major neutralization antigens located on the outer capsid and is encoded by RNA segment 7, 8 or 9 (depending on strain). The other outer capsid protein, VP4, is encoded by RNA segment 4 it protrudes from the outer capsid in the form of60 spikes. Antibodies to both VP7 and VP4 are independently associated with protection against illness in various animal models. Serotypes are characteristically determined by VP7, but a VP4 serotyping scheme has also been developed...

Race with Evolution A History of Influenza Vaccines

I would like to begin by showing a graph depicting the dramatic impact of influenza vaccination on the morbidity and mortality of the disease during the decades of its use. This, unfortunately, I cannot do not because the vaccine does not work, but because it is an underutilized vaccine for an unreportable disease. The data, therefore, are not available. I hope the following discussion will resolve this paradox. I hope, also, that I will be forgiven if I have focused narrowly on the complicated history of influenza vaccine development in a way which may appear to slight the scientific basis for its success. I am well aware of this basis, and in another recent

Rotavirus Vaccine and intussusception

After over 9 months of apparently successful use of the vaccine in the USA, on 16 July 1999 the CDC reported that between 1 Sept 1998 and 7 July 1999, according to the Vaccine Adverse Event Reporting System (VAERS), a passive system operated by FDA and CDC, 15 cases of intussusception had occurred following vaccination with RRV-TV (CDC 1999b). It was estimated that 1.8 million doses of RRV-TV had been distributed and that 1.5 million doses had been given. Although the number of intussusception cases reported was within the expected value (considering a New York State background rate of 51 per 100 000 infants < 12 months of age in the period 1991-1997 prior to RRV-TV licensure ), it was of concern that 11 of the 15 cases had occurred within 1 week of administration of the first dose of vaccine. Thus, the CDC recommended suspending further vaccination until additional data could be obtained. (ACIP 1999). Moreover, 57 of the cases had onset within 7 days of vaccination and 46 (81 ) of...

Vaccine Reactogenicity Technical Solutions

In part related to the increasing antigenic mass of polyvalent vaccines, and in part to poor standardization of production, early influenza vaccines gained a bad reputation as inducers of local and systemic symptoms. These problems have been largely solved by improved methods of viral purification (zonal centrifugation and chromatography) 15, 16 and by splitting of the viral lipid membrane with ether or detergents 15, 16, 18 . Split and subunit vaccines - the latter further purified by removal of most internal viral proteins - now dominate the market.

Cytokine Modified Tumor Cell Vaccines

Antitumor vaccination with irradiated autologous cancer cells, transfected ex vivo to express cytokine genes was exemplified by the use of GM-CSF gene modified cancer cell delivery (86,99). Promising initial preclinical studies with an antitumor vaccine comprised of irradiated autologous GM-CSF secreting-Dunning rat prostate carcinoma cells led to a clinical trial in which eight patients with prostate cancer were treated with autologous GM-CSF secreting, irradiated tumor cell vaccines prepared by ex vivo retroviral transduc-tion of surgically harvested cells (100). Insufficient cells were obtained from three other patients. Indeed, the major limitation of this approach was the poor prostate cancer cell recovery and growth from clinical specimens. Side effects were minimal and localized to the site of injection. The treatment resulted in DC and macrophage infiltration at the injection site. They also found activation of T- and B-cells against prostate cancer antigens, representing both...

Surveillance as an Essential Part of Influenza Vaccine Strategy

As a continually reemerging threat 35, 36 , influenza has been under systematic surveillance by the World Health Organization 37 in an effort to detect early virus mutations and this to anticipate prevalence in the coming year. In recent years, improved monitoring of China, the apparent source of most new epidemic strains, has made it possible to predict their seasonal invasion of the Western Hemisphere and to prepare appropriate vaccines in advance. Prognostic hints have also been provided by detection of so-called herald-strains 38 , which may appear at the end of epidemics.

The Role of Tissue Culture in Vaccine Development

Enders' leadership of this group was exemplary of his role for more than 20 years as a basic microbiologist. He had come late to the field, following an unsuccessful career as a real-estate salesman and 4 years in the study of Celtic and Teutonic languages as a doctoral candidate at Harvard. In one of those serendipitous events that markedly alter life patterns, he had obtained a room in a boarding house shared with several Harvard medical students, including Hugh Ward, an Australian Rhodes Scholar who was working in the laboratories of the famed Hans Zinsser. Captivated by the work of Ward and his associates, Enders abandoned his nearly completed PhD in English and joined the Department of Bacteriology and Immunology at Harvard Medical School where he finally received a doctorate and his first faculty appointment at the age of 32. He was a Renaissance scholar who knew literature, music and philosophy as well as microbiology. When, after 15 years with Zinsser, he established his own...

Was there an epidemic of intussusception because of vaccine use

Our initial doubts about the overall risk of this vaccine arose from evaluation of published data from CDC which failed to reveal a striking increase in the overall number of cases of intussusception that would have been anticipated from the extremely high odds ratios, noted above, that were presented for the first week following vaccination. For example, CDC reported the occurrence of three cases of intussusception in 9802 vaccinees in a California managed care study, which translated to an overall incidence of 30 cases per 100 000 over an unspecified period of time. However, because one of the three cases occurred during the first week after vaccination, CDC reported that the incidence of intussusception was 314 per 100 000 individuals during that period (CDC 1999b). However, the overall risk of the vaccine in this large cohort of children was not presented. Similarly, in a Minnesota study, five cases were reported in recipients of53 479 doses, an incidence of 9 per 100 000 doses...

Viral Vaccines and Cell Substrate A Historical Debate

Plotkin concerning the history of rubella vaccines and the cell substrate is an excellent illustration of the ballet performed around the problem of the acceptability criteria of cell substrate used in the development and preparation of viral vaccines. This problem came to my attention many years ago when I worked in the World Health Organization (WHO) experts groups, but in the last decade this topic had been an important concern for me since I act as an expert in virology operating in French and European regulatory systems. The importance of the cell substrate in the development of viral vaccines is illustrated in Table 1 in which it is shown that the outcome of a new generation of viral vaccines depended on an improvement of the technology used in the preparation of cell substrates destined for virus propaganda. When viral vaccine development is correlated with the appearance of adverse reactions after vaccine administration, it can be observed that each...

Obstacles To Hiv1 Vaccine Development 21 Introduction

The development of a vaccine for HIV-1 has been hindered by several factors. First, HIV-1 is subject to a significant amount of sequence divergence TABLEI Vaccination Strategies TABLEI Vaccination Strategies Vaccine type FIGURE 1. Proposed mechanism of nucleic acid vaccination. Intramuscular injection of plasmids results in the expression of the foreign proteins. These proteins can be secreted by the myocytes such that antigen-presenting cells can take up the protein and present the processed proteins via MHC class II to CD4 cells. Further, the secreted proteins can be presented to B cells for the inevitable production of antibodies. Finally, antigen-presenting cells can directly take up plasmid for the intracellular expression of proteins and presentation via MHC class I to CD8 cells. FIGURE 1. Proposed mechanism of nucleic acid vaccination. Intramuscular injection of plasmids results in the expression of the foreign proteins. These proteins can be secreted by the myocytes such that...

The Genome Of Hiv1 And Targets For Nucleic Acid Vaccination

With regard to improving the current HIV-1 vaccines, in addition to inducing both cellular and humoral immune response, another strategy of vaccine design is to include a variety of viral targets. Many of the earlier approaches focused on the HIV-1 envelope protein gp160 however, the HIV-1 genome is organized into three major structural and enzymatic genes, two regulatory genes, and four accessory genes. Each gene product represents a possible element for vaccine exploitation, as detailed below and illustrated in Fig. 2. FIGURE 2. Potential immunologic targets for DNA vaccination against HIV-1. The HIV-1 genome is organized into three major structural and enzymatic genes, two regulatory genes, and four accessory genes. The immunologic targets include env, gag, pol, and the four accessory genes. Furthermore, the high variability between the envelopes of various HIV-1 clades suggests that different envelope subtypes might be needed for an effective vaccine against HIV-1. The probability...

Other rotavirus vaccines

A presentation on rotavirus vaccines would not be complete if it did not consider the prospects for other rotavirus vaccines that may fill the void left by the withdrawal of the rhesus rotavirus-based vaccine. Table 2 summarizes the status of the various rotavirus vaccines that have been evaluated in efficacy trials in infants and young children. Evaluation of monovalent bovine or rhesus rotavirus vaccine has been discontinued because of the variable efficacy of these immunogens. The quadrivalent WC3 bovine rotavirus-based reassortant vaccine with G1, G2, G3 and P1A 8 specificity is undergoing active field testing. A quadrivalent UK bovine rotavirus-based reassortant vaccine with G1, G2, G3 and G4 specificity is 'on hold' pending developments with its counterpart rhesus rotavirus tetravalent vaccine. A monovalent attenuated human rotavirus G1 vaccine is under active clinical evaluation. As shown in Table 3, various other vaccine candidates have been evaluated in phase 1 safety and...

Genetic Vaccines for Cancer Therapy

A primary focus of current research on genetic vaccination is the development of strategies to activate nonresponsive antigen specific T-cells. The first consideration of any tumor therapy is the choice of cancer antigen in a genetic construct. Much effort has been devoted to the optimization of TAAs, and this work is described in detail elsewhere (11,12). Despite this optimization and the large number of genetic vaccine clinical trials for cancera, DNA vaccination in humans has not elicited as potent immune responses as observed in smaller animal models. For example, eliciting an immune response with intramuscular (im) naked DNA vaccination (plasmid DNA with no delivery vehicle) requires as much as 5mg of plasmid DNA in nonhuman primates (13), but only 50 to 300 g in mice (4). Although high doses of plasmid are generally well tolerated in humans (14), the need for additional technologies to boost the effectiveness of genetic vaccines is apparent. One of the earliest advances in DNA...

Methods Of Dna Vaccine Delivery 31 Electroporation

Studies on the delivery of TAA antigens using electroporation have yielded promising results. Mendiratta et al. reported vaccination using electroporation with both plasmid encoded human GP100 and mouse TPR2 antigen elicited complete protection from melanoma challenge (21). Lohr et al. demonstrated that introduction of plasmid encoding IL-2 and IL-12 (inflammatory cytokine signals) by electroporation at tumor sites caused transduction and inhibition of murine melanoma without the systemic cytokine levels experienced after adenoviral gene transfer (22). Further investigations have shown that electroporation can be used to facilitate the discovery of novel antigen encoded plasmid constructs. For example, Kalat et al. used electroporation methods to optimize tyrosinase related protein-2 antigens to elicit CD8+ responses and inhibition of melanoma growth in two challenge models (23). This same group later demonstrated that electroporation was capable of inducing immune responses...

Vaccination of contacts

Whenever HIV patients are susceptible to vaccine-preventable infections, particular care should be taken to vaccinate close contacts, who, after gaining protective immunity, will not transmit the disease. However, if contacts are vaccinated with certain live vaccines (e.g. oral polio vaccine), the HIV patient is at risk of acquiring vaccine-associated illness. Thus, oral polio vaccination of contact persons is con-traindicated and the inactivated vaccine should be used. Secondary transmission of MMR or varicella following vaccination is very unlikely only if contacts develop vaccine-associated varicella, the HIV patient should receive acyclovir prophylaxis.

Vaccinations in HIVinfected children

HIV-infected children should be vaccinated according to national children vaccination schedules, with the following exceptions for live vaccines < 750 l (0-12 months old), < 500 l (1-5 years old), and < 200 l (> 5 years old), or by relative CD4 counts < 15 , MMR vaccination is contraindicated. (2) In immunodeficient children, varicella vaccination is contraindicated in this case, guidelines vary to the extent of immunosuppression while German guidelines still set the threshold for contraindication at relative CD4+ T-cells < 25 (STIKO 2005), the US recently adopted a strategy in analogy to MMR supporting the vaccination of children with > 15 CD4+ T-cells (Kroger 2006). A possible strategy to avoid unnecessary live vaccines is to predict their probability of success by measuring the response to inactivated vaccines if there is no measurable response to diphtheria tetanus booster, a benefit from live vaccines such as MMR or varicella is unlikely, even if CD4+ T-cell counts...

Practical approach to vaccinations

Informed consent HIV patients should be circumstantially informed regarding the benefits and risks of vaccines, with particular attention to HIV-related vaccine problems. Some countries might require written information material and or a written informed consent. Vaccine information statements in different languages are available via the Internet (e.g. www.immunize.org). Timing of a vaccination Vaccination should be postponed in the presence of a moderate to severe acute infection a mild infection might be ignored. Live vaccines such as MMR, varicella or yellow fever have to be given either simultaneously or at least four weeks apart from one another. Live vaccines should not be administered within three months after a dose of immunoglobulin. When viral load measurements are crucial for decisions on ART, vaccinations should be postponed. Primary vaccination series or booster In general, a primary vaccination schedule is only necessary when no prior vaccination is reported or...

Details on individual vaccines

Tetanus Diphtheria Pertussis Following a primary series during childhood, lifelong protection should be maintained by boostering at regular intervals. According to a Danish study (Kurtzhals 1992) and our own experiences in Germany, adult HIV patients frequently have insufficient protection against diphtheria. Depending on their CD4+ T-cell count, HIV patients have a reduced booster response and an accelerated antibody waning (Moss 2003). Whenever possible, tetanus-diphtheria combination vaccines should be used, which, in Germany, are also available in combination with polio and or pertussis. In the context of a rising incidence of pertussis in adolescents and adults, boostering with acellular pertussis vaccine in ado lescents has recently been recommended, and is under discussion for adults (Hal-perin 2005). Since the adult pertussis booster vaccines are exclusively available in the above-mentioned combinations in Germany as well as in other countries, their use should be considered...

Targeting Genetic Vaccines

One of the most common cellular localization sequences used for targeting an antigen fusion partner to the MHC class I pathway is ubiquitin. Ubiquitin marks proteins for degradation by the proteosome into small peptides which are then transported to the endoplasmic reticulum for loading onto MHC class I molecules. Addition of ubiquitin to plasmid fusion constructs usually increases CTL responses at the cost of humoral responses (91-95). However, in one study, a ubiquitin fusion construct demonstrated a decrease in humoral response whereas CTL response remained unchanged (96). Further examination of ubiquitin fusion constructs will be required for generalization of this strategy. Calreticulin (CRT) is a particularly interesting candidate for cancer vaccines because it has both MHC class I targeting capacity and antiangiogenesis properties (the ability to inhibit blood vessel growth to the site of a tumor) (97-100). Addition of CRT to fusion constructs has shown to exhibit notable...

Tomorrows Genetic Vaccines

This ideal genetic vaccine formulation has already been described as having the following properties (1) low dose frequency, (2) low cost, (3) effective immune response, (4) high reproducibility, (5) pharmaceutical acceptability, and (6) a high safety profile (134). However, effective immune response, by definition, requires a strong elicitation of the immune system, a process which is currently believed to be intimately tied to danger signals (77). It is reasonable then to question whether effective genetic vaccines will have this high safety profile until our limited understanding of adjuvancy is substantially increased. One indication of this challenge is apparent in FDA clinical trials for conventional adjuvants. With approx 80 yr having passed since the first usage of alum in humans, there are still no additional FDA approved adjuvants. This could be the result of crude adjuvancy and low toxicity being mutually exclusive traits. In the short term, mastering the intricate balance...

Early Vaccine Studies

With its innocuity having been demonstrated in adults, studies were then undertaken in a small group of institutionalized youngsters in whom measles occurred annually with high morbidity and mortality. In parallel with the earlier cell culture and animal studies, serologic assays had been developed to test complement-fixing, virus-neutralizing and hemagglutination-inhibiting antibodies to measles virus. Susceptible children were chosen on the basis of absent antibodies and, after parental permission, they were the first children to receive the attenuated virus subcuta-neously 11 . The success of these studies led to further trials among home-dwelling children in five US cities 12 . Although significant numbers of the recipients developed fever, and some a mild rash, this occurred with apparent well-being and without discomfort. However, in attempts to modify this further, the vaccine was later accompanied by a small dose of immunoglobulin further attenuating its clinical reactivity....

Inactivated Virus Vaccine

Simultaneously with the licensure of live attenuated virus vaccines in the early 1960s, several pharmaceutical firms marketed a killed measles vaccine which was prepared by formalin inactivation of Edmonston virus. Two or three injections of this vaccine produced a detectable antibody response, but when such patients subsequently were exposed to wild measles virus, they developed a severe atypical illness with CNS obtundation, marked pneumonia and a centrifugal rash that was quite unlike that of natural measles 22 . In addition to the acute nodular pneumonia with effusion that many suffered, they were later found to have persistent pulmonary nodules that remained for years after this syndrome 23 . After approximately 4 years (1963-1967), the inactivated vaccine was removed from the US market. Studies suggest that formalin inactivation that denatured the fusion protein (F) of the virion, so that patients with atypical measles lacked antibodies to this protein.

Measles Control in the Vaccine

Various countries have approached measles control in differing fashions, but the most common has been to administer vaccine shortly before or after the first birthday, by which time most maternal transplacental measles antibody has been catabolized, so that the attenuated virus replicated successfully. With its high immunogenicity and prophylactic efficacy, a single dose of measles vaccine produces seroconversion in 95-97 of susceptible individuals and field efficacy of at least 90 . Nonetheless, with annual birth cohorts of millions of children, even if all receive measles vaccine, there would still be an annual increment of significant number (3-5 ) who would fail to respond to that initial dose. As a result, many countries have now instituted two dose schedules with the second dose given at varying times or ages after initial inoculation. With such a strategy, it has been possible to eliminate measles from some countries (Finland, Sweden) and to reduce the annual number of reported...

Mumps Vaccine Developments Background

The earlier history of attempted development of both killed and live mumps virus vaccines has been marked by abortive and inconsequential efforts to evolve vaccines having the needed attributes of high-level efficacy, lasting duration and apathogenicity 1, 6, 7 . The Jeryl Lynn strain live attenuated mumps virus vaccine 9, 10 , which was developed in our laboratories and brought to market in 1967, has been a paradigm for successful vaccine development because of its desirable properties of clinical nonreactivity, high-level protective immunity and durable immunity following a single dose of vaccine that may prove to be lifelong 11, 12 . Cochi et al. 1 listed ten live attenuated mumps vaccines being marketed worldwide as of 1988. Some, however, have been withdrawn from problems of reactogenicity (see later). The Leningrad strain of mumps vaccine developed by Smorodintsev 13 was used extensively in the Soviet Union, but causes mumps and meningitis is some recipients 14 . Wolinsky et al....

Development of the Jeryl Lynn Strain Mumps Vaccine Basic Concepts

Work toward the development of a live attenuated mumps virus vaccine 10, 16-19 was started in our laboratories in 1959 at the time when the development of live measles virus vaccine was already well along. It was conceived at the time that a new era for pediatric vaccinology might be created through the development of combinations and permutations of possible single-dose live virus vaccines (including measles, mumps, rubella, varicella and hepatitis A), even though all but the measles were still only theoretical possibilities. Mumps was chosen in what was conceived to be a possible initial combined vaccine containing measles and mumps components.

Problems in Selection of Parent Virus Strains for Vaccine

Clinical studies of individual measles, mumps, rubella and varicella vaccines shared the lack of suitable animal models that would prove a reliable preclinical appraisal of safety and efficacy when given to human beings. Hence, the development process was guided more by judgment than actual data. Determination of the proper passage level to assure safety in human subjects was made possible by the creation of numerous lots of vaccine, at sequential embryonated egg or egg cell culture passage levels that were presumed to correlate with increased attenuation. This was immensely difficult and costly since each test vaccine was akin to a vaccine production lot that needed to comply with the rigorous standards of the Federal Regulatory Authority (now FDA) applied to commercially distributed products. The largest problem was the need to make the judgment call as to which distant point in the attenuation cycle would serve to start first clinical tests. Once safety at A second hurdle in...

Special Problems in Developing Suitable Mumps Virus Vaccines Indigenous Viruses of Primary Chick Cell Cultures

A major problem in developing the Edmonston B measles virus vaccine in our laboratories in 1961 26 and its more attenuated successor 27 was the ubiquitous occurrence in chick cells, in culture, or viruses of the avian leukosis complex, including leukemia. Such viruses did not provide evidence for lack of safety for humans, based on many years of use of chick embryo-grown yellow fever virus vaccine. We were, however, restive and determined not to put that human population at possible, or even, remote risk to side effects due to leukemia virus. An answer to the leukosis problem was provided by the development of the resistance-inducing factor (RIF) test 28 that permitted in vitro detection of viruses of the avian leukosis complex. Acting on the finding that eggs laid by hens that had antibodies against leukosis, Hughes et al. 29 develop experimental chicken flocks that were free of leukosis virus. Use of chick embryos from these starter flocks to prepare cell cultures permitted our...

The Legacy of Measles Mumps and Rubella Vaccines

The benefits from use of mumps vaccine, singly or in combination, are best illustrated in Fig. 1, which show the reduction in occurrence in the United States of mumps, following introduction of the vaccine against them. All measles, mumps and rubella vaccines used in the United States have been exclusively of Merck & Co source, except for short-term use of the Schwartz strain measles vaccine and the Cendehill strain rubella vaccine. It is seen that each of the three diseases was dramatically reduced to inconsequential or near inconsequential levels within the decade following their introduction. It is also significant that measles, mumps and rubella each are caused by a single virus of constant immunologic specificity. Therefore, all the three diseases should be able to be eradicated worldwide, especially through the use of the combined vaccine, and this maybe a worthy target for the future. Protective immunity following proper initial response is of long, if not permanent,...

Experimental Infection and Vaccination

Impact of emotions on the functioning of the immune system. Most of the studies assessing immune responses to viral infection in healthy volunteers have been conducted by Dr. Sheldon Cohen's group at Carnegie Mellon University. This group has challenged subjects with different types of respiratory viruses, including rhi-novirus, respiratory synctial virus, corona virus, and influenza A virus (Cohen, 2005). To determine whether the viruses caused the subjects to become ill, cold symptoms, such as the production of nasal mucus, can be measured. Viral load in the nasal passages can be determined via standard virological methodology. In addition, immune measures, such as cytokine production, can be measured in circulation and in mucosal secretions (Cohen, 2005). While much can be learned from this type of study, this approach is not feasible to do for many investigators in the field of behavioral medicine, and determining links with subtle psychosocial factors are difficult due to the...

Formalin Inactivated WNV Vaccines

Inactivated whole virus vaccines have been developed against WNV, and are currently in use in veterinary practice (Ng et al. 2003). Administration of one or two doses of formalin-treated WNV vaccine to geese resulted in 42 and 89 protection, respectively, at 3 weeks post-immunization (Malkinson et al. 2001). Similarly, two doses of inactivated WNV completely protected hamsters from lethal WNV challenge and elicited the development of neutralizing WNV-specific antibodies (Tesh et al. 2002). Vaccination of horses with inactivated WNV also stimulated long-lived neutralizing antibody responses within 14 days of vaccination (Ng et al. 2003). Although killed WNV vaccines could be used to vaccinate the immunocompromised, their utility may be limited by their decreased immunogenicity. Administration of multiple vaccine doses may be required to elicit a protective immune response. Furthermore, it is unclear how durable immunity will be, as relatively low levels of neutralizing and...

Subunit Vaccines Nonreplicating Particles and DNA Vaccines

Vaccination of animals with recombinant WNV proteins or subviral (prM-E) particles also induces neutralizing antibody responses. Repeated immunization of mice or hamsters with purified, recombinant WNV E protein resulted in the development of complement-fixing and neutralizing anti-WNV antibodies that were protective against lethal WNV challenge at least 1 year after vaccination (Ledizet et al. 2005 Wang et al. 2001 Watts et al. 2006). Neutralizing antibody responses to recombinant E protein immunization in horses appeared to be more potent and durable than that observed following vaccination with inactivated virus (Ledizet et al. 2005). Co-expression of prM and E protein alone can induce the formation of Flavivirus subviral particles that are immunogenic in mice (Konishi et al. 1992 Kroeger et al. 2002). Repeated immunization of mice with WNV subviral particles induced neutralizing antibody responses and protected mice against lethal WNV challenge, although a transient viremia was...

Preclinical Vaccine Development

Fortunately, vaccine developers did not wait for the conclusions of the prospective epidemiology studies before initiating work on prophylactic HPV vaccines. Perhaps because these investigators were primarily laboratory-based researchers, and even, as in our case, involved in the studies of the HPV oncogenes, they were not unduly inhibited by the weak correlation between HPV infection and cervical disease seen in the early epidemiologic studies. In any event, considerable activity aimed toward developing HPV vaccines was underway by 1990. A vaccine based on a live attenuated HPV strain was not considered a viable option for two reasons. First, HPVs could not be propagated in replicating cells in culture, so there was no reasonable means of virus production. Second, the virus was known to contain at least three oncogenes, E5, E6, and E7, and a vaccine that delivered oncogenes might not be considered safe for general use as a prophylactic vaccine. Therefore, most efforts involved...

Characteristics of Rotaviruses Related to Vaccine Development

Rotaviruses have three important antigenic specificities group, subgroup, and serotype 8 . VP6, located between the outer and intermediate layers, is encoded by the sixth gene and determines group and subgroup specificities. There are six groups (serogroups) each designated by a letter (A-G), with group A being the epidemiologically most important by far, and therefore vaccines are aimed solely at preventing illnesses with this group. Two major subgroups (1 and 2) have been defined. Serotypes are determined by both VP7 (encoded by gene 7, 8, or 9 depending on the strain ) and VP4 (encoded by gene 4). VP7 is located on the outer layer whereas VP4 protrudes from the outer layer as 60 discrete spikes 10-12 nm in length. The VP4 spikes are not visible by routine negative stain electron microscopy. The geography of the triple-layered particle is shown in the schematic reconstruction in Fig. 6 16 . Both VP7 and VP4 induce neutralizing antibodies that in animal studies are independently...

Cytomegalovirus Vaccine Development

Spectrum of HCMV Disease, Rationale for Vaccine, and Target Population 362 A Compelling Argument for Vaccine HCMV Vaccine What Is the Ideal Target HCMV Vaccines in Clinical Live, Attenuated HCMV Subunit HCMV Vaccine Approaches in Preclinical Potential Role of Other Viral Proteins in HCMV Vaccine Dense Body Peptide-Based Novel Vaccine Abstract Although infection with human cytomegalovirus (HCMV) is ubiquitous and usually asymptomatic, there are individuals at high risk for serious HCMV disease. These include solid organ and hematopoietic stem cell (HSC) transplant patients, individuals with HIV infection, and the fetus. Since immunity to HCMV ameliorates the severity of disease, there have been efforts made for over 30 years to develop vaccines for use in these high-risk settings. However, in spite of these efforts, no HCMV vaccine appears to be approaching imminent licensure. The reasons for the failure to achieve the goal of a licensed HCMV vaccine are complex, but several key...

Strategies for a Rotavirus Vaccine

The need for a rotavirus vaccine received strong international endorsement from the World Health Organization. Approaches to vaccine development ranged from conventional growth in cell culture of human or animal rotavirus strains, to the use of molecular biological techniques with the aim being the prevention of serious illness caused by the four epidemiologically important rotavirus serotypes.

HCMV Vaccines in Clinical Trials

A number of HCMV vaccines have been evaluated in clinical trials. These vaccine candidates are summarized in Table 1. A variety of strategies have been employed, but generally HCMV vaccines can be conceptually subdivided into the categories of live, attenuated vaccines, and subunit vaccines that target individual proteins (see the chapter by W. Gibson, this volume). Progress in study of these vaccines is considered the next section. Table 1 HCMV vaccines that have undergone evaluation in clinical trials Live, attenuated vaccines AD169 vaccine Towne Toledo chimera vaccines Subunit vaccines in seronegative vaccine recipients Significant injection-site and systemic reactogenicity No ongoing studies active Elicits humoral and cellular immune responses Favorable safety profile no evidence for latency gB pp65 IE1 trivalent DNA vaccine gB pp65 bivalent DNA vaccine gB pp65 IE1 alphavirus replicon trivalent vaccine with Towne vaccine Favorable safety profile DNA vaccine with poloxamer adjuvant...

Live Attenuated HCMV Vaccines

HCMV has been the target of live, attenuated vaccine development efforts since the 1970s (reviewed in Schleiss and Heineman 2005). The first live, attenuated HCMV vaccine candidate tested in humans was based on the laboratory-adapted AD169 strain. Subsequent trials with another laboratory-adapted clinical isolate, the Towne strain, confirmed that live attenuated vaccines could elicit neutralizing antibodies, as well as CD4+ and CD8+ T lymphocyte responses. The efficacy of Towne vaccine was tested in a series of studies in renal transplant recipients. Although Towne failed to prevent HCMV infection after transplantation, vaccination did provide a protective impact on HCMV disease (Plotkin et al. 1994). Towne vaccine was also evaluated in a placebo-controlled study in seronegative mothers who had children attending group daycare. This study indicated that immunization with Towne failed to protect these women from acquiring HCMV infection from their children. The apparent failure of...

Development of the First Licensed Rotavirus Vaccine Rota Shield

We conducted stepwise safety and efficacy studies of the G1, G2, and G4 monovalent components of the individual components of the quadrivalent candidate reassortant vaccine in similar fashion as we did for the monovalent RRV strain 67, 73 . Our studies with the G1 component of the reassortant vaccine began in April 1986 proceeding from two adults with high levels of antibodies, to eight adults with the lowest available levels of serum antibodies and proceeded in stepwise fashion to the 2-4-month-age group over 6 months later 48 . Subsequently, the four reassortants were also combined into a quadrivalent vaccine. Twelve separate studies were carried out in 10-20-week-old infants to determine the most efficient and immunogenic dose. A regimen of three doses of the quadrivalent vaccine containing 1 x 105 plaque forming units (PFU) of each serotype was adopted for further testing 74-82 . Fig. 7 Human rotavirus (HRV) x Rhesus RV reassortant quadrivalent vaccine with VP7 serotype 1, 2, 3,...

HCMV Vaccine Approaches in Preclinical Development Alternative Expression Strategies for HCMV gB pp65 and IE1

In addition to the expression strategies outlined above that have made their way into human clinical trials, there are other modes of expression of HCMV subunit vaccine candidates that appear useful in preclinical study. These approaches are summarized in Table 2. One particularly promising approach is based on a recombinant attenuated poxvirus, modified vaccinia virus Ankara. A recombinant Ankara vaccine has been constructed that expresses a soluble, secreted form of Table 2 Alternative subunit vaccine expression strategies proposed for HCMV gB, pp65, and IE1 Modified vaccinia virus Ankara (MVA) High-level protein expression or trivalent vaccines) in single construct Preexisting immunity to poxvirus does not limit immune response (utility for vaccinees who have received smallpox vaccine) Recombinant adenovirus Potential for induction of mucosal immune responses in transgenic rice Offers potential for oral vaccination Potential for induction of mucosal immune responses No animal...

Potential Role of Other Viral Proteins in HCMV Vaccine Design

As noted, most efforts in clinical trials of candidate subunit HCMV vaccine development and testing have focused on the envelope glycoprotein gB and the T cell targets, pp65 and IE1. However, a plethora of other HCMV-encoded proteins play key roles in the host immune response and these warrant consideration in future clinical trials. To date, only animal model data are available to validate the potential role of these proteins as vaccines. This information is summarized in Table 3. In addition to gB, other envelope glycoproteins have been considered for vaccine development, although to date no candidates have been tested in human trials. Among the other HCMV glycoproteins, the gcII complex, consisting of gN (UL73) and gM (UL100), is of particular interest. Proteomic analyses of the HCMV virion have demonstrated that gcII is the most abundantly expressed glyc-oprotein in virus particles, emphasizing its potential importance in protective immunity (Varnum et al. 2004). HCMV infection...

CatchUp Vaccination Found to be Related to Intussusception

However, there was an important association that for the most part had eluded the various investigating groups, a relationship if known and acted upon may have rescued the vaccine. It was clear that routine administration of RotaShield in the US was doomed because no matter what the true incidence of intussusception was in the US, it was likely not small enough in the age schedule that had been used for RotaShield's administration. It is interesting to note that in September 1999, the interlude between suspension of the vaccine in July and its withdrawal in October, a communication regarding RotaShield's suspension provided an important clue on the effect of age on naturally occurring intussusception that was not pursued (Fig. 9a) 108 . The authors showed the incidence of intussusception by age in months in 833 infants hospitalized over a 2-year period at National Health Service Hospitals in England, where the vaccine was not in use. The authors noted that The highest incidence was in...

Age Factor Important for Current Rotavirus Vaccines

The age factor was not totally ignored by the WHO which, in a position paper in 2007 on newly available rotavirus vaccines, issued a firm admonition in a WHO position paper on the current rotavirus vaccines stating that the first dose of Rotarix 20 30 40 50 60 70 Days After Vaccination Days After Vaccination should be given no later than at the age of 12 weeks and for RotaTeq that Vaccination should not be initiated for infants aged > 12 weeks 119 . They concluded by noting that There is a potentially higher risk of intussusception when the first dose of these vaccines is given to infants aged > 12 weeks consequently, current rotavirus vaccines should not be used in catch-up vaccination campaigns, where the exact age of the vaccinees may be difficult to ascertain. It was apparent that the RotaShield experience with catch-up vaccination provided an important lesson on the age of administration of the new vaccines.

Peptide Based Vaccines

Another potential approach to HCMV vaccination is the use of peptide vaccination employing synthetic peptides comprising immunodominant cytotoxic T cell epitopes. This approach may ultimately prove to be most useful in the vaccine-mediated prevention of HCMV disease in the transplant setting, where specific peptide vaccine regimens could be tailored for donor-recipient pairs based on HLA genetics. Nasal peptide vaccination with the immunodominant MCMV IE1 epitope, YPHFMPTNL, in combination with cholera toxin adjuvant, protected mice against virulent MCMV challenge (Gopal et al. 2005). In a preclinical study relevant to HCMV vaccines, a pp65 human leukocyte antigen (HLA)-A2.1-restricted CTL epitope corresponding to an immunodominant region spanning amino acid residues 495-503, fused to the carboxyl terminus of a pan-DR T-help epitope, was capable of eliciting CTL responses from mice transgenic for the same human HLA molecule (BenMohamed et al. 2000). Since this epitope is highly...

Novel Vaccine Approaches

Several other vaccination approaches have been proposed for HCMV and have been validated in varying degrees in animal models. One approach is based on exploitation of viral genomes cloned in Escherichia coli as bacterial artificial chromosomes (BACs). Vaccination of mice with bacteria containing the MCMV genome cloned as a BAC conferred protective immunity against subsequent challenge (Cicin-Sain et al. 2003). In guinea pigs, a noninfectious BAC generated by transposon mutagenesis induced immune responses that protected against congenital GPCMV infection and disease (Schleiss et al. 2006). Given the ease of manipulation of BACs using mutagenesis techniques available for E. coli, future BAC studies provide the opportunity to generate recombinant, designer vaccines with specific genomic deletions or insertions that could modify the immune response or improve the safety profile of the candidate vaccine. Such modified BACs are being employed as immunocontra-ceptive vaccines for population...

Currently Licensed Rotavirus Vaccines and Intussusception

The recently (February 2006) licensed pentavalent rotavirus vaccine Rotateq described later in this book underwent extremely large prelicensure safety trials involving almost 70,000 infants because of the RotaShield experience 125 . Fortunately, intussusception was not associated with the vaccine. The age factor described above for RotaShield was controlled by stringent age restrictions in the Rotateq studies. The mean and median ages of the vaccinees and controls in this large safety trial were identical (< 3 months mean 68.6 days and median 70 days ). The package insert after licensure specified that the vaccine should be given . starting at 6-12 weeks of age. The intussusception cloud emerged for Rotateq in February 2007 about 1-year postlicensure after about 3.5 million doses had been distributed, when the FDA released a Public Health Notification with Information on RotaTeq and Intussusception in which the FDA notified health care providers and consumers about 28 postmarketing...

Benefits of Neonatal Vaccination

The schedule of beginning rotavirus vaccination in the neonatal period has several advantages (a) it may prove to be the safest time to administer an oral, live, attenuated vaccine (b) it may be a period of low reactogenicity RRV-TV did not induce a febrile response in infants vaccinated during the neonatal period and moreover, the neonatal dose gave significant protection against a febrile response at 2 months of age when compared to neonates who received a placebo neonatally 132 (c) RotaShield did not induce intussusception in 70,000 infants under the age of 60 months 110 (d) it is a relatively refractory period for naturally occurring intussusception (this may also apply to a vaccine) (e) a single dose may yield adequate protection vs. severe diarrhea (f) it may afford protection of vulnerable infants during the first 2 months of life who are now excluded by the conventional schedule starting at 2 months of age (g) there is more likely exposure to a health-care provider during the...

Why Is Another Vaccine Needed When There Are Already Two Licensed Rotavirus Vaccines

The advantage of RotaShield (and other vaccines being produced in developing countries) is that it is made under the auspices of a nonprofit foundation with later transfer to a developing country where it will be produced at an affordable price. This vaccine can be expanded and thereby designed as necessary in a formulation that will correspond to circulating newer serotypes such as G8, 9, or 10, which are available as single VP7 gene substitution reassortants 133 . It will also have sustainability because of manufacture by nonprofit sponsorship and ultimately by a developing country manufacturer.

Raising the Bar for Vaccine Safety Studies

Rotaviruses are one of the important causes of disease and death worldwide. For this reason, there has been a great deal of public and private interest in developing a vaccine. Unfortunately, because of a rare adverse event associated with the first marketed rotavirus vaccine, subsequent vaccines have been difficult to develop. In 1998, a rotavirus vaccine (RotaShield, Wyeth) was licensed and distributed in the USA. Ten months after licensure, it was found to be a rare cause of intestinal blockage (intussusception) affecting 1 per 10,000 vaccine recipients. When this rare adverse event was discovered, the Centers for Disease Control and Prevention (CDC) withdrew its recommendation for use. The problem with the first rotavirus vaccine did not end subsequent attempts to make a safer vaccine but it did dramatically increased the size of subsequent pre-licensure trials. Two new rotavirus vaccines (RotaTeq Merck and Rotarix GlaxoSmithKline ) have each been tested for safety and efficacy in...

Hope for a Vaccine Natural Infection Protects Against Disease Following Reinfection

The first rotavirus vaccines were made using the same approach as that used by Edward Jenner. Jenner had found that an animal strain of smallpox (cowpox) was similar enough to human smallpox to induce protective immunity but dissimilar enough so that it did not induce the disease. Unfortunately, the Jennerian approach to making a rotavirus vaccine was, in the end, disappointing.

DNA vaccines against tuberculosis

DNA plasmids encoding Mycobacterium tuberculosis antigen 85 (Ag85) were tested as vaccines in animal models. Ag85 DNA induced relevant immune responses (i.e. T helper (Th) cells, Th1 cytokines and cytotoxic T lymphocytes) and was protective in mouse and guinea pig models of mycobacterial disease. Therefore, DNA vaccination holds promise as an effective means of preventing tuberculosis in humans. Furthermore, this technique is amenable to identifying the protective antigens of M. tuberculosis. Tuberculosis causes more deaths ( 3 million per year) than any other disease caused by a single pathogen, despite the widespread availability of a tuberculosis vaccine. The lack of overall effectiveness of this vaccine, which is a live attenuated form of Mycobacterium bovis termed Bacillus Calmette Guerin (BCG), makes it imperative that a more effective vaccine be developed. To this end, research is active in several areas, including experimental tuberculosis vaccines based on subunit...

Conclusions on Vaccination Studies

It is difficult to assess and to compare the studies, particularly because the monitoring after immunization and after challenge is described insufficiently in some studies and the sensitivity of the tests to measure HDV viremia is not comparable. Together these results allow us, however, to conclude that immunization against HDV with conventional vaccines is not possible. Neither a good humoral nor a weak Th-cell immune response is sufficient to protect from HDV superinfection. Immunizations with vaccinia virus or DNA expressing HDAg were at least able to modulate the course of infection. In general, these approaches are known to induce a CTL response, which maybe essential for protection. In further studies HDV vaccination schemes should be optimized to enhance the cellular immune response, e.g., by using different combinations of DNA vaccines with woodchuck cytokine (Lohrengel et al. 1998, 2000). This approach has been shown to enhance the cellular immune response to other...

The Basis of Virus Vaccines

Pasteur performed all of his work on vaccines without knowing the mechanisms involved in the protection of vaccinated animals. For Pasteur, the virus vaccine concept involved a mild disease for producing immunity and was based on the idea that resistance was due to the depletion of an element that was crucial for the proliferation of microbes in the organism this depletion having necessarily to be induced by a mild disease.

Prospects for tuberculosis vaccine development

The data presented here and elsewhere (Huygen et al 1996) demonstrate Ag85A DNA vaccination against tuberculosis in animal models. DNA encoding hsp65 and the 38kDa antigen of M. tuberculosis have also been shown to confer protection (Tascon et al 1996, Zhu et al 1997). These data suggest that there may be several protective antigens in M. tuberculosis and that a combination of DNA plasmids encoding discrete antigens should be investigated. But which antigens There are likely to be several thousand proteins expressed by M. tuberculosis, thereby greatly complicating the determination of those that are protective against disease. One potential means of identifying these proteins is by taking advantage of the DNA vaccine technology itself. Johnston and colleagues recently showed that pools of many thousand different plasmids each containing a fragment of the genome of a pathogen (in this case Mycoplasmapulmonis) could be used to vaccinate and protect mice from challenge (Barry et al...

Footand Mouth Disease Vaccines

Among the examples of successful eradication of a disease under vaccinal coverage, special emphasis should be given to foot-and-mouth disease, which also marked a major milestone in the development of viral vaccines. Early attempts at developing modified virus vaccines failed. In 1925, the first inactivated vaccine, prepared from ground aphtae and treated with formaldehyde, was developed by Vall e, Carr and Rinjard 28 . In 1939, Schmidt suggested adsorbing the virus onto aluminum hydroxide in order to inactivate it 29 . This inactivation method, although not satisfactory, made it possible for Waldmann et al. to develop in 1941 an inactivated, adsorbed, formolized and heated vaccine prepared from cattle aphtae 30 . This approach, although relatively satisfactory, did not make it possible to produce vaccines in sufficient quantities and reasonable cost. It was Frenkel who developed in 1947 a method for growing foot-and-mouth disease virus in cattle lingual epitheliums 31, 32 . This...

Vaccine Strategies for HDV

If the immune response explanation of the genetic changes discussed above is correct, we could conclude that the stimulation of a potent immune response, which is inferred by the 27 week sequence changes in the animals that recovered from HDV infection, could be achieved by vaccination and that this response could clear the virus. Analysis of antibody responses to HDAg in patients and experimentally infected woodchucks indicated an immun-odominant domain between amino acids 52 and 93 (Bergmann et al. 1989 Wang et al. 1990). A preliminary report (Bergmann et al. 1993) described a vaccine strategy in which woodchucks were vaccinated with three HDAg peptides conjugated individually to keyhole limpet hemocyanin. Vaccinated woodchucks were challenged with a woodchuck-adapted HDV pool. All animals became infected with HDV, based on the ability to detect HDV RNA in serum (Bergmann et al. 1993). However, preliminary analysis of viral RNA levels suggested that viremia was lower and of shorter...

Present and Future of Veterinary Vaccines

While the first veterinary vaccines relied on Pasteur's work, and the vaccines prepared from the strains of virus or microorganisms of attenuated virulence are still in widespread use, the number of available vaccines and their features has increased, for epidemiological reasons as well as to meet both technical and economical requirements relating to their use.

Rabbit Vaccine Studies

Vaccine studies employing the outbred rabbit challenge model have also been successfully carried out, and is the most common model.57,114,116,134 This model, like the rat challenge model, is a model for HTLV-I infection only, as infected rabbits do not develop HTLV-I-associated diseases under normal circumstances. Similarly, most challenge stocks for rabbit challenge studies are xenogeneic and are usually ofhuman origin. In some studies, whole blood from an HTLV-I-infected rabbit was used to challenge rabbits passively immunized with anti-HTLV-I antibody of rabbit or human sources.114116 No systematic attempt has been made to use a rabbit T-cell line productively infected with HTLV-I as the source of challenge virus. Since rabbits have been shown to be successfully infected with whole blood from allogeneic HTLV-I-infected rabbits, it does not appear that the problems encountered with allogeneic challenge in the rat model will be seen in the rabbit model. Studies that determined the...

Neurologic Accidents Caused by the French Neurotropic Vaccine

Neurologic reactions noted by French workers during the wide-scale use of the mouse brain vaccine were attributed to the inherent neurotropism of the vaccine to low doses and a delayed immune response when the vaccine administered by poor scarification technique or after deterioration during field use. The evidence suggested that the accidents were the result of invasion of the brain by the vaccine virus, and not an allergic demyelinating process of the presence of an adventitious agent in the vaccine. American and English workers were reluctant to utilize the Dakar vaccine, but the occurrence of severe epidemics in eastern Nigeria in 1951-1952 and in Panama and Central America in 1950-1952 presented a formidable problem, as it was not practical to deploy the thermolabile 17D virus under prevailing conditions in remote areas. To combat the outbreaks, emergency use of the French vaccine appeared justified 65, 66 . Because of the concern about the safety of the vaccine, a careful...

Healthcare Costs Associated with Congenital HCMV Infection A Compelling Argument for Vaccine Development

The economic burden on the healthcare system in caring for neurodevelopmental disability in early childhood caused by congenital HCMV infection is substantial. Congenital HCMV infection is the most common infectious cause of brain damage in children, and HCMV causes more hearing loss in children than did Haemophilus influenzae meningitis in the pre-Hib vaccine era (Pass 1996). The economic costs to society associated with congenital HCMV infection present a compelling argument for vaccine development. In the early 1990s, the expense to the US healthcare system associated with congenital HCMV infection was estimated at approximately 1.9 billion annually, with an average cost per child of over 300,000 (Aran et al. 2004). Children with congenital HCMV infection often require long-term custodial care and extensive medical and surgical interventions. A recent economic analysis by the Institute of Medicine (IOM) examined the theoretical cost-effectiveness of a hypothetical HCMV vaccine...

Individual and Combined Live Measles Mumps and Rubella Vaccines

The combined live measles-mumps-rubella (MMR) vaccine was the realization of a long-term plan to create single-dose bi- and trivalent combinations of these three vaccines 40 . Development of the combined vaccines depended on prior development of the individual vaccines. Measles virus vaccine (Rubeovax) 26 , which was licensed in 1963 using the original Enders' Edmonston B strain 41 , was so virulent that reactogenicty needed to be reduced by giving virus to children simultaneously with measles immune globulin. The Edmonston strain was further attenuated biologically in our laboratories to create the more attenuated Enders' line, Moraten 27 , which was licensed (Attenuvax) in 1968. The development of the Jeryl Lynn mumps virus was described earlier. Licensed rubella virus vaccines were the sequel to our pioneering studies on the Merck Beno t strain 42-47 of duck cell culture attenuated virus isolated from a child names Beno t. The HPV-77 strain that was grown in monkey kidney cultures...

Acceptance of Jennerain Vaccination

However, the Chinese did not accept Jennerian vaccination exactly as it was understood in the West. There was a construction of the Chinese interpretation of vaccination, deciphering it effectiveness in terms conforming to Chinese orthodox medical thought. Basically, the classic notion o taidu (foetal toxin), to which the principle of variolation and vaccination was accommodated, persisted. According to this concept, toxic matters from the father and the mother - a result of physical desire, emotional instability, or unbalanced nutritional habits - were inevitably passed onto the fetus the moment it was conceived. The toxin would express itself at one moment or another during the lifetime of the child. Smallpox, measles, chickenpox, all sorts of skin eruptions, boils or ulcerations, were different manifestations of taidu. Vaccination, like variolation, was a way of controlled release and elimination of the taidu before any occurrence of smallpox epidemic. The principle for traditional...

Attenuated Human Rotavirus Vaccine Candidates A Monovalent Cell Culture Passaged Virus A Neonatal Strain and Cold

Volunteer studies were carried out with a human G1 rotavirus (the D strain) stool filtrate derived from an infant with diarrhea 17 . Oral administration of the inoculum induced a diarrheal illness in certain volunteers, allowing us to determine correlates of susceptibility to challenge 17, 18 . This gave us confidence that a vaccine could be evaluated in this model, an important prelude to the development of a vaccine for infants and young children. Human rotaviruses were considered to be fastidious agents as none had been propagated efficiently in cell cultures until the Wa human rotavirus strain (a G1, P1A 8 virus) derived from the stool of an infant with diarrhea was cultivated in primary African green monkey kidney (AGMK) cells after 11 passages in gnoto-biotic piglets 19 . This adapted mutant virus was triply plaque purified, and the 16th AGMK cell culture passage was evaluated first in animals and then adult volunteers as a potential oral vaccine candidate 18, 20, 21 . The oral...

The Adverse Effects of Subunit and Acellular Pertussis Vaccines

A description of the results of Phase 1, 2, and 3 trials for all the vaccines in Table 1 cannot be made here, but to summarize, the rates of local reactions are significantly lower for all acellular vaccines than for (any) whole-cell vaccine. The rate of local reactions to a monocomponent vaccine is also lower than that of a two-component vaccine 17 . It increases with successive doses of acellular vaccine, while the opposite is true for whole-cell vaccines. An acellular vaccine booster in a child primed with whole-cell vaccine results in almost no reactions. When acellular vaccine boosters are given to children primed with the same vaccine, larger (large) local reactions have been described (for some vaccines). The most common systemic reaction to whole-cell vaccines, i.e. fever, is significantly decreased with acellular vaccines. As a consequence, the rate of convulsions is also decreased since the majority of cases represent febrile convulsions. As for the reversible neurological...

Introduction of Typhoid Vaccination A Wright or R Pfeiffer

It now seems clear that this controversy should no longer continue and that both authors be given equal credit for the discovery of typhoid vaccine 7 . In September 1896, in the Lancet article, Almoth Wright, a British researcher, reported on the use of oral calcium chloride for the treatment of serous hemorrhages in patients suffering from defective blood coagulopathies, and also demonstrated its usefulness to control local side-effects after subcutaneous injection of typhoid bacilli 8 . In this article, he quoted experiments with heat-kill, phenol-preserved typhoid vaccine in a horse, and subsequently in two officers of the Indian Medical Corps, one of whom then received an inoculum of the wild type S. typhi and appeared protected. Wright was then sufficiently obstinate and convincing to obtain evaluation of his vaccine in 2,835 volunteers in the Indian Army 9 . Despite local and generalized adverse reactions that were carefully examined by several panels of experts, results were...

Pasteur and Toussaint and Their Competition for an Anthrax Vaccine

Irish Peasant Men With Stick

During his studies on chicken cholera Pasteur never forgot anthrax, his main subject and source of funding of that time. In July 1880, Toussaint, a competitor in the field of anthrax, disclosed a vaccine to immunize sheep and dogs. The concept of vaccine was from Pasteur, but the vaccine technique, from Toussaint defibrinated blood from a sheep freshly dead of anthrax heated at 55 C for 10 min with or without a filtration through paper or the addition of carbolic acid. Toussaint did experiments on sheep in Toulouse, then in Alfort with sheep of a herd belonging to the Ministry of Agriculture, so with official support. The results of the Toussaint vaccine inoculation were rather good with just a low percentage of sheep deaths from the vaccine injections, not really different from those sometimes observed in the Pasteur's subsequent experiments. Pasteur, very rapidly criticized Toussaint's vaccine, which was in principle dead and thus not in accordance with the exhaustion theory of...

Vaccine Thermostability The Chink in the Armor

A major limitation for use of yellow fever 17D vaccine in tropical countries has been its thermolability, both in the lyophilized state and after reconstruction. The early vaccines were produced without stabilizers and were found to deteriorate very rapidly when exposed to temperatures greater than 20 C 88, 89 . Between 1940 and 1970, this problem was a major obstacle in the distribution and use of the 17D vaccine, especially in Africa, and one of the principal reasons why immunization was not widely implemented in Anglophone countries. The difficulty in using a thermolabile product in areas with limited cold chain capability stimulated research on vaccine stabilizers. In 1970s, researchers in England 90 and France 91 systematically investigated stabilizing agents and devised successful formulations, now used by a number of manufacturers. One widely used stabilizer employs sugars (lactose, sorbitol), amino acids, and divalent cations. Addition of stabilizer reduces losses of virus...

Assessing the risk of a vaccination

Following a vaccination, a rise in viral load is often observed (e.g for tetanus, pneumococcus, influenza, HBV). This effect reflects the stimulation of cellular immunity viral replication peaks one to three weeks later. Thus, a routine viral load should not be performed within four weeks of vaccination. Numerous studies demonstrated that these viral load elevations are immunologically and clinically irrelevant. However, one study of influenza vaccinees showed 2 out of 34 patients whose HIV strains developed new RT- or protease-gene mutations (Kolber 2002). This risk should be considered in patients with limited therapeutic options. Furthermore, elevations of viral load might lead to an increased risk of materno-fetal transmission during pregnancy. Apart from that, adverse effects of inactivated vaccines are not increased in HIV patients. With live vaccines, however, life-threatening and fatal complications have been reported for smallpox, tuberculosis, measles, and yellow fever....

Vaccinia As A Cancer Vaccine

The experience with vaccinia in the eradication of smallpox led to research into its use as an antitumor vaccine. Vaccinia was engineered to express tumor antigens and serve as a cancer vaccine. The size of the potential transgene that can be put into the vaccinia vector allows for flexibility in engineering, such that immune enhancing genes and antigenetic genes can be recombined into the genome. The immunostimulatory effects and efficient transcriptional machinery of the virus were utilized to create various cancer vaccine vectors (Table 2). Recently, a phase I clinical trial of vaccinia expressing prostate specific antigen (PSA) in prostate cancer patients was published. In this trial the Wyeth strain virus was delivered intradermally every 4 wk for three doses without producing significant systemic toxicities. A cutaneous reaction, consistent with viral replication was seen in all patients treated with the virus at a dose of 2.65 x 107 pfu. Several patients developed T-cell immune...

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