Subunit Vaccine

12 Key excerpts on "Subunit Vaccine"

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  eBook - ePub

  Harnessing the Power of Viruses

  • Boriana Marintcheva(Author)
  • 2017(Publication Date)
  • Academic Press

    (Publisher)

  Depending on their composition, classical vaccines can be viewed as whole-agent vaccines or subunit/component vaccines. Whole-agent vaccines contain a safe form of the actual pathogen causing the disease the vaccine is preventing. The infectious agent is either dead (inactivated vaccines), killed by heat, chemical treatment, etc., or alive but in weakened form (attenuated vaccines). Advantage of whole vaccines is that they mimic the infectious agent best, triggering the rise of a range of antibodies with various specificities. Dead vaccines cannot cause disease; however, they cannot induce cellular immunity either, since no productive infection takes place. Attenuated vaccines can cause full-blown infection, thus the immune response is more robust and involves both humoral and cellular components. The infection itself is very mild and does not present health concerns except in immunocompromised individuals and pregnant women. A classical approach to create an attenuated vaccine strain is to subject a wild type strain to multiple passages while monitoring virulence and immunogenicity. This strategy takes advantage of the natural ability of viruses to mutate, and depending on the mechanism of attenuation, reversions to WT virus might be of concern. Attenuated strains with deletion mutations are preferred in comparison to ones with point mutations since reversion back to WT is physically impossible. Usage of whole-agent vaccines is somewhat restricted by the ability to grow unlimited amounts of viruses in tissue culture, as well as the need for refrigeration and preservatives for long-term storage.

  Subunit Vaccines consist of single components of the pathogen in question, cannot cause disease, and elicit mainly humoral immune response. Subunit Vaccines can be composed of inactivated toxins (toxoid vaccines against toxin-producing bacteria); surface molecules of pathogens (hemagglutinin and neuraminidase–based antiflu vaccine); or empty viral capsids (Gardasil/anti-HPV vaccine), etc. Subunit Vaccines generally require multiple booster injections to ensure strong protection. Today, most of the Subunit Vaccines conferring antiviral protection consist of recombinant proteins and are thus also classified as recombinant Subunit Vaccines. Not that long time ago such vaccines were considered experimental; however, at this moment the use of genetic engineering to produce large quantities of the protein of interest presents a rather standard practice and of course a great example of how science advancement positively impacts our life.

  Conjugate vaccines could be considered as a special case of Subunit Vaccines, mainly applicable to bacterial pathogens. Polysaccharides from the outer surface of bacteria are attached/conjugated to inactivated protein toxins and used for vaccination. The approach solves the problem with the relatively low immunogenicity of the polysaccharides and “forces” the immune system to execute a robust humoral response against them using the toxin molecule as a tool.

  8.4.2. Experimental Vaccines

  Many of the classical vaccines used today were originally developed around the mid-20th century. Despite the fact that they are continuously reevaluated and refined, the magnitude of change is not even a close match to the advancement of molecular biology and biotechnology approaches relevant to vaccine design and manufacturing. While there is no obvious reason to seek replacement of effective and safe vaccines, it is only for natural new technologies to change the landscape of the field. Efforts are currently focused on creating vaccines eliciting strong cellular and humoral responses, lowering the cost of production, and increasing vaccine shelf lives, along with developing alternative delivery mechanisms. A major trend in vaccine production is moving manufacturing outside animal cells and utilizing plant, bacterial and fungal model systems. The latter are not only more cost-efficient but also eliminate the danger of pathogen cross-contamination, which is a constant concern when vaccines are produced in tissue culture, especially if mammalian cells are used.

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  Molecular Biotechnology

  Principles and Applications of Recombinant DNA

  • Bernard R. Glick, Cheryl L. Patten(Authors)
  • 2022(Publication Date)
  • ASM Press

    (Publisher)

  Vaccines that use components of a pathogenic organism rather than the whole organism are called “subunit” vaccines. Safe and well-characterized Subunit Vaccines offer the potential to target immune responses toward specific epitopes. Since they are com-posed of well-defined components, they enable the production of custom vaccines beyond that provided by traditional whole-attenuated-pathogen approaches. Using recombinant DNA technology, the generation of libraries of different vaccine components permits the selection of vaccine constituents to stimulate immune responses that yield protective immunity against a specific pathogen. In addition to the identification of antigens and their components that can elicit protective or therapeutic immunity, the use of appropriate adjuvants that stimulate potent, antigen-specific immune responses is also important. The development of new Subunit Vaccine components is a rather important area of investigation upon which much future vaccine development will be based. 393 Vaccines There are advantages and disadvantages to the use of subunit vac-cines. On the positive side, using a purified protein(s) as an immunogen ensures that the preparation is stable and safe, is precisely defined chem-ically, and is free of extraneous proteins and nucleic acids that can ini-tiate undesirable side effects in the host organism. On the negative side, purification of a specific protein can be costly, and in certain instances, an isolated protein may not have the same conformation as it does in situ (within the viral capsid or envelope), with the result that its anti-genicity (immunogenicity) is decreased. Obviously, the decision to pro-duce a Subunit Vaccine depends on an assessment of both biological and economic factors. Herpes Simplex Virus Herpes simplex viruses 1 and 2 (HSV-1 and HSV-2) are, respectively, the causes of cold sores and genital herpes.

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  Microparticulate Systems for the Delivery of Proteins and Vaccines

  • Smadar Cohen, Howard Bernstein(Authors)
  • 2020(Publication Date)
  • CRC Press

    (Publisher)

  12

  Adjuvant-Active Polymeric Microparticulate Vaccine-Delivery Systems

  Douglas Kline

  Schering-Plough Research InstituteKenilworth, New Jersey

  Justin Hanes and Robert Langer

  Massachusetts Institute of TechnologyCambridge, Massachusetts

  I.     INTRODUCTION

  When Edward Jenner began injecting an extract of cowpox lesions into patients to prevent smallpox infection in the late 18th century [1 ], little could he have known how his crude inoculation would revolutionize the science of disease prevention and control. Since those humble beginnings, the science of vaccination has both spurred and adapted biotechnological advances to produce vaccines that are efficacious and safe.

  Most recently, developments in the fields of protein sequencing and genetic engineering have engendered the Subunit Vaccine approach, in which the whole-killed or attenuated agents often present in vaccine preparations are replaced with a peptide or protein subunit known to elicit an effective immune response toward the parent organism. Because Subunit Vaccines consist of well-characterized molecules, often produced by recombinant DNA technology, and do not contain the disease-causing agent, their safety profiles are superior to conventional whole-organism vaccines in which the absence of viable infectious agents must constantly be validated. This is of particular relevance as vaccines for more serious illnesses, such as hepatitis B and human immunodeficiency virus infection (HIV), are developed. Unfortunately, the improvement in safety afforded by Subunit Vaccines often comes at the expense of efficacy. Subunit Vaccines are frequently poorly immunogenic, necessitating several booster injections to achieve the desired antibody response and a more frequent revaccination schedule [2 ].

  In the administration of any vaccine program (subunit or conventional), the number and frequency of injections required for protection can become a crucial factor in its success. More booster injections translate into more patient visits, and patient compliance becomes a limiting factor. Usually, this was considered in terms of vaccination programs in developing countries where, even if the problems of inadequate storage and improper vaccination practices [3 ] could be overcome to ensure potent vaccine doses were correctly administered, the population can be nomadic or difficult to reach by health authorities. However, recent experience has shown that patient compliance can be problematic even with conventional vaccines in an industrialized country, such as the United States. Witness the recent outbreaks of measles among large numbers of unvaccinated children younger than 5 years of age and in unsuccessfully vaccinated children of school and college age [4 ]. In response to these recent epidemics, the Advisory Committee on Immunization Practices (ACIP) has set a goal for the year 2000 of 90% of children fully vaccinated (four doses of diphtheria, tetanus, and pertussis; three doses of oral polio; three doses of Haemophilus influenzae; and one dose of measles, mumps, and rubella) by age 2; however, studies show that the target still far exceeds the practice [5 ]. Opportunities to immunize children during contact with health care workers (such as at hospital emergency wards) was cited as a means of improving the vaccine coverage, but in one study, almost 40% of adults accompanying children to a pediatric emergency department provided inaccurate information about their measles immunization history [6

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  Biotechnology in Medical Sciences

  • Firdos Alam Khan(Author)
  • 2014(Publication Date)
  • CRC Press

    (Publisher)

  97 Chapter four: Virology and vaccines 4.8.1.5 Other vaccines Recently, various efforts have been made to make vaccines in different ways. An immune response can be achieved by introducing a protein subunit rather than introducing an inactivated or attenuated microorganism. Examples include the Subunit Vaccine against hepatitis B virus that is composed of only the surface proteins of the virus (previously extracted from the blood serum of chronically infected patients, but now produced by recombination of the viral genes into yeast), the virus-like particle (VLP) vaccine against HPV that is composed of the virus capsid protein, and the hemagglutinin and neuramini-dase subunits of the influenza virus. The vaccine can also be prepared by conjugating certain bacteria that have polysaccha-ride outer coats that are poorly immunogenic. Moreover, by connecting these outer coats to proteins, for example, toxins, the immune system can be led to recognize the polysaccha-ride as if it were a protein antigen. Interestingly, this approach is used in the Haemophilus influenzae type B vaccine development. Furthermore, by similar methods, dendritic cell vac-cines can also be made by combining dendritic cells with antigens in order to present the antigens to the body’s white blood cells, thus stimulating an immune reaction. These vac-cines have shown certain positive preliminary results for treating brain tumors. Moreover, vaccines can be monovalent or univalent or multivalent in nature. A monovalent vaccine can immunize against a single antigen or single microorganism, whereas a multivalent vaccine is developed to immunize against two or more strains of the same microorganism, or against two or more microorganisms, respectively. In certain cases, it has been observed that a monovalent vaccine may be preferable for rapidly developing a strong immune response.

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  Introduction to Modern Virology

  • Nigel J. Dimmock, Andrew J. Easton, Keith N. Leppard(Authors)
  • 2015(Publication Date)
  • Wiley-Blackwell

    (Publisher)

  Additionally, achieving the necessary multiple treatments may be hard in areas of the world where access to medical professionals is difficult. Inactivated vaccines must be delivered by injection, which is not attractive to recipients, and the site of injection is important and may play a role in the efficiency of the subsequent immunity that is induced. Linked with this, another problem is that killed vaccines do not reach and stimulate mucosal immunity in the intestinal and respiratory tracts where virus normally gains entry to the body, and may thus not stimulate the full range of immunity needed for the greatest levels of protection. However, providing that the killed vaccine is a potent immunogen, the high levels of serum IgG which result from vaccination can often serve in place of local immunity, presumably because there is a sufficient concentration of IgG to diffuse to the extremities. 26.4 Subunit Vaccines Subunit Vaccines can take several forms. They may consist of: ■ one or a subset of the virus proteins ■ non-infectious virus-like particles containing a subset of the virus structural proteins. A Subunit Vaccine, as the name suggests, consists of a component of the virus which is used to stimulate an antibody response. The subunit may be one or more proteins that are known to contain epitopes which stimulate an immune response. These usually include a protein(s) that forms part of the virus particle but may also include virus proteins which are normally found only within infected cells. Alternatively, such a vaccine may consist of a peptide or collection of peptides representing some of the epitopes contained within virus proteins. These components must be highly Chapter 26 Vaccines and immunotherapy: the prevention of virus diseases 421 Fig. 26.6 Virus-like particles (VLP) consisting of hepatitis B virus surface antigen. The virus protein was expressed in yeast cells in the absence of any other virus material.

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  Therapeutic Peptides and Proteins

  Formulation, Processing, and Delivery Systems, Third Edition

  • Ajay K. Banga(Author)
  • 2015(Publication Date)
  • CRC Press

    (Publisher)

  339 10 Recombinant Protein Subunit Vaccines and Delivery Methods 10.1 INTRODUCTION The focus of this chapter is on protein or recombinant protein–based subunit vac-cines as those fit in better with the overall scope of this book, especially since many of the products in development will have a therapeutic focus. Recombinant vaccines in development are listed in Table 10.1. Peptides and peptidomimetics are also in development as vaccines. Peptidomimetic vaccines contain antigenic fragments that mimic the antibody-binding site (Ho & Gibaldi, 2003). However, an introduction to vaccines in general will first be provided. Vaccines have eradicated smallpox and limited the spread of several dangerous infections. Among these are included tetanus, measles, hepatitis A, hepatitis B, and rotavirus. However, effective vaccines still need to be developed for other disorders such as rotavirus, human papillomavirus, malaria, herpes, hepatitis C, and newly emerging diseases such as SARS or West Nile viruses. Furthermore, a vaccina-tion approach may be needed for the threat of bioterrorism. Vaccines are a criti-cal component of U.S. government’s programs designed to make available modern effective countermeasures. Since vaccines enhance and modify body’s immune responses, recent efforts are also targeted toward developing therapeutic vaccines for cancer, heart disease, diabetes, and other conditions. Vaccines may be based on one of the following technologies: live attenuated, whole killed, subunit/subcellular, and nucleic acid based (Ellis, 2001b). Vaccines using the live attenuated or whole-killed pathogen constitute the majority of vaccines currently approved. These vac-cines retain the immunogenic activity without causing host pathogenic responses. Examples of live attenuated vaccines include smallpox vaccine and other viral vac-cines such as measles/mumps/rubella (MMR) and varicella zoster virus (VZV) vaccines.

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  Biomedical Engineering for Global Health

  • Rebecca Richards-Kortum(Author)
  • 2009(Publication Date)
  • Cambridge University Press

    (Publisher)

  The immune system treats live, attenuated vaccines in just the same way as it would an infectious pathogen. Thus, these vac-cines stimulate both humoral and cell-mediated immu-nity. As a result, they usually provide lifelong immunity. However, such vaccinations can produce disease in an immunocompromised host [ 5 ]. A technical challenge of this approach is that it is not always feasible to produce strains of a pathogen that have been attenuated suffi-ciently. In addition with pathogens that undergo anti-genic drift, there is a finite risk of reversion to a virulent form [ 14 ]. Vaccines based on live attenuated pathogens account for approximately 10% of total vaccine sales [ 15 ]. Subunit Vaccines Our immune system generally recognizes and responds to a portion of an infectious organism known as an anti-gen. If we can identify the antigen that will produce an immune response, we can purify that antigen and use it as the basis for a vaccine. This type of vaccine is very safe because there is no risk that it can lead to infection, even in an immunocompromised host [ 5 ]. Several strategies have been developed to produce sub-unit vaccines. For example, many bacteria produce dis-ease by secreting toxins that interfere with normal cell function. We can create an immune response to these toxins by vaccinating with purified bacterial toxins that have been chemically treated to make them harmless. This type of vaccine is known as a toxoid vaccine and it produces an immune response without symptoms of disease [ 14 ]. The diphtheria and tetanus vaccines are examples of toxoid vaccines [ 5 ]. Alternatively, a Subunit Vaccine can use part of a pathogen to induce an immune response but not disease. Our immune system responds to the polysaccharides found on the surface of certain bacteria. We can grow bacteria in culture and extract these polysaccharides from the culture media the bacte-ria are grown in to develop a vaccine.

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  Viruses

  Biology, Applications, and Control

  • David Harper(Author)
  • 2011(Publication Date)
  • Garland Science

    (Publisher)

  This problem can be offset by the use of an attenuated viral strain to prepare the vaccine, but current requirements specify a high level of certainty about such processes. Subunit Vaccines While the use of whole inactivated virus is usual, not all viral proteins are immunogenic. Antibodies tend to react to proteins on the exterior surface of the virus or of virus-infected cells. The presence of other viral proteins may dampen the immune response to the protective antigens and, in some cases, those internal proteins may lead to undesirable effects. As a result, some vaccines have been produced by purification of immunogenic viral components, including those for influenza (HA and NA proteins) and hepa-titis B (HBsAg protein). The hepatitis B virus grows poorly in cultured cells, so the first vaccine used hepatitis B surface antigen (HBsAg) which was purified from the blood of carriers of the virus, where high levels were present. There are two forms of HBsAg particle; small (17–25 nm) spheres, and extended tubular forms ( Fig-ure 5.4 ). These can be present at up to 10 13 particles per milliliter of blood. Extensive purification and treatment removed the larger, infectious (42 nm) viral particles prior to use as a vaccine. Cloned Subunit Vaccines The original hepatitis B vaccine has now been superseded by vaccines using cloned HBsAg produced in yeast cells (Engerix-B ® , made by GlaxoSmith-Kline, and Recombivax HB ® , made by Merck), avoiding any problems of residual infectivity. These, together with Gardasil ® (Merck) and Cervarix TM (GlaxoSmithKline) for the prevention of human papillomavirus infection, are the only cloned Subunit Vaccines currently available for use in humans. For both hepatitis B and papillomavirus, poor growth of the virus in cell culture prevents the use of classical purified subunit approaches.

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  Perspectives in Medical Virology, vol. 1

  Perspectives in Medical Virology, vol. 1

  • Brian Evans(Author)
  • 2003(Publication Date)
  • Elsevier

    (Publisher)

  Similarly with influenza virus, vaccines of formalin-inactivat- ed whole virus were developed as early as the 1940s when no clear details were avail- able about the antigenic structure of the virus. More recently, and with the advent of technological methods of virus purification on a large scale (such as continuous flow rate-zonal centrifugation) interest has in- creased in the development of subunit viral vaccines. In theory these should pro- duce fewer side reactions in recipients because unwanted viral proteins, lipids and virus nucleic acid are not present. Essentially these preparations should contain only the main immunogenic protein of the virus which induces protective antibody. Most work has been carried out with influenza Subunit Vaccine, but the principles could be extended to picornaviruses and also other enveloped viruses such as herpes virus. Early experiments in Australia in the 1960s established that detergent disrupt- ed influenza virus vaccine (which still contained all virus structural proteins, how- ever) produced fewer side reactions (particularly temperature elevation) in animal models and in children and yet was still immunogenic (Webster and Laver, 1966). In the last decade a further refinement has been the separation of the immunogenic membrane glycoproteins (HA and NA) by centrifugation techniques and reconsti- tution of the two subunits into vaccine by dialysing away the detergent used in the initial solubilization (Fig. 2.6). These vaccines are free of other influenza structural proteins such as MP, NP, polymerase proteins, viral lipids and RNA and have a low reactogenicity in children. Unfortunately the immunogenicity of these Subunit Vaccines is also reduced in persons such as children with no immunological memory to influenza HA, although they are as immunogenic as whole virus vaccines in ad- 61 Fig. 2.6. A: Whole influenza virus used in vaccine. B: Subunit influenza vaccine composed of HA or NA subunits.

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  Bioinformatics for Vaccinology

  • Darren R. Flower(Author)
  • 2008(Publication Date)
  • Wiley

    (Publisher)

  Examples of killed vac-cines used today include those against poliomyelitis, typhoid, influenza, cholera, bubonic plague and hepatitis A. Such vaccines typically induce incomplete or short-duration immune responses, necessitating booster shots. Subunit Vaccines constitute a third way to make vaccines; they comprise individ-ual pathogenic proteins, often being called ‘acellular vaccines’. Examples include vaccines against HBV, human papillomavirus and Haemophilus influenzae B. Sub-unit vaccines, which comprise highly immunogenic protein or carbohydrate, such as cell wall components, can stimulate measurable if typically weak immune re-sponses, necessitating booster shots to sustain protection long-term, yet are deemed safe for immunocompromised patients. Since they are based on single proteins, vaccines based on toxoids – a toxoid is a treated or inactivated toxin – share similarities with Subunit Vaccines and as 82 CH 3 VACCINES: HOW THEY WORK such need adjuvant to induce adequate immune responses. Diphtheria and tetanus vaccines are toxoid-based and are usually combined with the pertussis vaccine as adjuvant. Toxoid vaccines require booster shots every decade. Carbohydrate vaccines Not all vaccines are protein-based. A key type of vaccine is instead based on polysaccharides. Carbohydrate vaccines have a long history stretching back, at least, to the observations of Heidelberger and Avery in 1923. However, despite a flurry of early work, culminating in the identification of long-lasting immunity generated by pneumoccocal capsular polysaccharide vaccines, the subsequent development of small molecule drugs, specifically antibiotics, reduced interest in carbohydrate vaccines. Several factors, such as nascent antibiotic resistance, have combined to renew interest. Immunity to carbohydrate vaccines is generally mediated by antibodies, although certain carbohydrate vaccines can activate T cells via major histocompatibility com-plexes (MHCs).

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  Microbial Biotechnology

  Fundamentals of Applied Microbiology

  • Alexander N. Glazer, Hiroshi Nikaido(Authors)
  • 2007(Publication Date)
  • Cambridge University Press

    (Publisher)

  Presumably our immune systems, which have evolved to react against natural pathogens and thus respond well to the traditional vaccines, which are similar to the pathogens, often respond only feebly to Subunit Vaccines, which are radically differ- ent from the natural pathogens. Thus, whereas a detailed knowledge of the Mechanisms for Producing Immunity 179 mechanisms of immunity was not necessary for the development of whole- cell vaccines, researchers will need to acquire a more thorough understand- ing of immune defenses if they wish to find ways of improving the perfor- mance of Subunit Vaccines. A brief overview of the current understanding of those mechanisms is provided in the section that follows. MECHANISMS FOR PRODUCING IMMUNITY In vertebrates, the first lines of defense against pathogenic microorganisms are nonspecific. An infecting organism may be killed by the antimicrobial substances in tissues or ingested by macrophages in tissues or by polymor- phonuclear leucocytes migrating into infected tissues from the bloodstream. Most infections are presumably arrested at this stage. In recent years, the discovery of Toll-like receptors on phagocytic cells (a topic revisited in a later part of this chapter) has increased our understanding of this “innate immunity.” Only when the pathogens survive this initial defense are the body’s specific immune responses activated. PRODUCTION OF SPECIFIC ANTIBODIES In many cases, immunity is acquired through the production of antibodies, Antibody Heavy chain Light chain Antigen S S S S S S S S FIGURE 5.8 A schematic structure of an antibody of the immunoglobulin G (IgG) type. This type of antibody is composed of two heavy chains (the longer polypeptides shown in the center) and two light chains (the shorter polypep- tides shown on the sides), linked via disulfide bridges.

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  New Generation Vaccines

  • Myrone M. Levine, Myron M. Levine, Gordon Dougan, Michael F. Good, Margaret A. Liu, Gary J. Nabel, James P. Nataro, Rino Rappuoli, Myrone M. Levine, Myron M. Levine, Gordon Dougan, Michael F. Good, Gary J. Nabel, James P. Nataro, Rino Rappuoli, Myrone M. Levine, Myron M. Levine, Gordon Dougan, Michael F. Good, Gary J. Nabel, James P. Nataro, Rino Rappuoli(Authors)
  • 2016(Publication Date)
  • CRC Press

    (Publisher)

  Production, manu-facture, and delivery may be associated with high costs for vaccines against many of the pathogens for which vaccines are needed. Mucosal immune responses, characterized by production of secretory immunoglobulin A (sIgA) and the transport of these antibodies across the epithelium represent a first line of defense against pathogens that colonize and infect mucosal surfaces. As a result, stimulation of the mucosal immune system may be a particularly advantageous vaccination strategy. Further, mucosal vaccines that can be delivered by oral or nasal routes have the advantage of needle-free delivery, enhanced safety, and improved patient acceptance. Consequently, vac-cine development focuses on finding new vaccines and improvements to traditional vaccines in terms of both source of immunogen and route of administration. Subunit Vaccines that target stimulation of the mucosal immune system can potentially play an important role in vaccine development. To create these vaccines, a gene encoding a protective antigenic determinant from an infectious agent is cloned, put under the control of an appropriate expression system, and transferred into a host organism. The transgenic host will then produce a ‘‘subunit’’ of the pathogen, a protein that cannot cause disease but can elicit a protective immune response. In most studies of the last 15 years, Subunit Vaccines have been purified from transgenic ‘‘production hosts,’’ for example, cultured yeast cells, and have been delivered via parenteral injection to immunize against a specific disease. To date, the only recombinant Subunit Vaccines licensed for use in humans are a yeast-derived hepatitis B vaccine, an Escherichia coli recombinant Lyme disease vaccine (no longer marketed), and human papilloma virus vaccine, which are delivered by intramuscular injection.

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