Live Attenuated Vaccine

8 Key excerpts on "Live Attenuated Vaccine"

• 

  eBook - ePub

  Vaccinology

  Principles and Practice

  • W. John W. Morrow, Nadeem A. Sheikh, Clint S. Schmidt, D. Huw Davies, W. John W. Morrow, Nadeem A. Sheikh, Clint S. Schmidt, D. Huw Davies(Authors)
  • 2012(Publication Date)
  • Wiley-Blackwell

    (Publisher)

  In contrast, Live Attenuated Vaccines offer the potential advantage of administration via the natural route of infection to stimulate appropriate immune responses, often mucosal delivery inducing both systemic and mucosal immunity. Unlike killed and subunit vaccines, which are generally poor at inducing cellular immune responses, Live Attenuated Vaccines are able to induce cellular immune responses, which may be important for protection against intracellular bacterial pathogens. Such vaccines may also offer the further advantage of being easier and safer to administer than killed or subunit vaccines, which are given by injection.

  However, Live Attenuated Vaccines do have some limitations when compared to killed or sub-unit vaccines. Because they are live, they often require storage under carefully controlled conditions, and have limited shelf lives. More importantly, the ability of Live Attenuated Vaccines to induce protective immunity is dependent on a fine balance between ensuring the vaccine strain is able to survive in the host for a sufficient length of time and ensuring that the vaccine is sufficiently disabled that it is not able to cause disease. This latter consideration is especially important when the vaccine might be used in immunocompromised hosts. Newer approaches to the development of Live Attenuated Vaccines can help to minimize this problem, but some of the existing live attenuated bacterial vaccines are not considered to be safe for use in immunocompromised hosts.

  Existing Live Attenuated Vaccines

  Many of the live attenuated bacterial vaccines in use today have been generated using empirical approaches, and the reasons why these particular approaches were followed to generate the vaccines seems quite obscure. At the time of their discovery the genetic basis of attenuation was not known and for many live bacterial vaccines the molecular basis of attenuation is still not clear.

  It might be assumed that the availability of genome sequencing methodologies would now make the characterization and identification of attenuating mutations possible. In some cases this has proven to be the case, but for others the reasons for attenuation are still only partially understood. For example, although the genome sequence of the Bacille Calmette-Guérin (BCG) strain of Mycobacterium bovis

  Sign up to read

  Learn more about book
• 

  eBook - PDF

  New Vaccine Technologies

  • Ronald W. Ellis(Author)
  • 2001(Publication Date)
  • CRC Press

    (Publisher)

  Ellis. ©2001 Eurekah.com. 152 New Vaccine Technologies spectrum of immune response induced is usually limited to the humoral arm of the immune system .2 In contrast, Live Attenuated Vaccines (i.e., living viruses/bacteria that carry mutations ren­ dering them avirulent or significantly reduced in virulence) offer significant advantages in terms of manufacture and immunogenicity. For example, a single inoculation of live vaccine at a modest dose replicates in vivo to a very large immunogenic dose and expresses the majority of immunogens seen during natural disease. Moreover, the processing and presentation of these antigens more closely resembles natural infection, thereby often inducing convalescent-level’ immune responses that endure and protect the vaccinee for long periods o f time. Live vaccines can induce mucosal immune responses, sometimes required for long-lived protection, which are not elicited by systemically administered vaccines, and the mode of delivery of live vaccines can be quite simple (e.g., ingestion). Finally, because attenuated vaccines are living organisms they may be genetically engineered to express heterologous antigens, thus providing protection from more than one disease. Thirty-two commercialized vaccines were widely available and distributed in 1994 (Fig. 9.1). Seventeen were directed against viral pathogens and 15 were directed against bacte­ rial pathogens. An interesting contrast emerges when one examines the nature of these vaccines. O f the 17 viral vaccines, 8 are subunit or inactivated (e.g., hepatitis A and B) and 9 are live attenuated (e.g., mumps, measles, rubella (MMR) and oral polio) compared with 15 bacterial vaccines where 13 are subunit or inactivated (e.g., DPT) and only two (tuberculosis (BCG) and typhoid fever (Ty 21 a)) are live attenuated (Fig. 9 . 2 ).

  Sign up to read

  Learn more about book
• 

  eBook - PDF

  Pharmaceutical Biotechnology

  Fundamentals and Applications, Third Edition

  • Daan J. A. Crommelin, Robert D. Sindelar, Bernd Meibohm, Daan J. A. Crommelin, Robert D. Sindelar, Bernd Meibohm(Authors)
  • 2016(Publication Date)
  • CRC Press

    (Publisher)

  By mak-ing multiple deletions the risk of reversion to a virulent state during production or after administra-tion can be virtually eliminated. A prerequisite for attenuation by genetic engineering is that the factors responsible for virulence and the life cycle of the pathogen are known in detail. It is also obvious that the protective antigens must be known: attenuation must not result in reduced immunogenicity. 414 JISKOOT ET AL An example of an improved live vaccine obtained by homologous genetic engineering is an experimental, oral cholera vaccine. An effective cholera vaccine should induce a local, humoral response in order to prevent colonization of the small intestine. Initial trials with Vibrio cholerae cholera toxin (CT) mutants caused mild diarrhea, which was thought to be caused by the expression of accessory toxins. A natural mutant was isolated that was negative for these toxins. Next, CT was detoxified by rDNA technology. The resulting vaccine strain, called CVD 103, is well tolerated by volunteers (Suharyono et al., 1992; Tacket et al., 1999) and challenge experiments with adult volunteers showed protection (Garcia et al., 2005). Genetically attenuated live vaccines have the general drawbacks mentioned in the section “Live Attenuated Vaccines.” For these reasons, it is not surprising that homologous engineering is mainly restricted to pathogens that are used as starting materials for the production of subunit vaccines (see section “Genetically Improved Subunit Vaccines,” below). Live Vectored Vaccines A way to improve the safety or efficacy of vaccines is to use live, avirulent or attenuated organisms as a carrier to express protective antigens from a pathogen. Both bacteria and viruses can be used for this purpose; some of them are listed in Table 5. Live vectored vaccines are created by recombinant tech-nology, wherein one or more genes of the vector organism are replaced by one or more protective genes from the pathogen.

  Sign up to read

  Learn more about book
• 

  eBook - PDF

  Encyclopedia of Pharmaceutical Technology

  Volume 6

  • James Swarbrick(Author)
  • 2013(Publication Date)
  • CRC Press

    (Publisher)

  There have been instances in which inactivated vac-cines led to atypical disease or enhanced disease severity. For example, in the 1960s, formalin-inactivated respira-tory syncytial virus (RSV) vaccine actually enhanced the disease symptoms when vaccinated children were naturally exposed to RSV. [3,4] It was later discovered that a change in the antigenicity of RSV F and G glyco-proteins [5] resulted not only in alteration in humoral immune response but also in the Th1 and Th2 compo-nents of the CD4 þ T-cell response to RSV. [6] Encyclopedia of Pharmaceutical Technology DOI: 10.1081/E-EPT-100000445 Copyright # 2007 by Informa Healthcare USA, Inc. All rights reserved. 3908 Unit–Validation Live Attenuated Vaccines Mostly attenuated organisms are being used as live virus vaccines; however, in some instances, even virulent organisms could be used, provided they are not adminis-tered via the natural route of infection. For example, human adenovirus types 4 and 7 may cause acute respi-ratory infections in humans when administered via the oronasal route but provide protection when given orally in enteric-coated capsules. [7] There are different ways to attenuate pathogens for vaccine production. Attenuation of organisms can be achieved by growing them under abnormal conditions, which include cultivation in unnatural hosts or cell lines. Some organisms are attenuated when they repli-cate at different pH levels and/or temperatures. In cells infected with multiple viruses with a segmented genome (e.g., influenza virus, reovirus), genome seg-ments are randomly recombined in the progeny. This process of recombination is known as reassortment and is also useful in generating attenuated viruses.

  Sign up to read

  Learn more about book
• 

  eBook - PDF

  Vaccine Supply and Innovation

  • (Author)
  • 0(Publication Date)
  • The National Academies Press

    (Publisher)

  Preliminary experiments in nonhuman primates indicate that this approach may be efficacious. These recombinant DNA vaccines offer promise of effective products that are less reactive and less expensive. Polypeptide Synthesis The ability to define the amino acid sequence of protein subunits (peptides) has allowed researchers to characterize the structures of some immunogenic peptides. Based on this knowledge, several viral antigens have been synthesized. These early man-made antigens are less immunogenic than natural viral antigens, but researchers believe that this situation will improve with further study. In some cases, adjuvants may be required to boost immunogenicity. The synthetic antigens, because of their purity, are expected to be less reactogenic and safer than their natural counterparts. Also, the cost of large-scale production of these antigens probably will be relatively low. Specific Attenuation of Pathogens The third type consists of modified or attenuated live pathogens, usually viruses. The live, attenuated oral poliovirus vaccine is one example of how this approach can be used. The principal disadvantage of these vaccines is that they contain viruses that have the potential to revert to a virulent, disease-producing form. Fortunately, increasing knowledge of molecular biology is providing a better understanding of many of the changes or mutations that occur in the process of attenuation. Comparing the nucleotide sequences of fully attenuated viruses with those of partially attenuated or fully virulent forms ultimately may provide a mechanism for early recognition of potential mutation of a live vaccine to the more virulent, disease-producing form. Methods of manipulation that result in an attenuated virus incapable of reversion would be even more desirable.

  Sign up to read

  Learn more about book
• 

  eBook - PDF

  Perspectives in Medical Virology, vol. 1

  Perspectives in Medical Virology, vol. 1

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

    (Publisher)

  Another ‘early’ attenuated virus vaccine was yellow fever, developed in the 1940s by simply passaging the virus in embryonated hens’ eggs (Theiler and Smith, 1937). After the 17th passage in eggs the virus was found to be attenuated for man, in- duced neutralizing antibodies and induced protection against superinfection with wild yellow fever virus. Thus, by this time the general biological principle was estab- lished for live viral vaccine development: adaptation of a virus by serial passage 63 Fig. 2.7. Electron micrograph of influenza virosome (arrowed) mixed with true influenza virus particles. (Courtesy of Dr. D. Hockley.) in a foreign host and concurrent reduction in virulence for the original host. The genetic basis of attenuation of these viruses is still not known, but presumably the multiple passage selects an already existent subpopulation of virions with different genetic properties, viz. changed biological properties of virulence. Presumably the attenuated virus would have multiple and perhaps cumulative mutations which would be ;in advantage because the possibility for a reversion to virulence would thereby be lessened. Successful live vaccines produced in this way subsequently have been measles, rubella, polio and mumps. On the other hand, an apparently insur- mountable problem with certain viruses such as influenza has been the genetic insta- bility of the passaged virus. If influenza virus is passaged too many times in eggs, for example, then the virus is unable to infect man, whereas administration of un- derpassaged virus produces influenza-like symptoms in the recipient. These pro- blems led to exploration of the use of genetic approaches to producing live candi- date vaccine viruses, particularly since the influenza virus genome is in segments and can be easily manipulated in the laboratory.

  Sign up to read

  Learn more about book
• 

  eBook - PDF

  Veterinary Virology

  • Frederick A. Murphy, E. Paul J. Gibbs, Marian C. Horzinek, Michael J. Studdert(Authors)
  • 1999(Publication Date)
  • Academic Press

    (Publisher)

  Thus the principal objective of vaccination is to mimic natural infection, i.e., to elicit a high titer of neutralizing antibodies of the appropriate class, IgG and/or IgA, di- rected against the relevant epitopes on the virion in the hope of preventing infection. Special difficulties also attend vaccination against viruses known to establish persistent infections, such as herpesviruses and retroviruses; a vaccine must be out- standingly effective if it is to prevent not only the primary disease, but also the establishment of lifelong latency. Attenuated virus vaccines are generally found to be much more effective in eliciting cell-mediated immunity than inactivated viruses. Further, cell-mediated immunity is the most effective arm of the immune system in modulat- ing, if not eliminating, latent/persistent infections. Unclerattenuation Some attenuated virus vaccines in routine use produce some clinical signs in some animals--in effect, a very mild case of the disease. For example, some early canine parvovirus vaccines that had undergone few cell culture passages were used in an attempt to overcome residual maternal immunity, but were found to produce an unac- ceptably high incidence of disease. Attempts to attenuate virulence further by additional passages in cultured cells have been accompanied by a decline in the capacity of the virus to replicate in the vaccinated animal, with a corresponding loss of immunogenicity. Such side effects, as occur with current animal virus vaccines, are minimal and do not constitute a significant disincentive to vaccination. However, it is important that attenuated virus vaccines are used only in the species for which they were produced; for example, canine distem- per vaccines cause fatalities in some members of the family Mustelidae, such as the black footed ferret, where an inactivated whole virus vaccine must be used.

  Sign up to read

  Learn more about book
• 

  eBook - PDF

  Atlas of Immunology

  • Julius M. Cruse, MD, PhD, Robert E. Lewis(Authors)
  • 2010(Publication Date)
  • CRC Press

    (Publisher)

  Poliomyelitis vaccines: The three strains of poliomyelitis virus combined into a live attenuated oral poliomyelitis vac- cine was first introduced by Sabin. Replication in the gastro- intestinal tract stimulates effective local immunity associated with IgA antibody synthesis. Individuals to be immunized receive three oral doses of the vaccine. This largely replaces the Salk vaccine which was introduced in the early 1950s as a vaccine comprised of the three strains of poliovirus that had been killed with formalin. This preparation must be admin- istered subcutaneously. Live oral poliovirus vaccine is an immunizing preparation prepared from three types of live attenuated polioviruses. An advisory panel to the Centers for Disease Control and Prevention recommended in 1999 that its routine use be dis- continued. It contains a live yet weakened virus that has led to eight to ten cases of polio each year. Now that the polio epidemic has been eliminated in the United States, this risk is no longer acceptable. Also called Sabin vaccine. Measles vaccine is an attenuated virus vaccine administered as a single injection to children at 2 years of age or between 1 and 10 years old. Contraindications include a history of allergy or convulsions. Puppies may be protected against canine distem- per in the neonatal period by the administration of attenuated measles virus which represents a heterologous vaccine. Passive immunity from the mother precludes early immunization of puppies with live canine distemper vaccine. Live attenuated measles (rubeola) virus vaccine is an immunizing preparation that contains live measles virus strains. It is the preferred form except in patients with lymphoma, leukemia, or other generalized malignancies; radiation therapy; pregnancy; active tuberculosis; egg sensi- tivity; prolonged drug treatment that suppresses the immune response, such as corticosteroids or antimetabolites; or administration of gammaglobulin, blood, or plasma.

  Sign up to read

  Learn more about book