The identification of appropriate antigenic structures involves various considerations, based on the desired type of immune response . For example, if a neutralizing antibody response is sufficient to protect from infection, usually an antigenic structure from the bacterial/viral cell surface is selected. This has been done successfully for the H. influenzae type b, pneumococcal and meningococcal and hepatitis B vaccines, or from secreted toxins, like tetanus or diphtheria.

In the course of an antibody response, antigen -specific helper T cells are essential for the evolution of high-affinity antibodies and immune memory. Other antigen-specific T cells , including cytotoxic T cells, accomplish important effector functions, such as the targeted removal of host cells infected by intracellular pathogens, or support for macrophages in their removal of extracellular pathogens. In these latter cases an antigen has to be selected for the vaccine that enables these T cell effector-mediated responses. Hepatitis B vac cine s, for example, induce antibodies as well as hepatitis B-specific T cell responses [ 1 ], pertussis vaccines induce antibodies and stimulate helper T cells to produce interferon [ 2 , 3 ], and hepatitis A and IPV vaccines probably stimulate both T and B cells. As a matter of fact, in some instances the immune response induced by vaccination may even be stronger than the response observed after natural infection. This has been observed for human papillomavirus (HPV) vaccines that induce higher concentrations of neutralizing antibodies than in naturally occurring immune responses [ 4 ].

Purification of vaccine antigens is an important step to achieve vaccines with few unwanted side effects. Progress in biotechnology in recent years has allowed isolating subcomponents of pathogens and producing them in large quantities. By eliminating unwanted pathogenic components, the high specificity and purity of these antigens permit the development of vaccines with reduced reactogenicity and improved safety profiles. The first attempt to select antigenic structures and to eliminate unwanted material has been made with split- or subvirion vaccines. These vaccines are prepared by using a solvent (such as ether or a detergent) to dissolve or disrupt the viral lipid envelope [ 5 ]. The technology has been applied most successfully in the development of inactivated influenza vaccines [ 6 ]. Purification steps are also engaged in the production of subunit vaccines, comprising protein or polysaccharide antigens, such as acellular pertussis proteins [ 7 ], typhoid Vi- antigen , and pneumococci polysaccharides [ 8 , 9 ]. While split and subunit vaccines are less reactogenic than their conventional whole-cell counterparts, in many instances, this benefit is associated with reduced immunogenicity . For these vaccines the addition of adjuvants  often is required to induce sufficient immunological memory and maintain protection [ 10 ].

Impaired immunogenicity may also occur with purified antigens that are unable to address sufficient elements of the immune system relevant for the protective response. Immune response s to pure polysaccharide antigens can be particularly poor in comparison with those induced by protein antigens. Polysaccharide anti gens alone are not able to recruit T-helper cells in order to obtain B cell support by cell-mediated immunity. This phenomenon is especially significant in young infants and children as well as with the elderly [ 11 ]. As a result, immune response s to plain polysaccharide antigens are characterized by the secretion of low-affinity antibodies, mainly immunoglobulin M (IgM) molecules, and dis play a stereotyped “innate response” behavior. Repetitive encounters with the same antigen fail to induce a secondary, memory-like immune response [ 10 ]. This disadvantage was finally surmounted by the invention of the protein-conjugate technology. By covalently binding the polysaccharide antigen to a carrier protein, typically an inactivated toxoid like tetanus or diphtheria toxoid , conjugate vaccines dramatically improve immune responses to polysaccharides. With these vaccines, the polysaccharide component is recognized and bound by the B cell antigen receptor (i.e., the antibody molecule expressed on the cell surface), providing the first signal for B cell activation. Subsequently, the responding B cell serves as an antigen-presenting cell for T-helper cells that are specific for the conjugated carrier protein. The conjugated vac cine is internalized and processed and the antigen components of the conjugated protein are presented in the context of MHC molecules to be recognized by conjugate-protein/peptide-specific T-helper cells. Applying this approach, polysaccharide-specific B cells recruit help from conjugate-protein-specific T cells to get all signals needed to promote further activation as well as isotype switching to IgG production and generation of memory B cells. Today, this elegant technique is regularly applied to vac cines containing bacterial polysaccharides for the prevention of invasive diseases caused by encapsulated bacteria. Examples include H. influenzae type b, pneumococcal [ 9 ] and meningococcal vaccines .

Modern molecular biology techniques allow vaccinologists today to select antigenic structures at the gene level and produce recombinant vaccine s that contain only the antigen substructures relevant to elicit protective immunity [ 12 ]. The first recombinant vaccine , licensed in 1986, was achieved by cloning the gene for hepatitis B surface antigen (HBsAg) and was as effective as plasma- derived vaccines [ 13 ]. Two recombinant vaccines are also avail able against cervical cancer [ 14 ]. Both vaccines are based on HPV viruslike particles assembled from recombinant HPV L1 coat proteins. Quite recently research in this area has taken even a step further. By expressing multiple proteins identified in genome of meningococcus type B strains it was possible to identify new protein antigens on the surface of the microorganism that finally led to the successful development of a MenB vaccine. This technology, named reverse vaccinology , is now engaged to develop vac cines against microorganisms for which hitherto no vaccines were available, such as vaccines against Staphylococcus aureus or Pseudomonas strains.

However, as with subunit vaccines, the highly purified antigens obtained with peptide and recombinant technologies can have the disadvantage of weakened immunogenicity . The research for means to overcome this shortcoming has led to the development of innovative adjuvants to control and modify vaccine -induced immune response s, as described in the next section.

References

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[1] Banatvala JE, Van DP (2003) Hepatitis B vac cine—do we need boosters? J Viral Hepat 10:1–6

[2] Zepp F, Knuf M, Habermehl P et al (1997) Cell-mediated immunity after pertussis vaccination and after natural infection. Dev Biol Stand 89:307–314

[3] Mills KH, Ryan M, Ryan E et al (1998) A murine model in which protection correlates with pertussis vaccine efficacy in children reveals complementary roles for humoral and cell-mediated immunity in protection against Bordetella pertussis. Infect Immun 66:594–602

[4] Schwarz TF, Leo O (2008) Immune response to human papillomavirus after prophylactic vaccination with AS04-adjuvanted HPV- 16/18 vaccine: improving upon nature. Gynecol Oncol 110(3 Suppl 1):S1–S10

[5] Bridges CB, Katz JM, Levandowski RA et al (2008) Inactivated influenza vaccines. In: Plotkin SA, Orenstein WA, Offit PA (eds) Vaccines, 5th edn. Elsevier, New York, pp 259–290

[6] Leroux-Roels I, Leroux-Roels G (2009) Current status and progress of prepandemic and pandemic influenza vaccine development. Expert Rev Vaccines 8:401–423

[7] Edwards KM, Decker MD (2008) Pertussis vaccines. In: Plotkin SA, Orenstein WA, Offi t PA (eds) Vaccines, 5th edn. Elsevier, New York, pp 467–518

[8] Fraser A, Goldberg E, Acosta CJ et al (2007) Vaccines for preventing typhoid fever. Cochrane Database Syst Rev 3, CD001261

[9] Pletz MW, Maus U, Krug N et al (2008) Pneumococcal vaccines: mechanism of action, impact on epidemiology and adaption of the species. Int J Antimicrob Agents 32:199–206

[10] Moser M, Leo O (2010) Key concepts in immunology. Vaccine 28 Suppl 3:C2–C13

[11] Borrow R, Dagan R, Zepp F et al (2011) Glycoconjugate vaccines and immune interactions, and implications for vaccination sched ules. Expert Rev Vaccines 10:1621–1631

[12] McCullers JA (2007) Evolution, benefits, and shortcomings of vaccine management. J Manag Care Pharm 13(7 Suppl B):S2–S6

[13] André FE (1990) Overview of a 5-year clinical experience with a yeast-derived hepatitis B vac cine. Vaccine 8 Suppl: S74–S78

 [14] Rogers LJ, Eva LJ, Luesley DM (2008) Vaccines against cervical cancer. Curr Opin Oncol 20:570–574

مواضيع ذات صلة

Principles of Vaccine Development

A Brief History of Vaccination

Development of Vaccines for Tuberculosis and Meningitis

Development of Vaccines for Viral Hepatitis, Coronavirus, and Norovirus

Development of Powerful Influenza Vaccines

Vaccines for HIV and Ebola Virus

Vaccines for Diseases Associated with Urban Areas in the Developing Countries

HIV Vaccine

Yellow Fever Vaccine

Tuberculosis Vaccine

Rotavirus Vaccines

Pertussis Vaccines