Chapter 21 : Vaccines and Vaccination

Correlation of the immunogenicity of a bacterial polysaccharide antigen with its molecular size. Pools made of the largest polymers, which averaged ~450 kDa in size, were able to induce an IgG immune response, whereas pools made of polymers with an average size of ~100 kDa or ~10 kDa did not.

Demonstration of the specificity of protective antibodies to different antigenic epitopes. Patients with cystic fibrosis initially become infected with environmental strains of P. aeruginosa (A). Within a year or so the organisms undergo a phenotypic change to become mucoid (B). This change is due to the overproduction of an extracellular polysaccharide chemically related to seaweed alginate, a polymer of randomly linked mannuronic (or M residues) and guluronic (or G residues) acids (C). P. aeruginosa alginate differs from seaweed alginate due to the addition of acetate groups to the mannuronic acid residues by the bacterium. Antibodies that have been found to be protective against infection recognize epitopes with acetate on them, whereas most chronically infected patients produce only antibodies to epitopes lacking acetate and are thus unable to control the infection.

(A) Antigenic drift occurs when small changes in protective epitopes render antibody produced from a prior vaccine (antibody 2 [green]) ineffective against new epitopes (dark red), while some preexisting antibodies (antibody 1 [blue]) remain but are not fully effective against the new virus. (B) Antigenic shift occurs when influenza viruses from two different species infect a cell of an animal and exchange genetic information. Again new epitopes (blue) that avoid binding to any of the preexisting antibody induced by a prior vaccine can be produced.

Principles of some of the newer vaccination strategies being evaluated for vaccinating against disease. (A) The use of anti-idiotype antibodies as surrogate antigens. (B) Multivalent vaccines that can combine multiple vaccine epitopes in one vaccine. Such vaccines also can incorporate vaccine antigens in a liposomal or micellar structure that can fuse with membranes to deliver antigens to within the cells. (C) DNA vaccines allow activation of both helper and cytotoxic T cells and B cells.

Visualization of the essential steps of different concepts of adjuvanticity. (1) Facilitation of antigen transport, uptake, and presentation by antigen-capturing and -processing cells in the lymph node draining the vaccine injection site. (2) Repeated or prolonged release of antigen to lymphoid tissues (depot effect). (3) Signaling via pattern-recognition receptors (PRRs) activates innate immune cells to release cytokines necessary for upregulation of costimulatory molecules. (4) Danger signals from stressed or damaged tissues alert the APCs to upregulate costimulatory molecules. (5) Note that signaling by recombinant cytokines or costimulatory molecules mimics classical adjuvant activity. Steps 3, 4, and 5 allow signal 2 as well as signal 1 from APCs. Reprinted from V. E. Schijns, Curr. Opin. Immunol. 12:456–463, 2000, with permission.

Pathways whereby adjuvants activate cells. TLRs transduce signals following recognition of specific microbial structures known to have adjuvant activity. Immune response modifier drugs such as imidazoquinoline can also activate DCs through TLR7. Soluble complement factors can tag antigens with C 3d and improve the response of B cells to the antigen. NK T cells that express an invariant T-cell receptor (Inv+ TCR) and respond to glycolipid antigens, such as α-Gal-Cer, presented by CD1 MHC-like molecules can secrete cytokines that augment immune cell responses to coexisting antigens. Reproduced from A. Bendelac and R. Medzhitov, J. Exp. Med. 195:F19–F23, 2002, with permission.

Transfection of macrophages with costimulatory molecules and microbial antigen can elicit protective immunity. Mice were vaccinated with cells expressing CD40L and the gp63 antigen from Leishmania (L-gp63). Mice were injected with irradiated cells expressing both CD40L and gp63 (open squares) or with cells expressing gp63 alone (solid circles). Vaccinated mice were challenged with 5 × 105 Leishmania amazonensis promastigotes in the footpad 1 week after the final booster injection. Immunization with L cells expressing CD40L and microbial antigen resulted in reduced immunopathology, as determined by a footpad swelling response. In addition, the mice immunized with cells expressing CD40L and gp63 had lower levels of parasites in the infected tissues (inset). Reprinted from G. Chen et al., Infect. Immun. 69:3255–3263, 2001, with permission.

Construction of a viral vector vaccine containing DNA encoding a protective antigen from another organism. A DNA plasmid from a poxvirus engineered to contain a viral promoter in the middle of the nonessential thymidine kinase gene is used as a recipient for pathogen DNA. This DNA is inserted into the plasmid under the control of a viral promoter. When the recombinant plasmid is mixed with live virus in cell culture, some of the viral particles will recombine with the plasmid DNA and incorporate the pathogen DNA and the interrupted thymidine enzyme. Exposing cell cultures to bromodeoxyuridine (BUdR) kills the virus particles with intact thymidine kinase genes and selects for the particles with the pathogen antigen DNA interrupting the viral thymidine kinase gene.

Comparison of traditional methods used to develop vaccines and reverse vaccinology technology. This new technique relies on computer predictions of surface antigens based on structural characteristics, which can quickly lead to the preparation of a recombinant protein or DNA vaccine for evaluation. Application of this strategy for development of vaccines against group B N. meningitidis identified, within an 18-month period, 25 surface-exposed proteins that have vaccine potential. Many of these proteins were different from the conventional outer membrane proteins embedded in the organism's outer layer or secreted, which usually were too variable to be good vaccine candidates. Instead, the newly identified proteins were membrane-anchored lipoproteins (A and B) or secreted proteins (C). Reprinted from R. Rappuoli, Vaccine 19:2688–2691, 2001, with permission.

Major immunologic mechanism mediating protective immunity to bacterial pathogens is antibody to the cell surface capsule. Capsules protect bacterial pathogens from host defenses; to overcome the resistance of the bacteria to phagocytosis, antibodies to the capsule need to be elicited.

Replicative cycle of a virus and potential points of possible function of immune effectors. Viruses leaving a cell as either an enveloped particle, via budding, or a nonenveloped particle, via cytolysis, could be neutralized by antibody binding and complement activation or phagocytosis. Antibodies also can block viral receptors from binding to targets, prevent penetration, or prevent uncoating. Once viral replication is initiated in another cell, cell-mediated processes such as cytolytic T cells, antibody-dependent cellular cytotoxicity, and interferons could participate in preventing further production of virus.

Structure of the hemagglutinin of influenza virus. The binding cleft anchors the virus to sialic acid residues on host cells. In the areas designated as the tip, the loop, and the hinge, amino acid changes accumulate to produce antigenic drift. Within these regions are amino acids that change with the highest frequency. The crystal structure is from I. Wilson et al., Nature 289:366–373, 1981, with permission.

Survival curves of mice treated with monoclonal antibodies (MAbs) to different cryptococcal antigens. (Top) Two different monoclonal antibodies reactive to the capsular polysaccharide prolonged survival, with one antibody clearly better than the other in providing survival from infection. (Bottom) Two different monoclonal antibodies to the melanin antigen also resulted in prolonged survival following infection. Reprinted from J. Mukherjee et al., Infect. Immun. 60:4534–4541, 1992 (top), and A. L. Rosas et al., Infect. Immun. 69:3410–3412, 2001 (bottom), with permission.