Elsevier

Vaccine

Volume 26, Supplement 8, 30 December 2008, Pages I113-I117
Vaccine

Microbial complement inhibitors as vaccines

https://doi.org/10.1016/j.vaccine.2008.11.058Get rights and content

Abstract

Complement inhibiting surface proteins of pathogenic bacteria provide candidates for vaccines because of two reasons. First, an immune response against them would recognize the microbes and secondly, it would neutralize the key bacterial virulence mechanism. Prerequisites for a vaccine protein include the following: (i) it should show limited variability, (ii) it should be immunogenic and the immune response against it should cover a sufficiently broad range of microbial strains, (iii) it should not be hidden beneath a capsule, long LPS O-polysaccharide side chains or a protein coat and (iv) it should not raise unwanted immune responses against host structures. Bacterial complement inhibitors often act by binding the soluble inhibitors factor H or C4 bp, by blocking C3 or C5 activation or by enzymatically cleaving key complement components. Inhibitors have been found from all major types of pathogens and may offer promise as rational vaccine candidates for preventing diseases such as meningococcal meningitis, systemic pneumococcal or group B streptococcal disease and Lyme borreliosis.

Introduction

Current vaccines use primarily killed or live attenuated viruses or inactivated protein toxins or capsular polysaccharides from bacteria. Dating back over 100 years, the main underlying philosophy in their development was to induce sufficient immunity for neutralizing the pathogen or its toxin. With the existing new knowledge on microbial virulence mechanisms and genomes it is possible to develop new innovation- or knowledge-based vaccines [1].

An essential factor in microbial virulence is to escape the host's microbicidal complement system. Although both complement and microbes have been known for over 100 years it is only during the last 20 years that essential information on the various complement evasion mechanisms of pathogens has emerged. A natural development in this line of research is to design ways to counteract the microbial evasion mechanisms and use this information for the development of new vaccines. The need for new vaccines exists, e.g. for group B meningococcus, pneumococcus, tuberculosis, Lyme borreliosis, malaria and various viral illnesses, notably HIV/AIDS. In this review we will discuss principles and provide some examples on the potential use of microbial complement inhibitors as vaccines.

Section snippets

The complement system

The complement system is an important part of innate immunity. The functions of complement include defence against invading microbes and, on the other hand, clean-up of the host body of cell and tissue debris, immune complexes and apoptotic cells. Complement consists of over 30 soluble or membrane-bound proteins. The activation proceeds via three different pathways, all leading to the deposition of C3b on target surfaces and activation of the terminal pathway. The classical pathway is initiated

Factor H

Factor H is a fluid-phase regulator of the alternative pathway amplification loop. It is a soluble 150 kDa protein composed of 20 short consensus repeat (SCR) domains. Factor H regulates the alternative pathway by inhibiting the binding of factor B to C3b, acting as a cofactor for factor I-mediated cleavage of C3b (cofactor activity) and accelerating the decay of the alternative pathway convertase C3bBb (decay-accelerating activity). All these steps are essential in keeping the alternative

Complement and microbes

Complement has several functions in microbial defence. The most important function is opsonization by C3 activation products C3b and iC3b. Phagocytes have receptors for C3b (CR1) and iC3b (CR3 and CR4), of which CR3 (CD11b/18) is the major opsonophagocytic receptor. Enhancement of the inflammatory reaction by chemotactic and anaphylatoxic complement cleavage products C5a and C3a is another anti-microbial function. C5a has multiple functions in recruiting and activating phagocytes. Formation of

Bacterial evasion of complement

Virulent microbes have developed multiple mechanisms to evade complement attack [11], [12]. They can, e.g. avoid being recognized as “nonself”, inhibit deposition of opsonic complement components, cleave activation products or hijack host complement inhibitors, factor H, C4bp or CD59. Often multiple mechanisms are employed.

The ability to escape complement is one of the key discriminatory features between pathogens and nonpathogens. Polysaccharide capsules, peptidoglycan, protein coating and

Bacterial proteins for therapy?

Fungi have given us penicillin, which has saved lives of millions of people. What are prospects for using microbial complement inhibitors as therapeutic agents to prevent excessive complement activation during sepsis or other forms of acute inflammation? Recent studies have shown that staphylococci (Staphylococcus aureus) are masters in producing soluble complement inhibitors. As an example, the extracellular fibrinogen-binding protein (Efb) and its homologous protein Ehp bind C3b and inhibit

Complement evasion molecules in vaccine development

In contrast to the previous examples of using bacterial inhibitors of complement in therapeutics, as described above, immunization is a naturally desired effect when these molecules are developed into vaccines. Bacterial membrane proteins are thus suitable candidates for vaccines. Examples of bacterial proteins affecting the complement system, their properties and estimated potential as vaccines are listed in Table 1.

What is the rationale behind the use of microbial complement inhibitors,

Prerequisites for rational vaccines

The research until now has mainly focused on bacterial proteins that bind soluble inhibitors of complement. The prerequisites for a bacterial protein to be a good vaccine candidate are that it (1) is immunogenic, (2) does not exhibit extensive variation, (3) has suitable physicochemical properties and (4) raises an immune response that neutralizes an important virulence determinant, i.e. complement inhibitory activity in this case, on the bacteria.

Several bacterial proteins that bind complement

Potential bacterial vaccine candidates

N. meningitidis is a frequent colonizer of the nasopharynx but can also cause meningitis and sepsis. There is an efficient tetravalent polysaccharide vaccine against meningococcal serogroups A, C, W135 and Y in clinical use. However, the capsular polysaccharide of serogroup B consists of the α(2→8) N-acetyl neuraminic acid homopolymers, structures also found in human fetal neural tissue [33], [34]. Thus, because of the low immunogenicity of the serogroup B capsular polysaccharides and risk for

Words of caution

Bacterial infections are often followed by immunological postinfectious complications, like rheumatic heart disease (GAS), glomerulonephritis (GAS), reactive arthritis (Y. enterocolitica, Salmonella, Campylobacter) or Guillain–Barré syndrome (Campylobacter). The possibility that these diseases are induced by bacterial proteins or lipopolysaccharides has not been excluded. In addition to the previously described neuron-cross-reactive group B meningococcal polysialic acid another potential

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