[Note: Do not read this page without first looking at my Complement Modulation Strategies page (Go there.) This discussion hinges on information found on that page.]

Since the class for which this website was designed is called "The Development of Vaccines to Infectious Diseases," this discussion would be incomplete without addressing this topic. How does the understanding of pathogenic modulation of the complement system contribute to this topic? The short answer: not much. This site has covered a majority of the existing research on pathogenic modulation of the human complement system. Most of it is rather recent, which suggests that there may still be much more to discover about this critical interaction. Below, you will find a discussion of one particular vaccine strategy suggested by the study of complement modulation as well as some more general strategic considerations.

Possible HIV Vaccine Strategy

Adapted from Stoiber et al, 1997. (Color added)

In a review entitled "Role of Complement in HIV Infection", Stoiber et al discuss a possible vaccine strategy based on the interaction between HIV and the complement system. As described on the Complement Evasion Strategy page (Go there.), HIV subverts complement-mediated lysis in two ways:

1. It acquires the host membrane-bound complement control molecules DAF and CD59 when it buds from host cells.
2. A site on the viral glycoprotein gp41 binds the soluble complement control molecule, factor H (CFH in diagram.)

Based on these facts, they suggest that the factor H-binding site on HIV might be an appropriate site for directing protective antibodies. The idea is: stimulate the formation of antibodies that have this site-specificity. As a result, HIV will, in theory not be able to down-regulate complement and will be destroyed. This approach could possibly be augmented by antibodies which are specific to the DAF and CD59 molecules on the surface of the resistant HIV. However, it is not clear how such antibodies would avoid targeting host cells.

An advantage to this type of strategy is that protective antibodies could be use to passively immunize those already infected. (As opposed to active immunization which stimulates an immune response.)

The theory is backed up by some laboratory data. In one study, an antibody which neutralized a number of different lab strains of HIV-1 was found to bind to a site on gp41. This site was conserved in 72% of studied isolates (Muster et al, 1993), an important consideration in the development of a vaccine to the highly variable HIV. Although this study did not target the CFH binding sites mentioned above, it does demonstrate the general feasibility of such an approach.

One widely utilized vaccine approach uses attenuated organisms to stimulate an immune response that will protect the individual from a future encounter with the real pathogen. These attenuated live vaccines are used to protect thousands of people against organisms such as polio and were the basis for the highly successful smallpox vaccine. The knowledge that organisms may possess genes for complement control proteins may help produce less virulent attenuated vaccines. Pathogens with the genes for these molecules "knocked-out" may be safer. Studies are currently underway to test the safety and immunogenicity of vaccinia viruses lacking immunomodulatory proteins.

Although work in this direction may prove fruitful, caution must be taken. Not all proteins that modulate the host immune response are necessarily bad. As discussed previously, [go there] cowpox mutants lacking a particular complement modulatory protein were, in fact, more pathogenic to infected mice than was the normal virus. Careful studies are thus necessary to determine the full effects of deleting a gene from a pathogen. (see Kotwal et al., 1998 for a fuller discussion)

The question remains: What is the general advisability of using a vaccine to enhance an innate response such as complement? Improving such a response, which has neither memory nor selectivity, may actually decrease the effectiveness of a vaccine which targets the adaptive immune response. Strategies which utilize the adaptive response in concert with knowledge about complement and complement modulatory mechanisms (like the HIV strategy discussed above) may prove to be more effective than current vaccines for certain pathogens.

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