Tipo de mente matemática de los estudiantes.

Initially, OMP vaccines comprised OM components fi*om a common disease-causing meningococcal strain (section 1.10.2). However, it has been shown that immune responses to vaccines based on PorA are subtype-specific (Idanpaan-Heikkila et a l

1995). Hence, development o f these vaccines has relied on serological typing to identify epitopes, representative of the subtypes circulating in meningococcal

populations (van der Ley et a l 1993,1995; van der Ley & Poolman, 1992; Claassen

et a l 1996; Peeters et a l 1996). This work has shown that there are difficulties with this proposition (discussed in Chapter 5). Firstly, serological typing data greatly underestimates the extent o f antigenic diversity in PorA. Secondly, the existing set of serosubtyping mAbs are not representative o f common epitopes in meningococcal populations. Thirdly, murine mAbs are unlikely to accurately reflect the epitopes that are important in human immunity to meningococci.

Although PorA in serogroup A meningococci is stable, OMP vaccines have been designed principally to combat serogroup B meningococcal disease because o f the difficulties in developing a vaccine based on the group B polysaccharide (section

1.10). However, evidence suggests that there is greater antigenic diversity in PorA among serogroups B and C and that these organisms are continually under strong selection for change. The postulated global gene pool of Neisseria species provides

even greater potential for antigenic variation and thus it is vital that the population biology o f the Neisseria is considered before an OMP vaccination programme is implemented.

6.2.2 Population biology of the Neisseria

As serogroup B and C meningococcal populations are proposed to be rapidly evolving, there is a danger that the use o f OMP vaccines will put greater selective pressure on these organisms to generate novel antigenic variants. Although no new mutations were detected in vaccine failures during an OMP vaccine trial in Norway (Brooks et al. 1995b), novel PorA variants with altered immunological activities were reported in epitopes which were common in disease-causing strains (Wedege et a l 1993; McGuinness et a l 1991). Additionally, a previous study showed that use o f a serogroup A plus C polysaccharide vaccine increased carriage of serogroup Y organisms (Stroffolini et a l 1990). This illustrates that vaccination can have a selective effect on meningococcal populations.

By their ability to vary with such rapidity, meningococci, and Neisseria species in general, ensure that they will be able to exploit and survive in each new host

environment. An infecting organism gains nothing by causing disease in its human host, this is merely a by-product of the processes of evolution which may, by chance, trigger off a pathogenic train of events in a susceptible human. It is often assumed that infectious microorganisms will tend to evolve into less virulent forms because if they become too pathogenic they will ‘commit suicide’ by eliminating their own habitat. However, it is suggested that virulence is connected with ability to spread to uninfected hosts, thus evolution favours a balance between harm caused and rate of transmission (Ebert & Mangin, 1995).

It could therefore be argued that the target of vaccination should be, not just to eliminate meningococcal disease, but to eradicate potential disease-causing organisms.

6.2.3 Philosophy of vaccination

It seems unlikely that OMP preparations will fulfill all the criteria that are required for a successful vaccine (section 1.9). However, the OMP vaccines which have been developed may prevent a certain level of disease in the short term and the deleterious effects from increased selection for variation are purely speculative. Thus the ethical question is raised of whether a possible immediate benefit to a small number of individuals in implementing OMP vaccination outweighs the potential increased disease-susceptibility of the whole population in the longer term? Furthermore, as the incidence of pathogenesis among species of Neisseria is the exception rather than the norm, the necessity of vaccinating against such a rare disease is

questionable. The use of vaccines may reduce carriage of potentially pathogenic strains but natural herd immunity from carriage o f commensal species will also be reduced. Further information is required before these issues can be adequately addressed and detailed epidemiological analyses combined with properly controlled clinical trials will help to achieve this goal.

The view of a dispassionate philanthropist might be that there are diseases of far greater global importance than that caused by meningococci, for example malaria and diarrhoeal diseases cause millions o f deaths worldwide every year. However, vaccine development is currently driven mainly by the large pharmaceutical companies and as long as this situation continues, it is inevitable that research will focus on products with profit-making potential. This means that diseases affecting Western countries will attract more attention than those affecting the developing world. Nevertheless, this attitude may be rather short-sighted because, as this work has shown, disease-causing microorganisms are easily disseminated, particularly as intercontinental travel becomes more widespread (note the example o f the Hajj epidemic o f meningococcal disease, sections 1.11.3 and 4.2.4.2). Thus the management of infectious diseases must be considered on a global scale.

This thesis has not examined the effects on human populations of the evolution of pathogenesis in the Neisseria. The population biology of infectious diseases is a subject which has taxed many great minds (section 1.1, (Anderson & May, 1982)) and will probably continue to do so for many years to come. In section 6.1.1 the rapid evolutionary timescale of the human immune response was described. This is, in some respects, a mirror to antigenic variation in bacterial populations and the process o f selection in generating variation in the human antibody repertoire is a subject of investigation (Rajewsky, 1996).

It is interesting to speculate what the evolutionary consequences of our attempts to eliminate infectious diseases might be. The evolution of antibiotic resistant organisms, during the last two decades, illustrates the rapidity with which bacteria can respond to human intervention (Spratt et al. 1992; Coffey et a l 1991; Laible et a l 1991; Cohen, 1992). It is also possible that we need exposure to potential pathogens in order to stimulate a healthy immune system, and this is one human attribute which may have the capacity to evolve at the same pace as bacterial pathogens. Perhaps the emergence of ‘new’ infectious diseases (section 1.8) is a reflection of the decreasing fitness of the human population, or perhaps a sign that bacteria are prevailing in the struggle for existence?

6.3 F uture w ork suggested

There are parts o f these analyses which remain incomplete, for example: in Chapter 3, the expression of the two N. flavescens genes requires investigation, as does the possibility of two porin genes in N. gonorrhoeae; and throughout the work, additional statistical analyses could be carried out on the nucleotide sequences to estimate the extent o f selection and mosaic structure.

Two areas for further study are also suggested: