Drug resistance is one of the most medically relevant forms of pathogen evolution.
To date, vaccines have not failed with the same depressing regularity as drugs. Does
that then make vaccines evolution-proof? In the face of vaccination, pathogens are
thought to evolve in two ways: by evolving epitope changes at the antigenic target of
vaccination (epitope evolution); or by evolving changes at other antigenic loci, some
of which may involve virulence (virulence evolution). The fundamental difference
between these two forms of evolution is that virulence evolution could lead to
disease outcomes in unvaccinated people that are more severe than would have been
seen prior to evolution. One of the theoretical assumptions of virulence evolution is
that more virulent parasites will have a selective advantage over less virulent
parasites in an immunized host, and are thus more likely to be transmitted. The
assumption is that more virulent parasites may be competitively more superior in
mixed infections, or may be better able to evade/modulate the host immune response.
Thus, the aim of this thesis was to experimentally test whether more virulent
parasites have a within-host selective advantage in an immunized host or whether
vaccine efficacy is more likely to depend on genetic differences at the targeted sites
of vaccination.
I used clones (genotypes) of the rodent malaria Plasmodium chabaudi originally
derived from wild-caught Thicket (Thamnomys rutilans) rats to infect laboratory
mice and a rodent analogue of the candidate blood-stage malaria vaccine apical
membrane antigen 1 (AMA-1). I found that within-host selection did not depend on
parasite virulence, and that protective efficacy depended on genotype-specific
differences at the vaccine target. Vaccine-induced protection was not enhanced by
including a number of allelic variants. However, such genotype-specific responses
were only observed when the vaccine was tested against genetically distinct P.
chabaudi parasites. When one P. chabaudi genotype was serially passaged through
naïve mice the derived line was more virulent and was subsequently less well
controlled by vaccine-induced immunity. In other experiments I found within host
competition not to be immune-mediated. Thus my results suggest that vaccination
has the potential to select for more virulent parasites but that the selective advantage
is likely to be independent of competition. The selective advantage may be
attributable to the enhanced immune evasion of more virulent parasites. However,
without genetic markers of virulence, the mechanisms that mediate this selection
remain unknown.
My thesis contributes towards a growing body of evidence that vaccines have the
potential to differently alter the within-host parasite dynamics of particular pathogen
genotypes and that the selection imposed is likely to be system specific, depending
on the fine specificity of the vaccine-induced responses and the identity of infecting
parasites. Although vaccine potency may not be enhanced by including more than
one allelic variant of an antigen, multi-valent vaccines may be one of the best ways
to avoid the inadvertent selection for more virulent malaria parasites
