Experimental infection and protection against ... - TI Pharma

218 Chapter 11
antibodies induced by AMA1 in humans and rabbits and found that the avidity
and concentration of AMA1-induced antibodies are linked by a negative
feedback mechanism reaching saturation in most vaccinees (Chapter 4). Higher
titre AMA1 antibodies may thus not necessarily implicate better binding
efficiency and function (Chapter 4). The relevance of these findings for in vivo
protection is unclear. A correlation between antibody avidity, as measured by
thiocyanate ELISA, and protection was not found in a P. chabaudi rodent model,
but the combination of titres to refolded and reduced/alkylated recombinant
AMA1 proved an important predictor of protection [22]. These results illustrate
the importance of understanding the nature of AMA1 immunogenic epitopes,
their functionality and the antibody characteristics. Moreover, other Pf-specific
antibodies may interfere with the biological activity of anti-AMA1 antibodies
[23], underlining the fact that protection in the field is a composite of more than
just anti-AMA1 antibodies. An immunological marker for protection is essential
to assess immunogenicity of AMA1 vaccine candidates in an early stage of
clinical development.
The in vitro growth inhibition assay (GIA) has been developed as a functional
marker that include all antibody properties. The GIA is a biological assay
investigating the capacity of AMA-1 induced antibodies to inhibit parasite
growth [24]. Although promising at first, the inhibitory capacity measured in
vitro did not correlate with protection in rhesus monkeys [25] or in human trials
[18, 26]. The fact that we found substantial inhibition of AMA1-induced
antibodies in vitro, is thus no guarantee of protection in vivo.
Nonetheless, protection from Plasmodium falciparum malaria can be transferred
from one human to the other by the passive transfer of antibodies from malariaimmune
to non-immune subjects. Since 1917, such experiments were
performed in humans, when it was discovered that patients improved clinically
when inoculated with serum obtained from “chronic” cases. In the 60’s
experiments were repeated and antibodies taken from children in West Africa
proved sufficient for the treatment of children in East Africa [27], indicating that
antibodies can even overcome strain diversity. An antibody dependent cellular
inhibiting effect (ADCI) has been proposed as an effector mechanism to this
protection [28], relying on the help of cytokines such as IFNγ, IL-4 [28] and TNFα
[29] to upregulate phagocytic function of polymorphonuclear leukocytes or
monocytes. However, T-cells alone have also shown to adoptively transfer
protection against malaria in rodent models [30] and the central role of IFNγ in