Experimental infection and protection against ... - TI Pharma

General Discussion 219
mediating this protection is increasingly appreciated [31]. Indeed, also in
humans, repeated low grade blood stage infections can induce protection
against Pf malaria in the absence of detectable antibodies [32]. In addition,
multifunctional T-cell responses were identified following human AMA1
vaccination [33] and T-cell memory responses to T-cell epitopes from the AMA1
protein were detected in clinically immune subjects, although no clear-cut
association with parasitemia was found [34, 35]. To conclude, AMA1-specific Tcells
contribute to building an effective humoral response in mice [36-38], but
antibodies are generally still thought to be the most critical effector for blood
stage parasite inhibition [38, 39]. Apparently, not just the quantity of antibodies
but possibly also the quality and the interplay between cellular and humoral
responses play a role in building a protective immune response to AMA1.
In order to understand the mechanism by which AMA1 directed immune
responses effectuate parasite growth inhibition, more basic understanding of
the function of AMA1 is essential. AMA1 is expressed in merozoites and is
thought to help reorienting the merozoite when aligning with the erythrocyte
membrane and subsequently attaching with erythrocyte membrane proteins [1].
More recent mechanistic in vitro studies, however, also highlight a possible role
of AMA1 in parasite invasion into hepatocytes, showing expression of AMA1 in
sporozoites and inhibition of AMA1 antibodies with invasion of hepatocytes [40].
The possible clinical relevance of this function was confirmed by two controlled
malaria infection (CHMI) studies with human volunteers [18, 26], in which no
clinically relevant effect on prepatency or blood stage parasite inhibition could
be found in AMA1 immunized volunteers challenged by mosquito bite [26] or
blood stage parasites[18], but possible reduction of liver load parasites could be
detected by Q-PCR analysis of parasitemia in the former trial [26].
The versatility of AMA1 expression complicates the dissection of AMA1-induced
inhibiting and enhancing immune responses. The induction of exactly the right
quality and quantity immune responses, however, may be the key to AMA1
success in humans. Adjuvants are a very heterogenic group of pharmacological
or immunological agents that are co-administered with vaccines in order to
potentiate and/or direct immune responses in humans. Particularly in malaria
research adjuvants have proven to play a critical role: GlaxoSmithKline’s
proprietary adjuvant AS01/2 was found crucial for enhancing responses to RTS,S
to protective levels [41]. We found that adjuvants are also important
determinants of cellular and humoral immune responses when combined with