Experimental infection and protection against ... - TI Pharma

General Discussion 231
Conclusions and perspectives
Controlled human malaria infections (CHMI) provide a model to predict malaria
vaccine efficacy in a well-controlled clinical setting. The CHMI model using Pfinfected
mosquito bites is well established in several international sites and is
increasingly used as a crucial check point for the clinical development of preerythrocytic
stage malaria vaccines. The only candidate malaria vaccine showing
protective efficacy in Phase IIb field trials so far is RTS,S. This candidate vaccine
would almost certainly never have been developed without optimization after a
series of Phase IIa trials. Moreover, efficacy data from Phase IIa trials can help to
support the decision-making process by ethical boards and communities in
malaria-endemic countries to justify further testing candidate vaccines in Phase
IIb trials in susceptible populations.
Several caveats in standardisation lead to variability in the primary endpoints of
CHMI trials between institutions, which still need to be addressed. Nevertheless,
small CHMI trials are sufficiently powered to evaluate >50% effective bloodstage
vaccines (Chapter 6). CHMI can be strengthened by the administration of
sporozoites by needle and the availability of several heterologous field strains.
Particularly the needle administration of sporozoites can boost the setup of new
clinical trial settings hosted by institutions in malaria-endemic countries, ideally
mimicking local transmission and incorporating investigations on vaccine effects
in semi-immune individuals [134]. However, the availability of live sporozoites
for a larger number of trial centres also warrants increased efforts for
standardisation and quality control of the infrastructure. After all, the stringent
selection of volunteers and intense clinical follow-up schedule are important to
ensure safety of volunteers.
Clinical development of AMA1 vaccine development has also benefited from the
CHMI model, confirming satisfactory immunogenicity but lack of significant
effects on primary endpoints. Our incomplete understanding of immunological
correlates to AMA1-induced protection in humans seems the main hurdle on the
road to an effective AMA1 vaccine. CHMI can contribute to unravelling these
immunological correlates, provided trials are well designed. For example,
assuming that immunoglobulins are the main effectors to AMA1 induced
immunity, these specific antibodies should be capable of passively transferring
protection from one subject to the other, allowing for the identification of
specific antibodies responsible for protection. Such antibodies could be the longsought
for correlate of protection. Unfortunately, transfer of antigen specific