Experimental infection and protection against ... - TI Pharma

Induction of malaria in volunteers by intradermal injection of cryopreserved
Plasmodium falciparum sporozoites
the circulation [35]. The fact that Jeffery et al. achieved infection in 13 of 14
volunteers by intravenous injection of PfSPZ-infected salivary glands [25], and
the only negative case was at the lowest does of salivary glands, supports this
interpretation. To closer mimic the SPZ delivery of mosquitoes, administration of
PfSPZ Challenge will be optimized by modifying route of administration (e.g. ID,
subcutaneous, intramuscular, intravenous), inoculation volume, numbers of
inoculations, and sites of injection. Our sample sizes of 6 per group, in this firstin-humans
study, were not powered to be able show a modest difference
between groups. Thus, another explanation for the lack of difference in
infectivity or prepatent period between as the dose was increased 10-fold from
2,500 to 25,000 PfSPZ is that that sample sizes were too small to detect small
differences between groups. However, they should have been adequate to
detect a 10-fold difference, if the PfSPZ actually reached the bloodstream. Since
there was no difference as we increased the dose, it is possible that 2,500 PfSPZ
was above the threshold necessary to achieve infection, and even lower doses
might be equally successful.
Once administration of PfSPZ Challenge is optimized, the global capacity to
conduct CHMIs can be further expanded including sites in malaria endemic
areas. This will be critical for meeting the demand to assess the increasing
numbers of malaria vaccine candidates and anti-malarial drugs in development
[36-37]. Comparative analysis of CHMI by mosquito bite has shown that
variability of parasites may lead to significant variation in the primary outcome
variables between sites. By using needle administration of defined quantities of
PfSPZ Challenge from the same lot, variation in infectivity in CHMI will be
reduced, allowing comparisons of parallel and sequential clinical trials at
multiple sites, including in malaria endemic areas.
In addition to its use in CHMI, needle and syringe administration of
cryopreserved SPZ is critical for development of whole SPZ vaccines. PfSPZ
protective efficacy in humans was originally established by controlled exposure
of volunteers to bites of irradiated PfSPZ-infected mosquitoes [18-20]. The
potential impact of a radiation-attenuated PfSPZ vaccine was reappraised and
significant progress has been made in manufacturing and clinically testing such a
vaccine [27-28]. The aseptic, purified, cryopreserved PfSPZ Vaccine is
manufactured identically to PfSPZ Challenge, except that the parasites in the
vaccine are attenuated by irradiation and cannot fully develop in the liver. In the
first clinical trial the PfSPZ Vaccine was administered ID or subcutaneously. It
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