Stanisic et al. [14] present a pilot study evaluating the safety and immunogenicity of a chemically attenuated Plasmodium falciparum asexual blood-stage vaccine in malaria-naïve human subjects. This is the first clinical study of its kind. Moving this vaccine concept forward to testing in human subjects represents a significant advance. This initial effort focused on four key questions. First, can this vaccine be manufactured in compliance with regulatory standards? The group built on prior successes in which P. falciparum-infected erythrocytes were generated under conditions suitable for approval of trials involving infection of human subjects. Unique to the current study was the need to monitor the residual level of the drug used for attenuation (tafuramycin-A) in the final vaccine formulation, given the drug’s genotoxic potential. Residual drug concentrations well below threshold values of concern were observed. These initial results are very encouraging, but this matter will likely attract additional scrutiny as trials progress.
Second, can P. falciparum-parasitized erythrocytes be chemically treated in vitro to ensure no breakthrough infection in vivo, while maintaining the required level of viability? The answer appears to be yes. While breakthrough infections were noted with parasites treated with a low concentration of the drug, a four-fold higher concentration effectively achieved attenuation.
Third, is the vaccine safe? Safety was carefully monitored for a 90-day period. In routine assessments in volunteers who received the fully attenuated vaccine, no issues of concern were observed. The one exception of note was the detection of antibodies to a minor red blood cell (RBC) antigen in one subject. This prompted the team to produce attenuated vaccines for the remaining volunteers using their own RBCs. This is not a viable solution for vaccine manufacture, so this matter will need to be closely monitored moving forward. If the problem persists, further development of this attenuated vaccine will be in jeopardy.
The fourth question is particularly important: is the vaccine immunogenic? Considering the novelty of the vaccine design and potential safety issues, this first trial – by necessity – included a small number of subjects who received only one dose of attenuated P. falciparum-parasitized RBCs. As such, it was not unexpected to see heterogeneity in immune responses. The interpretation of immunogenicity data was also limited, to some degree, by the responsiveness of peripheral blood mononuclear cells from these malaria-naïve volunteers to in vitro stimulation with P. falciparum-infected RBCs at baseline. Despite these issues, it was notable that immunization with the fully attenuated vaccine primed antigen-specific T cells to proliferate and produce TNFα and IFNγ. These results are encouraging because these two cytokines contribute to protection against blood-stage parasites when their production is appropriately regulated.
Also of interest was the lack of detectable, antigen-specific antibody responses in this cohort. This may be attributed to the administration of a single priming dose. However, data from studies in naïve animals, which go back as far back as 1981 [15], and through the recent work of Good and colleagues with chemically attenuated P. chabaudi blood-stage vaccines [12], indicate that CD4+ T cell responses can contribute to protection, independent of antibody. Induction of cell-mediated immune mechanisms in human subjects by administration of an attenuated blood-stage vaccine would add a new dimension to the malaria vaccine effort. Current blood-stage vaccines almost exclusively target the production of parasite-neutralizing antibodies.
