Abstract
Plasmodium falciparum transmission-blocking vaccines (TBVs) targeting the Pfs25 antigen have shown promise in mice but the same efficacy has never been achieved in humans. We have previously published pre-clinical data related to a TBV candidate Pfs25-IMX313 encoded in viral vectors which was very promising and hence progressed to human clinical trials. The results from the clinical trial of this vaccine were very modest. Here we unravel why, contrary to mice, this vaccine has failed to induce robust antibody (Ab) titres in humans to elicit transmission-blocking activity. We examined Pfs25-specific B cell and T follicular helper (Tfh) cell responses in mice and humans after vaccination with Pfs25-IMX313 encoded by replication-deficient chimpanzee adenovirus serotype 63 (ChAd63) and the attenuated orthopoxvirus modified vaccinia virus Ankara (MVA) delivered in the heterologous prime-boost regimen via intramuscular route. We found that after vaccination, the Pfs25-IMX313 was immunologically suboptimal in humans compared to mice in terms of serum Ab production and antigen-specific B, CD4+ and Tfh cell responses. We identified that the key determinant for the poor anti-Pfs25 Ab formation in humans was the lack of CD4+ T cell recognition of Pfs25-IMX313 derived peptide epitopes. This is supported by correlations established between the ratio of proliferated antigen-specific CD4+/Tfh-like T cells, CXCL13 sera levels, and the corresponding numbers of circulating Pfs25-specific memory B cells, that consequently reflected on antigen-specific IgG sera levels. These correlations can inform the design of next-generation Pfs25-based vaccines for robust and durable blocking of malaria transmission.
Highlights
While several stages of the malaria parasite life cycle can be targeted with vaccination, a promising possibility for malaria elimination and eradication is the development of transmissionblocking vaccines (TBVs)
Responses are reported in mg/ml following conversion of ELISA arbitrary units (AU) by calibration-free concentration analysis (CFCA), as direct comparison between murine and human anti-Pfs25 Ab responses detected by ELISA could not be performed, due to different sensitivities of the secondary Abs used
We showed that chimpanzee adenovirus serotype 63 (ChAd63)/modified vaccinia virus Ankara (MVA) Pfs25-IMX313 vaccination induced T follicular helper (Tfh) responses in both mice and humans; inducible costimulator (ICOS)+PD1+ Tfh cells detected in healthy adult vaccinees demonstrated mainly Th2-like properties, while those in mice were of Th1-like cells, potentially explaining the differences in induced Pfs25-specific IgG subclasses and their corresponding Fc effector function profiles in mice and humans
Summary
While several stages of the malaria parasite life cycle can be targeted with vaccination, a promising possibility for malaria elimination and eradication is the development of transmissionblocking vaccines (TBVs). We have applied the IMX313 technology, based on a chimeric version of the oligomerization domain from chicken complement inhibitor C4binding protein (C4 bp), in order to obtain homogenous, selfassembling oligomers of Pfs25 This C4 bp oligomerization domain has been shown to spontaneously form soluble heptameric structures when expressed in E. coli [11] and we have already demonstrated in mice that Pfs fused to IMX313 domain improved Ab responses over the same amount of monomeric antigen when expressed in ChAd63 and MVA viral vectors [10]. The transmission reducing activity of the antibodies generated was weak, but both test vaccines were well tolerated and demonstrated a favourable safety profile in malaria-naive adults
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