Structural basis for recognition of the malaria vaccine candidate Pfs48/45 by a transmission blocking antibody

Lennartz, Frank; Brod, Florian; Dabbs, Rebecca A.; Miura, Kazutoyo; Mekhaiel, David; Marini, Arianna; Jore, Matthijs M.; Soegaard, Max; Jørgensen, Tina; Jongh, Willem A. de; Sauerwein, Robert W.; Long, Carole A.; Biswas, Sumi; Higgins, Matthew K.

doi:10.1038/s41467-018-06340-9

Cited by 42 publications

(80 citation statements)

References 39 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…One of the main features of the SpyTag/SpyCatcher technology is the possibility to orientate the antigen on the VLP surface to expose the functional epitopes, which leads to the generation of a better quality of response (22). Recent progresses in the malaria-TBV field unrevealed structures and mapped epitopes of important antigen candidates that had remained elusive for long time (42)(43)(44). The combination of the new insights into the structure of these antigens, including Pfs25, and the possibility to specifically orientate them on HBsAg::SpyCatcher, offers a unique advantage in the design of novel vaccine candidates.…”

Section: Discussionmentioning

confidence: 99%

A Universal Plug-and-Display Vaccine Carrier Based on HBsAg VLP to Maximize Effective Antibody Response

Marini

Zhou

et al. 2019

Front. Immunol.

Self Cite

View full text Add to dashboard Cite

Development of effective malaria vaccines requires delivery platforms to enhance the immunogenicity and efficacy of the target antigens. This is particularly challenging for transmission-blocking malaria vaccines (TBVs), and specifically for those based on the Pfs25 antigen, that need to elicit very high antibody titers to stop the parasite development in the mosquito host and its transmission. Presenting antigens to the immune system on virus-like particles (VLPs) is an efficient way to improve the quantity and quality of the immune response generated. Here we introduce for the first time a new VLP vaccine platform, based on the well-established hepatitis B surface antigen (HBsAg) fused to the SpyCatcher protein, so that the antigen of interest, linked to the SpyTag peptide, can be easily displayed on it (Plug-and-Display technology). As little as 10% of the SpyCatcher::HBsAg VLPs decorated with Pfs25::SpyTag (molar ratio) induces a higher antibody response and transmission-reducing activity in mice compared to the soluble protein, with 50 and 90% of the VLP coupled to the antigen further enhancing the response. Importantly, using this carrier that is a vaccine antigen itself could be beneficial, as we show that anti-HBsAg IgG antibodies are induced without interfering with the Pfs25-specific immune response generated. Furthermore, pre-existing anti-HBsAg immunity does not affect the antigen-specific response to Pfs25::SpyTag-SpyCatcher::HBsAg, suggesting that these VLPs can have a broad use as a vaccine platform.

show abstract

Section: Discussionmentioning

confidence: 99%

A Universal Plug-and-Display Vaccine Carrier Based on HBsAg VLP to Maximize Effective Antibody Response

Marini

Zhou

et al. 2019

Front. Immunol.

Self Cite

View full text Add to dashboard Cite

show abstract

“…Within this family of Pfs230-like proteins, structures have been resolved for two members, which form a complex with an unknown function, Pf12 17 , 18 and Pf41 19 . Recently, the carboxyl-terminal cysteine-rich domain of Pfs48/45, identified as 6C, was cocrystalized with a TB mAb, which may aid in future vaccine design of a Pfs48/45 immunogen 20 , 21 . Pfs230 is expressed in both male and female gametocytes without a known membrane anchor and appears on the surface of gametes as a complex with Pfs48/45 22 , a glycosylphosphatidylinositol (GPI) anchored protein 23 .…”

Section: Introductionmentioning

confidence: 99%

Structure and function of a malaria transmission blocking vaccine targeting Pfs230 and Pfs230-Pfs48/45 proteins

et al. 2020

View full text Add to dashboard Cite

Proteins Pfs230 and Pfs48/45 are Plasmodium falciparum transmission-blocking (TB) vaccine candidates that form a membrane-bound protein complex on gametes. The biological role of Pfs230 or the Pfs230-Pfs48/45 complex remains poorly understood. Here, we present the crystal structure of recombinant Pfs230 domain 1 (Pfs230D1M), a 6-cysteine domain, in complex with the Fab fragment of a TB monoclonal antibody (mAb) 4F12. We observed the arrangement of Pfs230 on the surface of macrogametes differed from that on microgametes, and that Pfs230, with no known membrane anchor, may exist on the membrane surface in the absence of Pfs48/45. 4F12 appears to sterically interfere with Pfs230 function. Combining mAbs against different epitopes of Pfs230D1 or of Pfs230D1 and Pfs48/45, significantly increased TB activity. These studies elucidate a mechanism of action of the Pfs230D1 vaccine, model the functional activity induced by a polyclonal antibody response and support the development of TB vaccines targeting Pfs230D1 and Pfs230D1-Pfs48/45.

show abstract

“…coli periplasm, which showed 93% reducing activity in standard membrane-feeding assay (SMFA) 13 . A 6C domain has been expressed using different expression systems 18,21 . However, since a 6C-fragment is smaller in size containing epitope I only, but excluding epitopes IIb and III, a higher dose of 6C protein was needed to elicit optimal TRA by SMFA, compared with 10C or full length Pfs48/45 18 .…”

Section: Introductionmentioning

confidence: 99%

A Plant-Produced in vivo deglycosylated full-length Pfs48/45 as a Transmission-Blocking Vaccine Candidate against malaria

Mamedov

Cicek

Miura

et al. 2019

Sci Rep

Self Cite

View full text Add to dashboard Cite

Pfs48/45 is a leading antigen candidate for a transmission blocking (TB) vaccine. However, efforts to produce affordable, safe and correctly folded full-length Pfs48/45 using different protein expression systems have not produced an antigen with satisfactory TB activity. Pfs48/45 has 16 cysteines involved in disulfide bond formation, and the correct formation is critical for proper folding and induction of TB antibodies. Moreover, Pfs48⁄45 is not a glycoprotein in the native hosts, but contains potential glycosylation sites, which are aberrantly glycosylated during expression in eukaryotic systems. Here, we demonstrate for the first time that full length, Endo H in vivo enzymatic deglycosylated Pfs48/45 antigen is produced at a high level in plants and is structurally stable at elevated temperatures. Sera from mice immunized with this antigen showed strong inhibition in SMFA. Thus, Endo H in vivo enzymatic deglycosylated Pfs48/45 is a promising candidate for the development of an affordable TB vaccine, which may have the potential to save millions.

show abstract

Structural basis for recognition of the malaria vaccine candidate Pfs48/45 by a transmission blocking antibody

Cited by 42 publications

References 39 publications

A Universal Plug-and-Display Vaccine Carrier Based on HBsAg VLP to Maximize Effective Antibody Response

A Universal Plug-and-Display Vaccine Carrier Based on HBsAg VLP to Maximize Effective Antibody Response

Structure and function of a malaria transmission blocking vaccine targeting Pfs230 and Pfs230-Pfs48/45 proteins

A Plant-Produced in vivo deglycosylated full-length Pfs48/45 as a Transmission-Blocking Vaccine Candidate against malaria

Contact Info

Product

Resources

About