RH5.1-CyRPA-Ripr antigen combination vaccine shows little improvement over RH5.1 in a preclinical setting

Healer, Julie; Thompson, J. K.; Mackwell, Karen L.; Browne, Cecille D.; Seager, Benjamin A; Ngo, Anna; Lowes, Kym N; Silk, Sarah E.; Pulido, David; King, Lloyd; Christen, Jayne M.; Noe, Amy R.; Kotraiah, Vinayaka; Masendycz, Paul; Rajagopalan, Rajkannan; Lucas, Leanne J.; Stanford, Marianne M.; Soisson, Lorraine; Diggs, Carter L.; Miller, Ruth; Youll, Susan; Wycherley, Kaye; Draper, Simon J.; Cowman, Alan F.

doi:10.3389/fcimb.2022.1049065

Cited by 10 publications

(6 citation statements)

References 33 publications

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“…However, none of the vaccine candidates tested targeting the RCR-complex could outperform full-length RH5 (RH5.1) alone in terms of functional antibody induction in rats. This is consistent with another recently reported study that attempted a similar strategy 53 . Our quantitative analysis of the antibody response to each antigen in µg/mL revealed this was due to both the immuno-dominance of RIPR (over RH5 and especially CyRPA) coupled with the relatively poor immuno-potency of anti-RIPR polyclonal IgG (in comparison to both anti-RH5 and -CyRPA polyclonal IgG).…”

Section: Discussionsupporting

confidence: 93%

Development of an improved blood-stage malaria vaccine targeting the essential RH5-CyRPA-RIPR invasion complex

Williams,

King,

Pulido

et al. 2024

Preprint

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In recent years, reticulocyte-binding protein homologue 5 (RH5) has emerged as a leading blood-stage Plasmodium falciparum malaria vaccine antigen. The most advanced blood-stage vaccine candidate in a Phase 2b clinical trial, RH5.1/Matrix-M[TM], is based on a full-length soluble protein-with-adjuvant formulation. RH5 interacts with cysteine-rich protective antigen (CyRPA) and RH5-interacting protein (RIPR) to form an essential heterotrimeric RCR-complex. Here, we investigated whether a vaccine candidate based on the ternary RCR-complex could substantially improve upon the leading clinical candidate RH5.1/Matrix-M[TM] in preclinical studies. Using a panel of monoclonal antibodies (mAbs) we confirm that parasite growth-inhibitory epitopes on each antigen are exposed on the surface of the RCR-complex and that mAb pairs binding to different antigens can function additively or synergistically to mediate parasite growth inhibition activity (GIA) in vitro. However, immunisation of rats with the RCR-complex consistently fails to outperform RH5.1 alone. We show this is due to immuno-dominance of RIPR coupled with the inferior potency of anti-full length RIPR polyclonal IgG antibodies as compared to the anti-RH5 and anti-CyRPA response. To address this, we identified the growth-inhibitory antibody epitopes of RIPR are clustered within C-terminal EGF-like domains of RIPR. A fusion of these EGF domains to CyRPA, called R78C, combined with RH5.1, provided a new vaccination strategy that improves upon the levels of in vitro GIA seen with RH5.1 alone. Superiority of the combination antigen vaccine candidate was achieved by the induction of a quantitatively higher, but qualitatively similar, polyclonal antibody response that demonstrated additive GIA across the three antigen targets. These preclinical data justified the advancement of the RH5.1+R78C/Matrix-M[TM] combination vaccine to a Phase 1 clinical trial.

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Section: Discussionsupporting

confidence: 93%

Development of an improved blood-stage malaria vaccine targeting the essential RH5-CyRPA-RIPR invasion complex

Williams,

King,

Pulido

et al. 2024

Preprint

Self Cite

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“…However, functional testing of the purified total IgG from RH5.2-VLP vaccinated rats showed significantly improved GIA over RH5.1, with a median 9.6-fold reduction in the EC50 of total IgG. To our knowledge, this is the first vaccine candidate to significantly outperform RH5.1 in terms of functional immunogenicity in a preclinical model, including comparison to vaccines targeting the wider RH5 invasion complex 42 . This improvement was driven by a significantly lower antigen-specific EC50 of the vaccine-induced IgG, with RH5.2-vaccinated rats achieving 50 % GIA at median levels of ~5 µg/mL RH5.1-specific antibody.…”

Section: Discussionmentioning

confidence: 85%

Preclinical Development of a Stabilized RH5 Virus-Like Particle Vaccine that Induces Improved Anti-Malarial Antibodies

King,

Pulido,

Barrett

et al. 2024

Preprint

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The development of a highly effective vaccine against the pathogenic blood-stage infection of human malaria will require a delivery platform that can induce an antibody response of both maximal quantity and functional quality. One strategy to achieve this includes presenting antigens to the immune system on virus-like particles (VLPs). Here we sought to improve the design and delivery of the blood-stagePlasmodium falciparumreticulocyte-binding protein homolog 5 (RH5) antigen, which is currently in a Phase 2 clinical trial as a full-length soluble protein-in-adjuvant vaccine candidate called RH5.1/Matrix-M™. We identify disordered regions of the full-length RH5 molecule induce non-growth inhibitory antibodies in human vaccinees, and a re-engineered and stabilized immunogen that includes just the alpha-helical core of RH5 induces a qualitatively superior growth-inhibitory antibody response in rats vaccinated with this protein formulated in Matrix-M™ adjuvant. In parallel, bioconjugation of this new immunogen, termed ″RH5.2″, to hepatitis B surface antigen VLPs using the ″plug-and-display″ SpyTag-SpyCatcher platform technology also enabled superior quantitative antibody immunogenicity over soluble antigen/adjuvant in vaccinated mice and rats. These studies identify a new blood-stage malaria vaccine candidate that may improve upon the current leading soluble protein vaccine candidate RH5.1/Matrix-M™. The RH5.2-VLP/Matrix-M™ vaccine candidate is now under evaluation in Phase 1a/b clinical trials.

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“…This may be because merozoite protein-loaded particles elicit antibodies against multiple antigens, including antiPfRH5, which then function synergistically to slow down erythrocyte invasion [36]. It must be noted that the non-polymorphic antigen PfRH5 alone is not sufficiently effective as an anti-blood stage vaccine, because only specific inhibitory antibodies against determined epitopes provide protection [37]; even when delivered in PfRH5 s natural complex with CYRPA and RIPR, invasion inhibition is not greatly augmented [38], indicating that more antigens are needed to block merozoite invasion. In this sense, samRNA encoding a number of different antigens against which antibodies exert invasion-inhibitory activity, seems to be an attractive avenue to follow in terms of vaccine development.…”

Section: Discussionmentioning

confidence: 99%

Establishment of an Antiplasmodial Vaccine Based on PfRH5-Encoding RNA Replicons Stabilized by Cationic Liposomes

et al. 2023

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Background: Nucleic acid-based vaccines have been studied for the past four decades, but the approval of the first messenger RNA (mRNA) vaccines during the COVID-19 pandemic opened renewed perspectives for the development of similar vaccines against different infectious diseases. Presently available mRNA vaccines are based on non-replicative mRNA, which contains modified nucleosides encased in lipid vesicles, allowing for entry into the host cell cytoplasm, and reducing inflammatory reactions. An alternative immunization strategy employs self-amplifying mRNA (samRNA) derived from alphaviruses, but lacks viral structural genes. Once incorporated into ionizable lipid shells, these vaccines lead to enhanced gene expression, and lower mRNA doses are required to induce protective immune responses. In the present study, we tested a samRNA vaccine formulation based on the SP6 Venezuelan equine encephalitis (VEE) vector incorporated into cationic liposomes (dimethyldioctadecyl ammonium bromide and a cholesterol derivative). Three vaccines were generated that encoded two reporter genes (GFP and nanoLuc) and the Plasmodium falciparum reticulocyte binding protein homologue 5 (PfRH5). Methods: Transfection assays were performed using Vero and HEK293T cells, and the mice were immunized via the intradermal route using a tattooing device. Results: The liposome–replicon complexes showed high transfection efficiencies with in vitro cultured cells, whereas tattooing immunization with GFP-encoding replicons demonstrated gene expression in mouse skin up to 48 h after immunization. Mice immunized with liposomal PfRH5-encoding RNA replicons elicited antibodies that recognized the native protein expressed in P. falciparum schizont extracts, and inhibited the growth of the parasite in vitro. Conclusion: Intradermal delivery of cationic lipid-encapsulated samRNA constructs is a feasible approach for developing future malaria vaccines.

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RH5.1-CyRPA-Ripr antigen combination vaccine shows little improvement over RH5.1 in a preclinical setting

Cited by 10 publications

References 33 publications

Development of an improved blood-stage malaria vaccine targeting the essential RH5-CyRPA-RIPR invasion complex

Development of an improved blood-stage malaria vaccine targeting the essential RH5-CyRPA-RIPR invasion complex

Preclinical Development of a Stabilized RH5 Virus-Like Particle Vaccine that Induces Improved Anti-Malarial Antibodies

Establishment of an Antiplasmodial Vaccine Based on PfRH5-Encoding RNA Replicons Stabilized by Cationic Liposomes

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