Analysis of the Diverse Antigenic Landscape of the Malaria Invasion Protein RH5 Identifies a Potent Vaccine-Induced Human Public Antibody Clonotype

Barrett, Jordan R.; Pipini, Dimitra; Wright, Nathan D.; Cooper, Andrew J. R.; Gorini, Giacomo; Quinkert, Doris; Lias, Amelia M.; Davies, Hannah; Rigby, Cassandra; Aleshnick, Maya; Williams, Barnabas G.; Bradshaw, William J.; Paterson, Neil G.; Martinson, Thomas; Kirtley, Payton; Picard, Luc; Wiggins, Christine D.; Donnellan, Francesca R.; King, Lloyd D. W.; Wang, Lawrence T.; Popplewell, Jonathan F.; Silk, Sarah E.; Swain, Jed de Ruiter; Skinner, Katherine; Kotraiah, Vinayaka; Noe, Amy R.; MacGill, Randall S.; King, C. Richter; Birkett, Ashley J.; Soisson, Lorraine A.; Minassian, Angela M.; Lauffenburger, Douglas A.; Miura, Kazutoyo; Long, Carole A.; Wilder, Brandon K.; Koekemoer, Lizbé; Tan, Joshua; Nielsen, Carolyn M.; McHugh, Kirsty; Draper, Simon J.

doi:10.1101/2023.10.04.560576

Cited by 6 publications

(1 citation statement)

References 68 publications

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“…Consistent with previous observations using RH5.1/AS01B in UK adults 15,25 , all the delayed booster regimens tested here in adults and infants also showed improvement in the avidity of anti-RH5 serum IgG, however, this did not impact the functional quality of these IgG in the assay of GIA. These observations have now been explained by analysis of anti-RH5 human mAbs that showed delayed boosting leads to improvement in the anti-RH5 antibody dissociation rates, but not in the antibody association rates which are strongly correlated with GIA potency 31 .…”

Section: Discussionmentioning

confidence: 99%

First Phase 1b, single-center, age de-escalation trial of theP. falciparumblood-stage malaria vaccine candidate RH5.1/Matrix-M^™: a delayed boost regimen induces high levels of functional antibodies in 5-17 month old Tanzanian infants

Silk,

Kalinga,

Salkeld

et al. 2024

Preprint

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Background RH5.1 is a soluble protein vaccine candidate for blood-stagePlasmodium falciparummalaria, previously trialed in healthy UK adults in combination with AS01Badjuvant. Here, RH5.1 was formulated with Matrix-M™ adjuvant to assess safety and immunogenicity in a malaria-endemic adult and pediatric population for the first time. Methods We conducted a Phase 1b, single-center, dose-escalation, age de-escalation, first-in-human trial of RH5.1/Matrix-M™ in Bagamoyo, Tanzania. Healthy adults (18-45 years) and infants (5-17 months) were recruited to receive the RH5.1/Matrix-M™ vaccine candidate in a variety of dosing regimens, including monthly dosing (0-1-2 month) or delayed booster dosing (0-1-6 month) using a 10 μg dose of RH5.1, or delayed fractional booster dosing (0-1-6 month) with the first two doses of RH5.1 at 50 μg and the third dose at 10 μg. All RH5.1 protein doses were formulated with 50 μg Matrix-M™ adjuvant. Primary outcomes for vaccine safety included solicited and unsolicited adverse events after each vaccination, along with any serious adverse events (SAEs) during the study period. Secondary outcome measures for immunogenicity included the concentration and avidity of anti-RH5.1 serum IgG antibodies by ELISA and their percentage growth inhibition activity (GIA)in vitroagainstP. falciparumparasites using purified IgG. All participants receiving at least one dose of vaccine were included in the primary analyses. Findings Between 25th January 2021 and 15th April 2021 a total of 60 adults and infants were enrolled; 57 of these completed the vaccination series, and 55 completed 22 months of follow-up post-third vaccination. Vaccinations were well-tolerated across both age groups. There were five SAEs involving four infant participants during the trial, none of which were deemed related to vaccination. RH5-specific T cell and serum antibody responses were induced by vaccination. The anti-RH5 serum IgG responses were significantly higher in the 5-17 month old infant groups as compared to adults. Serum antibody responses contracted over time post-third vaccination, but a similar hierarchy of responses across the age groups was maintained after 22 months follow-up (674 days post-third vaccination). Vaccine-induced anti-RH5 antibodies showedin vitroGIA with comparable functional quality across all age groups and dosing regimens. The highest anti-RH5 serum IgG responses were observed post-third vaccination in the 5-17 month old infants vaccinated with the 0-1-6 month delayed booster regimen using the 10 μg dose of RH5.1 (median 723 μg/mL ; range: 450-1436 μg/mL), resulting in 100 % (11/11 infants) showing >60 % GIA following dilution of total IgG to 2.5 mg/mL (median 88 %; range: 73-97 %). Interpretation The RH5.1/Matrix-M™ vaccine candidate shows an acceptable safety and reactogenicity profile and highly promising antibody immunogenicity in 5-17 month old infants residing in a malaria-endemic area. The 0-1-6 month delayed booster regimen in 5-17 month old infants induced the highest levels of functional GIA reported to-date following human vaccination, with all infants achieving a level of GIA previously associated with protective outcome against blood-stageP. falciparumchallenge in non-human primates. These data support onward efficacy assessment of this vaccine candidate against clinical malaria in young African infants. Funding The European and Developing Countries Clinical Trials Partnership (EDCTP). Trial Registration ClinicalTrials.gov:NCT04318002.

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Section: Discussionmentioning

confidence: 99%

First Phase 1b, single-center, age de-escalation trial of theP. falciparumblood-stage malaria vaccine candidate RH5.1/Matrix-M^™: a delayed boost regimen induces high levels of functional antibodies in 5-17 month old Tanzanian infants

Silk,

Kalinga,

Salkeld

et al. 2024

Preprint

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

Williams,

King,

Pulido

et al. 2024

Nat Commun

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Reticulocyte-binding protein homologue 5 (RH5), a leading blood-stage Plasmodium falciparum malaria vaccine target, interacts with cysteine-rich protective antigen (CyRPA) and RH5-interacting protein (RIPR) to form an essential heterotrimeric “RCR-complex”. We investigate whether RCR-complex vaccination can improve upon RH5 alone. Using monoclonal antibodies (mAbs) we show that parasite growth-inhibitory epitopes on each antigen are surface-exposed on the RCR-complex and that mAb pairs targeting different antigens can function additively or synergistically. However, immunisation of female rats with the RCR-complex fails to outperform RH5 alone due to immuno-dominance of RIPR coupled with inferior potency of anti-RIPR polyclonal IgG. We identify that all growth-inhibitory antibody epitopes of RIPR cluster within the C-terminal EGF-like domains and that a fusion of these domains to CyRPA, called “R78C”, combined with RH5, improves the level of in vitro parasite growth inhibition compared to RH5 alone. These preclinical data justify the advancement of the RH5.1 + R78C/Matrix-M™ vaccine candidate to Phase 1 clinical trial.

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

King,

Pulido,

Barrett

et al. 2024

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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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Analysis of the Diverse Antigenic Landscape of the Malaria Invasion Protein RH5 Identifies a Potent Vaccine-Induced Human Public Antibody Clonotype

Cited by 6 publications

References 68 publications

First Phase 1b, single-center, age de-escalation trial of theP. falciparumblood-stage malaria vaccine candidate RH5.1/Matrix-M^™: a delayed boost regimen induces high levels of functional antibodies in 5-17 month old Tanzanian infants

First Phase 1b, single-center, age de-escalation trial of theP. falciparumblood-stage malaria vaccine candidate RH5.1/Matrix-M^™: a delayed boost regimen induces high levels of functional antibodies in 5-17 month old Tanzanian infants

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

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Analysis of the Diverse Antigenic Landscape of the Malaria Invasion Protein RH5 Identifies a Potent Vaccine-Induced Human Public Antibody Clonotype

Cited by 6 publications

References 68 publications

First Phase 1b, single-center, age de-escalation trial of theP. falciparumblood-stage malaria vaccine candidate RH5.1/Matrix-M™: a delayed boost regimen induces high levels of functional antibodies in 5-17 month old Tanzanian infants

First Phase 1b, single-center, age de-escalation trial of theP. falciparumblood-stage malaria vaccine candidate RH5.1/Matrix-M™: a delayed boost regimen induces high levels of functional antibodies in 5-17 month old Tanzanian infants

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

Contact Info

Product

Resources

About

First Phase 1b, single-center, age de-escalation trial of theP. falciparumblood-stage malaria vaccine candidate RH5.1/Matrix-M^™: a delayed boost regimen induces high levels of functional antibodies in 5-17 month old Tanzanian infants

First Phase 1b, single-center, age de-escalation trial of theP. falciparumblood-stage malaria vaccine candidate RH5.1/Matrix-M^™: a delayed boost regimen induces high levels of functional antibodies in 5-17 month old Tanzanian infants