Human vaccination against RH5 induces neutralizing antimalarial antibodies that inhibit RH5 invasion complex interactions

Payne, Ruth; Silk, Sarah E.; Elias, Sean C.; Miura, Kazutoyo; Diouf, Ababacar; Galaway, Francis; Graaf, Hans de; Brendish, Nathan J; Poulton, Ian; Griffiths, Oliver; Edwards, Nick J.; Jin, Jing; Labbé, Geneviève; Alanine, Daniel G. W.; Siani, Loredana; Marco, Stefania Di; Roberts, Rachel; Green, Nicky; Berrie, Eleanor; Ishizuka, Andrew S.; Nielsen, Carolyn M.; Bardelli, Martino; Partey, Frederica Dedo; Ofori, Michael F.; Barfod, Lea; Wambua, Juliana; Murungi, Linda M.; Osier, Faith; Biswas, Sumi; McCarthy, James S.; Minassian, Angela M.; Ashfield, Rebecca; Viebig, Nicola K.; Nugent, Fay L.; Douglas, Alexander D.; Vekemans, Johan; Wright, Gavin J.; Faust, Saul N; Hill, Adrian V. S.; Long, Carole A.; Lawrie, Alison M.; Draper, Simon J.

doi:10.1172/jci.insight.96381

Cited by 118 publications

(210 citation statements)

References 69 publications

(144 reference statements)

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“…Consistent with previous reports of TFF of adenovirus products using various devices with polyethersulfone (PES) membranes with 300 kDa molecular weight cut-off (MWCO), we obtained satisfactory results using 300 kDa MWCO BioMax Ò PES C-screen Pellicon Ò XL50 or Pellicon Ò 2 Mini devices (Merck) [14,18,34]. With Pellicon Ò 2 Mini devices, recovery was typically c. 80% for all viruses after 10-fold concentration and 6 diavolumes (DV) of buffer exchange into anion exchange loading buffer.…”

Section: Selection Of Downstream Process Mediasupporting

confidence: 89%

Simian adenovirus vector production for early-phase clinical trials: A simple method applicable to multiple serotypes and using entirely disposable product-contact components

Fedosyuk¹,

Merritt²,

Peralta-Álvarez³

et al. 2019

Vaccine

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a b s t r a c tA variety of Good Manufacturing Practice (GMP) compliant processes have been reported for production of non-replicating adenovirus vectors, but important challenges remain. Most clinical development of adenovirus vectors now uses simian adenoviruses or rare human serotypes, whereas reported manufacturing processes mainly use serotypes such as AdHu5 which are of questionable relevance for clinical vaccine development. Many clinically relevant vaccine transgenes interfere with adenovirus replication, whereas most reported process development uses selected antigens or even model transgenes such as fluorescent proteins which cause little such interference. Processes are typically developed for a single adenovirus serotype -transgene combination, requiring extensive further optimization for each new vaccine.There is a need for rapid production platforms for small GMP batches of non-replicating adenovirus vectors for early-phase vaccine trials, particularly in preparation for response to emerging pathogen outbreaks. Such platforms must be robust to variation in the transgene, and ideally also capable of producing adenoviruses of more than one serotype. It is also highly desirable for such processes to be readily implemented in new facilities using commercially available single-use materials, avoiding the need for development of bespoke tools or cleaning validation, and for them to be readily scalable for later-stage studies.Here we report the development of such a process, using single-use stirred-tank bioreactors, a transgene-repressing HEK293 cell -promoter combination, and fully single-use filtration and ion exchange components. We demonstrate applicability of the process to candidate vaccines against rabies, malaria and Rift Valley fever, each based on a different adenovirus serotype. We compare performance of a range of commercially available ion exchange media, including what we believe to be the first published use of a novel media for adenovirus purification (NatriFlo Ò HD-Q, Merck). We demonstrate the need for minimal process individualization for each vaccine, and that the product fulfils regulatory quality expectations. Cell-specific yields are at the upper end of those previously reported in the literature, and volumetric yields are in the range 1 Â 10 13 -5 Â 10 13 purified virus particles per litre of culture, such that a 2-4 L process is comfortably adequate to produce vaccine for early-phase trials. The process is readily transferable to any GMP facility with the capability for mammalian cell culture and aseptic filling of sterile products.

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Section: Selection Of Downstream Process Mediasupporting

confidence: 89%

Simian adenovirus vector production for early-phase clinical trials: A simple method applicable to multiple serotypes and using entirely disposable product-contact components

Fedosyuk¹,

Merritt²,

Peralta-Álvarez³

et al. 2019

Vaccine

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“…A leading candidate antigen is P . falciparum reticulocyte binding protein homologue 5 (PfRh5; Payne et al, ).…”

Section: Introductionmentioning

confidence: 99%

Neutralising antibodies block the function of Rh5/Ripr/CyRPA complex during invasion of Plasmodium falciparum into human erythrocytes

Healer

Wong

Thompson

et al. 2019

Cellular Microbiology

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An effective vaccine is a priority for malaria control and elimination. The leading candidate in the Plasmodium falciparum blood stage is PfRh5. PfRh5 assembles into trimeric complex with PfRipr and PfCyRPA in the parasite, and this complex is essential for erythrocyte invasion. In this study, we show that antibodies specific for PfRh5 and PfCyRPA prevent trimeric complex formation. We identify the EGF‐7 domain on PfRipr as a neutralising epitope and demonstrate that antibodies against this region act downstream of complex formation to prevent merozoite invasion. Antibodies against the C‐terminal region of PfRipr were more inhibitory than those against either PfRh5 or PfCyRPA alone, and a combination of antibodies against PfCyRPA and PfRipr acted synergistically to reduce invasion. This study supports prioritisation of PfRipr for development as part of a next‐generation antimalarial vaccine.

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“…Antibodies that block the invasion process of the red blood cells by merozoites represent another possible approach. In studies of the merozoite protein RH5 (reticulocytebinding protein homologue 5) as a potential vaccine, some antibodies were described that could block the cycle of erythrocyte infection [135]. The specific merozoite epitopes are now being characterized, and this could form the basis of a second-generation antibody [136,137].…”

Section: Malariamentioning

confidence: 99%

Reassessing therapeutic antibodies for neglected and tropical diseases

et al. 2020

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In the past two decades there has been a significant expansion in the number of new therapeutic monoclonal antibodies (mAbs) that are approved by regulators. The discovery of these new medicines has been driven primarily by new approaches in inflammatory diseases and oncology, especially in immuno-oncology. Other recent successes have included new antibodies for use in viral diseases, including HIV. The perception of very high costs associated with mAbs has led to the assumption that they play no role in prophylaxis for diseases of poverty. However, improvements in antibody-expression yields and manufacturing processes indicate this is a cost-effective option for providing protection from many types of infection that should be revisited. Recent technology developments also indicate that several months of protection could be achieved with a single dose. Moreover, new methods in B cell sorting now enable the systematic identification of high-quality antibodies from humanized mice, or patients. This Review discusses the potential for passive immunization against schistosomiasis, fungal infections, dengue, and other neglected diseases.PLOS Neglected Tropical Diseases | https://doi.interactions have proved difficult to block. In addition, there has been great progress in the development of technology. Early generations of antibodies for human use were developed from mAbs developed in mice, antibodies that were then humanized. Recently, the technology used peptide and antibody display on phages, for which part of the 2018 Nobel Prize in Chemistry was awarded to Sir Gregory P. Winter [6]. More recently, new technologies have been developed to clone antibodies from memory B cells [7] or plasma B cells [8, 9], allowing the isolation of individual antibodies from patients with viral infections-approaches that can be applied to any infectious disease.A second reason for the popularity of antibodies in recent years is their success rate in clinical development. Once an antibody reaches testing in humans, it has a success rate of 17% to 25% for approval as a new medicine [10], compared with 5% to 10% for small molecules. This success rate is partly due to the exquisite selectivity of mAbs, enabling them to distinguish between closely related molecular targets. In the case of infectious disease, this selectivity can be absolute, since antibodies can be generated that are specific for the invading pathogen and do not cross-react with host tissues. This lack of cross-reactivity with human tissue can be confirmed by immunohistochemistry on both adult and embryonic tissues prior to the start of clinical trials. This is in stark contrast to small molecules, in which sometimes unexpected onand off-target safety signals are frequently seen in the later stages of clinical development, resulting in expensive late-stage attrition. In addition, antibodies show a relatively narrow range of variation in pharmacokinetic exposure, facilitating early estimation of the human effective dose. This is unlike true xenobiotics, whose metabolism an...

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Human vaccination against RH5 induces neutralizing antimalarial antibodies that inhibit RH5 invasion complex interactions

Cited by 118 publications

References 69 publications

Simian adenovirus vector production for early-phase clinical trials: A simple method applicable to multiple serotypes and using entirely disposable product-contact components

Simian adenovirus vector production for early-phase clinical trials: A simple method applicable to multiple serotypes and using entirely disposable product-contact components

Neutralising antibodies block the function of Rh5/Ripr/CyRPA complex during invasion of Plasmodium falciparum into human erythrocytes

Reassessing therapeutic antibodies for neglected and tropical diseases

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