Broadly potent spike-specific human monoclonal antibodies inhibit SARS-CoV-2 Omicron sub-lineages.

The continuous emergence of SARS-CoV-2 variants of concern has rendered many therapeutic monoclonal antibodies (mAbs) ineffective. To date, there are no clinically authorized therapeutic antibodies effective against the recently circulating Omicron sub-lineages BA.2.

Rational structure-guided design of a blood stage malaria vaccine immunogen presenting a single epitope from PfRH5.

There is an urgent need for improved malaria vaccine immunogens. Invasion of erythrocytes by Plasmodium falciparum is essential for its life cycle, preceding symptoms of disease and parasite transmission. Antibodies which target PfRH5 are highly effective at preventing erythrocyte invasion and the most potent growth-inhibitory antibodies bind a single epitope.

Leveraging Immunofocusing and Virus-like Particle Display to Enhance Antibody Responses to the Malaria Blood-Stage Invasion Complex Antigen PfCyRPA.

A vaccine protecting against malaria caused by is urgently needed. The blood-stage invasion complex PCRCR consists of the five malarial proteins PfPTRAMP, PfCSS, PfRipr, PfCyRPA, and PfRH5. As each subcomponent represents an essential and highly conserved antigen, PCRCR is considered a promising vaccine target.

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

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.

Atypical memory B cell frequency correlates with antibody breadth and function in malaria immune adults.

Clinical immunity to malaria develops slowly after repeated episodes of infection and antibodies are essential in naturally acquired immunity against malaria. However, chronic exposure to malaria has been linked to perturbation in B-cell homeostasis with the accumulation of atypical memory B cells. It is unclear how perturbations in B cell subsets influence antibody breadth, avidity, and function in individuals naturally exposed to malaria.

A complex equation - adding to Plasmodium falciparum invasion.

The Plasmodium falciparum invasion complex - consisting of the prime blood-stage vaccine candidates PfRH5, PfCyRPA and PfRipr - is essential and conserved. New data from Scally et al. reveal that the complex consists of two additional proteins, adding important knowledge to the current understanding of the biology behind the invasion process.

Cryo-EM reveals the conformational epitope of human monoclonal antibody PAM1.4 broadly reacting with polymorphic malarial protein VAR2CSA.

Malaria during pregnancy is a major global health problem caused by infection with Plasmodium falciparum parasites. Severe effects arise from the accumulation of infected erythrocytes in the placenta. Here, erythrocytes infected by late blood-stage parasites adhere to placental chondroitin sulphate A (CS) via VAR2CSA-type P.

SARS-CoV-2 RBD-Specific Antibodies Induced Early in the Pandemic by Natural Infection and Vaccination Display Cross-Variant Binding and Inhibition.

The development of vaccine candidates for COVID-19 has been rapid, and those that are currently approved display high efficacy against the original circulating strains. However, recently, new variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have emerged with increased transmission rates and less susceptibility to vaccine induced immunity. A greater understanding of protection mechanisms, including antibody longevity and cross-reactivity towards the variants of concern (VoCs), is needed.

Production of PfEMP1-Specific Human Monoclonal Antibodies from Naturally Immune Individuals.

Plasmodium falciparum parasites express variable surface antigens on the infected erythrocyte surface allowing adhesion to human host receptors on the blood and endothelial cells, which can result in immune evasion. One of the most studied and key antigens in adhesion is the highly polymorphic PfEMP1. However, despite the vast variation in the PfEMP1 antigens, they are the main targets of naturally acquired immunity and are therefore promising candidates for malaria vaccine development.

Production of PfEMP1-Specific Mouse Monoclonal Antibodies.

The PfEMP1 family of proteins expressed on the Plasmodium falciparum-infected erythrocyte (IE) surface is the main target of naturally acquired immunity against malaria. Antibodies capable of opsonizing the IEs and blocking the binding between PfEMP1 and human receptors seems to be one of the main protective mechanisms of the naturally acquired immunity. Therefore this family of antigens is intensively studied.

Enhancing neutralization of Plasmodium falciparum using a novel monoclonal antibody against the rhoptry-associated membrane antigen.

The pathogenesis of malaria is associated with blood-stage infection and there is strong evidence that antibodies specific to parasite blood-stage antigens can control parasitemia. This provides a strong rational for applying blood-stage antigen components in a multivalent vaccine, as the induced antibodies in combination can enhance protection. The Plasmodium falciparum rhoptry-associated membrane antigen (PfRAMA) is a promising vaccine target, due to its fundamental role in merozoite invasion and low level of polymorphism.

Strain-Dependent Inhibition of Erythrocyte Invasion by Monoclonal Antibodies Against CyRPA.

The highly conserved cysteine-rich protective antigen (PfCyRPA) is a key target for next-generation vaccines against blood-stage malaria. PfCyRPA constitute the core of a ternary complex, including the reticulocyte binding-like homologous protein 5 (PfRh5) and the Rh5-interacting protein (PfRipr), and is fundamental for merozoite invasion of erythrocytes. In this study, we show that monoclonal antibodies (mAbs) specific to PfCyRPA neutralize the growth of Ghanaian field isolates as well as numerous laboratory-adapted parasite lines.

Reduced blood-stage malaria growth and immune correlates in humans following RH5 vaccination.

Background: Development of an effective vaccine against the pathogenic blood-stage infection of human malaria has proved challenging, and no candidate vaccine has affected blood-stage parasitemia following controlled human malaria infection (CHMI) with blood-stage .

Methods: We undertook a phase I/IIa clinical trial in healthy adults in the United Kingdom of the RH5.1 recombinant protein vaccine, targeting the reticulocyte-binding protein homolog 5 (RH5), formulated in AS01 adjuvant.

Protein/AS01 vaccination elicits stronger, more Th2-skewed antigen-specific human T follicular helper cell responses than heterologous viral vectors.

Interactions between B cells and CD4 T follicular helper (Tfh) cells are key determinants of humoral responses. Using samples from clinical trials performed with the malaria vaccine candidate antigen merozoite protein (PfRH5), we compare the frequency, phenotype, and gene expression profiles of PfRH5-specific circulating Tfh (cTfh) cells elicited by two leading human vaccine delivery platforms: heterologous viral vector prime boost and protein with AS01 adjuvant. We demonstrate that the protein/AS01 platform induces a higher-magnitude antigen-specific cTfh cell response and that this correlates with peak anti-PfRH5 IgG concentrations, frequency of PfRH5-specific memory B cells, and antibody functionality.

Acquisition and decay of IgM and IgG responses to merozoite antigens after Plasmodium falciparum malaria in Ghanaian children.

Developing a vaccine against Plasmodium falciparum malaria has been challenging, primarily due to high levels of antigen polymorphism and a complex parasite lifecycle. Immunization with the P. falciparum merozoite antigens PfMSRP5, PfSERA9, PfRAMA, PfCyRPA and PfRH5 has been shown to give rise to growth inhibitory and synergistic antisera.

Functional Comparison of Blood-Stage Malaria Vaccine Candidate Antigens.

The malaria genome encodes over 5,000 proteins and many of these have also been proposed to be potential vaccine candidates, although few of these have been tested clinically. RH5 is one of the leading blood-stage malaria vaccine antigens and Phase I/II clinical trials of vaccines containing this antigen are currently underway. Its likely mechanism of action is to elicit antibodies that can neutralize merozoites by blocking their invasion of red blood cells (RBC).

Correction: Kinetics of antibody responses to PfRH5-complex antigens in Ghanaian children with Plasmodium falciparum malaria.

[This corrects the article DOI: 10.1371/journal.pone.

Kinetics of antibody responses to PfRH5-complex antigens in Ghanaian children with Plasmodium falciparum malaria.

Plasmodium falciparum PfRH5 protein binds Ripr, CyRPA and Pf113 to form a complex that is essential for merozoite invasion of erythrocytes. The inter-genomic conservation of the PfRH5 complex proteins makes them attractive blood stage vaccine candidates. However, little is known about how antibodies to PfRH5, CyRPA and Pf113 are acquired and maintained in naturally exposed populations, and the role of PfRH5 complex proteins in naturally acquired immunity.

One-step design of a stable variant of the malaria invasion protein RH5 for use as a vaccine immunogen.

Many promising vaccine candidates from pathogenic viruses, bacteria, and parasites are unstable and cannot be produced cheaply for clinical use. For instance, Plasmodium falciparum reticulocyte-binding protein homolog 5 (PfRH5) is essential for erythrocyte invasion, is highly conserved among field isolates, and elicits antibodies that neutralize in vitro and protect in an animal model, making it a leading malaria vaccine candidate. However, functional RH5 is only expressible in eukaryotic systems and exhibits moderate temperature tolerance, limiting its usefulness in hot and low-income countries where malaria prevails.

Plasmodium falciparum-infected erythrocyte knob density is linked to the PfEMP1 variant expressed.

Unlabelled: Members of the clonally variant Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) family mediate adhesion of infected erythrocytes (IEs) to vascular receptors. PfEMP1 expression is normally confined to nanoscale knob protrusions on the IE surface membrane. To investigate the relationship between the densities of these IE surface knobs and the PfEMP1 variant expressed, we used specific antibody panning to generate three sublines of the P.

Mapping the Binding Site of a Cross-Reactive Plasmodium falciparum PfEMP1 Monoclonal Antibody Inhibitory of ICAM-1 Binding.

The virulence of Plasmodium falciparum is linked to the ability of infected erythrocytes (IE) to adhere to the vascular endothelium, mediated by P. falciparum erythrocyte membrane protein 1 (PfEMP1). In this article, we report the functional characterization of an mAb that recognizes a panel of PfEMP1s and inhibits ICAM-1 binding.

Multiple Plasmodium falciparum Erythrocyte Membrane Protein 1 Variants per Genome Can Bind IgM via Its Fc Fragment Fcμ.

The Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) adhesive proteins expressed on the surfaces of infected erythrocytes (IEs) are of key importance in the pathogenesis of P. falciparum malaria. Several structurally and functionally defined PfEMP1 types have been associated with severe clinical manifestations, such as cerebral malaria in children and placental malaria in pregnant women.