Plasmodium falciparum merozoite surface protein 1 as asexual blood stage malaria vaccine candidate

Funding Information: Richard Thomson Luque is employed by Sumaya-Biotech GmbH & Co. KG that received support by the EU Malaria Fund. This work was supported in part by the U.S. National Institutes of Health (NIH) through awards R01 AI141900 and U19 AI110820 to JCS. The authors extend their heartfelt gratitude to the dedicated researchers, institutions, and study volunteers participating in malaria vaccine studies who have relentlessly pursued the formidable objective of jointly creating a malaria vaccine candidate centered around the merozoite surface antigen 1. The collective endeavors of the malaria research community have profoundly driven scientific advancements presented in this manuscript. Publisher Copyright: © 2023 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.Introduction: Malaria represents a public health challenge in tropical and subtropical regions, and currently deployed control strategies are likely insufficient to drive elimination of malaria. Development and improvement of malaria vaccines might be key to reduce disease burden. Vaccines targeting asexual blood stages of the parasite have shown limited efficacy when studied in human trials conducted over the past decades. Areas covered: Vaccine candidates based on the merozoite surface protein 1 (MSP1) were initially envisioned as one of the most promising approaches to provide immune protection against asexual blood-stage malaria. Successful immunization studies in monkey involved the use of the full-length MSP1 (MSP1FL) as vaccine construct. Vaccines using MSP1FL for immunization have the potential benefit of including numerous conserved B-cell and T-cell epitopes. This could result in improved parasite strain-transcending, protective immunity in the field. We review outcomes of clinical trials that utilized a variety of MSP1 constructs and formulations, including MSP1FL, either alone or in combination with other antigens, in both animal models and humans. Expert opinion: Novel approaches to analyze breadth and magnitude of effector functions of MSP1-targeting antibodies in volunteers undergoing experimental vaccination and controlled human malaria infection will help to define correlates of protective immunity.publishersversionpublishe

Plasmodium falciparum transcription in different clinical presentations of malaria associates with circulation time of infected erythrocytes

Following Plasmodium falciparum infection, individuals can remain asymptomatic, present with mild fever in uncomplicated malaria cases, or show one or more severe malaria symptoms. Several studies have investigated associations between parasite transcription and clinical severity, but no broad conclusions have yet been drawn. Here, we apply a series of bioinformatic approaches based on P. falciparum’s tightly regulated transcriptional pattern during its ~48-hour intraerythrocytic developmental cycle (IDC) to publicly available transcriptomes of parasites obtained from malaria cases of differing clinical severity across multiple studies. Our analysis shows that within each IDC, the circulation time of infected erythrocytes without sequestering to endothelial cells decreases with increasing parasitaemia or disease severity. Accordingly, we find that the size of circulating infected erythrocytes is inversely related to parasite density and disease severity. We propose that enhanced dhesiveness of infected erythrocytes leads to a rapid increase in parasite burden, promoting higher parasitaemia and increased disease severity

Increased circulation time of Plasmodium falciparum underlies persistent asymptomatic infection in the dry season

The dry season is a major challenge for Plasmodium falciparum parasites in many malaria endemic regions, where water availability limits mosquito vectors to only part of the year. How P. falciparum bridges two transmission seasons months apart, without being cleared by the human host or compromising host survival, is poorly understood. Here we show that low levels of P. falciparum parasites persist in the blood of asymptomatic Malian individuals during the 5- to 6-month dry season, rarely causing symptoms and minimally affecting the host immune response. Parasites isolated during the dry season are transcriptionally distinct from those of individuals with febrile malaria in the transmission season, coinciding with longer circulation within each replicative cycle of parasitized erythrocytes without adhering to the vascular endothelium. Low parasite levels during the dry season are not due to impaired replication but rather to increased splenic clearance of longer-circulating infected erythrocytes, which likely maintain parasitemias below clinical and immunological radar. We propose that P. falciparum virulence in areas of seasonal malaria transmission is regulated so that the parasite decreases its endothelial binding capacity, allowing increased splenic clearance and enabling several months of subclinical parasite persistence

Nurses' perceptions of aids and obstacles to the provision of optimal end of life care in ICU

Contains fulltext : 172380.pdf (publisher's version ) (Open Access

Study on the target cell fro the establishment of an in vitro culture system for plasmodium vivax

Tesis inédita de la Universidad Complutense de Madrid, Facultad de Veterinaria, leída el 21-02-2022La malaria es un claro representante de enfermedad infecciosa relacionada con la pobreza y el subdesarrollo económico. Las infecciones causadas por Plasmodium falciparum (P. falciparum) y Plasmodium vivax (P. vivax) son las más prevalentes en la malaria humana. P. vivax es el parásito causante de malaria con mayor distribución geográfica y responsable de millones de casos clínicos cada año acompañados de un alto nivel de morbilidad y con amplio espectro de presentación clínica (incluidas la enfermedad grave y la muerte). El cultivo in vitro de P. vivax en ciclo continuo, no está aún disponible hoy día, siendo, como es, imprescindible para comprender los mecanismos biológicos de su propagación en el ser humano y por tanto el desarrollo de tecnologías con esta finalidad se vislumbran como herramientas claves para progresar hacia la erradicación de la malaria. El objetivo de este trabajo de investigación es el de realizar un análisis integrador de los datos experimentales del doctorando, obtenidos mediante el empleo de modelos animales de primates no humanos y la caracterización fenotípica de reticulocitos mediante citometría de masas que, junto con un estudio crítico de la literatura existente con respecto al cultivo y la célula huésped -el reticulocito- nos permita aportar sugerencias sobre mejoras de las condiciones de cultivo y en concreto acerca del subtipo específico de reticulocitos más adecuado para avanzar en la consecución de un sistemade cultivo continuo in vitro para estadios sanguíneos de P. vivax...Malaria represents the paradigm of infectious diseases related to poverty and underdevelopment. Malaria caused by P. falciparum and P. vivax parasites are the most prevalent. P. vivax is the most widely distributed human malaria parasite, responsible for millions of clinical cases each year, a very high level of morbidity, and a broad spectrum of clinical presentation (including serious illness and death). Advances in the development of technologies aimed at achieving a continuous in vitro culture system for blood stages of P. vivax, still unavailable today, has been seen as a key tool to progress towards the eradication of malaria. The objective of this research work is to carry out an integrative analysis of experimental data from the doctoral student obtained with the use of non-human primate animal models experimentation as well as mass cytometry phenotypic approaches applied to the study of reticulocytes which, together with a critical review of the literature, will provide suggestions of improvements on in vitro culture conditions and specifically on the most appropriate reticulocyte subtype to be used in order to advance in obtaining a continuous in vitro culture system for blood stages of P. vivax...Fac. de VeterinariaTRUEunpu

IgG Subclass Switch in Volunteers Repeatedly Immunized with the Full-Length <i>Plasmodium falciparum</i> Merozoite Surface Protein 1 (MSP1)

Vaccines are highly effective tools against infectious diseases and are also considered necessary in the fight against malaria. Vaccine-induced immunity is frequently mediated by antibodies. We have recently conducted a first-in-human clinical trial featuring SumayaVac-1, a malaria vaccine based on the recombinant, full-length merozoite surface protein 1 (MSP1FL) formulated with GLA-SE as an adjuvant. Vaccination with MSP1FL was safe and elicited sustainable IgG antibody titers that exceeded those observed in semi-immune populations from Africa. Moreover, IgG antibodies stimulated various Fc-mediated effector mechanisms associated with protection against malaria. However, these functionalities gradually waned. Here, we show that the initial two doses of SumayaVac-1 primarily induced the cytophilic subclasses IgG1 and IgG3. Unexpectedly, a shift in the IgG subclass composition occurred following the third and fourth vaccinations. Specifically, there was a progressive transition to IgG4 antibodies, which displayed a reduced capacity to engage in Fc-mediated effector functions and also exhibited increased avidity. In summary, our analysis of antibody responses to MSP1FL vaccination unveils a temporal shift towards noninflammatory IgG4 antibodies. These findings underscore the importance of considering the impact of IgG subclass composition on vaccine-induced immunity, particularly concerning Fc-mediated effector functions. This knowledge is pivotal in guiding the design of optimal vaccination strategies against malaria, informing decision making for future endeavors in this critical field

A novel erythrocyte binding protein of Plasmodium vivax suggests an alternate invasion pathway into Duffy-positive reticulocytes

Submitted by Nuzia Santos ([email protected]) on 2017-04-17T17:15:47Z No. of bitstreams: 1 ve_Ntumngia_Francis_A Novel Erythrocyte_CPqRR_2016 .pdf: 389451 bytes, checksum: b5a5db76dc128a7a88fc1c6bb916f89b (MD5)Approved for entry into archive by Nuzia Santos ([email protected]) on 2017-04-17T17:19:45Z (GMT) No. of bitstreams: 1 ve_Ntumngia_Francis_A Novel Erythrocyte_CPqRR_2016 .pdf: 389451 bytes, checksum: b5a5db76dc128a7a88fc1c6bb916f89b (MD5)Made available in DSpace on 2017-04-17T17:19:45Z (GMT). No. of bitstreams: 1 ve_Ntumngia_Francis_A Novel Erythrocyte_CPqRR_2016 .pdf: 389451 bytes, checksum: b5a5db76dc128a7a88fc1c6bb916f89b (MD5) Previous issue date: 2016University of South Florida. College of Public Health. Center for Global Health and Infectious Diseases Research. Tampa, Florida, USAUniversity of South Florida. College of Public Health. Center for Global Health and Infectious Diseases Research. Tampa, Florida, USAUniversity of South Florida. College of Public Health. Center for Global Health and Infectious Diseases Research. Tampa, Florida, USA/Fundação Oswaldo Cruz. Centro de Pesquisas René Rachou. Belo Horizonte, MG, BrazilNational Institutes of Health. National Institute of Allergy and Infectious Diseases. Laboratory of Malaria and Vector Research. Rockville, Maryland, USAFundação Oswaldo Cruz. Centro de Pesquisas René Rachou. Belo Horizonte, MG, BrazilUniversity of South Florida. College of Public Health. Center for Global Health and Infectious Diseases Research. Tampa, Florida, USAErythrocyte invasion by malaria parasites is essential for blood-stage development and an important determinant of host range. In Plasmodium vivax, the interaction between the Duffy binding protein (DBP) and its cognate receptor, the Duffy antigen receptor for chemokines (DARC), on human erythrocytes is central to blood-stage infection. Contrary to this established pathway of invasion, there is growing evidence of P. vivax infections occurring in Duffy blood group-negative individuals, suggesting that the parasite might have gained an alternative pathway to infect this group of individuals. Supporting this concept, a second distinct erythrocyte binding protein (EBP2), representing a new member of the DBP family, was discovered in P. vivax and may be the ligand in an alternate invasion pathway. Our study characterizes this novel ligand and determines its potential role in reticulocyte invasion by P. vivax merozoites. EBP2 binds preferentially to young (CD71high) Duffy-positive (Fy+) reticulocytes and has minimal binding capacity for Duffy-negative reticulocytes. Importantly, EBP2 is antigenically distinct from DBP and cannot be functionally inhibited by anti-DBP antibodies. Consequently, our results do not support EBP2 as a ligand for invasion of Duffy-negative blood cells, but instead, EBP2 may represent a novel ligand for an alternate invasion pathway of Duffy-positive reticulocytes. IMPORTANCE For decades, P. vivax infections in humans have been defined by a unique requirement for the interaction between the Duffy binding protein ligand of the parasite and the Duffy blood group antigen receptor (DARC). Recent reports of P. vivax infections in Duffy-negative individuals challenge this paradigm and suggest an alternate pathway of infection, potentially using the recently discovered EBP2. However, we demonstrate that EBP2 host cell specificity is more restricted than DBP binding and that EBP2 binds preferentially to Duffy-positive, young reticulocytes. This finding indicates that this DBP paralog does mediate a Duffy-independent pathway of infection

Multifunctional IgG/IgM antibodies and cellular cytotoxicity are elicited by the full-length MSP1 SumayaVac-1 malaria vaccine

Abstract Radical control of malaria likely requires a vaccine that targets both the asymptomatic liver stages and the disease-causing blood stages of the human malaria parasite Plasmodium falciparum. While substantial progress has been made towards liver stage vaccines, the development of a blood stage vaccine is lagging behind. We have recently conducted a first-in-human clinical trial to evaluate the safety and immunogenicity of the recombinant, full-length merozoite surface protein 1 (MSP1FL) formulated with GLA-SE as adjuvant. Here, we show that the vaccine, termed SumayaVac-1, elicited both a humoral and cellular immune response as well as a recall T cell memory. The induced IgG and IgM antibodies were able to stimulate various Fc-mediated effector mechanisms associated with protection against malaria, including phagocytosis, release of reactive oxygen species, production of IFN-γ as well as complement activation and fixation. The multifunctional activity of the humoral immune response remained for at least 6 months after vaccination and was comparable to that of naturally acquired anti-MSP1 antibodies from semi-immune adults from Kenya. We further present evidence of SumayaVac-1 eliciting a recallable cellular cytotoxicity by IFN-γ producing CD8+ T cells. Our study revitalizes MSP1FL as a relevant blood stage vaccine candidate and warrants further evaluation of SumayaVac-1 in a phase II efficacy trial

Insights into an Optimization of Plasmodium vivax Sal-1 In Vitro Culture: The Aotus Primate Model

Malaria is one of the most significant tropical diseases, and of the Plasmodium species that cause human malaria, P. vivax is the most geographically widespread. However, P. vivax remains a relatively neglected human parasite since research is typically limited to laboratories with direct access to parasite isolates from endemic field settings or from non-human primate models. This restricted research capacity is in large part due to the lack of a continuous P. vivax in vitro culture system, which has hampered the ability for experimental research needed to gain biological knowledge and develop new therapies. Consequently, efforts to establish a long-term P. vivax culture system are confounded by our poor knowledge of the preferred host cell and essential nutrients needed for in vitro propagation. Reliance on very heterogeneous P. vivax field isolates makes it difficult to benchmark parasite characteristics and further complicates development of a robust and reliable culture method. In an effort to eliminate parasite variability as a complication, we used a well-defined Aotus-adapted P. vivax Sal-1 strain to empirically evaluate different short-term in vitro culture conditions and compare them with previous reported attempts at P. vivax in vitro culture Most importantly, we suggest that reticulocyte enrichment methods affect invasion efficiency and we identify stabilized forms of nutrients that appear beneficial for parasite growth, indicating that P. vivax may be extremely sensitive to waste products. Leuko-depletion methods did not significantly affect parasite development. Formatting changes such as shaking and static cultures did not seem to have a major impact while; in contrast, the starting haematocrit affected both parasite invasion and growth. These results support the continued use of Aotus-adapted Sal-1 for development of P. vivax laboratory methods; however, further experiments are needed to optimize culture conditions to support long-term parasite development