A Phase 3 Trial of RTS,S/AS01 Malaria Vaccine in African Infants

Agnandji, Selidji Todagbé; Lell, Bertrand; Fernandes, José Francisco; Abossolo, Béatrice Peggy; Methogo, Barbara Gaelle Nfono Ondo; Kabwende, Anita L.; Adegnika, Ayôla Akim; Mordmüller, Benjamin; Issifou, Saadou; Kremsner, Peter G.; Sacarlal, Jahit; Aíde, Pedro; Lanaspa, Miguel; Aponte, John J.; Machevo, Sónia; Acácio, Sozinho; Bulo, Helder; Sigaùque, Betuel; Macete, Eusébio; Alonso, Pedro L.; Abdulla, Salim; Salim, Nahya; Minja, Rose; Mpina, Maxmillian; Ahmed, Saumu; Ali, Ali Mohammed; Mtoro, Ali; Hamad, Ali; Mutani, Paul; Tanner, Marcel; Tinto, Halidou; D’Alessandro, Umberto; Sorgho, Hermann; Valéa, Innocent; Bihoun, Biébo; Guiraud, Issa; Kaboré, Bérenger Y. L.; Sombié, Olivier; Guiguemdé, Robert Tinga; Ouédraogo, Jean Bosco; Hamel, Mary J.; Kariuki, Simon; Oneko, Martina; Odero, Chris; Otieno, Kephas; Awino, Norbert; McMorrow, Meredith; Muturi-Kioi, Vincent; Laserson, Kayla F.; Slutsker, Laurence; Otieno, Walter; Otieno, Lucas; Otsyula, Nekoye; Gondi, Stacey M. O.; Otieno, Allan; Owira, Victorine; Oguk, Esther; Odongo, George; Woods, Jon Ben; Ogutu, Bernhards; Njuguna, Patricia; Chilengi, Roma; Akoo, Pauline; Kerubo, Christine; Maingi, Charity; Lang, Trudie; Olotu, Ally; Bejon, Philip; Marsh, Kevin; Mwambingu, Gabriel; Owusu‐Agyei, Seth; Asante, Kwaku Poku; Osei-Kwakye, Kingsley; Boahen, Owusu; Dosoo, David; Asante, Isaac; Adjei, George; Kwara, Evans; Chandramohan, Daniel; Greenwood, Brian; Lusingu, John; Gesase, Samwel; Malabeja, Anangisye; Abdul, Omari; Mahende, Coline; Liheluka, Edwin; Malle, Lincoln; Lemnge, Martha; Theander, Thor G.; Drakeley, Chris; Ansong, Daniel; Agbenyega, Tsiri; Adjei, Samuel; Boateng, Harry Owusu; Rettig, Theresa; Bawa, John; Sylverken, Justice; Sambian, David; Sarfo, Anima; Agyekum, Alex; Martinson, Francis; Hoffman, Irving; Mvalo, Tisungane; Kamthunzi, Portia; Nkomo, Rutendo; Tembo, Tapiwa; Tegha, Gerald; Tsidya, Mercy; Kilembe, Jane; Chawinga, Chimwemwe; Ballou, W. Ripley; Cohen, Joe; Guerra, Yolanda; Jongert, Erik; Lapierre, Didier; Leach, Amanda; Lievens, Marc; Ofori-Anyinam, Opokua; Olivier, Aurélie; Vekemans, Johan; Carter, Terrell; Kaslow, David C.; Leboulleux, Didier; Loucq, Christian; Radford, Afiya; Savarese, Barbara; Schellenberg, David; Sillman, Marla; Vansadia, Preeti

doi:10.1056/nejmoa1208394

Cited by 612 publications

(335 citation statements)

References 26 publications

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“…For example, the site participated in several multicenter clinical trials of the RTS,S/AS01 malaria vaccine, including the large phase 3 trial in African children in which episodes of both clinical and severe malaria in children receiving the vaccine at 5–17 months of age were reduced by approximately 50% [28]. The RTS,S/ASO1 vaccine is expected to be incorporated into routine immunization schedules soon after it has been licensed and approved for use.…”

Section: Discussionmentioning

confidence: 99%

Cause-specific mortality in the Kombewa health and demographic surveillance systems site, rural Western Kenya from 2011–2015

Sifuna

Otieno

Ogwang

et al. 2018

Global Health Action

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Background: The vast majority of deaths in the health and Kombewa demographic surveillance system (HDSS) study area are not registered and reported through official systems of vital registration. As a result, few data are available regarding causes of death in this population. Objectives: To describe causes of death among residents of all ages in the Kombewa HDSS, located in rural Western Kenya. Methods: Verbal autopsy (VA) interviews at the site were conducted using the modified 2007 and later 2012 standardized WHO questionnaires. Assignment of causes of death was made using the InterVA-4 model version 4.02. Cox regression model, adjusted for sex, was built to evaluate the influence of age on mortality. Results: There were a total of 5196 deaths recorded between 2011 and 2015 at the site. VA interviews were successfully completed for 3903 of these deaths (75.1%). Mortality rates were highest among neonates HR = 38.54 (<0.001) and among Infants HR = 2.07 (<0.006) in the Kombewa HDSS. Among those deaths in which VA was performed, the top causes of death were HIV/AIDS (12.6%), Malaria (10.3%), Pneumonia (10.1%), Acute abdomen (7.0%), Stroke (5.2%) and TB (4.9%) for the whole population in general. Stroke, acute abdomen heart diseases and Pneumonia were common causes of death (CODs) among the elderly over the age of 65. Conclusions: The analysis established the main CODs among people of all ages within the area served by the Kombewa HDSS. We hope that information generated from this study will help better address preventable deaths in the surveyed community as well as help mitigate negative health impacts in other rural communities throughout the Western Kenya region.

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Section: Discussionmentioning

confidence: 99%

Cause-specific mortality in the Kombewa health and demographic surveillance systems site, rural Western Kenya from 2011–2015

Sifuna

Otieno

Ogwang

et al. 2018

Global Health Action

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“…Trifluoroacetic acid (0.05%, vol/vol) was used to quench the enzymatic reaction and degrade the RapiGest SF surfactant. The pH of the samples was adjusted to 10 by adding 10 l of 1 N NH 4 OH for effective trapping on the first-dimension column. Samples were spiked with alcohol dehydrogenase before loading the two-dimensional NanoAcquity ultraperformance liquid chromatograph for load normalization.…”

Section: Quantitative Analysis Of Native Csp By Lc/ms Ementioning

confidence: 99%

“…The leading malaria vaccine (RTS,S), currently in phase 3 trials, contains a formulated virus-like particle that encompasses the central and carboxyl-terminal domains of the circumsporozoite protein (CSP) fused to the hepatitis B virus surface antigen (2) and protects approximately 30% to 50% of infants or children from clinical disease for a limited duration (3,4). Naturally derived human antibodies against a portion of the N-terminal region, including region 1, are associated with a reduced risk of disease (5), providing a basis to design new CSP vaccines.…”

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confidence: 99%

Reversible Conformational Change in the Plasmodium falciparum Circumsporozoite Protein Masks Its Adhesion Domains

et al. 2015

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fThe extended rod-like Plasmodium falciparum circumsporozoite protein (CSP) is comprised of three primary domains: a charged N terminus that binds heparan sulfate proteoglycans, a central NANP repeat domain, and a C terminus containing a thrombospondin-like type I repeat (TSR) domain. Only the last two domains are incorporated in RTS,S, the leading malaria vaccine in phase 3 trials that, to date, protects about 50% of vaccinated children against clinical disease. A seroepidemiological study indicated that the N-terminal domain might improve the efficacy of a new CSP vaccine. Using a panel of CSP-specific monoclonal antibodies, well-characterized recombinant CSPs, label-free quantitative proteomics, and in vitro inhibition of sporozoite invasion, we show that native CSP is N-terminally processed in the mosquito host and undergoes a reversible conformational change to mask some epitopes in the N-and C-terminal domains until the sporozoite interacts with the liver hepatocyte. Our findings show the importance of understanding processing and the biophysical change in conformation, possibly due to a mechanical or molecular signal, and may aid in the development of a new CSP vaccine.T he development of a vaccine to aid in the control of malaria is critical, as Plasmodium falciparum has evolved resistance to all antimalarial drugs deployed so far, including artemisinin (1). The leading malaria vaccine (RTS,S), currently in phase 3 trials, contains a formulated virus-like particle that encompasses the central and carboxyl-terminal domains of the circumsporozoite protein (CSP) fused to the hepatitis B virus surface antigen (2) and protects approximately 30% to 50% of infants or children from clinical disease for a limited duration (3, 4). Naturally derived human antibodies against a portion of the N-terminal region, including region 1, are associated with a reduced risk of disease (5), providing a basis to design new CSP vaccines. This N-terminal region of the CSP is absent from RTS,S.The importance of understanding protein structure because of its impact on the induction of broadly neutralizing antibodies and subsequent vaccine design continues to be revealed in the HIV arena (6, 7). In malaria, the importance of protein conformation for the induction of neutralizing antibodies was recently shown in vivo for an orthologue of the leading asexual-stage malaria vaccine antigen apical membrane antigen-1 (AMA-1). Only a recombinant AMA-1 forming a stable complex with a constrained synthetic rhoptry neck protein-2 peptide induced protective antibodies in vivo against a lethal blood-stage challenge malaria parasite infection (8). When developing a novel CSP vaccine, these more recent developments need to be considered with regard to the potential for changes within the CSP, such as through in vivo processing or conformational changes (9, 10) in a protein with a known extended rod-like structure (11), that could mask the adhesion domains located at the N-and C-terminal domains (9).To address these questions, a panel of CSP-speci...

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“…These Ku-independent processes include microhomologymediated end joining (MMEJ) (Fig. 4B) and single-strand annealing (SSA) (98) (Fig. 4C).…”

Section: Possible Alternative End-joining Mechanisms In Plasmodiummentioning

confidence: 99%

DNA Repair Mechanisms and Their Biological Roles in the Malaria Parasite Plasmodium falciparum

Lee

Fidock

2014

Microbiol Mol Biol Rev

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SUMMARY Research into the complex genetic underpinnings of the malaria parasite Plasmodium falciparum is entering a new era with the arrival of site-specific genome engineering. Previously restricted only to model systems but now expanded to most laboratory organisms, and even to humans for experimental gene therapy studies, this technology allows researchers to rapidly generate previously unattainable genetic modifications. This technological advance is dependent on DNA double-strand break repair (DSBR), specifically homologous recombination in the case of Plasmodium . Our understanding of DSBR in malaria parasites, however, is based largely on assumptions and knowledge taken from other model systems, which do not always hold true in Plasmodium . Here we describe the causes of double-strand breaks, the mechanisms of DSBR, and the differences between model systems and P. falciparum . These mechanisms drive basic parasite functions, such as meiosis, antigen diversification, and copy number variation, and allow the parasite to continually evolve in the contexts of host immune pressure and drug selection. Finally, we discuss the new technologies that leverage DSBR mechanisms to accelerate genetic investigations into this global infectious pathogen.

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A Phase 3 Trial of RTS,S/AS01 Malaria Vaccine in African Infants

Cited by 612 publications

References 26 publications

Cause-specific mortality in the Kombewa health and demographic surveillance systems site, rural Western Kenya from 2011–2015

Cause-specific mortality in the Kombewa health and demographic surveillance systems site, rural Western Kenya from 2011–2015

Reversible Conformational Change in the Plasmodium falciparum Circumsporozoite Protein Masks Its Adhesion Domains

DNA Repair Mechanisms and Their Biological Roles in the Malaria Parasite Plasmodium falciparum

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