Washington, DC, United States
Washington, DC, United States

Time filter

Source Type

Lee S.-M.,PATH Malaria Vaccine Initiative MVI | Wu C.-K.,PATH Malaria Vaccine Initiative MVI | Plieskatt J.,PATH Malaria Vaccine Initiative MVI | McAdams D.H.,PATH | And 3 more authors.
Malaria Journal | Year: 2016

Background: Transmission-blocking vaccines (TBVs) have become a focus of strategies to control and eventually eliminate malaria as they target the entry of sexual stage into the Anopheles stephensi mosquito thereby preventing transmission, an essential component of the parasite life cycle. Such vaccines are envisioned as complements to vaccines that target human infection, such as RTS,S as well as drug treatment, and vector control strategies. A number of conserved proteins, including Pfs25, have been identified as promising TBV targets in research or early stage development. Pfs25 is a 25 kDa protein of Plasmodium falciparum expressed on the surface of zygotes and ookinetes. Its complex tertiary structure, including numerous cysteines, has led to difficulties in the expression of a recombinant protein that is homogeneous, with proper conformation, and free of glycosylation, a phenomenon not found in native parasite machinery. Methods: While the expression and purification of Pfs25 in various systems, has been previously independently reported, here a parallel analysis of Pfs25 is presented to inform on the biochemical features of Pfs25 and their impact on functionality. Three scalable expression systems were used to express, purify, and evaluate Pfs25 both in vitro and in vivo, including the ability of each protein to produce functional antibodies through the standard membrane feeding assay. Results: Through numerous attempts, soluble, monomeric Pfs25 derived from Escherichia coli was not achieved, while Pichia pastoris presented Pfs25 as an inhomogeneous product with glycosylation. In comparison, baculovirus produced a pure, monomeric protein free of glycosylation. The glycosylation present for Pichia produced Pfs25, showed no notable decrease in the ability to elicit transmission reducing antibodies in functional evaluation, while a reduced and alkylated Pfs25 (derived from plant and used as a control) was found to have significantly decreased transmission reducing activity, emphasizing the importance of ensuring correct disulfide stabilized conformation during vaccine design and production. Conclusions: In this study, the biochemical features of Pfs25, produced from different expression systems, are described along with their impact on the ability of the protein to elicit functional antibodies. Pfs25 expressed using baculovirus and Pichia showed promise as candidates for vaccine development. © 2016 The Author(s).


PubMed | National Institute of Allergy and Infectious Diseases, PATH and PATH Malaria Vaccine Initiative MVI
Type: Journal Article | Journal: Malaria journal | Year: 2016

Transmission-blocking vaccines (TBVs) have become a focus of strategies to control and eventually eliminate malaria as they target the entry of sexual stage into the Anopheles stephensi mosquito thereby preventing transmission, an essential component of the parasite life cycle. Such vaccines are envisioned as complements to vaccines that target human infection, such as RTS,S as well as drug treatment, and vector control strategies. A number of conserved proteins, including Pfs25, have been identified as promising TBV targets in research or early stage development. Pfs25 is a 25kDa protein of Plasmodium falciparum expressed on the surface of zygotes and ookinetes. Its complex tertiary structure, including numerous cysteines, has led to difficulties in the expression of a recombinant protein that is homogeneous, with proper conformation, and free of glycosylation, a phenomenon not found in native parasite machinery.While the expression and purification of Pfs25 in various systems, has been previously independently reported, here a parallel analysis of Pfs25 is presented to inform on the biochemical features of Pfs25 and their impact on functionality. Three scalable expression systems were used to express, purify, and evaluate Pfs25 both in vitro and in vivo, including the ability of each protein to produce functional antibodies through the standard membrane feeding assay.Through numerous attempts, soluble, monomeric Pfs25 derived from Escherichia coli was not achieved, while Pichia pastoris presented Pfs25 as an inhomogeneous product with glycosylation. In comparison, baculovirus produced a pure, monomeric protein free of glycosylation. The glycosylation present for Pichia produced Pfs25, showed no notable decrease in the ability to elicit transmission reducing antibodies in functional evaluation, while a reduced and alkylated Pfs25 (derived from plant and used as a control) was found to have significantly decreased transmission reducing activity, emphasizing the importance of ensuring correct disulfide stabilized conformation during vaccine design and production.In this study, the biochemical features of Pfs25, produced from different expression systems, are described along with their impact on the ability of the protein to elicit functional antibodies. Pfs25 expressed using baculovirus and Pichia showed promise as candidates for vaccine development.


Cummings J.F.,U.S. Army | Spring M.D.,U.S. Army | Schwenk R.J.,U.S. Army | Ockenhouse C.F.,U.S. Army | And 28 more authors.
Vaccine | Year: 2010

Plasmodium falciparum Liver Stage Antigen 1 (LSA-1) is a pre-erythrocytic stage antigen. Our LSA-1 vaccine candidate is a recombinant protein with full-length C- and N-terminal flanking domains and two of the 17 amino acid repeats from the central repeat region termed " LSA-NRC." We describe the first Phase I/II study of this recombinant LSA-NRC protein formulated with either the AS01 or AS02 adjuvant system. We conducted an open-label Phase I/II study. Thirty-six healthy malaria-naïve adults received one of four formulations by intra-deltoid injection on a 0 and 1 month schedule; low dose (LD) LSA-NRC/AS01:10 μg LSA-NRC/0.5. ml AS01 (n= 5), high dose (HD) LSA-NRC/AS01: 50 μg LSA-NRC/0.5. ml AS01 (n= 13); LD LSA-NRC/AS02: 10 μg LSA-NRC/0.5. ml AS02 (n= 5) and HD LSA-NRC/AS02: 50 μg LSA-NRC/0.5. ml AS02 (n= 13). Two weeks post-second immunization, the high dose vaccinees and 6 non-immunized infectivity controls underwent experimental malaria sporozoite challenge. The vaccines showed a reassuring safety profile but were moderately reactogenic. There were no serious adverse events. All subjects seroconverted after the first immunization. Following the second immunization, LSA-1-specific CD4+ T cells producing two cytokines (IL-2 and IFN-γ) were found by intra-cellular staining in all subjects in the LD LSA-NRC/AS01B group and in 3 of 5 subjects in the LD LSA-NRC/AS02 group. In contrast, the HD LSA-NRC/AS01 and HD LSA-NRC/AS02 group subjects had fewer LSA-1-specific CD4+ T cells, and minimal to no IFN-γ responses. There was no increase in LSA-1-specific CD8+ T cells found in any group. Per protocol, 22 high dose vaccinees, but no low dose vaccinees, underwent P. falciparum homologous malaria challenge (3D7 clone). All vaccinees became parasitemic and there was no delay in their pre-patent period versus controls (p= 0.95).LSA-NRC/AS01 and LSA-NRC/AS02 elicited antigen-specific antibody and CD4+ T cell responses, but elicited no protective immunity. Although the optimal antigen dose of LSA-NRC may not have been selected for the challenge portion of the protocol, further vaccine development based upon LSA-1 should not be excluded and should include alternative vaccine platforms able to elicit additional effector mechanisms such as CD8+ T cells. © 2009.


Bingham A.,PATH Kenya | Gaspar F.,Traditional Medicine Institute | Lancaster K.,University of North Carolina at Chapel Hill | Conjera J.,M and e | And 2 more authors.
Malaria Journal | Year: 2012

Background: Malaria is a leading cause of mortality and morbidity in Mozambique, with nearly three-quarters of the country's malaria-related deaths occurring in children younger than five years. A malaria vaccine is not yet available, but planning is underway for a possible introduction, as soon as one becomes available. In an effort to inform the planning process, this study explored sociocultural and health communications issues among individuals at the community level who are both responsible for decisions about vaccine use and who are likely to influence decisions about vaccine use. Methods. Researchers conducted a qualitative study in two malaria-endemic districts in southern Mozambique. Using criterion-based sampling, they conducted 23 focus group discussions and 26 in-depth interviews. Implementation was guided by the engagement of community stakeholders. Results: Community members recognize that malaria contributes to high death rates and affects the workforce, school attendance, and the economy. Vaccines are seen as a means to reduce the threat of childhood illnesses and to keep children and the rest of the community healthy. Perceived constraints to accessing vaccine services include long queues, staff shortages, and a lack of resources at health care facilities. Local leaders play a significant role in motivating caregivers to have their children vaccinated. Participants generally felt that a vaccine could help to prevent malaria, although some voiced concern that the focus was only on young children and not on older children, pregnant women, and the elderly. Probed on their understanding of vaccine efficacy, participants voiced various views, including the perception that while some vaccines did not fully prevent disease they still had important benefits. Overall, it would be essential for local leaders to be involved in the design of specific messages for a future malaria vaccine communications strategy, and for those messages to be translated into local languages. Conclusions: Acceptance of routine childhood vaccines bodes well for a future malaria vaccine. Vaccinating children is a well-established routine that is viewed favourably in Mozambique. A communications strategy would need to build on existing immunization efforts and use trusted sources-including current government dissemination arrangements-to deliver health information. © 2012 Bingham et al.; licensee BioMed Central Ltd.


PubMed | Structural Biology Research Center, PATH Malaria Vaccine Initiative MVI, Rue Of Linstitut 89, Ghent University and U.S. Army
Type: Journal Article | Journal: Malaria journal | Year: 2016

The malaria vaccine candidate RTS,S/AS01 (GSK Vaccines) induces high IgG concentration against the circumsporozoite protein (CSP) of Plasmodium falciparum. In human vaccine recipients circulating anti-CSP antibody concentrations are associated with protection against infection but appear not to be the correlate of protection. However, in a humanized mouse model of malaria infection prophylactic administration of a human monoclonal antibody (MAL1C), derived from a RTS,S/AS01-immunized volunteer, directed against the CSP repeat region, conveyed full protection in a dose-dependent manner suggesting that antibodies alone are able to prevent P. falciparum infection when present in sufficiently high concentrations. A competition ELISA was developed to measure the presence of MAL1C-like antibodies in polyclonal sera from RTS,S/AS01 vaccine recipients and study their possible contribution to protection against infection.MAL1C-like antibodies present in polyclonal vaccine-induced sera were evaluated for their ability to compete with biotinylated monoclonal antibody MAL1C for binding sites on the capture antigen consisting of the recombinant protein encompassing 32 NANP repeats of CSP (R32LR). Serum samples were taken at different time points from participants in two RTS,S/AS01vaccine studies (NCT01366534 and NCT01857869). Vaccine-induced protection status of the study participants was determined based on the outcome of experimental challenge with infected mosquito bites after vaccination. Optimal conditions were established to reliably detect MAL1C-like antibodies in polyclonal sera. Polyclonal anti-CSP antibodies and MAL1C-like antibody content were measured in 276 serum samples from RTS,S/AS01 vaccine recipients using the standard ELISA and MAL-1C competition ELISA, respectively. A strong correlation was observed between the results from these assays. However, no correlation was found between the results of either assay and protection against infection.The competition ELISA to measure MAL1C-like antibodies in polyclonal sera from RTS,S/AS01 vaccine recipients was robust and reliable but did not reveal the elusive correlate of protection.


Olotu A.,Kenya Medical Research Institute | Moris P.,Glaxosmithkline | Mwacharo J.,Kenya Medical Research Institute | Vekemans J.,Glaxosmithkline | And 14 more authors.
PLoS ONE | Year: 2011

Background: RTS,S/AS01 E is the lead candidate pre-erythrocytic malaria vaccine. In Phase IIb field trials the safety profile was acceptable and the efficacy was 53% (95%CI 31%-72%) for protecting children against clinical malaria caused by P. falciparum. We studied CS-specific T cell responses in order to identify correlates of protection. Methods and Findings: We used intracellular cytokine staining (for IL2, IFNγ, and TNFα), ex-vivo ELISPOTs (IFNγ and IL2) and IFNγ cultured ELISPOT assays to characterize the CS-specific cellular responses in 407 children (5-17 months of age) in a phase IIb randomized controlled trial of RTS,S/AS01 E (NCT00380393). RTS,S/ AS01 E vaccinees had higher frequencies of CS-specific CD4+ T cells producing IFNγ, TNFα or IL2 compared to control vaccinees. In a multivariable analysis TNFα + CD4 + T cells were independently associated with a reduced risk for clinical malaria among RTS,S/AS01 E vaccinees (HR = 0.64, 95%CI 0.49-0.86, p = 0.002). There was a non-significant tendency towards reduced risk among control vaccinees (HR = 0.80, 95%CI 0.62-1.03, p = 0.084), albeit with lower CS-specific T cell frequencies and higher rates of clinical malaria. When data from both RTS,S/AS01 E vaccinees and control vaccinees were combined (with adjusting for vaccination group), the HR was 0.74 (95%CI 0.62-0.89, p = 0.001). After a Bonferroni correction for multiple comparisons (n-18), the finding was still significant at p = 0.018. There was no significant correlation between cultured or ex vivo ELISPOT data and protection from clinical malaria. The combination of TNFα + CD4 + T cells and anti-CS antibody statistically accounted for the protective effect of vaccination in a Cox regression model. Conclusions: RTS,S/AS01 E induces CS-specific Th1 T cell responses in young children living in a malaria endemic area. The combination of anti-CS antibody concentrations titers and CS-specific TNFα + CD4 + T cells could account for the level of protection conferred by RTS,S/AS01 E. The correlation between CS-specific TNFα + CD4 + T cells and protection needs confirmation in other datasets. © 2011 Olotu et al.


Birkett A.J.,PATH Malaria Vaccine Initiative MVI
Vaccine | Year: 2016

Despite recent progress in reducing deaths attributable to malaria, it continues to claim approximately 500,000 lives per year and is associated with approximately 200 million infections. New tools, including safe and effective vaccines, are needed to ensure that the gains of the last 15 years are leveraged toward achieving the ultimate goal of malaria parasite eradication. In 2015, the European Medicines Agency announced the adoption of a positive opinion for the malaria vaccine candidate most advanced in development, RTS,S/AS01, which provides modest protection against clinical malaria; in early 2016, WHO recommended large-scale pilot implementations of RTS,S in settings of moderate-to-high malaria transmission. In alignment with these advancements, the community goals and preferred product characteristics for next-generation vaccines have been updated to inform the development of vaccines that are highly efficacious in preventing clinical malaria, and those needed to accelerate parasite elimination. Next-generation vaccines, targeting all stages of the parasite lifecycle, are in early-stage development with the most advanced in Phase 2 trials. Importantly, progress is being made in the definition of feasible regulatory pathways to accelerate timelines, including for vaccines designed to interrupt transmission of parasites from humans to mosquitoes. The continued absence of financially lucrative, high-income markets to drive investment in malaria vaccine development points to continued heavy reliance on public and philanthropic funding. © 2016 The Author.


PubMed | PATH Malaria Vaccine Initiative MVI
Type: Journal Article | Journal: Vaccine | Year: 2016

Despite recent progress in reducing deaths attributable to malaria, it continues to claim approximately 500,000 lives per year and is associated with approximately 200 million infections. New tools, including safe and effective vaccines, are needed to ensure that the gains of the last 15 years are leveraged toward achieving the ultimate goal of malaria parasite eradication. In 2015, the European Medicines Agency announced the adoption of a positive opinion for the malaria vaccine candidate most advanced in development, RTS,S/AS01, which provides modest protection against clinical malaria; in early 2016, WHO recommended large-scale pilot implementations of RTS,S in settings of moderate-to-high malaria transmission. In alignment with these advancements, the community goals and preferred product characteristics for next-generation vaccines have been updated to inform the development of vaccines that are highly efficacious in preventing clinical malaria, and those needed to accelerate parasite elimination. Next-generation vaccines, targeting all stages of the parasite lifecycle, are in early-stage development with the most advanced in Phase 2 trials. Importantly, progress is being made in the definition of feasible regulatory pathways to accelerate timelines, including for vaccines designed to interrupt transmission of parasites from humans to mosquitoes. The continued absence of financially lucrative, high-income markets to drive investment in malaria vaccine development points to continued heavy reliance on public and philanthropic funding.


PubMed | PATH Malaria Vaccine Initiative MVI
Type: Journal Article | Journal: Vaccine | Year: 2015

Despite impressive gains over the last 15 years in reducing the mortality associated with malaria, it remains a public health emergency. New interventions, such as vaccines, are needed to ensure that previous gains serve as a foundation for future progress. Vaccines have the potential to prevent severe disease and death in those most vulnerable, and to accelerate elimination and eradication by breaking the cycle of parasite transmission. The pipeline is as healthy as it has ever been, with approaches targeting different stages of the parasite lifecycle using an array of technologies. This article reviews recent progress and reviews key considerations in the quest to develop products that are aligned with the unmet medical need.


Birkett A.J.,PATH Malaria Vaccine Initiative MVI
Vaccine | Year: 2015

Despite impressive gains over the last 15 years in reducing the mortality associated with malaria, it remains a public health emergency. New interventions, such as vaccines, are needed to ensure that previous gains serve as a foundation for future progress. Vaccines have the potential to prevent severe disease and death in those most vulnerable, and to accelerate elimination and eradication by breaking the cycle of parasite transmission. The pipeline is as healthy as it has ever been, with approaches targeting different stages of the parasite lifecycle using an array of technologies. This article reviews recent progress and reviews key considerations in the quest to develop products that are aligned with the unmet medical need. © 2015 The Author.

Loading PATH Malaria Vaccine Initiative MVI collaborators
Loading PATH Malaria Vaccine Initiative MVI collaborators