scholarly journals Multi-functional antibodies are induced by the RTS,S malaria vaccine and associated with protection in a phase I/IIa trial

2019 ◽  
Author(s):  
Liriye Kurtovic ◽  
Tanmaya Atre ◽  
Gaoqian Feng ◽  
Bruce D. Wines ◽  
Jo-Anne Chan ◽  
...  
Keyword(s):  
Malaria Vaccine ◽  
Protective Efficacy ◽  
Vaccine Dose ◽  
Functional Activities ◽  
Effector Functions ◽  
Malaria Vaccines ◽  
Multiple Regions ◽  
Protective Antibodies ◽  
Malaria Vaccine Candidate ◽  
Functional Antibodies

ABSTRACTBackgroundRTS,S is the leading malaria vaccine candidate, but only confers partial efficacy against malaria in children. RTS,S is based on the major Plasmodium falciparum sporozoite surface antigen, circumsporozoite protein (CSP). The induction of anti-CSP antibodies is important for protection, however, it is unclear how protective antibodies function.MethodsWe quantified the induction of functional anti-CSP antibody responses in healthy malaria-naïve adults (N=45) vaccinated with RTS,S/AS01. This included the ability to mediate effector functions via the fragment crystallizable (Fc) region, such as interacting with human complement proteins and Fcγ-receptors (FcγRs) that are expressed on immune cells, which promote various immunological functions.ResultsOur major findings were i) RTS,S-induced antibodies mediate Fc-dependent effector functions, ii) functional antibodies were generally highest after the second vaccine dose; iii) functional antibodies targeted multiple regions of CSP, iv) participants with higher levels of functional antibodies had a reduced probability of developing parasitemia following homologous challenge (p<0.05); v) non-protected subjects had higher levels of anti-CSP IgM.ConclusionsOur data suggests a role for Fc-dependent antibody effector functions in RTS,S-induced immunity. Enhancing the induction of these functional activities may be a strategy to improve the protective efficacy of RTS,S or other malaria vaccines.

scholarly journals Multifunctional Antibodies Are Induced by the RTS,S Malaria Vaccine and Associated With Protection in a Phase 1/2a Trial

2020 ◽  
Author(s):  
Liriye Kurtovic ◽  
Tanmaya Atre ◽  
Gaoqian Feng ◽  
Bruce D Wines ◽  
Jo-Anne Chan ◽  
...  
Keyword(s):  
Malaria Vaccine ◽  
Protective Efficacy ◽  
Phase 1 ◽  
Vaccine Dose ◽  
Effector Functions ◽  
Malaria Vaccines ◽  
Multiple Regions ◽  
Protective Antibodies ◽  
Falciparum Sporozoite ◽  
Functional Antibodies

Abstract Background RTS,S is the leading malaria vaccine candidate but only confers partial efficacy against malaria in children. RTS,S is based on the major Plasmodium falciparum sporozoite surface antigen, circumsporozoite protein (CSP). The induction of anti-CSP antibodies is important for protection; however, it is unclear how these protective antibodies function. Methods We quantified the induction of functional anti-CSP antibody responses in healthy malaria-naive adults (N = 45) vaccinated with RTS,S/AS01. This included the ability to mediate effector functions via the fragment crystallizable (Fc) region, such as interacting with human complement proteins and Fcγ-receptors (FcγRs) that are expressed on immune cells, which promote various immunological functions. Results Our major findings were (1) RTS,S-induced antibodies mediated Fc-dependent effector functions, (2) functional antibodies were generally highest after the second vaccine dose, (3) functional antibodies targeted multiple regions of CSP, (4) participants with higher levels of functional antibodies had a reduced probability of developing parasitemia following homologous challenge (P &lt; .05), and (5) nonprotected subjects had higher levels of anti-CSP IgM. Conclusions Our data suggest a role for Fc-dependent antibody effector functions in RTS,S-induced immunity. Enhancing the induction of these functional activities may be a strategy to improve the protective efficacy of RTS,S or other malaria vaccines. Clinical Trials Registration NCT00075049

scholarly journals Human Immunization With a Polymorphic Malaria Vaccine Candidate Induced Antibodies to Conserved Epitopes That Promote Functional Antibodies to Multiple Parasite Strains

2018 ◽  
Vol 218 (1) ◽  
pp. 35-43 ◽  
Author(s):  
Gaoqian Feng ◽  
Michelle J Boyle ◽  
Nadia Cross ◽  
Jo-Anne Chan ◽  
Linda Reiling ◽  
...  
Keyword(s):  
Malaria Vaccine ◽  
Immune Escape ◽  
Vaccine Candidate ◽  
Antigenic Diversity ◽  
Malaria Vaccines ◽  
Malaria Vaccine Candidate ◽  
Functional Antibodies ◽  
Parasite Strains

Human immunization with a polymorphic malaria vaccine candidate, MSP2, induced functional cross-reactive antibodies targeting conserved epitopes. This contrasts with naturally acquired antibodies, which target polymorphic epitopes, mediating immune escape. Findings reveal potential to overcome antigenic diversity for effective malaria vaccines.

scholarly journals Novel Virus-Like Particle Vaccine Encoding the Circumsporozoite Protein of Plasmodium falciparum Is Immunogenic and Induces Functional Antibody Responses in Mice

2021 ◽  
Vol 12 ◽  
Author(s):  
Liriye Kurtovic ◽  
David Wetzel ◽  
Linda Reiling ◽  
Damien R. Drew ◽  
Catherine Palmer ◽  
...  
Keyword(s):  
Hepatitis B Virus ◽  
Hepatitis B ◽  
Protective Efficacy ◽  
Circumsporozoite Protein ◽  
Small Surface ◽  
Functional Activities ◽  
Duck Hepatitis ◽  
Virus Like Particle ◽  
B Virus ◽  
Multiple Regions

RTS,S is the leading malaria vaccine in development, but has demonstrated only moderate protective efficacy in clinical trials. RTS,S is a virus-like particle (VLP) that uses the human hepatitis B virus as scaffold to display the malaria sporozoite antigen, circumsporozoite protein (CSP). Particle formation requires four-fold excess scaffold antigen, and as a result, CSP represents only a small portion of the final vaccine construct. Alternative VLP or nanoparticle platforms that reduce the amount of scaffold antigen and increase the amount of the target CSP antigen present in particles may enhance vaccine immunogenicity and efficacy. Here, we describe the production and characterization of a novel VLP that uses the small surface antigen (dS) of duck hepatitis B virus to display CSP. The CSP-dS fusion protein successfully formed VLPs without the need for excess scaffold antigen, and thus CSP represented a larger portion of the vaccine construct. CSP-dS formed large particles approximately 31-74 nm in size and were confirmed to display CSP on the surface. CSP-dS VLPs were highly immunogenic in mice and induced antibodies to multiple regions of CSP, even when administered at a lower vaccine dosage. Vaccine-induced antibodies demonstrated relevant functional activities, including Fc-dependent interactions with complement and Fcγ-receptors, previously identified as important in malaria immunity. Further, vaccine-induced antibodies had similar properties (epitope-specificity and avidity) to monoclonal antibodies that are protective in mouse models. Our novel platform to produce VLPs without excess scaffold protein has wide implications for the future development of vaccines for malaria and other infectious diseases.

scholarly journals The Malaria Vaccine Candidate GMZ2 Elicits Functional Antibodies in Individuals From Malaria Endemic and Non-Endemic Areas

2013 ◽  
Vol 208 (3) ◽  
pp. 479-488 ◽  
Author(s):  
Micha Phill Grønholm Jepsen ◽  
Prajakta S. Jogdand ◽  
Susheel K. Singh ◽  
Meral Esen ◽  
Michael Christiansen ◽  
...  
Keyword(s):  
Malaria Vaccine ◽  
Vaccine Candidate ◽  
Malaria Vaccine Candidate ◽  
Endemic Areas ◽  
Functional Antibodies

scholarly journals Attenuated PfSPZ Vaccine induces strain-transcending T cells and durable protection against heterologous controlled human malaria infection

2017 ◽  
Vol 114 (10) ◽  
pp. 2711-2716 ◽  
Author(s):  
Kirsten E. Lyke ◽  
Andrew S. Ishizuka ◽  
Andrea A. Berry ◽  
Sumana Chakravarty ◽  
Adam DeZure ◽  
...  
Keyword(s):  
T Cells ◽  
Plasmodium Falciparum ◽  
T Cell ◽  
Vaccine Strain ◽  
Malaria Infection ◽  
Malaria Vaccine ◽  
Protective Efficacy ◽  
Vaccine Dose ◽  
Human Malaria ◽  
Controlled Human Malaria Infection

A live-attenuated malaria vaccine,Plasmodium falciparumsporozoite vaccine (PfSPZ Vaccine), confers sterile protection against controlled human malaria infection (CHMI) withPlasmodium falciparum(Pf) parasites homologous to the vaccine strain up to 14 mo after final vaccination. No injectable malaria vaccine has demonstrated long-term protection against CHMI using Pf parasites heterologous to the vaccine strain. Here, we conducted an open-label trial with PfSPZ Vaccine at a dose of 9.0 × 105PfSPZ administered i.v. three times at 8-wk intervals to 15 malaria-naive adults. After CHMI with homologous Pf parasites 19 wk after final immunization, nine (64%) of 14 (95% CI, 35–87%) vaccinated volunteers remained without parasitemia compared with none of six nonvaccinated controls (P= 0.012). Of the nine nonparasitemic subjects, six underwent repeat CHMI with heterologous Pf7G8 parasites 33 wk after final immunization. Five (83%) of six (95% CI, 36–99%) remained without parasitemia compared with none of six nonvaccinated controls. PfSPZ-specific T-cell and antibody responses were detected in all vaccine recipients. Cytokine production by T cells from vaccinated subjects after in vitro stimulation with homologous (NF54) or heterologous (7G8) PfSPZ were highly correlated. Interestingly, PfSPZ-specific T-cell responses in the blood peaked after the first immunization and were not enhanced by subsequent immunizations. Collectively, these data suggest durable protection against homologous and heterologous Pf parasites can be achieved with PfSPZ Vaccine. Ongoing studies will determine whether protective efficacy can be enhanced by additional alterations in the vaccine dose and number of immunizations.

scholarly journals Malaria vaccine candidate based on Duffy-binding protein elicits strain transcending functional antibodies in a Phase I trial

npj Vaccines ◽  
2018 ◽  
Vol 3 (1) ◽  
Author(s):  
Kavita Singh ◽  
Paushali Mukherjee ◽  
Ahmad Rushdi Shakri ◽  
Ankita Singh ◽  
Gaurav Pandey ◽  
...  
Keyword(s):  
Phase I ◽  
Phase I Trial ◽  
Malaria Vaccine ◽  
Vaccine Candidate ◽  
Binding Protein ◽  
Duffy Binding Protein ◽  
Malaria Vaccine Candidate ◽  
Functional Antibodies

scholarly journals Comparison of immunogenicity and safety outcomes of a malaria vaccine FMP013/ALFQ in rhesus macaques (Macaca mulatta) of Indian and Chinese origin

2019 ◽  
Vol 18 (1) ◽  
Author(s):  
Monica L. Martin ◽  
Alexis A. Bitzer ◽  
Andrew Schrader ◽  
Elke S. Bergmann-Leitner ◽  
Kim Soto ◽  
...  
Keyword(s):  
T Cell ◽  
Malaria Vaccine ◽  
Rhesus Macaques ◽  
T Cell Responses ◽  
Next Generation ◽  
Development Activity ◽  
Cell Responses ◽  
Malaria Vaccines ◽  
Chinese Origin ◽  
Functional Antibodies

Abstract Background Indian-origin rhesus (InR) are preferred for research, but strict export restrictions continue to limit their use. Chinese-origin rhesus (ChR), although easier to procure, are genetically distinct from InR and differ in their immune response to infectious agents, such as the Simian Immunodeficiency Virus. The most advanced malaria vaccine, RTS,S (GlaxoSmithKline), is based on the circumsporozoite protein (CSP) of Plasmodium falciparum. The efficacy of RTS,S vaccine in the field remains low and short-lived; efforts are underway to improve CSP-based vaccines. Rhesus models can accelerate preclinical down-selection of the next generation of malaria vaccines. This study was used to determine if the safety and immunogenicity outcomes following vaccination with a CSP vaccine would differ in the InR and ChR models, given the genetic differences between the two sub-populations of rhesus. Methods The FMP013 vaccine, was composed of nearly full-length soluble P. falciparum CSP produced in Escherichia coli and was adjuvanted with the Army liposomal formulation (ALFQ). Three doses of the vaccine were administered in InR and ChR (n = 6) at 1-month intervals and the antibody and T cell responses were assessed. Results Local and systemic toxicity profile of FMP013 vaccine in InR and ChR were similar and they revealed that the FMP013 vaccine was safe and caused only mild and transient inflammatory adverse reactions. Following the first 2 vaccines, there was a slower acquisition of antibodies to the CSP repeat region in ChR. However after the 3rd vaccination the titers in the two models were comparable. The ChR group repeat-specific antibodies had higher avidity and ChR group showed higher inhibition of liver stage development activity compared to InR. There was no difference in T-cell responses to the FMP013 vaccine between the two models. Conclusions A difference in the quality of serological responses was detected between the two sub-populations of rhesus. However, both models confirmed that FMP013/ALFQ vaccine was safe, highly immunogenic, elicited functional antibodies and T-cell responses. Overall, the data suggests that rhesus of Indian and Chinese origins can be interchangeably used to compare the safety and immunogenicity of next-generation of malaria vaccines and adjuvants.

scholarly journals APPROACHING THE TARGET: THE PATH TOWARDS AN EFFECTIVE MALARIA VACCINE

2012 ◽  
Vol 4 (1) ◽  
pp. e2012015 ◽  
Author(s):  
Alberto L. García-Basteiro ◽  
Quique Bassat ◽  
Pedro L. Alonso
Keyword(s):  
Malaria Vaccine ◽  
Phase Iii ◽  
Phase Iii Trial ◽  
Malaria Vaccines ◽  
Great Progress ◽  
Clinical Episode ◽  
Large Phase ◽  
Phases Of Development ◽  
Malaria Vaccine Candidate ◽  
Falciparum Protein

Eliciting an effective malaria vaccine has been the goal of the scientific community for many years. A malaria vaccine, added to existing tools and strategies, would further prevent and decrease the unacceptable malaria morbidity and mortality burden. Great progress has been made over the last decade, with some vaccine candidates in the clinical phases of development. The RTS,S malaria vaccine candidate, based on a recombinant P. falciparum protein, is the most advanced of such candidates, currently undergoing a large phase III trial. RTS,S has consistently shown an efficacy of around 50% against the first clinical episode of malaria, with protection in some cases extending up to 4 years of duration. Thus, it is hoped that this candidate vaccine will eventually become the first licensed malaria vaccine. This first vaccine against a human parasite is a groundbreaking achievement, but improved malaria vaccines conferring higher protection will be needed if the aspiration of malaria eradication is to be achieved

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