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

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 < .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

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

10.1101/851725 ◽

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.

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

The Journal of Infectious Diseases ◽

10.1093/infdis/jiy170 ◽

2018 ◽

Vol 218 (1) ◽

pp. 35-43 ◽

Cited By ~ 13

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.

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Quantification of wild-type and radiation attenuated Plasmodium falciparum sporozoite motility in human skin

Scientific Reports ◽

10.1038/s41598-019-49895-3 ◽

2019 ◽

Vol 9 (1) ◽

Cited By ~ 1

Author(s):

Béatrice M. F. Winkel ◽

Clarize M. de Korne ◽

Matthias N. van Oosterom ◽

Diego Staphorst ◽

Mark Meijhuis ◽

...

Keyword(s):

Plasmodium Falciparum ◽

Human Skin ◽

Human Tissue ◽

Malaria Vaccine ◽

Protective Efficacy ◽

Wild Type ◽

Additional Tool ◽

Falciparum Sporozoite ◽

Skin Explants ◽

Movement Angle

Abstract Given the number of global malaria cases and deaths, the need for a vaccine against Plasmodium falciparum (Pf) remains pressing. Administration of live, radiation-attenuated Pf sporozoites can fully protect malaria-naïve individuals. Despite the fact that motility of these attenuated parasites is key to their infectivity and ultimately protective efficacy, sporozoite motility in human tissue (e.g. skin) remains wholly uncharacterized to date. We show that the ability to quantitatively address the complexity of sporozoite motility in human tissue provides an additional tool in the development of attenuated sporozoite vaccines. We imaged Pf movement in the skin of its natural host and compared wild-type and radiation-attenuated GFP-expressing Pf sporozoites. Using custom image analysis software and human skin explants we were able to quantitatively study their key motility features. This head-to-head comparison revealed that radiation attenuation impaired the capacity of sporozoites to vary their movement angle, velocity and direction, promoting less refined movement patterns. Understanding and overcoming these changes in motility will contribute to the development of an efficacious attenuated parasite malaria vaccine.

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

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1615324114 ◽

2017 ◽

Vol 114 (10) ◽

pp. 2711-2716 ◽

Cited By ~ 104

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.

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

Malaria Journal ◽

10.1186/s12936-019-3014-5 ◽

2019 ◽

Vol 18 (1) ◽

Cited By ~ 2

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.

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A three-antigen Plasmodium falciparum DNA prime—Adenovirus boost malaria vaccine regimen is superior to a two-antigen regimen and protects against controlled human malaria infection in healthy malaria-naïve adults

PLoS ONE ◽

10.1371/journal.pone.0256980 ◽

2021 ◽

Vol 16 (9) ◽

pp. e0256980

Author(s):

Marvin J. Sklar ◽

Santina Maiolatesi ◽

Noelle Patterson ◽

Martha Sedegah ◽

Keith Limbach ◽

...

Keyword(s):

Plasmodium Falciparum ◽

Risk Ratio ◽

Malaria Infection ◽

Malaria Vaccine ◽

Protective Efficacy ◽

Phase 1 ◽

Rank Test ◽

Human Malaria ◽

Log Rank Test ◽

Controlled Human Malaria Infection

Background A DNA-prime/human adenovirus serotype 5 (HuAd5) boost vaccine encoding Plasmodium falciparum (Pf) circumsporozoite protein (PfCSP) and Pf apical membrane antigen-1 (PfAMA1), elicited protection in 4/15 (27%) of subjects against controlled human malaria infection (CHMI) that was statistically associated with CD8+ T cell responses. Subjects with high level pre-existing immunity to HuAd5 were not protected, suggesting an adverse effect on vaccine efficacy (VE). We replaced HuAd5 with chimpanzee adenovirus 63 (ChAd63), and repeated the study, assessing both the two-antigen (CSP, AMA1 = CA) vaccine, and a novel three-antigen (CSP, AMA1, ME-TRAP = CAT) vaccine that included a third pre-erythrocytic stage antigen [malaria multiple epitopes (ME) fused to the Pf thrombospondin-related adhesive protein (TRAP)] to potentially enhance protection. Methodology This was an open label, randomized Phase 1 trial, assessing safety, tolerability, and VE against CHMI in healthy, malaria naïve adults. Forty subjects (20 each group) were to receive three monthly CA or CAT DNA priming immunizations, followed by corresponding ChAd63 boost four months later. Four weeks after the boost, immunized subjects and 12 infectivity controls underwent CHMI by mosquito bite using the Pf3D7 strain. VE was assessed by determining the differences in time to parasitemia as detected by thick blood smears up to 28-days post CHMI and utilizing the log rank test, and by calculating the risk ratio of each treatment group and subtracting from 1, with significance calculated by the Cochran-Mantel-Haenszel method. Results In both groups, systemic adverse events (AEs) were significantly higher after the ChAd63 boost than DNA immunizations. Eleven of 12 infectivity controls developed parasitemia (mean 11.7 days). In the CA group, 15 of 16 (93.8%) immunized subjects developed parasitemia (mean 12.0 days). In the CAT group, 11 of 16 (63.8%) immunized subjects developed parasitemia (mean 13.0 days), indicating significant protection by log rank test compared to infectivity controls (p = 0.0406) and the CA group (p = 0.0229). VE (1 minus the risk ratio) in the CAT group was 25% compared to -2% in the CA group. The CA and CAT vaccines induced robust humoral (ELISA antibodies against CSP, AMA1 and TRAP, and IFA responses against sporozoites and Pf3D7 blood stages), and cellular responses (IFN-γ FluoroSpot responses to CSP, AMA1 and TRAP) that were not associated with protection. Conclusions This study demonstrated that the ChAd63 CAT vaccine exhibited significant protective efficacy, and confirmed protection was afforded by adding a third antigen (T) to a two-antigen (CA) formulation to achieve increased VE. Although the ChAd63-CAT vaccine was associated with increased frequencies of systemic AEs compared to the CA vaccine and, historically, compared to the HuAd5 vectored malaria vaccine encoding CSP and AMA1, they were transient and associated with increased vector dosing.

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Evaluation of health system readiness and coverage of intermittent preventive treatment of malaria in infants (IPTi) in Kambia district to inform national scale-up in Sierra Leone

Malaria Journal ◽

10.1186/s12936-021-03615-3 ◽

2021 ◽

Vol 20 (1) ◽

Author(s):

Maria Lahuerta ◽

Roberta Sutton ◽

Anthony Mansaray ◽

Oliver Eleeza ◽

Brigette Gleason ◽

...

Keyword(s):

Sierra Leone ◽

Phase 1 ◽

Scale Up ◽

Intermittent Preventive Treatment ◽

Vaccine Dose ◽

Preventive Treatment ◽

Household Survey ◽

Phase 2 ◽

Pentavalent Vaccine

Abstract Background Intermittent preventive treatment of malaria in infants (IPTi) with sulfadoxine-pyrimethamine (SP) is a proven strategy to protect infants against malaria. Sierra Leone is the first country to implement IPTi nationwide. IPTi implementation was evaluated in Kambia, one of two initial pilot districts, to assess quality and coverage of IPTi services. Methods This mixed-methods evaluation had two phases, conducted 3 (phase 1) and 15–17 months (phase 2) after IPTi implementation. Methods included: assessments of 18 health facilities (HF), including register data abstraction (phases 1 and 2); a knowledge, attitudes and practices survey with 20 health workers (HWs) in phase 1; second-generation sequencing of SP resistance markers (pre-IPTi and phase 2); and a cluster-sample household survey among caregivers of children aged 3–15 months (phase 2). IPTi and vaccination coverage from the household survey were calculated from child health cards and maternal recall and weighted for the complex sampling design. Interrupted time series analysis using a Poisson regression model was used to assess changes in malaria cases at HF before and after IPTi implementation. Results Most HWs (19/20) interviewed had been trained on IPTi; 16/19 reported feeling well prepared to administer it. Nearly all HFs (17/18 in phase 1; 18/18 in phase 2) had SP for IPTi in stock. The proportion of parasite alleles with dhps K540E mutations increased but remained below the 50% WHO-recommended threshold for IPTi (4.1% pre-IPTi [95%CI 2–7%]; 11% post-IPTi [95%CI 8–15%], p < 0.01). From the household survey, 299/459 (67.4%) children ≥ 10 weeks old received the first dose of IPTi (versus 80.4% for second pentavalent vaccine, given simultaneously); 274/444 (62.5%) children ≥ 14 weeks old received the second IPTi dose (versus 65.4% for third pentavalent vaccine); and 83/217 (36.4%) children ≥ 9 months old received the third IPTi dose (versus 52.2% for first measles vaccine dose). HF register data indicated no change in confirmed malaria cases among infants after IPTi implementation. Conclusions Kambia district was able to scale up IPTi swiftly and provide necessary health systems support. The gaps between IPTi and childhood vaccine coverage need to be further investigated and addressed to optimize the success of the national IPTi programme.

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Protective efficacy of a SARS-CoV-2 DNA vaccine in wild-type and immunosuppressed Syrian hamsters

npj Vaccines ◽

10.1038/s41541-020-00279-z ◽

2021 ◽

Vol 6 (1) ◽

Author(s):

Rebecca L. Brocato ◽

Steven A. Kwilas ◽

Robert K. Kim ◽

Xiankun Zeng ◽

Lucia M. Principe ◽

...

Keyword(s):

Dna Vaccine ◽

Neutralizing Antibodies ◽

Protective Efficacy ◽

Phase 1 ◽

Severe Disease ◽

Disease Model ◽

Wild Type ◽

Jet Injection ◽

Syrian Hamsters ◽

Dna Targeting

AbstractA worldwide effort to counter the COVID-19 pandemic has resulted in hundreds of candidate vaccines moving through various stages of research and development, including several vaccines in phase 1, 2 and 3 clinical trials. A relatively small number of these vaccines have been evaluated in SARS-CoV-2 disease models, and fewer in a severe disease model. Here, a SARS-CoV-2 DNA targeting the spike protein and delivered by jet injection, nCoV-S(JET), elicited neutralizing antibodies in hamsters and was protective in both wild-type and transiently immunosuppressed hamster models. This study highlights the DNA vaccine, nCoV-S(JET), we developed has a great potential to move to next stage of preclinical studies, and it also demonstrates that the transiently-immunosuppressed Syrian hamsters, which recapitulate severe and prolonged COVID-19 disease, can be used for preclinical evaluation of the protective efficacy of spike-based COVID-19 vaccines.

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A Phase 1 study of the blood-stage malaria vaccine candidate AMA1-C1/Alhydrogel® with CPG 7909, using two different formulations and dosing intervals

Vaccine ◽

10.1016/j.vaccine.2009.04.077 ◽

2009 ◽

Vol 27 (31) ◽

pp. 4104-4109 ◽

Cited By ~ 45

Author(s):

Ruth D. Ellis ◽

Gregory E.D. Mullen ◽

Mark Pierce ◽

Laura B. Martin ◽

Kazutoyo Miura ◽

...

Keyword(s):

Malaria Vaccine ◽

Vaccine Candidate ◽

Phase 1 ◽

Blood Stage ◽

Phase 1 Study ◽

Malaria Vaccine Candidate ◽

Dosing Intervals ◽

Blood Stage Malaria

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Structural and molecular basis for foot-and-mouth disease virus neutralization by two potent protective antibodies

10.1101/2020.12.31.424923 ◽

2021 ◽

Author(s):

Hu Dong ◽

Pan Liu ◽

Manyuan Bai ◽

Kang Wang ◽

Rui Feng ◽

...

Keyword(s):

Neutralizing Antibodies ◽

Protective Efficacy ◽

Foot And Mouth Disease ◽

Therapeutic Benefit ◽

Mouth Disease ◽

Economic Losses ◽

Viral Particles ◽

Mouth Disease Virus ◽

Foot And Mouth ◽

Protective Antibodies

Outbreaks of Foot-and-mouth disease (FMD) caused by FMD virus result in significant economic losses. Vaccination is helpful, but the benefits are diminished with antigenic diversity within serotypes, instability of the immunogen and inability to confer protection for long durations. Here we have further dissected the mechanisms underpinning the protective efficacy of two previously reported neutralizing antibodies (NAbs), M8 and M170. The atomic details of the epitopes of M8 and M170 unveiled suggest that protection is conferred by disrupting the virus-receptor interactions. Consequently, administration of these NAbs conferred prophylactic and therapeutic benefit in guinea pigs, raising the possibility of administering NAbs before or during vaccination to confer immediate protection; well before the bolstering of the immune response by the vaccine. Differences in the residues and the conformation of elements making up the epitopes explain the differences in specificities of M8 and M170. An ability to bind 146S viral particles specifically, but not 12S degraded components, highlights a likely role for M170 in the quality control of vaccines.

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