RESUMO
The highly conserved and essential Plasmodium falciparum reticulocyte-binding protein homolog 5 (PfRH5) has emerged as the leading target for vaccines against the disease-causing blood stage of malaria. However, the features of the human vaccine-induced antibody response that confer highly potent inhibition of malaria parasite invasion into red blood cells are not well defined. Here, we characterize 236 human IgG monoclonal antibodies, derived from 15 donors, induced by the most advanced PfRH5 vaccine. We define the antigenic landscape of this molecule and establish that epitope specificity, antibody association rate, and intra-PfRH5 antibody interactions are key determinants of functional anti-parasitic potency. In addition, we identify a germline IgG gene combination that results in an exceptionally potent class of antibody and demonstrate its prophylactic potential to protect against P. falciparum parasite challenge in vivo. This comprehensive dataset provides a framework to guide rational design of next-generation vaccines and prophylactic antibodies to protect against blood-stage malaria.
RESUMO
Malaria, one of the most common vector borne human diseases, is a major world health issue. In 2015 alone, more than 200 million people were infected with malaria, out of which, 429â¯000 died. Even though artemisinin-based combination therapies (ACT) are highly effective at treating malaria infections, novel efforts toward development of vaccines to prevent transmission are still needed. Pfs25, a postfertilization stage parasite surface antigen, is a leading transmission-blocking vaccine (TBV) candidate. It is postulated that Pfs25 anchors to the cell membrane using a glycosylphosphatidylinositol (GPI) linker, which itself possesses pro-inflammatory properties. In this study, Escherichia coli derived extract (XtractCF+TM) was used in cell free protein synthesis [CFPS] to successfully express >200 mg/L of recombinant Pfs25 with a C-terminal non-natural amino acid (nnAA), namely, p-azidomethyl phenylalanine (pAMF), which possesses a reactive azide group. Thereafter, a unique conjugate vaccine (CV), namely, Pfs25-GPI was generated with dibenzocyclooctyne (DBCO) derivatized glycan core of malaria GPI using a simple but highly efficient copper free click chemistry reaction. In mice immunized with Pfs25 or Pfs25-GPI, the Pfs25-GPI group showed significantly higher titers compared to the Pfs25 group. Moreover, only purified IgGs from Pfs25-GPI group were able to significantly block transmission of parasites to mosquitoes, as judged by a standard membrane feeding assay [SMFA]. To our knowledge, this is the first report of the generation of a CV using Pfs25 and malaria specific GPI where the GPI is shown to enhance the ability of Pfs25 to elicit transmission blocking antibodies.
Assuntos
Glicosilfosfatidilinositóis/uso terapêutico , Vacinas Antimaláricas/uso terapêutico , Malária Falciparum/prevenção & controle , Plasmodium falciparum/imunologia , Proteínas de Protozoários/uso terapêutico , Animais , Formação de Anticorpos , Glicosilfosfatidilinositóis/imunologia , Humanos , Imunização , Malária , Vacinas Antimaláricas/imunologia , Malária Falciparum/imunologia , Malária Falciparum/transmissão , Camundongos , Proteínas de Protozoários/imunologia , Vacinas Conjugadas/imunologia , Vacinas Conjugadas/uso terapêutico , Vacinas Sintéticas/imunologia , Vacinas Sintéticas/uso terapêuticoRESUMO
BACKGROUND: Models of controlled human malaria infection (CHMI) initiated by mosquito bite have been widely used to assess efficacy of preerythrocytic vaccine candidates in small proof-of-concept phase 2a clinical trials. Efficacy testing of blood-stage malaria parasite vaccines, however, has generally relied on larger-scale phase 2b field trials in malaria-endemic populations. We report the use of a blood-stage P. falciparum CHMI model to assess blood-stage vaccine candidates, using their impact on the parasite multiplication rate (PMR) as the primary efficacy end point. METHODS: Fifteen healthy United Kingdom adult volunteers were vaccinated with FMP2.1, a protein vaccine that is based on the 3D7 clone sequence of apical membrane antigen 1 (AMA1) and formulated in Adjuvant System 01 (AS01). Twelve vaccinees and 15 infectivity controls subsequently underwent blood-stage CHMI. Parasitemia was monitored by quantitative real-time polymerase chain reaction (PCR) analysis, and PMR was modeled from these data. RESULTS: FMP2.1/AS01 elicited anti-AMA1 T-cell and serum antibody responses. Analysis of purified immunoglobulin G showed functional growth inhibitory activity against P. falciparum in vitro. There were no vaccine- or CHMI-related safety concerns. All volunteers developed blood-stage parasitemia, with no impact of the vaccine on PMR. CONCLUSIONS: FMP2.1/AS01 demonstrated no efficacy after blood-stage CHMI. However, the model induced highly reproducible infection in all volunteers and will accelerate proof-of-concept testing of future blood-stage vaccine candidates. CLINICAL TRIALS REGISTRATION: NCT02044198.
Assuntos
Antígenos de Protozoários/imunologia , Vacinas Antimaláricas/imunologia , Malária Falciparum/prevenção & controle , Proteínas de Membrana/imunologia , Plasmodium falciparum/imunologia , Proteínas de Protozoários/imunologia , Adulto , ELISPOT , Eritrócitos/parasitologia , Feminino , Humanos , Imunogenicidade da Vacina , Estágios do Ciclo de Vida , Malária Falciparum/parasitologia , Masculino , Pessoa de Meia-Idade , Modelos Biológicos , Plasmodium falciparum/fisiologia , Adulto JovemRESUMO
BACKGROUND: Three full doses of RTS,S/AS01 malaria vaccine provides partial protection against controlled human malaria parasite infection (CHMI) and natural exposure. Immunization regimens, including a delayed fractional third dose, were assessed for potential increased protection against malaria and immunologic responses. METHODS: In a phase 2a, controlled, open-label, study of healthy malaria-naive adults, 16 subjects vaccinated with a 0-, 1-, and 2-month full-dose regimen (012M) and 30 subjects who received a 0-, 1-, and 7-month regimen, including a fractional third dose (Fx017M), underwent CHMI 3 weeks after the last dose. Plasmablast heavy and light chain immunoglobulin messenger RNA sequencing and antibody avidity were evaluated. Protection against repeat CHMI was evaluated after 8 months. RESULTS: A total of 26 of 30 subjects in the Fx017M group (vaccine efficacy [VE], 86.7% [95% confidence interval [CI], 66.8%-94.6%]; P < .0001) and 10 of 16 in the 012M group (VE, 62.5% [95% CI, 29.4%-80.1%]; P = .0009) were protected against infection, and protection differed between schedules (P = .040, by the log rank test). The fractional dose boosting increased antibody somatic hypermutation and avidity and sustained high protection upon rechallenge. DISCUSSIONS: A delayed third fractional vaccine dose improved immunogenicity and protection against infection. Optimization of the RTS,S/AS01 immunization regimen may lead to improved approaches against malaria. CLINICAL TRIALS REGISTRATION: NCT01857869.
Assuntos
Esquemas de Imunização , Vacinas Antimaláricas/administração & dosagem , Vacinas Antimaláricas/imunologia , Malária/prevenção & controle , Vacinas Sintéticas/administração & dosagem , Vacinas Sintéticas/imunologia , Adolescente , Adulto , Anticorpos Antiprotozoários/biossíntese , Anticorpos Antiprotozoários/imunologia , Afinidade de Anticorpos , Feminino , Humanos , Cadeias Pesadas de Imunoglobulinas/biossíntese , Cadeias Leves de Imunoglobulina/biossíntese , Masculino , Pessoa de Meia-Idade , Adulto JovemRESUMO
BACKGROUND: The infectivity of Plasmodium gametocytes is typically determined by microscopically examining the midguts of mosquitoes that have taken a blood meal containing potentially infectious parasites. Such assessments are required for the development and evaluation of transmission-reducing interventions (TRI), but are limited by subjectivity, technical complexity and throughput. The detection of circumsporozoite protein (CSP) by enzyme-linked immunosorbent assay (ELISA) and enhanced chemiluminescent slot-blot (ECL-SB) may be used as objective, scalable alternatives to microscopy for the determination of infection prevalence. METHODS: To compare the performance of the CSP ELISA and ECL-SB for the detection of mosquito infection, four groups of Anopheles stephensi mosquitoes were infected with cultured Plasmodium falciparum gametocytes. At day-8 post-infection (PI), parasite status was determined by microscopy for a sample of mosquitoes from each group. At days 8 and 10 PI, the parasite status of separate mosquito samples was analysed by both CSP ELISA and ECL-SB. RESULTS: When mosquito samples were analysed 8 days PI, the ECL-SB determined similar infection prevalence to microscopy; CSP ELISA lacked the sensitivity to detect CSP in all infected mosquitoes at this early time point. When mosquitoes were analysed 48 h later (10 days PI) both assays performed as well as microscopy for infection detection. CONCLUSIONS: Whilst microscopical examination of mosquito guts is of great value when quantification of parasite burden is required, ECL-SB and CSP ELISA are suitable alternatives at day 10 PI when infection prevalence is the desired endpoint, although CSP ELISA is not suitable at day 8 PI. These results are important to groups considering large-scale implementation of TRI.
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Anopheles/parasitologia , Antígenos de Protozoários/análise , Ensaio de Imunoadsorção Enzimática/métodos , Immunoblotting/métodos , Oocistos/química , Plasmodium falciparum/isolamento & purificação , Proteínas de Protozoários/análise , Animais , Feminino , Plasmodium falciparum/químicaRESUMO
Plasmodium falciparum reticulocyte-binding protein homolog 5 (RH5) is a leading blood-stage malaria vaccine antigen target, currently in a phase 2b clinical trial as a full-length soluble protein/adjuvant vaccine candidate called RH5.1/Matrix-M. We identify that disordered regions of the full-length RH5 molecule induce non-growth inhibitory antibodies in human vaccinees and that a re-engineered and stabilized immunogen (including just the alpha-helical core of RH5) induces a qualitatively superior growth inhibitory antibody response in rats vaccinated with this protein formulated in Matrix-M adjuvant. In parallel, bioconjugation of this immunogen, termed "RH5.2," to hepatitis B surface antigen virus-like particles (VLPs) using the "plug-and-display" SpyTag-SpyCatcher platform technology also enables superior quantitative antibody immunogenicity over soluble protein/adjuvant in vaccinated mice and rats. These studies identify a blood-stage malaria vaccine candidate that may improve upon the current leading soluble protein vaccine candidate RH5.1/Matrix-M. The RH5.2-VLP/Matrix-M vaccine candidate is now under evaluation in phase 1a/b clinical trials.
Assuntos
Anticorpos Antiprotozoários , Vacinas Antimaláricas , Plasmodium falciparum , Proteínas de Protozoários , Vacinas de Partículas Semelhantes a Vírus , Animais , Vacinas Antimaláricas/imunologia , Anticorpos Antiprotozoários/imunologia , Plasmodium falciparum/imunologia , Vacinas de Partículas Semelhantes a Vírus/imunologia , Humanos , Camundongos , Proteínas de Protozoários/imunologia , Ratos , Malária Falciparum/prevenção & controle , Malária Falciparum/imunologia , Antígenos de Protozoários/imunologia , Feminino , Proteínas de Transporte/imunologia , Camundongos Endogâmicos BALB CRESUMO
Reticulocyte-binding protein homologue 5 (RH5), a leading blood-stage Plasmodium falciparum malaria vaccine target, interacts with cysteine-rich protective antigen (CyRPA) and RH5-interacting protein (RIPR) to form an essential heterotrimeric "RCR-complex". We investigate whether RCR-complex vaccination can improve upon RH5 alone. Using monoclonal antibodies (mAbs) we show that parasite growth-inhibitory epitopes on each antigen are surface-exposed on the RCR-complex and that mAb pairs targeting different antigens can function additively or synergistically. However, immunisation of female rats with the RCR-complex fails to outperform RH5 alone due to immuno-dominance of RIPR coupled with inferior potency of anti-RIPR polyclonal IgG. We identify that all growth-inhibitory antibody epitopes of RIPR cluster within the C-terminal EGF-like domains and that a fusion of these domains to CyRPA, called "R78C", combined with RH5, improves the level of in vitro parasite growth inhibition compared to RH5 alone. These preclinical data justify the advancement of the RH5.1 + R78C/Matrix-M™ vaccine candidate to Phase 1 clinical trial.
Assuntos
Anticorpos Monoclonais , Anticorpos Antiprotozoários , Antígenos de Protozoários , Vacinas Antimaláricas , Malária Falciparum , Plasmodium falciparum , Proteínas de Protozoários , Vacinas Antimaláricas/imunologia , Vacinas Antimaláricas/administração & dosagem , Animais , Plasmodium falciparum/imunologia , Proteínas de Protozoários/imunologia , Feminino , Malária Falciparum/prevenção & controle , Malária Falciparum/imunologia , Malária Falciparum/parasitologia , Antígenos de Protozoários/imunologia , Ratos , Anticorpos Antiprotozoários/imunologia , Anticorpos Monoclonais/imunologia , Humanos , Epitopos/imunologia , Proteínas de Transporte/imunologia , Proteínas de Transporte/metabolismoRESUMO
The ectodomain of matrix protein 2 (M2e) of influenza A virus is an attractive target for a universal influenza A vaccine: the M2e sequence is highly conserved across influenza virus subtypes, and induced humoral anti-M2e immunity protects against a lethal influenza virus challenge in animal models. Clinical phase I studies with M2e vaccine candidates have been completed. However, the in vivo mechanism of immune protection induced by M2e-carrier vaccination is unclear. Using passive immunization experiments in wild-type, FcRγ(-/-), FcγRI(-/-), FcγRIII(-/-), and (FcγRI, FcγRIII)(-/-) mice, we report in this study that Fc receptors are essential for anti-M2e IgG-mediated immune protection. M2e-specific IgG1 isotype Abs are shown to require functional FcγRIII for in vivo immune protection but other anti-M2e IgG isotypes can rescue FcγRIII(-/-) mice from a lethal challenge. Using a conditional cell depletion protocol, we also demonstrate that alveolar macrophages (AM) play a crucial role in humoral M2e-specific immune protection. Additionally, we show that adoptive transfer of wild-type AM into (FcγRI, FcγRIII)(-/-) mice restores protection by passively transferred anti-M2e IgG. We conclude that AM and Fc receptor-dependent elimination of influenza A virus-infected cells are essential for protection by anti-M2e IgG.
Assuntos
Imunoglobulina G/metabolismo , Vírus da Influenza A/imunologia , Vacinas contra Influenza/imunologia , Macrófagos Alveolares/imunologia , Infecções por Orthomyxoviridae/prevenção & controle , Domínios e Motivos de Interação entre Proteínas/imunologia , Receptores Fc/fisiologia , Proteínas da Matriz Viral/imunologia , Animais , Morte Celular/genética , Morte Celular/imunologia , Citotoxicidade Imunológica , Modelos Animais de Doenças , Feminino , Imunização Passiva , Imunoglobulina G/toxicidade , Vírus da Influenza A/genética , Vacinas contra Influenza/genética , Vacinas contra Influenza/uso terapêutico , Depleção Linfocítica/métodos , Macrófagos Alveolares/patologia , Macrófagos Alveolares/virologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Infecções por Orthomyxoviridae/imunologia , Infecções por Orthomyxoviridae/patologia , Domínios e Motivos de Interação entre Proteínas/genética , Receptores Fc/deficiência , Receptores Fc/uso terapêutico , Receptores de IgG/deficiência , Receptores de IgG/metabolismo , Receptores de IgG/fisiologia , Proteínas da Matriz Viral/genética , Proteínas da Matriz Viral/uso terapêuticoRESUMO
BACKGROUND: Malaria elimination requires interruption of the highly efficient transmission of Plasmodium parasites by mosquitoes. TB31F is a humanised monoclonal antibody that binds the gamete surface protein Pfs48/45 and inhibits fertilisation, thereby preventing further parasite development in the mosquito midgut and onward transmission. We aimed to evaluate the safety and efficacy of TB31F in malaria-naive participants. METHODS: In this open-label, first-in-human, dose-escalation, phase 1 clinical trial, healthy, malaria-naive, adult participants were administered a single intravenous dose of 0·1, 1, 3, or 10 mg/kg TB31F or a subcutaneous dose of 100 mg TB31F, and monitored until day 84 after administration at a single centre in the Netherlands. The primary outcome was the frequency and magnitude of adverse events. Additionally, TB31F serum concentrations were measured by ELISA. Transmission-reducing activity (TRA) of participant sera was assessed by standard membrane feeding assays with Anopheles stephensi mosquitoes and cultured Plasmodium falciparum gametocytes. The trial is registered with Clinicaltrials.gov, NCT04238689. FINDINGS: Between Feb 17 and Dec 10, 2020, 25 participants were enrolled and sequentially assigned to each dose (n=5 per group). No serious or severe adverse events occurred. In total, 33 grade 1 and six grade 2 related adverse events occurred in 20 (80%) of 25 participants across all groups. Serum of all participants administered 1 mg/kg, 3 mg/kg, or 10 mg/kg TB31F intravenously had more than 80% TRA for 28 days or more, 56 days or more, and 84 days or more, respectively. The TB31F serum concentration reaching 80% TRA was 2·1 µg/mL (95% CI 1·9-2·3). Extrapolating the duration of TRA from antibody kinetics suggests more than 80% TRA is maintained for 160 days (95% CI 136-193) following a single intravenous 10 mg/kg dose. INTERPRETATION: TB31F is a well tolerated and highly potent monoclonal antibody capable of completely blocking transmission of P falciparum parasites from humans to mosquitoes. In areas of seasonal transmission, a single dose might cover an entire malaria season. FUNDING: PATH's Malaria Vaccine Initiative.
Assuntos
Antimaláricos , Vacinas Antimaláricas , Malária Falciparum , Adulto , Animais , Humanos , Plasmodium falciparum , Anticorpos Monoclonais/uso terapêutico , Malária Falciparum/tratamento farmacológico , Malária Falciparum/prevenção & controle , Malária Falciparum/parasitologiaRESUMO
Introduction: RTS,S/AS01 is currently the most advanced malaria vaccine but provides incomplete, short-term protection. It was developed for use within the expanded program on immunizations (EPI) for African children. Another use could be adding mass RTS,S/AS01 vaccination to the integrated malaria elimination strategy in the Greater Mekong Subregion (GMS), where multidrug-resistant P.falciparum strains have emerged and spread. Prior to evaluating RTS,S/AS01 in large-scale trials we assessed whether the vaccine, administered with and without antimalarial drugs, is safe and immunogenic in Asian populations.Methods: An open-label, randomized, controlled phase 2 trial was conducted in healthy, adult Thai volunteers. Seven vaccine regimens with and without antimalarial drugs (dihydroartemisinin-piperaquine plus a single low dose primaquine) were assessed. Antibody titres against the PfCSP full-length (NANP) 6, PfCSP anti-C-term, PfCSP full-length (N + C-Terminal) were measured by standard enzyme-linked immunosorbent assays. Liquid chromatography was used to measure piperaquine, primaquine and carboxy-primaquine concentrations.Results: 193 volunteers were enrolled and 186 study participants completed the 6 months follow-up period. One month after the last vaccination all study participants had seroconverted to the PfCSP (NANP)6, and the PfCSP Full Length (N + C-Terminal). More than 90% had seroconverted to the Pfanti-C-Term CSP. There was no indication that drug concentrations were influenced by vaccine regimens or the antibody levels by the drug regimens. Adverse events were similarly distributed between the seven treatment groups. No serious adverse events attributable to the study interventions were detected.Conclusion: This study found that RTS,S/AS01 with and without dihydroartemisinin-piperaquine plus a single low dose primaquine was safe and immunogenic in a healthy, adult Asian population.
Assuntos
Antimaláricos/administração & dosagem , Erradicação de Doenças , Imunogenicidade da Vacina , Vacinas Antimaláricas/imunologia , Malária Falciparum/prevenção & controle , Adulto , Anticorpos Antiprotozoários/sangue , Antimaláricos/farmacocinética , Artemisininas/administração & dosagem , Quimioterapia Combinada , Feminino , Voluntários Saudáveis , Humanos , Programas de Imunização , Esquemas de Imunização , Vacinas Antimaláricas/administração & dosagem , Malária Falciparum/epidemiologia , Masculino , Primaquina/administração & dosagem , Quinolinas/administração & dosagem , Tailândia/epidemiologia , VacinaçãoRESUMO
For some diseases, successful vaccines have been developed using a nonpathogenic counterpart of the causative microorganism of choice. The nonpathogenicity of the rodent Plasmodium berghei (Pb) parasite in humans prompted us to evaluate its potential as a platform for vaccination against human infection by Plasmodium falciparum (Pf), a causative agent of malaria. We hypothesized that the genetic insertion of a leading protein target for clinical development of a malaria vaccine, Pf circumsporozoite protein (CSP), in its natural pre-erythrocytic environment, would enhance Pb's capacity to induce protective immunity against Pf infection. Hence, we recently generated a transgenic Pb sporozoite immunization platform expressing PfCSP (PbVac), and we now report the clinical evaluation of its biological activity against controlled human malaria infection (CHMI). This first-in-human trial shows that PbVac is safe and well tolerated, when administered by a total of ~300 PbVac-infected mosquitoes per volunteer. Although protective efficacy evaluated by CHMI showed no sterile protection at the tested dose, significant delays in patency (2.2 days, P = 0.03) and decreased parasite density were observed after immunization, corresponding to an estimated 95% reduction in Pf liver parasite burden (confidence interval, 56 to 99%; P = 0.010). PbVac elicits dose-dependent cross-species cellular immune responses and functional PfCSP-dependent antibody responses that efficiently block Pf sporozoite invasion of liver cells in vitro. This study demonstrates that PbVac immunization elicits a marked biological effect, inhibiting a subsequent infection by the human Pf parasite, and establishes the clinical validation of a new paradigm in malaria vaccination.
Assuntos
Vacinas Antimaláricas , Malária Falciparum , Malária , Parasitos , Animais , Anticorpos Antiprotozoários , Imunização , Malária Falciparum/prevenção & controle , Plasmodium falciparum , Proteínas de Protozoários/genética , Roedores , VacinaçãoRESUMO
The transmission-blocking vaccine candidate Pfs48/45 from the human malaria parasite Plasmodium falciparum is known to be difficult to express in heterologous systems, either as full-length protein or as correctly folded protein fragments that retain conformational epitopes. In this study we express full-length Pfs48/45 in the rodent parasite P. berghei. Pfs48/45 is expressed as a transgene under control of the strong P. berghei schizont-specific msp1 gene promoter (Pfs48/45@PbMSP1). Pfs48/45@PbMSP1 schizont-infected red blood cells produced full-length Pfs48/45 and the structural integrity of Pfs48/45 was confirmed using a panel of conformation-specific monoclonal antibodies that bind to different Pfs48/45 epitopes. Sera from mice immunized with transgenic Pfs48/45@PbMSP1 schizonts showed strong transmission-reducing activity in mosquitoes infected with P. falciparum using standard membrane feeding. These results demonstrate that transgenic rodent malaria parasites expressing human malaria antigens may be used as means to evaluate immunogenicity and functionality of difficult to express malaria vaccine candidate antigens.
Assuntos
Antígenos de Protozoários/imunologia , Vacinas Antimaláricas/imunologia , Proteínas de Membrana/imunologia , Plasmodium berghei/genética , Plasmodium falciparum/genética , Proteínas Recombinantes/imunologia , Animais , Antígenos de Protozoários/biossíntese , Antígenos de Protozoários/genética , Modelos Animais de Doenças , Transmissão de Doença Infecciosa/prevenção & controle , Expressão Gênica , Malária/prevenção & controle , Proteínas de Membrana/biossíntese , Proteínas de Membrana/genética , Camundongos , Regiões Promotoras Genéticas , Proteínas Recombinantes/biossíntese , Proteínas Recombinantes/genética , TransgenesRESUMO
Reticulocyte invasion by Plasmodium vivax requires interaction of the Duffy-binding protein (PvDBP) with host Duffy antigen receptor for chemokines (DARCs). The binding domain of PvDBP maps to a cysteine-rich region referred to as region II (PvDBPII). Blocking this interaction offers a potential path to prevent P. vivax blood-stage growth and P. vivax malaria. This forms the rationale for development of a vaccine based on PvDBPII. Here we report results of a Phase I randomized trial to evaluate the safety and immunogenicity of recombinant PvDBPII formulated with glucopyranosyl lipid adjuvant-stable emulsion (GLA-SE). Thirty-six malaria-naive, healthy Indian male subjects aged 18-45 years were assigned into three cohorts corresponding to doses of 10, 25 and 50 µg of PvDBPII formulated with 5 µg of GLA-SE. Each cohort included nine PvDBPII/GLA-SE vaccinees and three hepatitis B control vaccine recipients. Each subject received the assigned vaccine intramuscularly on days 0, 28 and 56, and was followed up till day 180. No serious AE was reported and PvDBPII/GLA-SE was well-tolerated and safe. Analysis by ELISA showed that all three doses of PvDBPII elicited antigen-specific binding-inhibitory antibodies. The 50 µg dose elicited antibodies against PvDBPII that had the highest binding-inhibitory titres and were most persistent. Importantly, the antibody responses were strain transcending and blocked receptor binding of diverse PvDBP alleles. These results support further clinical development of PvDBPII/GLA-SE to evaluate efficacy against sporozoite or blood-stage challenge in controlled human malaria infection (CHMI) models and against natural P. vivax challenge in malaria endemic areas.
RESUMO
The search for an efficacious vaccine against malaria is ongoing, and it is now widely believed that to confer protection a vaccine must induce very strong cellular and humoral immunity concurrently. We studied the immune response in mice immunized with the recombinant viral vaccines fowlpox strain FP9 and modified virus Ankara (MVA), a protein vaccine (CV-1866), or a combination of the two; all vaccines express parts of the same preerythrocytic malaria antigen, the Plasmodium berghei circumsporozoite protein (CSP). Mice were then challenged with P. berghei sporozoites to determine the protective efficacies of different vaccine regimens. Two immunizations with the protein vaccine CV-1866, based on the hepatitis B core antigen particle, induced strong humoral immunity to the repeat region of CSP that was weakly protective against sporozoite challenge. Prime-boost with the viral vector vaccines, FP9 followed by MVA, induced strong T-cell immunity to the CD8+ epitope Pb9 and partially protected animals from challenge. Physically mixing CV-1866 with FP9 or MVA and then immunizing with the resultant combinations in a prime-boost regimen induced both cellular and humoral immunity and afforded substantially higher levels of protection (combination, 90%) than either vaccine alone (CV-1866, 12%; FP9/MVA, 37%). For diseases such as malaria in which different potent immune responses are required to protect against different stages, using combinations of partially effective vaccines may offer a more rapid route to achieving deployable levels of efficacy than individual vaccine strategies.
Assuntos
Vacinas Antimaláricas/imunologia , Malária/imunologia , Vacinas Virais/imunologia , Animais , Anopheles/parasitologia , Anticorpos Antiprotozoários/biossíntese , Anticorpos Antiprotozoários/imunologia , Afinidade de Anticorpos/imunologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Epitopos de Linfócito B/imunologia , Feminino , Antígenos do Núcleo do Vírus da Hepatite B/genética , Antígenos do Núcleo do Vírus da Hepatite B/imunologia , Malária/parasitologia , Malária/prevenção & controle , Vacinas Antimaláricas/genética , Vacinas Antimaláricas/farmacologia , Camundongos , Camundongos Endogâmicos BALB C , Plasmodium berghei/imunologia , Proteínas de Protozoários/genética , Proteínas de Protozoários/imunologia , Esporozoítos/imunologia , Células Th1/imunologia , Vacinas Combinadas/genética , Vacinas Combinadas/imunologia , Vacinas Combinadas/farmacologia , Vacinas de Subunidades Antigênicas/genética , Vacinas de Subunidades Antigênicas/imunologia , Vacinas de Subunidades Antigênicas/farmacologia , Vacinas Sintéticas/genética , Vacinas Sintéticas/imunologia , Vacinas Sintéticas/farmacologia , Vacinas Virais/genética , Vacinas Virais/farmacologiaRESUMO
Remarkable progress has been made in coordinated malaria control efforts with substantial reductions in malaria-associated deaths and morbidity achieved through mass administration of drugs and vector control measures including distribution of long-lasting insecticide-impregnated bednets and indoor residual spraying. However, emerging resistance poses a significant threat to the sustainability of these interventions. In this light, the malaria research community has been charged with the development of a highly efficacious vaccine to complement existing malaria elimination measures. As the past 40 years of investment in this goal attests, this is no small feat. The malaria parasite is a highly complex organism, exquisitely adapted for survival under hostile conditions within human and mosquito hosts. Here we review current vaccine strategies to accelerate elimination and the potential for novel and innovative approaches to vaccine design through a better understanding of the host-parasite interaction.
Assuntos
Vacinas Antimaláricas/uso terapêutico , Malária/prevenção & controle , Malária/transmissão , Animais , Humanos , Mosquitos Vetores/parasitologia , VacinaçãoRESUMO
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.
Assuntos
Vacinas Antimaláricas/uso terapêutico , Malária/prevenção & controle , Animais , Pesquisa Biomédica/tendências , Ensaios Clínicos como Assunto , Culicidae/parasitologia , HumanosRESUMO
BACKGROUND: A vaccine to prevent infection and disease caused by Plasmodium vivax is needed both to reduce the morbidity caused by this parasite and as a key component in efforts to eradicate malaria worldwide. Vivax malaria protein 1 (VMP001), a novel chimeric protein that incorporates the amino- and carboxy- terminal regions of the circumsporozoite protein (CSP) and a truncated repeat region that contains repeat sequences from both the VK210 (type 1) and the VK247 (type 2) parasites, was developed as a vaccine candidate for global use. METHODS: We conducted a first-in-human Phase 1 dose escalation vaccine study with controlled human malaria infection (CHMI) of VMP001 formulated in the GSK Adjuvant System AS01B. A total of 30 volunteers divided into 3 groups (10 per group) were given 3 intramuscular injections of 15 µg, 30 µg, or 60 µg respectively of VMP001, all formulated in 500 µL of AS01B at each immunization. All vaccinated volunteers participated in a P. vivax CHMI 14 days following the third immunization. Six non-vaccinated subjects served as infectivity controls. RESULTS: The vaccine was shown to be well tolerated and immunogenic. All volunteers generated robust humoral and cellular immune responses to the vaccine antigen. Vaccination did not induce sterile protection; however, a small but significant delay in time to parasitemia was seen in 59% of vaccinated subjects compared to the control group. An association was identified between levels of anti-type 1 repeat antibodies and prepatent period. SIGNIFICANCE: This trial was the first to assess the efficacy of a P. vivax CSP vaccine candidate by CHMI. The association of type 1 repeat-specific antibody responses with delay in the prepatency period suggests that augmenting the immune responses to this domain may improve strain-specific vaccine efficacy. The availability of a P. vivax CHMI model will accelerate the process of P. vivax vaccine development, allowing better selection of candidate vaccines for advancement to field trials.
Assuntos
Vacinas Antimaláricas/imunologia , Malária Vivax/prevenção & controle , Plasmodium vivax/imunologia , Proteínas de Protozoários/imunologia , Adolescente , Adulto , Anticorpos Antiprotozoários/imunologia , Feminino , Humanos , Vacinas Antimaláricas/administração & dosagem , Vacinas Antimaláricas/efeitos adversos , Malária Vivax/imunologia , Malária Vivax/parasitologia , Masculino , Pessoa de Meia-Idade , Proteínas de Protozoários/administração & dosagem , Proteínas de Protozoários/efeitos adversos , Vacinação , Adulto JovemRESUMO
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.