Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 220
Filtrar
1.
EBioMedicine ; 108: 105364, 2024 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-39353279

RESUMO

BACKGROUND: PfSPZ Vaccine, a promising pre-erythrocytic stage malaria vaccine candidate based on whole, radiation-attenuated Plasmodium falciparum (Pf) sporozoites (SPZ), has proven safe and effective in mediating sterile protection from malaria in malaria-naïve and exposed healthy adults. Vaccine-induced protection presumably depends on cellular responses to early parasite liver stages, but humoral immunity contributes. METHODS: On custom-made Pf protein microarrays, we profiled IgG and IgM responses to PfSPZ Vaccine and subsequent homologous controlled human malaria infection (CHMI) in 21 Tanzanian adults with (n = 12) or without (n = 9) HIV infection. Expression of the main identified immunogens in the pre-erythrocytic parasite stage was verified by immunofluorescence detection using freshly purified PfSPZ and an in vitro model of primary human hepatocytes. FINDINGS: Independent of HIV infection status, immunisation induced focused IgG and IgM responses to circumsporozoite surface protein (PfCSP) and merozoite surface protein 5 (PfMSP5). We show that PfMSP5 is detectable on the surface and in the apical complex of PfSPZ. INTERPRETATION: Our data demonstrate that HIV infection does not affect the quantity of the total IgG and IgM antibody responses to PfCSP and PfMSP5 after immunization with PfSPZ Vaccine. PfMSP5 represents a highly immunogenic, so far underexplored, target for vaccine-induced antibodies in malaria pre-exposed volunteers. FUNDING: This work was supported by the Equatorial Guinea Malaria Vaccine Initiative (EGMVI), the Clinical Trial Platform of the German Center for Infection Research (TTU 03.702), the Swiss Government Excellence Scholarships for Foreign Scholars and Artists (grant 2016.0056) and the Interdisciplinary Center for Clinical Research doctoral program of the Tübingen University Hospital. The funders had no role in design, analysis, or reporting of this study.


Assuntos
Anticorpos Antiprotozoários , Imunidade Humoral , Imunoglobulina G , Vacinas Antimaláricas , Malária Falciparum , Plasmodium falciparum , Humanos , Vacinas Antimaláricas/imunologia , Vacinas Antimaláricas/administração & dosagem , Plasmodium falciparum/imunologia , Tanzânia/epidemiologia , Adulto , Malária Falciparum/imunologia , Malária Falciparum/prevenção & controle , Malária Falciparum/parasitologia , Masculino , Imunoglobulina G/sangue , Imunoglobulina G/imunologia , Anticorpos Antiprotozoários/imunologia , Feminino , Imunoglobulina M/imunologia , Infecções por HIV/imunologia , Esporozoítos/imunologia , Proteínas de Protozoários/imunologia , Antígenos de Protozoários/imunologia , Pessoa de Meia-Idade
2.
Lancet Glob Health ; 12(11): e1838-e1848, 2024 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-39424572

RESUMO

BACKGROUND: Several important vaccines differ in immunogenicity and efficacy between populations. We hypothesised that malaria suppresses responses to unrelated vaccines and that this effect can be reversed-at least partially-by monthly malaria intermittent preventive treatment (IPT) in high-transmission settings. METHODS: We conducted an individually randomised, double-blind, placebo-controlled trial of the effect of malaria IPT with dihydroartemisinin-piperaquine on vaccine responses among schoolchildren aged 9-17 years in Jinja district, Uganda. Participants were recruited from two schools and did not have exposure to vaccines of interest after the age of 5 years, with the exception of human papillomavirus (HPV). Computer-generated 1:1 randomisation was implemented in REDCap. 3-day courses of dihydroartemisinin-piperaquine (dosage by weight) or placebo were administered monthly, including twice before the first vaccination. Trial participants were vaccinated with the live parenteral BCG vaccine (Serum Institute of India, Pune, India) at week 0; yellow fever vaccine (YF-17D; Sanofi Pasteur, Lyon, France); live oral typhoid vaccine (Ty21a; PaxVax, London, UK), and quadrivalent virus-like particle HPV vaccine (Merck, Rahway, NJ, USA) at week 4; and toxoid vaccines (tetanus-diphtheria; Serum Institute of India) and an HPV booster at week 28. An additional HPV vaccination at week 8 was provided to female participants older than 14 years who had not previously been vaccinated, and a tetanus-diphtheria booster was given after completion of the trial at week 52. Primary outcomes were vaccine responses at week 8 and, for tetanus-diphtheria, at week 52, and analysis was done in the intention-to-treat population. Malaria parasite prevalence at enrolment and during follow-up was determined retrospectively by PCR. The safety population comprised all randomly allocated participants. The trial was registered at the ISRCTN Registry (ISRCTN62041885) and is complete. FINDINGS: Between May 25 and July 14, 2021, we assessed 388 potential participants for eligibility. We enrolled and randomly allocated 341 participants to the two groups (170 [50%] to dihydroartemisinin-piperaquine and 171 [50%] to placebo); 192 (56%) were female and 149 (44%) participants were male. 145 (85%) participants in the dihydroartemisinin-piperaquine group and 140 participants (82%) in the placebo group were followed up until the week 52 endpoint. At enrolment, 109 (64%) of all participants in the dihydroartemisinin-piperaquine group and 99 (58%) of 170 participants in the placebo group had malaria; this reduced to 6% or lower at all follow-up visits in the dihydroartemisinin-piperaquine group. There was no effect of dihydroartemisinin-piperaquine versus placebo on primary outcomes: BCG-specific IFNγ ELISpot response had a geometric mean ratio (GMR) of 1·09 (95% CI 0·93-1·29), p=0·28; yellow fever neutralising antibody was 1·19 (0·91-1·54), p=0·20 for plaque reduction neutralising reference tests (PRNT50) titres (the reciprocal of the last plasma dilution that reduced by 50%) and 1·24 (0·97-1·58), p=0·09 for PRNT90 titres (reciprocal of the last plasma dilution that reduced by 90%); and IgG to Salmonella enterica serovar Typhi O-lipopolysaccharide was 1·09 (0·81-1·46), p=0·58, HPV-16 was 0·72 (0·44-1·77), p=0·19, HPV-18 was 0·71 (0·47-1·09), p=0·11; tetanus toxoid was 1·22 (0·91-1·62), p=0·18, and diphtheria toxoid was 0·97 (0·83-1·13), p=0·72. There was some evidence that dihydroartemisinin-piperaquine reduced waning of the yellow fever response. INTERPRETATION: IPT for malaria with dihydroartemisinin-piperaquine did not improve peak vaccine responses, despite reducing malaria prevalence. Possible longer-term effects on response waning should be further explored. FUNDING: UK Medical Research Council. TRANSLATION: For the Luganda translation of the abstract see Supplementary Materials section.


Assuntos
Antimaláricos , Artemisininas , Vacinas Antimaláricas , Quinolinas , Humanos , Uganda , Criança , Feminino , Método Duplo-Cego , Masculino , Adolescente , Artemisininas/uso terapêutico , Artemisininas/administração & dosagem , Quinolinas/administração & dosagem , Quinolinas/uso terapêutico , Antimaláricos/uso terapêutico , Antimaláricos/administração & dosagem , Vacinas Antimaláricas/administração & dosagem , Vacinas Antimaláricas/imunologia , Malária/prevenção & controle , População Rural/estatística & dados numéricos , Piperazinas
3.
Nat Commun ; 15(1): 4857, 2024 Jun 07.
Artigo em Inglês | MEDLINE | ID: mdl-38849365

RESUMO

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/metabolismo
4.
Front Immunol ; 15: 1372584, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38745665

RESUMO

Among Plasmodium spp. responsible for human malaria, Plasmodium vivax ranks as the second most prevalent and has the widest geographical range; however, vaccine development has lagged behind that of Plasmodium falciparum, the deadliest Plasmodium species. Recently, we developed a multistage vaccine for P. falciparum based on a heterologous prime-boost immunization regimen utilizing the attenuated vaccinia virus strain LC16m8Δ (m8Δ)-prime and adeno-associated virus type 1 (AAV1)-boost, and demonstrated 100% protection and more than 95% transmission-blocking (TB) activity in the mouse model. In this study, we report the feasibility and versatility of this vaccine platform as a P. vivax multistage vaccine, which can provide 100% sterile protection against sporozoite challenge and >95% TB efficacy in the mouse model. Our vaccine comprises m8Δ and AAV1 viral vectors, both harboring the gene encoding two P. vivax circumsporozoite (PvCSP) protein alleles (VK210; PvCSP-Sal and VK247; -PNG) and P25 (Pvs25) expressed as a Pvs25-PvCSP fusion protein. For protective efficacy, the heterologous m8Δ-prime/AAV1-boost immunization regimen showed 100% (short-term; Day 28) and 60% (long-term; Day 242) protection against PvCSP VK210 transgenic Plasmodium berghei sporozoites. For TB efficacy, mouse sera immunized with the vaccine formulation showed >75% TB activity and >95% transmission reduction activity by a direct membrane feeding assay using P. vivax isolates in blood from an infected patient from the Brazilian Amazon region. These findings provide proof-of-concept that the m8Δ/AAV1 vaccine platform is sufficiently versatile for P. vivax vaccine development. Future studies are needed to evaluate the safety, immunogenicity, vaccine efficacy, and synergistic effects on protection and transmission blockade in a non-human primate model for Phase I trials.


Assuntos
Dependovirus , Vetores Genéticos , Vacinas Antimaláricas , Malária Vivax , Plasmodium vivax , Animais , Vacinas Antimaláricas/imunologia , Vacinas Antimaláricas/administração & dosagem , Plasmodium vivax/imunologia , Plasmodium vivax/genética , Malária Vivax/prevenção & controle , Malária Vivax/transmissão , Malária Vivax/imunologia , Camundongos , Dependovirus/genética , Dependovirus/imunologia , Feminino , Proteínas de Protozoários/imunologia , Proteínas de Protozoários/genética , Anticorpos Antiprotozoários/imunologia , Anticorpos Antiprotozoários/sangue , Modelos Animais de Doenças , Vaccinia virus/genética , Vaccinia virus/imunologia , Humanos , Camundongos Endogâmicos BALB C , Imunização Secundária , Eficácia de Vacinas
5.
JCI Insight ; 9(11)2024 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-38687615

RESUMO

A systems analysis was conducted to determine the potential molecular mechanisms underlying differential immunogenicity and protective efficacy results of a clinical trial of the radiation-attenuated whole-sporozoite PfSPZ vaccine in African infants. Innate immune activation and myeloid signatures at prevaccination baseline correlated with protection from P. falciparum parasitemia in placebo controls. These same signatures were associated with susceptibility to parasitemia among infants who received the highest and most protective PfSPZ vaccine dose. Machine learning identified spliceosome, proteosome, and resting DC signatures as prevaccination features predictive of protection after highest-dose PfSPZ vaccination, whereas baseline circumsporozoite protein-specific (CSP-specific) IgG predicted nonprotection. Prevaccination innate inflammatory and myeloid signatures were associated with higher sporozoite-specific IgG Ab response but undetectable PfSPZ-specific CD8+ T cell responses after vaccination. Consistent with these human data, innate stimulation in vivo conferred protection against infection by sporozoite injection in malaria-naive mice while diminishing the CD8+ T cell response to radiation-attenuated sporozoites. These data suggest a dichotomous role of innate stimulation for malaria protection and induction of protective immunity by whole-sporozoite malaria vaccines. The uncoupling of vaccine-induced protective immunity achieved by Abs from more protective CD8+ T cell responses suggests that PfSPZ vaccine efficacy in malaria-endemic settings may be constrained by opposing antigen presentation pathways.


Assuntos
Imunidade Inata , Vacinas Antimaláricas , Malária Falciparum , Plasmodium falciparum , Esporozoítos , Vacinas Atenuadas , Vacinas Antimaláricas/imunologia , Vacinas Antimaláricas/administração & dosagem , Imunidade Inata/imunologia , Humanos , Animais , Malária Falciparum/prevenção & controle , Malária Falciparum/imunologia , Plasmodium falciparum/imunologia , Camundongos , Vacinas Atenuadas/imunologia , Vacinas Atenuadas/administração & dosagem , Esporozoítos/imunologia , Esporozoítos/efeitos da radiação , Linfócitos T CD8-Positivos/imunologia , Lactente , Proteínas de Protozoários/imunologia , Anticorpos Antiprotozoários/imunologia , Feminino , Parasitemia/imunologia , Parasitemia/prevenção & controle , Imunoglobulina G/imunologia , Imunoglobulina G/sangue , Eficácia de Vacinas
6.
Am J Trop Med Hyg ; 110(5): 892-901, 2024 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-38531102

RESUMO

Malaria eradication efforts prioritize safe and efficient vaccination strategies, although none with high-level efficacy against malaria infection are yet available. Among several vaccine candidates, Sanaria® PfSPZ Vaccine and Sanaria PfSPZ-CVac are, respectively, live radiation- and chemo-attenuated sporozoite vaccines designed to prevent infection with Plasmodium falciparum, the leading cause of malaria-related morbidity and mortality. We are conducting a randomized normal saline placebo-controlled trial called IDSPZV1 that will analyze the safety, tolerability, immunogenicity, and efficacy of PfSPZ Vaccine and PfSPZ-CVac administered pre-deployment to malaria-naive Indonesian soldiers assigned to temporary duties in a high malaria transmission area. We describe the manifold challenges of enrolling and immunizing 345 soldier participants at their home base in western Indonesia before their nearly 6,000-km voyage to eastern Indonesia, where they are being monitored for incident P. falciparum and Plasmodium vivax malaria cases during 9 months of exposure. The unique regulatory, ethical, and operational complexities of this trial demonstrate the importance of thorough planning, frequent communication, and close follow-up with stakeholders. Effective engagement with the military community and the ability to adapt to unanticipated events have proven key to the success of this trial.


Assuntos
Vacinas Antimaláricas , Malária Falciparum , Malária Vivax , Militares , Plasmodium falciparum , Esporozoítos , Vacinas Atenuadas , Humanos , Vacinas Antimaláricas/imunologia , Vacinas Antimaláricas/uso terapêutico , Vacinas Antimaláricas/administração & dosagem , Indonésia/epidemiologia , Malária Falciparum/prevenção & controle , Malária Falciparum/epidemiologia , Esporozoítos/imunologia , Vacinas Atenuadas/imunologia , Vacinas Atenuadas/uso terapêutico , Plasmodium falciparum/imunologia , Malária Vivax/prevenção & controle , Malária Vivax/epidemiologia , Masculino , Adulto , Adulto Jovem , Plasmodium vivax/imunologia , Feminino
7.
Front Immunol ; 12: 732667, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34659219

RESUMO

Plasmodium falciparum transmission-blocking vaccines (TBVs) targeting the Pfs25 antigen have shown promise in mice but the same efficacy has never been achieved in humans. We have previously published pre-clinical data related to a TBV candidate Pfs25-IMX313 encoded in viral vectors which was very promising and hence progressed to human clinical trials. The results from the clinical trial of this vaccine were very modest. Here we unravel why, contrary to mice, this vaccine has failed to induce robust antibody (Ab) titres in humans to elicit transmission-blocking activity. We examined Pfs25-specific B cell and T follicular helper (Tfh) cell responses in mice and humans after vaccination with Pfs25-IMX313 encoded by replication-deficient chimpanzee adenovirus serotype 63 (ChAd63) and the attenuated orthopoxvirus modified vaccinia virus Ankara (MVA) delivered in the heterologous prime-boost regimen via intramuscular route. We found that after vaccination, the Pfs25-IMX313 was immunologically suboptimal in humans compared to mice in terms of serum Ab production and antigen-specific B, CD4+ and Tfh cell responses. We identified that the key determinant for the poor anti-Pfs25 Ab formation in humans was the lack of CD4+ T cell recognition of Pfs25-IMX313 derived peptide epitopes. This is supported by correlations established between the ratio of proliferated antigen-specific CD4+/Tfh-like T cells, CXCL13 sera levels, and the corresponding numbers of circulating Pfs25-specific memory B cells, that consequently reflected on antigen-specific IgG sera levels. These correlations can inform the design of next-generation Pfs25-based vaccines for robust and durable blocking of malaria transmission.


Assuntos
Anticorpos Antiprotozoários/sangue , Linfócitos T CD4-Positivos/efeitos dos fármacos , Imunidade Humoral/efeitos dos fármacos , Imunogenicidade da Vacina , Vacinas Antimaláricas/administração & dosagem , Malária Falciparum/prevenção & controle , Plasmodium falciparum/imunologia , Proteínas de Protozoários/administração & dosagem , Proteínas Recombinantes/administração & dosagem , Adolescente , Adulto , Animais , Linfócitos B/efeitos dos fármacos , Linfócitos B/imunologia , Linfócitos B/parasitologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/parasitologia , Células Cultivadas , Modelos Animais de Doenças , Epitopos , Feminino , Humanos , Vacinas Antimaláricas/imunologia , Malária Falciparum/imunologia , Malária Falciparum/parasitologia , Malária Falciparum/transmissão , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Pessoa de Meia-Idade , Plasmodium falciparum/patogenicidade , Proteínas de Protozoários/imunologia , Proteínas Recombinantes/imunologia , Especificidade da Espécie , Vacinação , Adulto Jovem
8.
Nat Med ; 27(9): 1636-1645, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34518679

RESUMO

The radiation-attenuated Plasmodium falciparum sporozoite (PfSPZ) vaccine provides protection against P. falciparum infection in malaria-naïve adults. Preclinical studies show that T cell-mediated immunity is required for protection and is readily induced in humans after vaccination. However, previous malaria exposure can limit immune responses and vaccine efficacy (VE) in adults. We hypothesized that infants with less previous exposure to malaria would have improved immunity and protection. We conducted a multi-arm, randomized, double-blind, placebo-controlled trial in 336 infants aged 5-12 months to determine the safety, tolerability, immunogenicity and efficacy of the PfSPZ Vaccine in infants in a high-transmission malaria setting in western Kenya ( NCT02687373 ). Groups of 84 infants each received 4.5 × 105, 9.0 × 105 or 1.8 × 106 PfSPZ Vaccine or saline three times at 8-week intervals. The vaccine was well tolerated; 52 (20.6%) children in the vaccine groups and 20 (23.8%) in the placebo group experienced related solicited adverse events (AEs) within 28 d postvaccination and most were mild. There was 1 grade 3-related solicited AE in the vaccine group (0.4%) and 2 in the placebo group (2.4%). Seizures were more common in the highest-dose group (14.3%) compared to 6.0% of controls, with most being attributed to malaria. There was no significant protection against P. falciparum infection in any dose group at 6 months (VE in the 9.0 × 105 dose group = -6.5%, P = 0.598, the primary statistical end point of the study). VE against clinical malaria 3 months after the last dose in the highest-dose group was 45.8% (P = 0.027), an exploratory end point. There was a dose-dependent increase in antibody responses that correlated with VE at 6 months in the lowest- and highest-dose groups. T cell responses were undetectable across all dose groups. Detection of Vδ2+Vγ9+ T cells, which have been correlated with induction of PfSPZ Vaccine T cell immunity and protection in adults, were infrequent. These data suggest that PfSPZ Vaccine-induced T cell immunity is age-dependent and may be influenced by Vδ2+Vγ9+ T cell frequency. Since there was no significant VE at 6 months in these infants, these vaccine regimens will likely not be pursued further in this age group.


Assuntos
Vacinas Antimaláricas/administração & dosagem , Malária Falciparum/tratamento farmacológico , Plasmodium falciparum/efeitos dos fármacos , Vacinas Atenuadas/administração & dosagem , Adulto , Formação de Anticorpos/efeitos dos fármacos , Formação de Anticorpos/imunologia , Linfócitos B/efeitos dos fármacos , Linfócitos B/imunologia , Método Duplo-Cego , Humanos , Lactente , Quênia/epidemiologia , Vacinas Antimaláricas/efeitos adversos , Malária Falciparum/imunologia , Malária Falciparum/parasitologia , Malária Falciparum/prevenção & controle , Plasmodium falciparum/patogenicidade , Esporozoítos/efeitos dos fármacos , Esporozoítos/patogenicidade , Linfócitos T/efeitos dos fármacos , Vacinação , Vacinas Atenuadas/efeitos adversos
9.
PLoS One ; 16(9): e0256980, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34495988

RESUMO

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.


Assuntos
Vacinas contra Adenovirus/imunologia , Adenovirus dos Símios/imunologia , Antígenos de Protozoários/imunologia , DNA de Protozoário/imunologia , DNA Recombinante/imunologia , Imunização Secundária/métodos , Vacinas Antimaláricas/imunologia , Malária Falciparum/prevenção & controle , Proteínas de Membrana/imunologia , Plasmodium falciparum/imunologia , Proteínas de Protozoários/imunologia , Vacinas de DNA/imunologia , Vacinas contra Adenovirus/administração & dosagem , Vacinas contra Adenovirus/efeitos adversos , Adenovirus dos Símios/genética , Adulto , Antígenos de Protozoários/genética , Linfócitos T CD8-Positivos/imunologia , DNA de Protozoário/genética , Epitopos/genética , Epitopos/imunologia , Feminino , Vetores Genéticos/administração & dosagem , Vetores Genéticos/imunologia , Voluntários Saudáveis , Humanos , Imunogenicidade da Vacina/imunologia , Vacinas Antimaláricas/administração & dosagem , Vacinas Antimaláricas/efeitos adversos , Malária Falciparum/imunologia , Malária Falciparum/parasitologia , Masculino , Proteínas de Membrana/genética , Proteínas de Protozoários/genética , Resultado do Tratamento , Vacinas de DNA/administração & dosagem , Vacinas de DNA/efeitos adversos , Adulto Jovem
10.
Front Immunol ; 12: 694759, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34335606

RESUMO

Background: Transmission blocking vaccines targeting the sexual-stages of the malaria parasite could play a major role to achieve elimination and eradication of malaria. The Plasmodium falciparum Pfs25 protein (Pfs25) is the most clinically advanced candidate sexual-stage antigen. IMX313, a complement inhibitor C4b-binding protein that forms heptamers with the antigen fused to it, improve antibody responses. This is the first time that viral vectors have been used to induce antibodies in humans against an antigen that is expressed only in the mosquito vector. Methods: Clinical trial looking at safety and immunogenicity of two recombinant viral vectored vaccines encoding Pfs25-IMX313 in healthy malaria-naive adults. Replication-deficient chimpanzee adenovirus serotype 63 (ChAd63) and the attenuated orthopoxvirus modified vaccinia virus Ankara (MVA), encoding Pfs25-IMX313, were delivered by the intramuscular route in a heterologous prime-boost regimen using an 8-week interval. Safety data and samples for immunogenicity assays were taken at various time-points. Results: The reactogenicity of the vaccines was similar to that seen in previous trials using the same viral vectors encoding other antigens. The vaccines were immunogenic and induced both antibody and T cell responses against Pfs25, but significant transmission reducing activity (TRA) was not observed in most volunteers by standard membrane feeding assay. Conclusion: Both vaccines were well tolerated and demonstrated a favorable safety profile in malaria-naive adults. However, the transmission reducing activity of the antibodies generated were weak, suggesting the need for an alternative vaccine formulation. Trial Registration: Clinicaltrials.gov NCT02532049.


Assuntos
Imunogenicidade da Vacina , Vacinas Antimaláricas/administração & dosagem , Malária Falciparum/prevenção & controle , Plasmodium falciparum/imunologia , Vacinas Sintéticas/administração & dosagem , Anticorpos Antiprotozoários/sangue , Células Cultivadas , Inglaterra , Voluntários Saudáveis , Humanos , Imunização , Vacinas Antimaláricas/efeitos adversos , Vacinas Antimaláricas/imunologia , Malária Falciparum/imunologia , Malária Falciparum/parasitologia , Malária Falciparum/transmissão , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia , Linfócitos T/parasitologia , Fatores de Tempo , Vacinas Sintéticas/efeitos adversos , Vacinas Sintéticas/imunologia
11.
N Engl J Med ; 385(11): 1005-1017, 2021 09 09.
Artigo em Inglês | MEDLINE | ID: mdl-34432975

RESUMO

BACKGROUND: Malaria control remains a challenge in many parts of the Sahel and sub-Sahel regions of Africa. METHODS: We conducted an individually randomized, controlled trial to assess whether seasonal vaccination with RTS,S/AS01E was noninferior to chemoprevention in preventing uncomplicated malaria and whether the two interventions combined were superior to either one alone in preventing uncomplicated malaria and severe malaria-related outcomes. RESULTS: We randomly assigned 6861 children 5 to 17 months of age to receive sulfadoxine-pyrimethamine and amodiaquine (2287 children [chemoprevention-alone group]), RTS,S/AS01E (2288 children [vaccine-alone group]), or chemoprevention and RTS,S/AS01E (2286 children [combination group]). Of these, 1965, 1988, and 1967 children in the three groups, respectively, received the first dose of the assigned intervention and were followed for 3 years. Febrile seizure developed in 5 children the day after receipt of the vaccine, but the children recovered and had no sequelae. There were 305 events of uncomplicated clinical malaria per 1000 person-years at risk in the chemoprevention-alone group, 278 events per 1000 person-years in the vaccine-alone group, and 113 events per 1000 person-years in the combination group. The hazard ratio for the protective efficacy of RTS,S/AS01E as compared with chemoprevention was 0.92 (95% confidence interval [CI], 0.84 to 1.01), which excluded the prespecified noninferiority margin of 1.20. The protective efficacy of the combination as compared with chemoprevention alone was 62.8% (95% CI, 58.4 to 66.8) against clinical malaria, 70.5% (95% CI, 41.9 to 85.0) against hospital admission with severe malaria according to the World Health Organization definition, and 72.9% (95% CI, 2.9 to 92.4) against death from malaria. The protective efficacy of the combination as compared with the vaccine alone against these outcomes was 59.6% (95% CI, 54.7 to 64.0), 70.6% (95% CI, 42.3 to 85.0), and 75.3% (95% CI, 12.5 to 93.0), respectively. CONCLUSIONS: Administration of RTS,S/AS01E was noninferior to chemoprevention in preventing uncomplicated malaria. The combination of these interventions resulted in a substantially lower incidence of uncomplicated malaria, severe malaria, and death from malaria than either intervention alone. (Funded by the Joint Global Health Trials and PATH; ClinicalTrials.gov number, NCT03143218.).


Assuntos
Amodiaquina/uso terapêutico , Antimaláricos/uso terapêutico , Vacinas Antimaláricas , Malária Falciparum/prevenção & controle , Pirimetamina/uso terapêutico , Sulfadoxina/uso terapêutico , Antimaláricos/efeitos adversos , Burkina Faso/epidemiologia , Quimioprevenção , Terapia Combinada , Método Duplo-Cego , Combinação de Medicamentos , Quimioterapia Combinada , Feminino , Hospitalização/estatística & dados numéricos , Humanos , Lactente , Vacinas Antimaláricas/administração & dosagem , Vacinas Antimaláricas/efeitos adversos , Malária Falciparum/epidemiologia , Malária Falciparum/mortalidade , Masculino , Mali/epidemiologia , Estações do Ano , Convulsões Febris/etiologia
12.
Front Immunol ; 12: 612910, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34248928

RESUMO

Hepatocyte infection by malaria sporozoites is a bottleneck in the life-cycle of Plasmodium spp. including P. falciparum, which causes the most lethal form of malaria. Therefore, developing an effective vaccine capable of inducing the strong humoral and cellular immune responses necessary to block the pre-erythrocytic stage has potential to overcome the spatiotemporal hindrances pertaining to parasite biology and hepatic microanatomy. We recently showed that when combined with a human adenovirus type 5 (AdHu5)-priming vaccine, adeno-associated virus serotype 1 (AAV1) is a potent booster malaria vaccine vector capable of inducing strong and long-lasting protective immune responses in a rodent malaria model. Here, we evaluated the protective efficacy of a hepatotropic virus, adeno-associated virus serotype 8 (AAV8), as a booster vector because it can deliver a transgene potently and rapidly to the liver, the organ malaria sporozoites initially infect and multiply in following sporozoite injection by the bite of an infected mosquito. We first generated an AAV8-vectored vaccine expressing P. falciparum circumsporozoite protein (PfCSP). Intravenous (i.v.) administration of AAV8-PfCSP to mice initially primed with AdHu5-PfCSP resulted in a hepatocyte transduction rate ~2.5 times above that seen with intramuscular (i.m.) administration. This immunization regimen provided a better protection rate (100% sterile protection) than that of the i.m. AdHu5-prime/i.m. AAV8-boost regimen (60%, p < 0.05), i.m. AdHu5-prime/i.v. AAV1-boost (78%), or i.m. AdHu5-prime/i.m. AAV1-boost (80%) against challenge with transgenic PfCSP-expressing P. berghei sporozoites. Compared with the i.m. AdHu5-prime/i.v. AAV1-boost regimen, three other regimens induced higher levels of PfCSP-specific humoral immune responses. Importantly, a single i.v. dose of AAV8-PfCSP recruited CD8+ T cells, especially resident memory CD8+ T cells, in the liver. These data suggest that boost with i.v. AAV8-PfCSP can improve humoral and cellular immune responses in BALB/c mice. Therefore, this regimen holds great promise as a next-generation platform for the development of an effective malaria vaccine.


Assuntos
Dependovirus/imunologia , Imunização Secundária/métodos , Fígado/imunologia , Vacinas Antimaláricas/imunologia , Malária Falciparum/prevenção & controle , Plasmodium falciparum/imunologia , Vacinas contra Adenovirus/imunologia , Animais , Anticorpos Antiprotozoários/imunologia , Antígenos de Protozoários/imunologia , Linfócitos T CD8-Positivos/imunologia , Linhagem Celular , Dependovirus/genética , Modelos Animais de Doenças , Feminino , Células HEK293 , Humanos , Memória Imunológica , Fígado/citologia , Fígado/efeitos dos fármacos , Vacinas Antimaláricas/administração & dosagem , Malária Falciparum/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Proteínas de Protozoários/imunologia , Vacinas de DNA/imunologia
13.
Malar J ; 20(1): 308, 2021 Jul 09.
Artigo em Inglês | MEDLINE | ID: mdl-34243763

RESUMO

BACKGROUND: Vaccination with radiation-attenuated Plasmodium falciparum sporozoites is known to induce protective immunity. However, the mechanisms underlying this protection remain unclear. In this work, two recent radiation-attenuated sporozoite vaccination studies were used to identify potential transcriptional correlates of vaccination-induced protection. METHODS: Longitudinal whole blood RNAseq transcriptome responses to immunization with radiation-attenuated P. falciparum sporozoites were analysed and compared across malaria-naïve adult participants (IMRAS) and malaria-experienced adult participants (BSPZV1). Parasite dose and method of delivery differed between trials, and immunization regimens were designed to achieve incomplete protective efficacy. Observed protective efficacy was 55% in IMRAS and 20% in BSPZV1. Study vaccine dosings were chosen to elicit both protected and non-protected subjects, so that protection-associated responses could be identified. RESULTS: Analysis of comparable time points up to 1 week after the first vaccination revealed a shared cross-study transcriptional response programme, despite large differences in number and magnitude of differentially expressed genes between trials. A time-dependent regulatory programme of coherent blood transcriptional modular responses was observed, involving induction of inflammatory responses 1-3 days post-vaccination, with cell cycle responses apparent by day 7 in protected individuals from both trials. Additionally, strongly increased induction of inflammation and interferon-associated responses was seen in non-protected IMRAS participants. All individuals, except for non-protected BSPZV1 participants, showed robust upregulation of cell-cycle associated transcriptional responses post vaccination. CONCLUSIONS: In summary, despite stark differences between the two studies, including route of vaccination and status of malaria exposure, responses were identified that were associated with protection after PfRAS vaccination. These comprised a moderate early interferon response peaking 2 days post vaccination, followed by a later proliferative cell cycle response steadily increasing over the first 7 days post vaccination. Non-protection is associated with deviations from this model, observed in this study with over-induction of early interferon responses in IMRAS and failure to mount a cell cycle response in BSPZV1.


Assuntos
Vacinas Antimaláricas/uso terapêutico , Malária Falciparum/prevenção & controle , Anticorpos Antiprotozoários/sangue , Ensaios Clínicos como Assunto , Humanos , Vacinas Antimaláricas/administração & dosagem , Plasmodium falciparum/genética , Plasmodium falciparum/imunologia , Proteínas de Protozoários/genética , Esporozoítos/genética , Esporozoítos/imunologia , Transcrição Gênica , Vacinas Atenuadas/administração & dosagem , Vacinas Atenuadas/uso terapêutico
14.
Cell Rep ; 35(2): 108996, 2021 04 13.
Artigo em Inglês | MEDLINE | ID: mdl-33852850

RESUMO

Antibodies targeting the NANP/NVDP repeat domain of the Plasmodium falciparum circumsporozoite protein (CSPRepeat) can protect against malaria. However, it has also been suggested that the CSPRepeat is a decoy that prevents the immune system from mounting responses against other domains of CSP. Here, we show that, following parasite immunization, B cell responses to the CSPRepeat are immunodominant over responses to other CSP domains despite the presence of similar numbers of naive B cells able to bind these regions. We find that this immunodominance is driven by avid binding of the CSPRepeat to cognate B cells that are able to expand at the expense of B cells with other specificities. We further show that mice immunized with repeat-truncated CSP molecules develop responses to subdominant epitopes and are protected against malaria. These data demonstrate that the CSPRepeat functions as a decoy, but truncated CSP molecules may be an approach for malaria vaccination.


Assuntos
Anticorpos Antiprotozoários/biossíntese , Imunização/métodos , Vacinas Antimaláricas/administração & dosagem , Malária/prevenção & controle , Peptídeos/administração & dosagem , Plasmodium berghei/efeitos dos fármacos , Proteínas de Protozoários/genética , Animais , Anopheles/parasitologia , Anticorpos Neutralizantes/biossíntese , Linfócitos B/imunologia , Linfócitos B/parasitologia , Feminino , Expressão Gênica , Malária/imunologia , Malária/parasitologia , Vacinas Antimaláricas/biossíntese , Vacinas Antimaláricas/genética , Camundongos , Camundongos Endogâmicos C57BL , Peptídeos/genética , Peptídeos/imunologia , Plasmodium berghei/imunologia , Plasmodium berghei/patogenicidade , Plasmodium falciparum/efeitos dos fármacos , Plasmodium falciparum/imunologia , Plasmodium falciparum/patogenicidade , Ligação Proteica , Proteínas de Protozoários/imunologia , Esporozoítos/imunologia , Esporozoítos/efeitos da radiação , Transgenes , Vacinas Atenuadas
15.
Cell Rep Med ; 2(3): 100207, 2021 03 16.
Artigo em Inglês | MEDLINE | ID: mdl-33763653

RESUMO

Interactions between B cells and CD4+ T follicular helper (Tfh) cells are key determinants of humoral responses. Using samples from clinical trials performed with the malaria vaccine candidate antigen Plasmodium falciparum merozoite protein (PfRH5), we compare the frequency, phenotype, and gene expression profiles of PfRH5-specific circulating Tfh (cTfh) cells elicited by two leading human vaccine delivery platforms: heterologous viral vector prime boost and protein with AS01B adjuvant. We demonstrate that the protein/AS01B platform induces a higher-magnitude antigen-specific cTfh cell response and that this correlates with peak anti-PfRH5 IgG concentrations, frequency of PfRH5-specific memory B cells, and antibody functionality. Furthermore, our data indicate a greater Th2/Tfh2 skew within the polyfunctional response elicited following vaccination with protein/AS01B as compared to a Th1/Tfh1 skew with viral vectors. These data highlight the impact of vaccine platform on the cTfh cell response driving humoral immunity, associating a high-magnitude, Th2-biased cTfh response with potent antibody production.


Assuntos
Anticorpos Antiprotozoários/biossíntese , Proteínas de Transporte/imunologia , Imunidade Humoral/efeitos dos fármacos , Vacinas Antimaláricas/imunologia , Malária Falciparum/prevenção & controle , Plasmodium falciparum/imunologia , Adenoviridae/genética , Adenoviridae/imunologia , Adolescente , Adulto , Linfócitos B/citologia , Linfócitos B/imunologia , Proteínas de Transporte/administração & dosagem , Proteínas de Transporte/genética , Feminino , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Vetores Genéticos/química , Vetores Genéticos/imunologia , Humanos , Imunogenicidade da Vacina , Interferon gama/genética , Interferon gama/imunologia , Interleucina-5/genética , Interleucina-5/imunologia , Lipídeo A/administração & dosagem , Lipídeo A/análogos & derivados , Vacinas Antimaláricas/administração & dosagem , Vacinas Antimaláricas/genética , Malária Falciparum/imunologia , Malária Falciparum/parasitologia , Masculino , Pessoa de Meia-Idade , Receptores CXCR5/genética , Receptores CXCR5/imunologia , Saponinas/administração & dosagem , Células T Auxiliares Foliculares/citologia , Células T Auxiliares Foliculares/imunologia , Células Th2/citologia , Células Th2/imunologia , Vacinação , Vacinas de Subunidades Antigênicas , Vaccinia virus/genética , Vaccinia virus/imunologia
16.
Nat Commun ; 12(1): 1750, 2021 03 19.
Artigo em Inglês | MEDLINE | ID: mdl-33741942

RESUMO

Malaria elimination requires tools that interrupt parasite transmission. Here, we characterize B cell receptor responses among Malian adults vaccinated against the first domain of the cysteine-rich 230 kDa gamete surface protein Pfs230, a key protein in sexual stage development of P. falciparum parasites. Among nine Pfs230 human monoclonal antibodies (mAbs) that we generated, one potently blocks transmission to mosquitoes in a complement-dependent manner and reacts to the gamete surface; the other eight show only low or no blocking activity. The structure of the transmission-blocking mAb in complex with vaccine antigen reveals a large discontinuous conformational epitope, specific to domain 1 of Pfs230 and comprising six structural elements in the protein. The epitope is conserved, suggesting the transmission-blocking mAb is broadly functional. This study provides a rational basis to improve malaria vaccines and develop therapeutic antibodies for malaria elimination.


Assuntos
Anticorpos Monoclonais/farmacologia , Anticorpos Antiprotozoários/farmacologia , Epitopos/imunologia , Células Germinativas/imunologia , Malária Falciparum/prevenção & controle , Plasmodium falciparum/efeitos dos fármacos , Adulto , Animais , Anticorpos Monoclonais/imunologia , Anticorpos Antiprotozoários/imunologia , Antígenos de Protozoários/química , Antígenos de Protozoários/imunologia , Sítios de Ligação , Células Cultivadas , Epitopos/química , Interações Hospedeiro-Parasita/efeitos dos fármacos , Interações Hospedeiro-Parasita/imunologia , Humanos , Vacinas Antimaláricas/administração & dosagem , Vacinas Antimaláricas/imunologia , Malária Falciparum/parasitologia , Malária Falciparum/transmissão , Mosquitos Vetores/parasitologia , Plasmodium falciparum/imunologia , Plasmodium falciparum/fisiologia , Conformação Proteica , Proteínas de Protozoários/química , Proteínas de Protozoários/imunologia
17.
Am J Trop Med Hyg ; 104(2): 695-699, 2020 11 23.
Artigo em Inglês | MEDLINE | ID: mdl-33236704

RESUMO

Providing medical care for participants in clinical trials in resource-limited settings can be challenging and costly. Evaluation and treatment of a young man who developed cervical lymphadenopathy during a malaria vaccine trial in Equatorial Guinea required concerted efforts of a multinational, multidisciplinary team. Once a diagnosis of diffuse large B-cell lymphoma was made, the patient was taken to India to receive immunochemotherapy. This case demonstrates how high-quality medical care was provided for a serious illness that occurred during a trial that was conducted in a setting in which positron emission tomography for diagnostic staging, an oncologist for supervision of treatment, and an optimal therapeutic intervention were not available. Clinical researchers should anticipate the occurrence of medical conditions among study subjects, clearly delineate the extent to which health care will be provided, and set aside funds commensurate with those commitments.


Assuntos
Serviços Técnicos Hospitalares , Linfoma Difuso de Grandes Células B/diagnóstico , Vacinas Antimaláricas/administração & dosagem , Malária/prevenção & controle , Adulto , Ensaios Clínicos Fase I como Assunto , Guiné Equatorial/epidemiologia , Humanos , Índia , Linfoma Difuso de Grandes Células B/terapia , Malária/epidemiologia , Masculino , Centros de Atenção Terciária
18.
Biologicals ; 67: 42-48, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32718776

RESUMO

Plasmodium falciparum leads to a virulent form of malaria. Progress has been achieved in understanding the mechanisms involved in the malarial infection, still there is no effective vaccine to prevent severe infection. An effective vaccine against malaria should be one which can induce immune responses against multiple epitopes in the context of predominantly occurring HLA alleles. In this study, an integrated approach was employed to identify promiscuous peptides of a well-defined sequence of erythrocyte binding antigen-175 and promiscuous peptides for HLA alleles were designed using bioinformatics tools. A peptide with 15 amino acids (ILAIAIYESRILKRK) was selected based on its high binding affinity score and synthesized. This promiscuous peptide was used as stimulating antigen in lymphoproliferative responses to evaluate the cellular immune response. It was observed this peptide evokes lymphoproliferative and cytokine responses in individuals naturally exposed to the malaria parasite. The intensity of PBMCs proliferation was observed to be higher in sera obtained from P. falciparum exposed as compared to unexposed healthy individuals, suggesting earlier recognition of peptide of this region by T cells. Furthermore, the binding mode of HLA-peptide complex and their interaction may lead to a rational and selective peptide-based vaccine candidate design approach which can be used as a malaria prophylaxis.


Assuntos
Antígenos de Protozoários/imunologia , Vacinas Antimaláricas/imunologia , Malária Falciparum/imunologia , Peptídeos/imunologia , Plasmodium falciparum/imunologia , Proteínas de Protozoários/imunologia , Alelos , Sequência de Aminoácidos , Antígenos de Protozoários/metabolismo , Células Cultivadas , Desenho de Fármacos , Antígenos HLA/genética , Antígenos HLA/imunologia , Antígenos HLA/metabolismo , Humanos , Interferon gama/imunologia , Interferon gama/metabolismo , Interleucina-4/imunologia , Interleucina-4/metabolismo , Vacinas Antimaláricas/administração & dosagem , Malária Falciparum/parasitologia , Malária Falciparum/prevenção & controle , Simulação de Acoplamento Molecular , Peptídeos/química , Peptídeos/metabolismo , Plasmodium falciparum/metabolismo , Plasmodium falciparum/fisiologia , Ligação Proteica , Proteínas de Protozoários/metabolismo , Linfócitos T/imunologia , Linfócitos T/metabolismo , Linfócitos T/parasitologia
19.
Int J Biol Macromol ; 158: 159-179, 2020 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-32360460

RESUMO

Human malaria is a pathogenic disease mainly caused by Plasmodium falciparum, which was responsible for about 405,000 deaths globally in the year 2018. To date, several vaccine candidates have been evaluated for prevention, which failed to produce optimal output at various preclinical/clinical stages. This study is based on designing of polypeptide vaccines (PVs) against human malaria that cover almost all stages of life-cycle of Plasmodium and for the same 5 genome derived predicted antigenic proteins (GDPAP) have been used. For the development of a multi-immune inducer, 15 PVs were initially designed using T-cell epitope ensemble, which covered >99% human population as well as linear B-cell epitopes with or without adjuvants. The immune simulation of PVs showed higher levels of T-cell and B-cell activities compared to positive and negative vaccine controls. Furthermore, in silico cloning of PVs and codon optimization followed by enhanced expression within Lactococcus lactis host system was also explored. Although, the study has sound theoretical and in silico findings, the in vitro/in vivo evaluation seems imperative to warrant the immunogenicity and safety of PVs towards management of P. falciparum infection in the future.


Assuntos
Epitopos/química , Vacinas Antimaláricas/química , Simulação de Acoplamento Molecular , Plasmodium falciparum/imunologia , Administração Oral , Afinidade de Anticorpos , Sítios de Ligação de Anticorpos , Epitopos/imunologia , Humanos , Imunogenicidade da Vacina , Vacinas Antimaláricas/administração & dosagem , Vacinas Antimaláricas/imunologia , Vacinas de Subunidades Antigênicas/administração & dosagem , Vacinas de Subunidades Antigênicas/química , Vacinas de Subunidades Antigênicas/imunologia
20.
Eur J Cancer ; 129: 80-96, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32145473

RESUMO

The main goal of peptide-based cancer vaccines is to induce the immune system and activation of effective T cell responses against cancerous cells. Nevertheless, the potency of peptide vaccines is insufficient in most of cases and had limited clinical success. Therefore, the optimization of peptide-based cancer vaccine is essential to achieve powerful therapeutic outcomes. One strategy to enhanced potency of peptide vaccines and induce strong immune responses is the preparation of multi-epitope peptide formulation containing both Th- and cytotoxic T lymphocyte-induced responses epitope using suitable delivery system. For this reason, we studied the effect of Dioleoylphosphatidylethanolamine-containing liposomal vaccine composed of a mixture of short peptides AE36 and E75 (HER2/neu-derived peptides) and long multi-epitope peptide E75-AE36 (linkage of short peptides) in combination with a Pan HLA-DR epitope (PADRE) peptide. These formulations were examined using a series of subcutaneously injection to HER-2+ TUBO-tumoured mice in prophylactic and therapeutic model. We observed that mice vaccinated with liposomal long peptide in combination with PADRE resulted in the superior induction of CD4+ and CD8+ T cells responses and significantly enhanced production of IFN-γ compared with liposomal short peptides and non-liposomal peptides formulations. Moreover, liposome-long peptide with PADRE led to the considerable reduction of tumour growth and lifespan induction in mouse model. In conclusion, our study indicated that liposomal formulation containing long multi-epitope peptide E75-AE36 with PADRE could be used as an effective multi-epitope prophylactic/therapeutic vaccine to generate potent antigen-specific CD8+ T-cell immune response and may be introduced as a possible candidate peptide vaccine for breast cancer.


Assuntos
Neoplasias da Mama/terapia , Vacinas Anticâncer/administração & dosagem , Imunogenicidade da Vacina , Vacinas Antimaláricas/administração & dosagem , Fragmentos de Peptídeos/administração & dosagem , Animais , Neoplasias da Mama/imunologia , Vacinas Anticâncer/imunologia , Linhagem Celular Tumoral/transplante , Modelos Animais de Doenças , Feminino , Humanos , Lipossomos , Vacinas Antimaláricas/imunologia , Camundongos , Nanopartículas , Fragmentos de Peptídeos/imunologia , Receptor ErbB-2/imunologia , Linfócitos T Citotóxicos/imunologia , Linfócitos T Auxiliares-Indutores/imunologia , Vacinas de Subunidades Antigênicas/administração & dosagem , Vacinas de Subunidades Antigênicas/imunologia
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA