RESUMEN
RTS,S is an advanced malaria vaccine candidate and confers significant protection against Plasmodium falciparum infection in humans. Little is known about the molecular mechanisms driving vaccine immunity. Here, we applied a systems biology approach to study immune responses in subjects receiving three consecutive immunizations with RTS,S (RRR), or in those receiving two immunizations of RTS,S/AS01 following a primary immunization with adenovirus 35 (Ad35) (ARR) vector expressing circumsporozoite protein. Subsequent controlled human malaria challenge (CHMI) of the vaccinees with Plasmodium-infected mosquitoes, 3 wk after the final immunization, resulted in â¼50% protection in both groups of vaccinees. Circumsporozoite protein (CSP)-specific antibody titers, prechallenge, were associated with protection in the RRR group. In contrast, ARR-induced lower antibody responses, and protection was associated with polyfunctional CD4+ T-cell responses 2 wk after priming with Ad35. Molecular signatures of B and plasma cells detected in PBMCs were highly correlated with antibody titers prechallenge and protection in the RRR cohort. In contrast, early signatures of innate immunity and dendritic cell activation were highly associated with protection in the ARR cohort. For both vaccine regimens, natural killer (NK) cell signatures negatively correlated with and predicted protection. These results suggest that protective immunity against P. falciparum can be achieved via multiple mechanisms and highlight the utility of systems approaches in defining molecular correlates of protection to vaccination.
Asunto(s)
Inmunidad Adaptativa/efectos de los fármacos , Anticuerpos Antiprotozoarios/biosíntesis , Inmunidad Innata/efectos de los fármacos , Vacunas contra la Malaria/administración & dosificación , Malaria Falciparum/inmunología , Proteínas Protozoarias/administración & dosificación , Vacunas Sintéticas/administración & dosificación , Adenoviridae/genética , Adenoviridae/inmunología , Linfocitos B/efectos de los fármacos , Linfocitos B/inmunología , Linfocitos B/metabolismo , Linfocitos T CD4-Positivos/efectos de los fármacos , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/metabolismo , Células Dendríticas/efectos de los fármacos , Células Dendríticas/inmunología , Células Dendríticas/metabolismo , Perfilación de la Expresión Génica , Regulación de la Expresión Génica , Vectores Genéticos/química , Vectores Genéticos/inmunología , Humanos , Inmunización Secundaria/métodos , Inmunogenicidad Vacunal , Células Asesinas Naturales/efectos de los fármacos , Células Asesinas Naturales/inmunología , Células Asesinas Naturales/metabolismo , Malaria Falciparum/parasitología , Malaria Falciparum/prevención & control , Plasmodium falciparum/inmunología , Plasmodium falciparum/patogenicidad , Proteínas Protozoarias/genética , Proteínas Protozoarias/inmunología , Vacunación/métodosRESUMEN
BACKGROUND: The 2014 West African outbreak of Ebola virus disease highlighted the urgent need to develop an effective Ebola vaccine. METHODS: We undertook 2 phase 1 studies assessing safety and immunogenicity of the viral vector modified vaccinia Ankara virus vectored Ebola Zaire vaccine (MVA-EBO-Z), manufactured rapidly on a new duck cell line either alone or in a heterologous prime-boost regimen with recombinant chimpanzee adenovirus type 3 vectored Ebola Zaire vaccine (ChAd3-EBO-Z) followed by MVA-EBO-Z. Adult volunteers in the United Kingdom (n = 38) and Senegal (n = 40) were vaccinated and an accelerated 1-week prime-boost regimen was assessed in Senegal. Safety was assessed by active and passive collection of local and systemic adverse events. RESULTS: The standard and accelerated heterologous prime-boost regimens were well-tolerated and elicited potent cellular and humoral immunogenicity in the United Kingdom and Senegal, but vaccine-induced antibody responses were significantly lower in Senegal. Cellular immune responses measured by flow cytometry were significantly greater in African vaccinees receiving ChAd3 and MVA vaccines in the same rather than the contralateral limb. CONCLUSIONS: MVA biomanufactured on an immortalized duck cell line shows potential for very large-scale manufacturing with lower cost of goods. This first trial of MVA-EBO-Z in humans encourages further testing in phase 2 studies, with the 1-week prime-boost interval regimen appearing to be particularly suitable for outbreak control. CLINICAL TRIALS REGISTRATION: NCT02451891; NCT02485912.
Asunto(s)
Vacunas contra el Virus del Ébola/farmacología , Adolescente , Adulto , Vacunas contra el Virus del Ébola/administración & dosificación , Vacunas contra el Virus del Ébola/efectos adversos , Vacunas contra el Virus del Ébola/inmunología , Ebolavirus/inmunología , Femenino , Humanos , Esquemas de Inmunización , Inmunización Secundaria/efectos adversos , Inmunización Secundaria/métodos , Masculino , Persona de Mediana Edad , Senegal , Reino Unido , Adulto JovenRESUMEN
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.
Asunto(s)
Esquemas de Inmunización , Vacunas contra la Malaria/administración & dosificación , Vacunas contra la Malaria/inmunología , Malaria/prevención & control , Vacunas Sintéticas/administración & dosificación , Vacunas Sintéticas/inmunología , Adolescente , Adulto , Anticuerpos Antiprotozoarios/biosíntesis , Anticuerpos Antiprotozoarios/inmunología , Afinidad de Anticuerpos , Femenino , Humanos , Cadenas Pesadas de Inmunoglobulina/biosíntesis , Cadenas Ligeras de Inmunoglobulina/biosíntesis , Masculino , Persona de Mediana Edad , Adulto JovenRESUMEN
BACKGROUND: Blood-stage malaria vaccines are intended to prevent clinical disease. The malaria vaccine FMP2.1/AS02(A), a recombinant protein based on apical membrane antigen 1 (AMA1) from the 3D7 strain of Plasmodium falciparum, has previously been shown to have immunogenicity and acceptable safety in Malian adults and children. METHODS: In a double-blind, randomized trial, we immunized 400 Malian children with either the malaria vaccine or a control (rabies) vaccine and followed them for 6 months. The primary end point was clinical malaria, defined as fever and at least 2500 parasites per cubic millimeter of blood. A secondary end point was clinical malaria caused by parasites with the AMA1 DNA sequence found in the vaccine strain. RESULTS: The cumulative incidence of the primary end point was 48.4% in the malaria-vaccine group and 54.4% in the control group; efficacy against the primary end point was 17.4% (hazard ratio for the primary end point, 0.83; 95% confidence interval [CI], 0.63 to 1.09; P=0.18). Efficacy against the first and subsequent episodes of clinical malaria, as defined on the basis of various parasite-density thresholds, was approximately 20%. Efficacy against clinical malaria caused by parasites with AMA1 corresponding to that of the vaccine strain was 64.3% (hazard ratio, 0.36; 95% CI, 0.08 to 0.86; P=0.03). Local reactions and fever after vaccination were more frequent with the malaria vaccine. CONCLUSIONS: On the basis of the primary end point, the malaria vaccine did not provide significant protection against clinical malaria, but on the basis of secondary results, it may have strain-specific efficacy. If this finding is confirmed, AMA1 might be useful in a multicomponent malaria vaccine. (Funded by the National Institute of Allergy and Infectious Diseases and others; ClinicalTrials.gov number, NCT00460525.).
Asunto(s)
Anticuerpos Antiprotozoarios/sangre , Vacunas contra la Malaria , Malaria Falciparum/prevención & control , Antígenos de Protozoos/inmunología , Preescolar , Método Doble Ciego , Femenino , Humanos , Estimación de Kaplan-Meier , Vacunas contra la Malaria/efectos adversos , Vacunas contra la Malaria/inmunología , Malaria Falciparum/parasitología , Masculino , Plasmodium falciparum/inmunología , Plasmodium falciparum/aislamiento & purificación , Modelos de Riesgos Proporcionales , Vacunas AntirrábicasRESUMEN
BACKGROUND: The RTS,S/AS malaria candidate vaccine is being developed with the intent to be delivered, if approved, through the Expanded Programme on Immunization (EPI) of the World Health Organization. Safety, immunogenicity and efficacy of the RTS,S/AS02(D) vaccine candidate when integrated into a standard EPI schedule for infants have been reported over a nine-month surveillance period. This paper describes results following 20 months of follow up. METHODS: This Phase IIb, single-centre, randomized controlled trial enrolled 340 infants in Tanzania to receive three doses of RTS,S/AS02(D) or hepatitis B vaccine at 8, 12, and 16 weeks of age. All infants also received DTPw/Hib (diphtheria and tetanus toxoids, whole-cell pertussis vaccine, conjugated Haemophilus influenzae type b vaccine) at the same timepoints. The study was double-blinded to month 9 and single-blinded from months 9 to 20. RESULTS: From month 0 to 20, at least one SAE was reported in 57/170 infants who received RTS,S/AS02(D) (33.5%; 95% confidence interval [CI]: 26.5, 41.2) and 62/170 infants who received hepatitis B vaccine (36.5%; 95% CI: 29.2, 44.2). The SAE profile was similar in both vaccine groups; none were considered to be related to vaccination. At month 20, 18 months after completion of vaccination, 71.8% of recipients of RTS,S/AS02(D) and 3.8% of recipients of hepatitis B vaccine had seropositive titres for anti-CS antibodies; seroprotective levels of anti-HBs antibodies remained in 100% of recipients of RTS,S/AS02(D) and 97.7% recipients of hepatitis B vaccine. Anti-HBs antibody GMTs were higher in the RTS,S/AS02(D) group at all post-vaccination time points compared to control. According to protocol population, vaccine efficacy against multiple episodes of malaria disease was 50.7% (95% CI: -6.5 to 77.1, p = 0.072) and 26.7% (95% CI: -33.1 to 59.6, p = 0.307) over 12 and 18 months post vaccination, respectively. In the Intention to Treat population, over the 20-month follow up, vaccine efficacy against multiple episodes of malaria disease was 14.4% (95% CI: -41.9 to 48.4, p = 0.545). CONCLUSIONS: The acceptable safety profile and good tolerability of RTS,S/AS02(D) in combination with EPI vaccines previously reported from month 0 to 9 was confirmed over a 20 month surveillance period in this infant population. Antibodies against both CS and HBsAg in the RTS,S/AS02(D) group remained significantly higher compared to control for the study duration. Over 18 months follow up, RTS,S/AS02(D) prevented approximately a quarter of malaria cases in the study population. CLINICAL TRIALS: Gov identifier: NCT00289185.
Asunto(s)
Vacunas contra la Malaria/efectos adversos , Vacunas contra la Malaria/inmunología , Malaria/prevención & control , Vacunación/métodos , Anticuerpos Antiprotozoarios/sangre , Anticuerpos Antivirales/sangre , Vacuna contra Difteria, Tétanos y Tos Ferina/administración & dosificación , Método Doble Ciego , Interacciones Farmacológicas , Enfermedades Endémicas , Femenino , Vacunas contra Haemophilus/administración & dosificación , Vacunas contra Hepatitis B/administración & dosificación , Humanos , Lactante , Malaria/epidemiología , Vacunas contra la Malaria/administración & dosificación , Masculino , Tanzanía/epidemiología , Vacunación/efectos adversosRESUMEN
BACKGROUND: The development of an asexual blood stage vaccine against Plasmodium falciparum malaria based on the major merozoite surface protein-1 (MSP1) antigen is founded on the protective efficacy observed in preclinical studies and induction of invasion and growth inhibitory antibody responses. The 42 kDa C-terminus of MSP1 has been developed as the recombinant protein vaccine antigen, and the 3D7 allotype, formulated with the Adjuvant System AS02A, has been evaluated extensively in human clinical trials. In preclinical rabbit studies, the FVO allele of MSP142 has been shown to have improved immunogenicity over the 3D7 allele, in terms of antibody titres as well as growth inhibitory activity of antibodies against both the heterologous 3D7 and homologous FVO parasites. METHODS: Two Phase 1 clinical studies were conducted to examine the safety, reactogenicity and immunogenicity of the FVO allele of MSP142 in the adjuvant system AS01 administered intramuscularly at 0-, 1-, and 2-months: one in the USA and, after evaluation of safety data results, one in Western Kenya. The US study was an open-label, dose escalation study of 10 and 50 µg doses of MSP142 in 26 adults, while the Kenya study, evaluating 30 volunteers, was a double-blind, randomized study of only the 50 µg dose with a rabies vaccine comparator. RESULTS: In these studies it was demonstrated that this vaccine formulation has an acceptable safety profile and is immunogenic in malaria-naïve and malaria-experienced populations. High titres of anti-MSP1 antibodies were induced in both study populations, although there was a limited number of volunteers whose serum demonstrated significant inhibition of blood-stage parasites as measured by growth inhibition assay. In the US volunteers, the antibodies generated exhibited better cross-reactivity to heterologous MSP1 alleles than a MSP1-based vaccine (3D7 allele) previously tested at both study sites. CONCLUSIONS: Given that the primary effector mechanism for blood stage vaccine targets is humoral, the antibody responses demonstrated to this vaccine candidate, both quantitative (total antibody titres) and qualitative (functional antibodies inhibiting parasite growth) warrant further consideration of its application in endemic settings. TRIAL REGISTRATIONS: Clinical Trials NCT00666380.
Asunto(s)
Anticuerpos Antiprotozoarios/inmunología , Antígenos de Protozoos/inmunología , Vacunas contra la Malaria/administración & dosificación , Malaria Falciparum/prevención & control , Proteína 1 de Superficie de Merozoito/inmunología , Plasmodium falciparum/inmunología , Adyuvantes Inmunológicos , Adulto , Formación de Anticuerpos , Reacciones Cruzadas/inmunología , Método Doble Ciego , Ensayo de Inmunoadsorción Enzimática , Femenino , Humanos , Inyecciones Intramusculares , Vacunas contra la Malaria/efectos adversos , Malaria Falciparum/inmunología , Malaria Falciparum/parasitología , MasculinoRESUMEN
BACKGROUND: The RTS,S/AS malaria vaccine is being developed for delivery through the World Health Organization's Expanded Program on Immunization (EPI). We assessed the feasibility of integrating RTS,S/AS02D into a standard EPI schedule for infants. METHODS: In this phase 2B, single-center, double-blind, controlled trial involving 340 infants in Bagamoyo, Tanzania, we randomly assigned 340 infants to receive three doses of either the RTS,S/AS02D vaccine or the hepatitis B vaccine at 8, 12, and 16 weeks of age. All infants also received a vaccine containing diphtheria and tetanus toxoids, whole-cell pertussis vaccine, and conjugated Haemophilus influenzae type b vaccine (DTPw/Hib). The primary objectives were the occurrence of serious adverse events during a 9-month surveillance period and a demonstration of noninferiority of the responses to the EPI vaccines (DTPw/Hib and hepatitis B surface antigen) with coadministration of the RTS,S/AS02D vaccine, as compared with the hepatitis B vaccine. The detection of antibodies against Plasmodium falciparum circumsporozoite and efficacy against malaria infection were secondary objectives. RESULTS: At least one serious adverse event was reported in 31 of 170 infants who received the RTS,S/AS02D vaccine (18.2%; 95% confidence interval [CI], 12.7 to 24.9) and in 42 of 170 infants who received the hepatitis B vaccine (24.7%; 95% CI, 18.4 to 31.9). The results showed the noninferiority of the RTS,S/AS02D vaccine in terms of antibody responses to EPI antigens. One month after vaccination, 98.6% of infants receiving the RTS,S/AS02D vaccine had seropositive titers for anticircumsporozoite antibodies on enzyme-linked immunosorbent assay (ELISA). During the 6-month period after the third dose of vaccine, the efficacy of the RTS,S/AS02D vaccine against first infection with P. falciparum malaria was 65.2% (95% CI, 20.7 to 84.7; P=0.01). CONCLUSIONS: The use of the RTS,S/AS02D vaccine in infants had a promising safety profile, did not interfere with the immunologic responses to coadministered EPI antigens, and reduced the incidence of malaria infection. (ClinicalTrials.gov number, NCT00289185.)
Asunto(s)
Vacunas contra la Malaria , Malaria Falciparum/prevención & control , Animales , Anticuerpos Antiprotozoarios/sangre , Vacunas Bacterianas , Método Doble Ciego , Femenino , Antígenos de Superficie de la Hepatitis B/inmunología , Humanos , Lactante , Estimación de Kaplan-Meier , Vacunas contra la Malaria/administración & dosificación , Vacunas contra la Malaria/efectos adversos , Vacunas contra la Malaria/inmunología , Malaria Falciparum/epidemiología , Malaria Falciparum/inmunología , Masculino , Plasmodium falciparum/inmunología , Proteínas Protozoarias/inmunologíaRESUMEN
BACKGROUND: Plasmodium falciparum malaria is a pressing global health problem. A previous study of the malaria vaccine RTS,S (which targets the circumsporozoite protein), given with an adjuvant system (AS02A), showed a 30% rate of protection against clinical malaria in children 1 to 4 years of age. We evaluated the efficacy of RTS,S given with a more immunogenic adjuvant system (AS01E) in children 5 to 17 months of age, a target population for vaccine licensure. METHODS: We conducted a double-blind, randomized trial of RTS,S/AS01E vaccine as compared with rabies vaccine in children in Kilifi, Kenya, and Korogwe, Tanzania. The primary end point was fever with a falciparum parasitemia density of more than 2500 parasites per microliter, and the mean duration of follow-up was 7.9 months (range, 4.5 to 10.5). RESULTS: A total of 894 children were randomly assigned to receive the RTS,S/AS01E vaccine or the control (rabies) vaccine. Among the 809 children who completed the study procedures according to the protocol, the cumulative number in whom clinical malaria developed was 32 of 402 assigned to receive RTS,S/AS01E and 66 of 407 assigned to receive the rabies vaccine; the adjusted efficacy rate for RTS,S/AS01E was 53% (95% confidence interval [CI], 28 to 69; P<0.001) on the basis of Cox regression. Overall, there were 38 episodes of clinical malaria among recipients of RTS,S/AS01E, as compared with 86 episodes among recipients of the rabies vaccine, with an adjusted rate of efficacy against all malarial episodes of 56% (95% CI, 31 to 72; P<0.001). All 894 children were included in the intention-to-treat analysis, which showed an unadjusted efficacy rate of 49% (95% CI, 26 to 65; P<0.001). There were fewer serious adverse events among recipients of RTS,S/AS01E, and this reduction was not only due to a difference in the number of admissions directly attributable to malaria. CONCLUSIONS: RTS,S/AS01E shows promise as a candidate malaria vaccine. (ClinicalTrials.gov number, NCT00380393.)
Asunto(s)
Vacunas contra la Malaria , Malaria Falciparum/prevención & control , Animales , Anticuerpos Antiprotozoarios/sangre , Método Doble Ciego , Femenino , Humanos , Lactante , Estimación de Kaplan-Meier , Vacunas contra la Malaria/administración & dosificación , Vacunas contra la Malaria/efectos adversos , Vacunas contra la Malaria/inmunología , Malaria Falciparum/inmunología , Masculino , Plasmodium falciparum/inmunología , Modelos de Riesgos Proporcionales , Proteínas Protozoarias/inmunologíaRESUMEN
BACKGROUND: GlaxoSmithKline Biologicals and the PATH Malaria Vaccine Initiative are working in partnership to develop a malaria vaccine to protect infants and children living in malaria endemic regions of sub-Saharan Africa, which can be delivered through the Expanded Programme on Immunization. The RTS,S/AS candidate vaccine has been evaluated in multiple phase I/II studies and shown to have a favourable safety profile and to be well-tolerated in both adults and children. This paper details the design of the phase III multicentre efficacy trial of the RTS,S/AS01 malaria vaccine candidate, which is pivotal for licensure and policy decision-making. METHODS: The phase III trial is a randomized, controlled, multicentre, participant- and observer-blind study on-going in 11 centres associated with different malaria transmission settings in seven countries in sub-Saharan Africa. A minimum of 6,000 children in each of two age categories (6-12 weeks, 5-17 months) have been enrolled. Children were randomized 1:1:1 to one of three study groups: (1) primary vaccination with RTS,S/AS01 and booster dose of RTS,S/AS01; (2) primary vaccination with RTS,S/AS01 and a control vaccine at time of booster; (3) primary vaccination with control vaccine and a control vaccine at time of booster. Primary vaccination comprises three doses at monthly intervals; the booster dose is administered at 18 months post-primary course. Subjects will be followed to study month 32. The co-primary objectives are the evaluation of efficacy over one year post-dose 3 against clinical malaria when primary immunization is delivered at: (1) 6-12 weeks of age, with co-administration of DTPwHepB/Hib antigens and OPV; (2) 5-17 months of age. Secondary objectives include evaluation of vaccine efficacy against severe malaria, anaemia, malaria hospitalization, fatal malaria, all-cause mortality and other serious illnesses including sepsis and pneumonia. Efficacy of the vaccine against clinical malaria under different transmission settings, the evolution of efficacy over time and the potential benefit of a booster will be evaluated. In addition, the effect of RTS,S/AS01 vaccination on growth, and the safety and immunogenicity in HIV-infected and malnourished children will be assessed. Safety of the primary course of immunization and the booster dose will be documented in both age categories. CONCLUSIONS: This pivotal phase III study of the RTS,S/AS01 candidate malaria vaccine in African children was designed and implemented by the Clinical Trials Partnership Committee. The study will provide efficacy and safety data to fulfil regulatory requirements, together with data on a broad range of endpoints that will facilitate the evaluation of the public health impact of the vaccine and will aid policy and implementation decisions. TRIAL REGISTRATION: Clinicaltrials.gov NCT00866619.
Asunto(s)
Vacunas contra la Malaria/administración & dosificación , Vacunas contra la Malaria/inmunología , Malaria/prevención & control , África , África del Sur del Sahara , Método Doble Ciego , Aprobación de Drogas , Humanos , Inmunización Secundaria/métodos , Lactante , Malaria/inmunología , Vacunas contra la Malaria/efectos adversos , Resultado del Tratamiento , Vacunación/métodosRESUMEN
BACKGROUND: Patterns of expressed genes in the peripheral blood mononuclear cells of persons who were receiving RTS,S/AS01 or RTS,S/AS02 malaria vaccine and were undergoing experimental challenge with mosquito-borne falciparum malaria were examined to identify markers associated with protection. METHODS: Thirty-nine vaccine recipients were assessed at study entry; on the day of the third vaccination; at 24 h, 72 h, and 2 weeks after vaccination; and on day 5 after challenge. Of 39 vaccine recipients, 13 were protected and 26 were not. Eleven vaccine recipients exhibited delayed onset of parasitemia. All infectivity control subjects developed parasitemia. Prediction analysis of microarrays identified genes corresponding with protection. Gene set enrichment analysis identified sets of genes associated with protection after the third vaccination and before challenge. RESULTS: After the third vaccination and before challenge, differential expression of genes in the immunoproteasome pathway distinguished protected and nonprotected persons. At 5 days after challenge, differential expression of genes associated with programmed cell death distinguished between subjects protected and not protected from malaria blood-stage infection. CONCLUSIONS: The up-regulation of genes associated with the efficient processing of major histocompatibility complex peptides suggests a potential role of the vaccine in conferring major histocompatibility complex class 1-mediated protection and may represent a useful surrogate marker of vaccine efficacy without the need for challenge.
Asunto(s)
Complejo Mayor de Histocompatibilidad/inmunología , Vacunas contra la Malaria/inmunología , Complejo de la Endopetidasa Proteasomal/genética , Complejo de la Endopetidasa Proteasomal/inmunología , Adyuvantes Inmunológicos/administración & dosificación , Presentación de Antígeno/genética , Presentación de Antígeno/inmunología , Proteínas Reguladoras de la Apoptosis/genética , Proteínas Reguladoras de la Apoptosis/inmunología , Células Cultivadas , Biología Computacional/métodos , Femenino , Perfilación de la Expresión Génica/métodos , Humanos , Leucocitos Mononucleares/inmunología , Complejo Mayor de Histocompatibilidad/genética , Vacunas contra la Malaria/administración & dosificación , Masculino , Análisis de Secuencia por Matrices de Oligonucleótidos/métodosRESUMEN
An effective vaccine would be a valuable tool for malaria control and elimination; however, the leading malaria vaccine in development, RTS,S/AS01, provided only partial protection in a Phase 3 trial. R21 is a next-generation RTS,S-like vaccine. We have previously shown in mice that R21 administered in Matrix-M is highly immunogenic, able to elicit complete protection against sporozoite challenge, and can be successfully administered with TRAP based viral-vectors resulting in enhanced protection. In this study, we developed a novel, GMP-compatible purification process for R21, and evaluated the immunogenicity and protective efficacy of ultra-low doses of both R21 and RTS,S when formulated in AS01. We demonstrated that both vaccines are highly immunogenic and also elicit comparable high levels of protection against transgenic parasites in BALB/c mice. By lowering the vaccine dose there was a trend for increased immunogenicity and sterile protection, with the highest dose vaccine groups achieving the lowest efficacy (50% sterile protection). We also evaluated the ability to combine RTS,S/AS01 with TRAP based viral-vectors and observed concurrent induction of immune responses to both antigens with minimal interference when mixing the vaccines prior to administration. These studies suggest that R21 or RTS,S could be combined with viral-vectors for a multi-component vaccination approach and indicate that low dose vaccination should be fully explored in humans to maximize potential efficacy.
Asunto(s)
Anticuerpos Antiprotozoarios/sangre , Vacunas contra la Malaria/administración & dosificación , Malaria/prevención & control , Vacunas Sintéticas/administración & dosificación , Animales , Relación Dosis-Respuesta a Droga , Sinergismo Farmacológico , Femenino , Humanos , Inmunización , Malaria/inmunología , Vacunas contra la Malaria/inmunología , Ratones , Ratones Endogámicos BALB C , Ratones Transgénicos , Vacunas Sintéticas/inmunología , Vacunas de Partículas Similares a Virus/administración & dosificación , Vacunas de Partículas Similares a Virus/inmunologíaRESUMEN
The RTS,S/AS01 vaccine provides partial protection against Plasmodium falciparum infection but determinants of protection and/or disease are unclear. Previously, anti-circumsporozoite protein (CSP) antibody titers and blood RNA signatures were associated with RTS,S/AS01 efficacy against controlled human malaria infection (CHMI). By analyzing host blood transcriptomes from five RTS,S vaccination CHMI studies, we demonstrate that the transcript ratio MX2/GPR183, measured 1 day after third immunization, discriminates protected from non-protected individuals. This ratiometric signature provides information that is complementary to anti-CSP titer levels for identifying RTS,S/AS01 immunized people who developed protective immunity and suggests a role for interferon and oxysterol signaling in the RTS,S mode of action.
Asunto(s)
Vacunas contra la Malaria/inmunología , Malaria Falciparum/genética , Malaria Falciparum/prevención & control , Proteínas de Resistencia a Mixovirus/genética , Plasmodium falciparum/inmunología , Receptores Acoplados a Proteínas G/genética , Transcriptoma , Vacunación , Vacunas Sintéticas/inmunología , Anticuerpos Antiprotozoarios/inmunología , Estudios de Cohortes , Humanos , Inmunogenicidad Vacunal/genética , Control de Infecciones/métodos , Malaria Falciparum/inmunología , Malaria Falciparum/parasitología , Proteínas Protozoarias/inmunología , RNA-Seq , Análisis de la Célula IndividualRESUMEN
Results from clinical trials in areas where malaria is endemic have shown that immunization with RTS,S/AS02A malaria vaccine candidate induces partial protection in adults and children and cellular effector and memory responses in adults. For the first time in a malaria vaccine trial, we sought to assess the cell-mediated immune responses to RTS,S antigen components in infants under 1 year of age participating in a clinical phase I/IIb trial of RTS,S/AS02D in Mozambique. Circumsporozoite protein (CSP)-specific responses were detected in approximately half of RTS,S-immunized infants and included gamma interferon (IFN-gamma), interleukin-2 (IL-2), and combined IL-2/IL-4 responses. The median stimulation indices of cytokine-producing CD4(+) and CD8(+) cells were very low but significantly higher in RTS,S-immunized infants than in infants that received the comparator vaccine. Protection against subsequent malarial infection tended to be associated with a higher percentage of individuals with CSP-specific IL-2 in the supernatant (P = 0.053) and with higher CSP-specific IFN-gamma-producing CD8(+) T-cell responses (P = 0.07). These results report for the first time the detection of malaria-specific cellular immune responses after vaccination of infants less than 1 year of age and pave the way for future field studies of cellular immunity to malaria vaccine candidates.
Asunto(s)
Leucocitos Mononucleares/inmunología , Vacunas contra la Malaria/inmunología , Malaria Falciparum/prevención & control , Plasmodium falciparum/inmunología , Subgrupos de Linfocitos T/inmunología , Adulto , Animales , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD8-positivos/inmunología , Femenino , Humanos , Lactante , Recién Nacido , Interferón gamma/metabolismo , Interleucina-2/metabolismo , Interleucina-4/metabolismo , Mozambique , Placebos/administración & dosificación , Embarazo , Proteínas Protozoarias/inmunologíaRESUMEN
The RTS,S/AS candidate malaria vaccine has demonstrated efficacy against a variety of endpoints in Phase IIa and Phase IIb trials over more than a decade. A multi-country phase III trial of RTS,S/AS01 is now underway with submission as early as 2012, if vaccine safety and efficacy are confirmed. The immunologic basis for how the vaccine protects against both infection and disease remains uncertain. It is, therefore, timely to review the information currently available about the vaccine with regard to how it impacts the human-Plasmodium falciparum host-pathogen relationship. In this article, what is known about mechanisms involved in partial protection against malaria induced by RTS,S is reviewed.
Asunto(s)
Benzamidas/farmacología , Vacunas contra la Malaria/inmunología , Malaria Falciparum/inmunología , Malaria Falciparum/prevención & control , Plasmodium falciparum/inmunología , Piridinas/farmacología , Animales , Ensayos Clínicos como Asunto , HumanosRESUMEN
RTS,S is a pre-erythrocytic malaria vaccine candidate antigen based on the circumsporozoite surface protein of Plasmodium falciparum fused to HBsAg, incorporating a novel Adjuvant System (AS02). The first field efficacy of RTS,S/AS02 against infection was demonstrated in a trial initiated in The Gambia in 1998. This paper presents the five-year safety and immunogenicity follow up of the 306 men who were enrolled in the original trial. In the primary study men aged 18 to 45 years were randomized to receive either RTS,S/AS02 or rabies vaccine at 0, 1, 5 months followed by a booster dose at month 19. The subjects were observed for long term safety and immunogenicity continuously until month 58. Of the 153 subjects in each group at enrollment, 80 (52%) subjects in the RTS,S/AS02 group and 83 (54%) subjects in the rabies group returned for the final long-term follow-up visit at month 58. The main reason for non-attendance at month 58 was migration (76% of all drop-outs). Nine subjects in the RTS,S/AS02 group and seven in the rabies group experienced serious adverse events (SAEs) over the 58 month surveillance period, of which seven had a fatal outcome (five RTS,S/AS02 and two rabies group). None of the SAEs with fatal outcome were attributed to the study vaccine. Anti-CS antibody persistence compared to control was observed for five years, although titres had waned from post-booster levels; similar responses in anti-HBs antibody persistence were observed in initially HBsAg seronegative subjects. This study provides the first indication of the long-term safety and persistence of anti-CS and anti-HBs antibodies of the RTS,S vaccine candidate in combination with the novel AS02 Adjuvant System.
Asunto(s)
Vacunas contra la Malaria/efectos adversos , Vacunas contra la Malaria/inmunología , Malaria Falciparum/epidemiología , Malaria Falciparum/prevención & control , Plasmodium falciparum/inmunología , Adolescente , Adulto , Animales , Anticuerpos Antiprotozoarios/sangre , Antígenos de Protozoos/inmunología , Enfermedades Endémicas/prevención & control , Estudios de Seguimiento , Gambia/epidemiología , Humanos , Masculino , Persona de Mediana Edad , Vacunas Antirrábicas/efectos adversos , Vacunas Antirrábicas/inmunología , Adulto JovenRESUMEN
Tuberculosis (TB) remains uncontrolled in many parts of the world and the development of an effective vaccine against TB represents a high priority unmet medical need. Healthy PPD (tuberculin purified protein derivative)-negative adult volunteers, aged 18-40 years received three doses of the candidate Mtb72F/AS02A vaccine according to a 0-1-2 months schedule in an open-label Phase I study (NCT00730795). Solicited, unsolicited and serious adverse events (AEs), hematological and biochemical laboratory parameters were assessed. Mtb72F-specific humoral responses were assessed by ELISA and cell-mediated immune (CMI) responses by intracellular cytokine staining (ICS) and short-term ELISPOT assays. CMI responses to the component peptides (Mtb39a and the Mtb32a C- and N-terminal antigen domains, Mtb32C and Mtb32N) were also assessed by ICS. The Mtb72F/AS02A vaccine appeared to be mainly locally reactogenic but this was considered acceptable, since these AEs were usually transient and resolved within 1-2 days. Most AEs reported were mild in intensity, no serious AEs occurred, no medically significant biochemical or hematological abnormalities related to vaccination were measured and all AEs resolved without sequelae. The vaccine induced statistically significant changes in humoral and CMI response measures. The Mtb72F antigen induced good production of IL-2 and IFNgamma in the ELISPOT assay and CD4(+) T cells expressing at least two activation markers (mainly CD40-L and IL-2) were observed with ICS. A similar CMI profile was observed with Mtb39a and Mtb32N. The induced CMI responses persisted for at least 6 months post-vaccination. All subjects were seropositive for anti-Mtb72F antibodies one month post-dose 2 and 6 months post-dose 3. This first trial in humans found Mtb72F/AS02A to have an acceptable tolerability, to be immunogenic in healthy adults and warrants further development of the vaccine.
Asunto(s)
Vacunas contra la Tuberculosis/efectos adversos , Vacunas contra la Tuberculosis/inmunología , Adulto , Anticuerpos Antibacterianos/sangre , Linfocitos T CD4-Positivos/química , Linfocitos T CD4-Positivos/inmunología , Antígenos CD40/análisis , Citocinas/biosíntesis , Citocinas/metabolismo , Ensayo de Inmunoadsorción Enzimática/métodos , Femenino , Experimentación Humana , Humanos , Inmunización Secundaria/métodos , Leucocitos Mononucleares/inmunología , Masculino , Persona de Mediana Edad , Enfermedades de la Piel/inducido químicamente , Vacunas contra la Tuberculosis/administración & dosificación , Adulto JovenRESUMEN
BACKGROUND: Malaria remains a leading global health problem that requires the improved use of existing interventions and the accelerated development of new control methods. We aimed to assess the safety, immunogenicity, and initial efficacy of the malaria vaccine RTS,S/AS02D in infants in Africa. METHODS: We did a phase I/IIb double-blind randomised trial of 214 infants in Mozambique. Infants were randomly assigned to receive three doses either of RTS,S/AS02D or the hepatitis B vaccine Engerix-B at ages 10 weeks, 14 weeks, and 18 weeks of age, as well as routine immunisation vaccines given at 8, 12, and 16 weeks of age. The primary endpoint was safety of the RTS,S/AS02D during the first 6 months of the study, and analysis was by intention to treat. Secondary endpoints included immunogenicity and analysis of new Plasmodium falciparum infections during a 3-month follow up after the third dose. Time to new infections in the per-protocol cohort were compared between groups using Cox regression models. This study is registered with ClinicalTrials.gov, number NCT00197028. FINDINGS: There were 17 children (15.9%; 95% CI 9.5-24.2) with serious adverse events in each group. In the follow-up which ended on March 6, 2007, there were 31 serious adverse events in the RTS,S/AS02D group and 30 serious adverse events in the Engerix-B group, none of which were reported as related to vaccination. There were four deaths during this same follow-up period; all of them after the active detection of infection period had finished at study month 6 (two in RTSS/AS02D group and two in the Engerix-B group). RTS,S/AS02D induced high titres of anti-circumsporozoite antibodies. 68 first or only P falciparum infections were documented: 22 in the RTS,S/AS02D group and 46 in the control group. The adjusted vaccine efficacy was 65.9% (95% CI 42.6-79.8%, p<0.0001). INTERPRETATION: The RTS,S/AS02D malaria vaccine was safe, well tolerated, and immunogenic in young infants. These findings set the stage for expanded phase III efficacy studies to confirm vaccine efficacy against clinical malaria disease.
Asunto(s)
Vacunas contra la Malaria/efectos adversos , Malaria/prevención & control , Plasmodium falciparum/inmunología , Animales , Anticuerpos Antiprotozoarios/sangre , Método Doble Ciego , Femenino , Humanos , Esquemas de Inmunización , Lactante , Vacunas contra la Malaria/administración & dosificación , Masculino , MozambiqueRESUMEN
GlaxoSmithKline Biologicals (GSK) is committed to the development of a safe and effective malaria vaccine. Its research program in this field was initiated in 1984 and has been continuously active to this day, making it unparalleled within the vaccine industry. Although it works in partnerships with several leading organizations from the public sector, this effort has required GSK to invest major financial and human resource commitments, and its partners rely heavily on the company's global infrastructure and expertise in research, advanced clinical development, regulatory, large-scale manufacturing, and commercialization. Through GSK's pioneering business model and working in partnership with global vaccine funding agencies, the company is committed to seeing that, once approved, a safe and effective malaria vaccine will be available to everyone that needs it.
Asunto(s)
Vacunas contra la Malaria , Malaria/terapia , Animales , Industria Farmacéutica , Humanos , Malaria/parasitología , Malaria/prevención & control , Plasmodium/inmunología , InvestigaciónRESUMEN
The RTS,S candidate malaria vaccine can protect against controlled human malaria infection (CHMI), but how protection is achieved remains unclear. Here, we have analyzed longitudinal peripheral blood transcriptome and immunogenicity data from a clinical efficacy trial in which healthy adults received three RTS,S doses 4 weeks apart followed by CHMI 2 weeks later. Multiway partial least squares discriminant analysis (N-PLS-DA) of transcriptome data identified 110 genes that could be used in predictive models of protection. Among the 110 genes, 42 had known immune-related functions, including 29 that were related to the NF-κB-signaling pathway and 14 to the IFN-γ-signaling pathway. Post-dose 3 serum IFN-γ concentrations were also correlated with protection; and N-PLS-DA of IFN-γ-signaling pathway transcriptome data selected almost all (44/45) of the representative genes for predictive models of protection. Hence, the identification of the NF-κB and IFN-γ pathways provides further insight into how vaccine-mediated protection may be achieved.