RESUMO
Combination of tumor antigens with immunostimulants is a promising approach in cancer immunotherapy. We assessed animal model toxicity of AS15 combined with various tumor antigens: WT1 (rabbits), or p501, dHER2 and recPRAME (cynomolgus monkeys), administered in seven or 20 dose regimens versus a saline control. Clinical and ophthalmological examinations, followed by extensive post-mortem pathological examinations, were performed on all animals. Blood hematology and biochemistry parameters were also assessed. Antigen-specific antibody titers were determined by enzyme-linked immunosorbent assay. Additional assessments in monkeys included electrocardiography and immunohistochemical evaluations of the p501 expression pattern. Transient increases in body temperature were observed 4 h or 24 h after injections of recPRAME + AS15 and dHER2 + AS15. Edema and erythema were observed up to 1 week after most injections of recPRAME + AS15 and all injections of dHER2 + AS15. No treatment-related effects were observed for electrocardiography parameters. Mean fibrinogen levels were significantly higher in all treated groups compared to controls, but no differences could be observed at the end of the treatment-free period. Transient but significant differences in biochemistry parameters were observed post-injection: lower albumin/globulin ratios (p501 + AS15), and higher bilirubin, urea and creatinine (dHER2 + AS15). Pathology examinations revealed significant increases in axillary lymph node mean weights (recPRAME + AS15) compared to controls. A 100% seroconversion rate was observed in all treated groups, but not in controls. p501 protein expression was observed in prostates of all monkeys from studies assessing p501 + AS15. These results suggest a favorable safety profile of the AS15-containing candidate vaccines, supporting the use of AS15 for clinical development of potential anticancer vaccines.
Assuntos
Adjuvantes Imunológicos/administração & dosagem , Adjuvantes Imunológicos/uso terapêutico , Antígenos de Neoplasias/administração & dosagem , Antígenos de Neoplasias/uso terapêutico , Neoplasias/tratamento farmacológico , Neoplasias/imunologia , Adjuvantes Imunológicos/toxicidade , Animais , Antígenos de Neoplasias/toxicidade , Feminino , Haplorrinos , Injeções Intramusculares , Masculino , Modelos Animais , CoelhosRESUMO
Bovine serum albumin (BSA), employed as a model ligand, was covalently linked (about 16% of the amount used) to small unilamellar vesicles (SUV) composed of phospholipid, cholesterol and N-(p-aminophenyl)stearylamide (APSA) (molar ratios 1:1:0.05). SUV with bound BSA were then used to generate dehydration-rehydration vesicles (DRV) in the presence of tetanus toxoid and/or carboxyfluorescein (CF). Nearly all of the SUV-bound BSA (about 15% of the original amount) was recovered in the multilamellar DRV formed, with a considerable proportion (42-62%) of the ligand becoming available on the outer bilayers. This apparent spatial reorientation of BSA within DRV also caused the entrapped toxoid to shift to some extent to the liposomal surface. There was no significant difference in the z average mean size between DRV with and without coupled BSA (543 and 555 nm diameter, respectively). Percent number diameter distribution data revealed that 71.2 (BSA-free) and 76.4% (BSA-containing DRV) of the vesicles had diameters of about 300-440 and 330-420 nm, respectively. However, in terms of percent mass diameter distribution, 69.5% (BSA-free) and 65.2% (BSA-containing DRV) of the mass was in vesicles with corresponding ranges of diameter of 1381-2975 and 1086-2840 nm. Vesicle size heterogeneity in both preparations was confirmed by freeze-fracture electron microscopy which also indicated that structures with or without bound BSA, were mostly vesicular of the multilamellar type. Judging from CF latency values, ligand-bearing DRV were stable on incubation with blood plasma at 37 degrees C for 24 h. Stability was, however, reduced significantly when the amount of ligand bound was excessive. The present approach allows for the coupling of ligands to and the entrapment of antigens and other labile solutes in liposomes independently, thus avoiding potential damage of such solutes by the coupling reagents.
Assuntos
Ligantes , Lipossomos/química , Colesterol/química , Fluoresceínas , Técnica de Fratura por Congelamento , Microscopia Eletrônica , Tamanho da Partícula , Fosfolipídeos/química , Soroalbumina Bovina/química , Toxoide TetânicoRESUMO
We assessed potential toxic effects of the MAGE-A3 Cancer Immunotherapeutic on female fertility and embryo-fetal, pre- and post-natal development in rats and on male fertility in rats and monkeys. Three groups of 48 female (Study 1) or 22 male (Study 2) CD rats received 5 or 3 injections of 100µL of saline, AS15 immunostimulant, or MAGE-A3 Cancer Immunotherapeutic (MAGE-A3 recombinant protein combined with AS15) at various timepoints pre- or post-mating. Male Cynomolgus monkeys (Study 3) received 8 injections of 500µL of saline (n=2) or the MAGE-A3 Cancer Immunotherapeutic (n=6) every 2 weeks. Rats were sacrificed on gestation day 20 or lactation day 25 (Study 1) or 9 weeks after first injection (Study 2) and monkeys, 3 days or 8 weeks after last injection. Injections were well tolerated. Female rat mating performance or fertility, pre- and post-natal survival, offspring development up to 25 days of age, and male mating performance (rats) or fertility parameters (rats and monkeys) were unaffected.
Assuntos
Antígenos de Neoplasias/imunologia , Vacinas Anticâncer/farmacologia , Desenvolvimento Embrionário/efeitos dos fármacos , Fertilidade/efeitos dos fármacos , Desenvolvimento Fetal/efeitos dos fármacos , Proteínas de Neoplasias/imunologia , Reprodução/efeitos dos fármacos , Animais , Anticorpos/sangue , Feminino , Imunoterapia , Macaca fascicularis , Masculino , RatosRESUMO
Systemically administered CsA has not consistently suppressed the pulmonary immunoreactivity that leads to rejection in lung transplant patients. Pulmonary T cells from patients given CsA systemically still retain their immunoreactivity, which can be suppressed with added CsA. Direct application of CsA by aerosol to the respiratory epithelium should achieve high lung concentrations with minimum systemic effects. In the present study, CsA was most efficiently incorporated into liposomes composed of egg yolk phosphatidylcholine at a molar ratio of CsA to egg yolk phosphatidylcholine of 1:20. These CsA liposomes retained their biological activity and were as effective as free CsA in the suppression of anti-CD3-stimulated [3H]thymidine incorporation by mouse spleen cells. The generation of a small-particle aerosol of CsA liposomes had no effect on this biological activity. CsA liposome aerosol particles have a mass median aerodynamic diameter of 2 microns, which allows for distribution of drug throughout the respiratory tract. Quantitation of CsA in the lungs and blood of mice exposed to CsA liposome aerosols for 4 days showed that as little as 15 min daily (0.11 mg/kg/day) was sufficient to achieve an estimated concentration of CsA in respiratory secretions of 6 micrograms/ml without detectable blood levels. Thus, CsA liposomes can be produced and aerosolized that achieve pulmonary concentrations with sufficient immunosuppressive activity to be effective in the treatment of lung diseases.
Assuntos
Ciclosporina/administração & dosagem , Aerossóis , Animais , Divisão Celular/efeitos dos fármacos , Ciclosporina/farmacocinética , Ciclosporina/farmacologia , Portadores de Fármacos , Lipossomos , Pulmão/metabolismo , Linfócitos/efeitos dos fármacos , Linfócitos/imunologia , Linfócitos/metabolismo , Camundongos , Fosfatidilcolinas , Baço/efeitos dos fármacos , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia , Linfócitos T/metabolismo , Timidina/metabolismo , Distribuição TecidualRESUMO
Interaction of the antiviral compound, enviroxime (E), with natural and synthetic phosphatidylcholines in organic and aqueous media was studied. Although insoluble in chloroform, E dissolved in chloroform solutions containing phosphatidylcholines. Solvation was directly related to the length of the fatty acid chains of the phospholipid. Proton spin resonance studies suggested an interaction of the fatty acid chains with the aromatic rings of E. Suspension of E-phosphatidylcholine mixtures of molar ratios up to 0.7:1.0 in aqueous media resulted in the formation of multilamellar liposomes. Liposomes containing E were more stable permeability barriers than those prepared with phospholipid alone, a property previously observed with cholesterol. Competition experiments suggested that E bound to the same sites in lipid bilayers as does cholesterol. These data indicate that E is incorporated into lipid bilayers of liposomes and that it alters the physical properties of the liposomes in a manner similar to that of cholesterol.
Assuntos
Benzimidazóis/metabolismo , Lipossomos , Fosfatidilcolinas/metabolismo , Clorofórmio , Bicamadas Lipídicas , Oximas , Permeabilidade , Fosfatidilcolinas/síntese química , Solubilidade , Sulfonamidas , ÁguaRESUMO
To ascertain whether live attenuated or inactivated vaccines can be considered equivalent, we examined the primary antibody response of children following vaccination with influenza virus antigens in three different formulations. Nine children received cold recombinant vaccine (CRV) containing A/Korea/82 (H3N2) and A/Dunedin/83 (H1N1) variants. Eight of these children responded to HA of the H3N2 subtype and the major portion of the elicited antibody was in the IgG1 subclass. Antibody of low titer in the IgG2 and IgG3 subclasses was detected in two and six serum specimens, respectively. Six of the nine children administered with CRV responded to the H1 antigen and only IgG1 antibody was detected. Serum specimens from eight children less than one year of age (5 less than 6 months of age) who had developed an antibody response to trivalent inactivated vaccine (TIV) vaccination were examined. High levels of IgG1 antibody to purified H3 were detected in all eight children. Low titers of antibody in IgG2 and IgG3 subclasses were detected in two and five children, respectively. Antibody responses to purified H1 showed a similar subclass distribution. In order to examine secondary response, eight children primed by immunization with TIV vaccine were subsequently given a single booster dose of purified hemagglutinin (HA) conjugated to diphtheria toxoid (HA-D). In 6/8 specimens antibody rises were detected to purified H3 and H1 antigens. Prior to the HA-D immunization, low levels of HA specific IgG1 antibody were detected in all serum specimens and vaccine induced responses were primarily of the IgG1 subclass.(ABSTRACT TRUNCATED AT 250 WORDS)
Assuntos
Anticorpos Antivirais/biossíntese , Imunoglobulina G/biossíntese , Vacinas contra Influenza/imunologia , Vacinação , Vacinas Atenuadas/imunologia , Vacinas de Produtos Inativados/imunologia , Animais , Anticorpos Monoclonais , Anticorpos Antivirais/classificação , Anticorpos Antivirais/imunologia , Especificidade de Anticorpos , Humanos , Imunização , Imunoglobulina G/classificação , Imunoglobulina G/imunologia , Lactente , Influenza Humana/imunologia , Influenza Humana/prevenção & controle , Camundongos , Vacinas Sintéticas/imunologiaRESUMO
The design of a thymus-dependent synthetic vaccine that will provide a universal T cell epitope for B cell epitopes is described in this study. Simultaneous incorporation into liposomes of both a peptide recognized by Th lymphocytes and a lipophilic hapten and the IgG antibody responses to this hapten were assessed in outbred mice. DNP-aminocaproyl phosphatidylethanolamine (DNP-CapPE) is a well characterized T-independent hapten Ag. HA2 peptide derived from the hemagglutinin protein of influenza virus contains amino acid sequences recognized by Th and T cytotoxic lymphocytes. In addition, HA2 contains a sequence of hydrophobic amino acids near the carboxyl terminus, allowing its incorporation into liposomes. Results of immunization show that (i), when DNP-CapPE is carried by liposomes without the HA2 peptide, an IgM antibody response is induced, (ii) liposomes carrying both HA2 and DNP-CapPE elicit an IgG antibody response to DNP in a dose-dependent fashion for both HA2 and DNP, (iii) the liposomes must be processed intracellularly in order to elicit a response, (iv) the system leads to a memory response for DNP, and (v) all of the IgG subclasses are elicited. These data suggest that liposomes containing the HA2 peptide exhibit a T-dependent carrier effect for a T-independent Ag. The significance of these findings is discussed in conjunction with the characteristics of the liposome model used.
Assuntos
Lipossomos/administração & dosagem , Linfócitos T/imunologia , Vacinas/administração & dosagem , Animais , Dinitrobenzenos/imunologia , Feminino , Hemaglutininas/imunologia , Imunização , Imunoglobulina G/biossíntese , Memória Imunológica , CamundongosRESUMO
The effect of the ligand mannosylated albumin, covalently coupled to the surface of tetanus toxoid-containing dehydration-rehydration vesicles (DRV), on their adjuvanticity was investigated. Toxoid-containing DRV coated with mannosylated albumin bound in vitro to mouse (BALB/c) peritoneal macrophages selectively and to a greater extent than non-mannosylated DRV. ELISA assays of anti-toxoid IgG1 and IgG2b in the sera of BALB/c mice immunized with various toxoid-containing DRV preparations suggest that mannosylated liposomes are superior in immunoadjuvant action to conventional ones. Such targeted adjuvanticity appears to be influenced by the number of ligand molecules available on the surface of liposomes rather than the number of mannose residues on albumin.
Assuntos
Adjuvantes Imunológicos/farmacologia , Lipossomos/imunologia , Manose/imunologia , Animais , Anticorpos Antibacterianos/biossíntese , Lipossomos/metabolismo , Macrófagos/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Toxoide Tetânico/imunologiaRESUMO
The design of an adjuvant for eliciting a thymus-dependent response to LPS, a well-defined thymus-independent antigen, is presented. Hybrid liposomes containing LPS and HA2 peptide from the hemagglutinin protein of influenza virus within the liposome bilayer were prepared (LPS/HA2 liposomes). The HA2 polypeptide contains epitopes recognized by T-helper lymphocytes and T-cytotoxic lymphocytes. Outbred mice immunized with LPS/HA2 liposomes produced anti-LPS-specific IgG responses. IgG subclass analysis indicated that IgG1, IgG2, and IgG3 antibodies were produced by these animals. LPS liposomes (liposomes without HA2) stimulated a T-independent response only. This was demonstrated by the detection of IgG3 but not IgG1 or IgG2 in serum of mice immunized with LPS liposomes. These results support the concept that the simultaneous incorporation into liposomes of a polypeptide with T-cell recognition sites along with a T-independent antigen can lead to the generation of cognate T-cell help for the T-independent antigen. The synthesis and characterization of a neo-lipopolysaccharide T-independent antigen for incorporation in hybrid HA2 liposomes are also presented. Findings are discussed relative to the liposome model used and implications for development of vaccines for use in humans.
Assuntos
Anticorpos Antibacterianos/biossíntese , Antígenos T-Independentes/imunologia , Hemaglutininas Virais/imunologia , Lipopolissacarídeos/imunologia , Lipossomos/imunologia , Subpopulações de Linfócitos T/imunologia , Animais , Antígenos T-Independentes/administração & dosagem , Cápsulas Bacterianas , Dinitrofenóis , Epitopos/imunologia , Feminino , Vacinas Anti-Haemophilus/administração & dosagem , Vacinas Anti-Haemophilus/imunologia , Haemophilus influenzae/imunologia , Haptenos , Glicoproteínas de Hemaglutininação de Vírus da Influenza , Hemaglutininas Virais/administração & dosagem , Imunização , Imunoglobulina G/biossíntese , Imunoglobulina M/biossíntese , Vírus da Influenza A/imunologia , Lipopolissacarídeos/administração & dosagem , Camundongos , Polissacarídeos Bacterianos/administração & dosagem , Polissacarídeos Bacterianos/imunologia , Linfócitos T Auxiliares-Indutores/imunologia , Vacinas Sintéticas/imunologiaRESUMO
Over 90% of cervical cancers are associated with HPV infection, the commonest being the HPV-16 subtype. Two early viral genes, E6 and 7, play major roles in the development and maintenance of the malignant phenotype. The vaccine potential of a recombinant HPV16 E7 protein was examined in two murine models of E7-expressing tumours. Formulations including the immunostimulants MPL and QS21 induced therapeutically active immune responses leading to regression of pre-established TC1 tumour lesions, associated with induction of IgG antibodies, lymphoproliferation and CTL. Our data provide a clear incentive to investigate the clinical application of this approach in cancer immunotherapy.
Assuntos
Vacinas Anticâncer/uso terapêutico , Papillomaviridae , Infecções por Papillomavirus/terapia , Infecções Tumorais por Vírus/terapia , Neoplasias do Colo do Útero/terapia , Vacinas Virais/uso terapêutico , Adjuvantes Imunológicos/uso terapêutico , Animais , Anticorpos Antineoplásicos/biossíntese , Anticorpos Antivirais/biossíntese , Vacinas Anticâncer/genética , Feminino , Imunoglobulina G/biossíntese , Técnicas In Vitro , Neoplasias Pulmonares/secundário , Ativação Linfocitária , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Nus , Proteínas Oncogênicas Virais/genética , Proteínas Oncogênicas Virais/imunologia , Proteínas E7 de Papillomavirus , Infecções por Papillomavirus/imunologia , Infecções por Papillomavirus/patologia , Linfócitos T Citotóxicos/imunologia , Infecções Tumorais por Vírus/imunologia , Infecções Tumorais por Vírus/patologia , Neoplasias do Colo do Útero/imunologia , Neoplasias do Colo do Útero/patologia , Vacinas Sintéticas/genética , Vacinas Sintéticas/uso terapêutico , Vacinas Virais/genéticaRESUMO
The mechanisms by which administration of a formalin-inactivated respiratory syncytial virus vaccine resulted in enhanced disease among children after they later became naturally infected with the virus remains largely undefined. After immunization and live virus challenge, the cotton rat demonstrated the histopathologic marker of the enhanced disease, polymorphonuclear leukocyte infiltration of lung alveolar spaces. We now report that immunization with formalin-inactivated vaccine formulated with the adjuvant, 3-deacylated monophosphoryl lipid A, dramatically reduces or eliminates the polymorphonuclear leukocyte infiltration within the alveoli of cotton rats post-challenge. We suggest, that this or similar adjuvants may be beneficial components of candidate non-replicating respiratory syncytial virus vaccines, whose development has been hampered by safety concerns.
Assuntos
Adjuvantes Imunológicos/administração & dosagem , Lipídeo A/administração & dosagem , Vírus Sinciciais Respiratórios/imunologia , Vacinas Virais/efeitos adversos , Vacinas Virais/toxicidade , Animais , Criança , Feminino , Formaldeído , Humanos , Lipídeo A/análogos & derivados , Masculino , Alvéolos Pulmonares/patologia , Infecções por Vírus Respiratório Sincicial/imunologia , Infecções por Vírus Respiratório Sincicial/patologia , Infecções por Vírus Respiratório Sincicial/prevenção & controle , Segurança , Sigmodontinae , Vacinas de Produtos Inativados/efeitos adversos , Vacinas de Produtos Inativados/toxicidadeRESUMO
Several formulations of a recombinant chimeric respiratory syncytial virus (RSV) vaccine consisting of the extramembrane domains of the F and G glycoproteins (FG) were tested in cotton rats to evaluate efficacy and safety. The FG vaccine was highly immunogenic, providing nearly complete resistance to pulmonary infection at doses as low as 25 ng in spite of inducing relatively low levels of serum neutralizing antibody at low vaccine doses. Upon RSV challenge animals primed with FG vaccine showed quite mild alveolitis and interstitial pneumonitis, which were eliminated by the addition of monophosphoryl lipid A to the formulation.
Assuntos
Infecções por Vírus Respiratório Sincicial/prevenção & controle , Vacinas contra Vírus Sincicial Respiratório , Vírus Sinciciais Respiratórios/imunologia , Proteínas Virais/imunologia , Animais , Anticorpos Antivirais/sangue , Pulmão/patologia , Pulmão/virologia , Doenças Pulmonares Intersticiais/prevenção & controle , Testes de Neutralização , Pneumonia Viral/prevenção & controle , Proteínas Recombinantes de Fusão/imunologia , Vacinas contra Vírus Sincicial Respiratório/administração & dosagem , Vacinas contra Vírus Sincicial Respiratório/imunologia , Vírus Sinciciais Respiratórios/isolamento & purificação , Sigmodontinae , Vacinação , Proteínas Virais/genéticaRESUMO
BACKGROUND: The candidate vaccines against malaria are poorly immunogenic and thus have been ineffective in preventing infection. We developed a vaccine based on the circumsporozoite protein of Plasmodium falciparum that incorporates adjuvants selected to enhance the immune response. METHODS: The antigen consists of a hybrid in which the circumsporozoite protein fused to hepatitis B surface antigen (HBsAg) is expressed together with unfused HBsAg. We evaluated three formulations of this antigen in an unblinded trial in 46 subjects who had never been exposed to malaria. RESULTS: Two of the vaccine formulations were highly immunogenic. Four subjects had adverse systemic reactions that may have resulted from the intensity of the immune response after the second dose, which led us to reduce the third dose. Twenty-two vaccinated subjects and six unimmunized controls underwent a challenge consisting of bites from mosquitoes infected with P. falciparum. Malaria developed in all six control subjects, seven of eight subjects who received vaccine 1, and five of seven subjects who received vaccine 2. In contrast, only one of seven subjects who received vaccine 3 became infected (relative risk of infection, 0.14; 95 percent confidence interval, 0.02 to 0.88; P<0.005). CONCLUSIONS: A recombinant vaccine based on fusion of the circumsporozoite protein and HBsAg plus a potent adjuvant can protect against experimental challenge with P. falciparum sporozoites. After additional studies of protective immunity and the vaccination schedule, field trials are indicated for this new vaccine against P. falciparum malaria.
Assuntos
Antígenos de Protozoários/imunologia , Vacinas Antimaláricas/imunologia , Malária Falciparum/imunologia , Proteínas de Protozoários/imunologia , Vacinas Sintéticas/imunologia , Adjuvantes Imunológicos , Adolescente , Adulto , Anticorpos Antiprotozoários/sangue , Epitopos , Feminino , Antígenos de Superfície da Hepatite B/sangue , Antígenos de Superfície da Hepatite B/imunologia , Humanos , Imunoglobulina G/sangue , Vacinas Antimaláricas/efeitos adversos , Malária Falciparum/prevenção & controle , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento , Vacinas Sintéticas/efeitos adversosRESUMO
Mice vaccinated with a recombinant protein containing the two EGF-like modules of Plasmodium yoelii merozoite surface protein-1 in liposomes or combined with the formulations SBAS2.1 and SBAS2, were protected against a lethal malaria infection. The protection achieved with these adjuvants developed for clinical use was as good as or better than that achieved with Freund's adjuvant. A parasite-specific response was needed for protection. Analysis of the immunoglobulin sub-class response showed that MSP-1-specific IgG1, and to a lesser extent IgG2a and IgG2b, were induced, suggesting that these antibodies were important for protection. Mice passively immunized with serum or purified IgG from vaccinated mice had delayed onset of parasitemia and were able to control the infection.
Assuntos
Vacinas Antimaláricas/imunologia , Fragmentos de Peptídeos/imunologia , Plasmodium yoelii/imunologia , Precursores de Proteínas/imunologia , Proteínas de Protozoários/imunologia , Vacinas Sintéticas/imunologia , Adjuvantes Imunológicos/farmacologia , Animais , Anticorpos Antiprotozoários/sangue , Feminino , Imunização Passiva , Proteína 1 de Superfície de Merozoito , Camundongos , Camundongos Endogâmicos BALB C , VacinaçãoRESUMO
Although more than 95% of the vaccinated population responds to the currently licensed vaccines against hepatitis B, some groups were found to be low responders. Lipid A as adjuvant, through its ability to activate macrophages, might improve humoral as well as cellular immune response. Therefore we evaluated the profile of a hepatitis B vaccine with the new adjuvant system SBAS4. 150 young adults were enrolled and randomized into three groups: one received the SBAS4 hepatitis B vaccine, the second Engerix-B(TM) and the third a hepatitis B vaccine with an alternative formulation on alum. Vaccinations were at 0 and 6 months. The vaccine was well tolerated. At month 7 all vaccinees were protected but with significant differences in GMTs between groups: 13,271 mIU/ml for the SBAS4 group versus 1203 and 1823 mIU/ml. Hence the hepatitis B vaccine with the new adjuvant system is more immunogenic compared to the other vaccines containing the same antigen and could be suitable for a two dose schedule.
Assuntos
Adjuvantes Imunológicos , Compostos de Alúmen , Vacinas contra Hepatite B/imunologia , Lipídeo A , Adjuvantes Imunológicos/efeitos adversos , Adolescente , Adulto , Compostos de Alúmen/efeitos adversos , Método Duplo-Cego , Edema/etiologia , Fadiga/etiologia , Feminino , Seguimentos , Cefaleia/etiologia , Anticorpos Anti-Hepatite B/biossíntese , Anticorpos Anti-Hepatite B/sangue , Vacinas contra Hepatite B/efeitos adversos , Humanos , Imunidade Celular , Imunização Secundária/efeitos adversos , Lipídeo A/efeitos adversos , Ativação Linfocitária , Masculino , Dor/etiologia , Segurança , Estudos Soroepidemiológicos , Vacinas Sintéticas/efeitos adversos , Vacinas Sintéticas/imunologiaRESUMO
The malaria sporozoite vaccine candidate RTS,S, formulated with an oil-in-water emulsion plus the immunostimulants monophosphoryl lipid A and the saponin derivative QS21 (vaccine 3), recently showed superior efficacy over two other experimental formulations. Immunized volunteers were followed to determine the duration of protective immune responses. Antibody levels decreased to between one-third and one-half of peak values 6 months after the last dose of vaccine. T cell proliferation and interferon-gamma production in vitro were observed in response to RTS,S or hepatitis B surface antigen. Seven previously protected volunteers received sporozoite challenge, and 2 remained protected (1/1 for vaccine 1, 0/1 for vaccine 2, and 1/5 for vaccine 3). The prepatent period was 10.8 days for the control group and 13.2 days for the vaccinees (P < .01). Immune responses did not correlate with protection. Further optimization in vaccine composition and/or immunization schedule will be required to induce longer-lasting protective immunity.