Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 5 de 5
Filter
Add more filters










Database
Language
Publication year range
1.
NPJ Vaccines ; 3: 49, 2018.
Article in English | MEDLINE | ID: mdl-30323956

ABSTRACT

We assessed a combination multi-stage malaria vaccine schedule in which RTS,S/AS01B was given concomitantly with viral vectors expressing multiple-epitope thrombospondin-related adhesion protein (ME-TRAP) in a 0-month, 1-month, and 2-month schedule. RTS,S/AS01B was given as either three full doses or with a fractional (1/5th) third dose. Efficacy was assessed by controlled human malaria infection (CHMI). Safety and immunogenicity of the vaccine regimen was also assessed. Forty-one malaria-naive adults received RTS,S/AS01B at 0, 4 and 8 weeks, either alone (Groups 1 and 2) or with ChAd63 ME-TRAP at week 0, and modified vaccinia Ankara (MVA) ME-TRAP at weeks 4 and 8 (Groups 3 and 4). Groups 2 and 4 received a fractional (1/5th) dose of RTS,S/AS01B at week 8. CHMI was delivered by mosquito bite 11 weeks after first vaccination. Vaccine efficacy was 6/8 (75%), 8/9 (88.9%), 6/10 (60%), and 5/9 (55.6%) of subjects in Groups 1, 2, 3, and 4, respectively. Immunological analysis indicated significant reductions in anti-circumsporozoite protein antibodies and TRAP-specific T cells at CHMI in the combination vaccine groups. This reduced immunogenicity was only observed after concomitant administration of the third dose of RTS,S/AS01B with the second dose of MVA ME-TRAP. The second dose of the MVA vector with a four-week interval caused significantly higher anti-vector immunity than the first and may have been the cause of immunological interference. Co-administration of ChAd63/MVA ME-TRAP with RTS,S/AS01B led to reduced immunogenicity and efficacy, indicating the need for evaluation of alternative schedules or immunization sites in attempts to generate optimal efficacy.

2.
Front Immunol ; 9: 1660, 2018.
Article in English | MEDLINE | ID: mdl-30090099

ABSTRACT

A malaria vaccine strategy targeting multiple lifecycle stages may be required to achieve a high level of efficacy. In two Phase IIa clinical trials, we tested immunogenicity and efficacy of RTS,S/AS01B administered alone, in a staggered regimen with viral-vectored vaccines or co-administered with viral-vectored vaccines. RTS,S/AS01B induces high titers of antibody against sporozoites and viral-vectored vaccines ChAd63 ME-TRAP and MVA ME-TRAP induce potent T cell responses against infected hepatocytes. By combining these two strategies, we aimed to improve efficacy by inducing immune responses targeting multiple parasite antigens. Vaccination with RTS,S/AS01B alone or in a staggered regimen with viral vectors produced strong immune responses and demonstrated high levels of protection against controlled human malaria infection. However, concomitant administration of these vaccines significantly reduced humoral immunogenicity and protective efficacy. Strong Th1-biased cytokine responses induced by MVA ME-TRAP were associated with a skew in circulating T follicular helper cells toward a CXCR3+ phenotype and a reduction in antibody quantity and quality. This study illustrates that while a multistage-targeting vaccine strategy could provide high-level efficacy, the regimen design will require careful optimization.

3.
N Engl J Med ; 377(15): 1438-1447, 2017 10 12.
Article in English | MEDLINE | ID: mdl-29020589

ABSTRACT

BACKGROUND: The safety and efficacy of vaccines to prevent Ebola virus disease (EVD) were unknown when the incidence of EVD was peaking in Liberia. METHODS: We initiated a randomized, placebo-controlled, phase 3 trial of the chimpanzee adenovirus 3 vaccine (ChAd3-EBO-Z) and the recombinant vesicular stomatitis virus vaccine (rVSV∆G-ZEBOV-GP) in Liberia. A phase 2 subtrial was embedded to evaluate safety and immunogenicity. Because the incidence of EVD declined in Liberia, the phase 2 component was expanded and the phase 3 component was eliminated. RESULTS: A total of 1500 adults underwent randomization and were followed for 12 months. The median age of the participants was 30 years; 36.6% of the participants were women. During the week after the administration of vaccine or placebo, adverse events occurred significantly more often with the active vaccines than with placebo; these events included injection-site reactions (in 28.5% of the patients in the ChAd3-EBO-Z group and 30.9% of those in the rVSV∆G-ZEBOV-GP group, as compared with 6.8% of those in the placebo group), headache (in 25.1% and 31.9%, vs. 16.9%), muscle pain (in 22.3% and 26.9%, vs. 13.3%), feverishness (in 23.9% and 30.5%, vs. 9.0%), and fatigue (in 14.0% and 15.4%, vs. 8.8%) (P<0.001 for all comparisons); these differences were not seen at 1 month. Serious adverse events within 12 months after injection were seen in 40 participants (8.0%) in the ChAd3-EBO-Z group, in 47 (9.4%) in the rVSV∆G-ZEBOV-GP group, and in 59 (11.8%) in the placebo group. By 1 month, an antibody response developed in 70.8% of the participants in the ChAd3-EBO-Z group and in 83.7% of those in the rVSV∆G-ZEBOV-GP group, as compared with 2.8% of those in the placebo group (P<0.001 for both comparisons). At 12 months, antibody responses in participants in the ChAd3-EBO-Z group (63.5%) and in those in the rVSV∆G-ZEBOV-GP group (79.5%) remained significantly greater than in those in the placebo group (6.8%, P<0.001 for both comparisons). CONCLUSIONS: A randomized, placebo-controlled phase 2 trial of two vaccines that was rapidly initiated and completed in Liberia showed the capability of conducting rigorous research during an outbreak. By 1 month after vaccination, the vaccines had elicited immune responses that were largely maintained through 12 months. (Funded by the National Institutes of Allergy and Infectious Diseases and the Liberian Ministry of Health; PREVAIL I ClinicalTrials.gov number, NCT02344407 .).


Subject(s)
Ebola Vaccines/adverse effects , Ebola Vaccines/immunology , Ebolavirus/immunology , Hemorrhagic Fever, Ebola/prevention & control , Adenoviridae , Adult , Animals , Disease Outbreaks , Double-Blind Method , Female , Fever/etiology , HIV Seropositivity/complications , Headache/etiology , Hemorrhagic Fever, Ebola/complications , Hemorrhagic Fever, Ebola/immunology , Humans , Injections, Intramuscular/adverse effects , Liberia , Male , Myalgia/etiology , Pan troglodytes , RNA, Viral/blood , Reverse Transcriptase Polymerase Chain Reaction , Vesiculovirus
4.
J Infect Dis ; 214(5): 772-81, 2016 Sep 01.
Article in English | MEDLINE | ID: mdl-27307573

ABSTRACT

BACKGROUND: The need for a highly efficacious vaccine against Plasmodium falciparum remains pressing. In this controlled human malaria infection (CHMI) study, we assessed the safety, efficacy and immunogenicity of a schedule combining 2 distinct vaccine types in a staggered immunization regimen: one inducing high-titer antibodies to circumsporozoite protein (RTS,S/AS01B) and the other inducing potent T-cell responses to thrombospondin-related adhesion protein (TRAP) by using a viral vector. METHOD: Thirty-seven healthy malaria-naive adults were vaccinated with either a chimpanzee adenovirus 63 and modified vaccinia virus Ankara-vectored vaccine expressing a multiepitope string fused to TRAP and 3 doses of RTS,S/AS01B (group 1; n = 20) or 3 doses of RTS,S/AS01B alone (group 2; n = 17). CHMI was delivered by mosquito bites to 33 vaccinated subjects at week 12 after the first vaccination and to 6 unvaccinated controls. RESULTS: No suspected unexpected serious adverse reactions or severe adverse events related to vaccination were reported. Protective vaccine efficacy was observed in 14 of 17 subjects (82.4%) in group 1 and 12 of 16 subjects (75%) in group 2. All control subjects received a diagnosis of blood-stage malaria parasite infection. Both vaccination regimens were immunogenic. Fourteen protected subjects underwent repeat CHMI 6 months after initial CHMI; 7 of 8 (87.5%) in group 1 and 5 of 6 (83.3%) in group 2 remained protected. CONCLUSIONS: The high level of sterile efficacy observed in this trial is encouraging for further evaluation of combination approaches using these vaccine types. CLINICAL TRIALS REGISTRATION: NCT01883609.


Subject(s)
Drug Carriers , Immunization Schedule , Malaria Vaccines/adverse effects , Malaria Vaccines/immunology , Malaria, Falciparum/prevention & control , Protozoan Proteins/immunology , Adenoviridae/genetics , Adolescent , Adult , Animals , Drug-Related Side Effects and Adverse Reactions/epidemiology , Drug-Related Side Effects and Adverse Reactions/pathology , Female , Healthy Volunteers , Humans , Malaria Vaccines/administration & dosage , Male , Middle Aged , Protozoan Proteins/administration & dosage , Treatment Outcome , Vaccines, Combined/administration & dosage , Vaccines, Combined/adverse effects , Vaccines, Combined/immunology , Vaccines, Synthetic/administration & dosage , Vaccines, Synthetic/immunology , Vaccinia virus/genetics , Young Adult
5.
Vaccine ; 27(52): 7428-35, 2009 Dec 09.
Article in English | MEDLINE | ID: mdl-19683087

ABSTRACT

The immunogenicity and lot-to-lot consistency of an AS03-adjuvanted H5N1 vaccine were evaluated in 1206 Asian adults, randomised to receive two doses of adjuvanted (3.75 microg haemagglutinin) or diluent-mixed vaccines, 21 days apart. Post-Dose 2, 96.0% of vaccinees in the H5N1-AS03 group demonstrated a four-fold increase in neutralising antibody titres against the vaccine strain A/Vietnam/1194/2004 and 91.4% against strain A/Indonesia/05/2005. Haemagglutination-inhibiting antibodies (titre > or = 1:40) against A/Vietnam/1194/2004 and A/Indonesia/05/2005 strains were observed in 94.3% and 50.2% of subjects, respectively. Lot-to-lot consistency of the AS03-adjuvanted vaccine combinations was demonstrated. The AS03-adjuvanted vaccine was well tolerated, induced a high frequency of immune responses to the vaccine strain, allowed antigen sparing and promoted cross-clade immunity. These characteristics make it suitable for presumptive use if an H5N1 pandemic were considered to be imminent.


Subject(s)
Adjuvants, Immunologic/pharmacology , Influenza Vaccines/immunology , Influenza, Human/prevention & control , Adjuvants, Immunologic/administration & dosage , Adolescent , Adult , Antibodies, Viral/blood , Cross Reactions/immunology , Female , Hemagglutination Tests , Hemagglutinin Glycoproteins, Influenza Virus/immunology , Humans , Immunization, Secondary , Influenza A Virus, H5N1 Subtype/immunology , Influenza Vaccines/administration & dosage , Male , Middle Aged , Neutralization Tests , Young Adult
SELECTION OF CITATIONS
SEARCH DETAIL
...