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6 results on '"RTS,S/AS02A"'

1. Safety of the RTS,S/AS02A malaria vaccine in Mozambican children during a Phase IIb trial

Author

Sacarlal, Jahit, Aponte, John J., Aide, Pedro, Mandomando, Inácio, Bassat, Quique, Guinovart, Caterina, Leach, Amanda, Milman, Jessica, Macete, Eusebio, Espasa, Mateu, Ofori-Anyinam, Opokua, Thonnard, Joelle, Corachan, Sabine, Dubois, Marie-Claude, Lievens, Marc, Dubovsky, Filip, Ballou, W. Ripley, Cohen, Joe, and Alonso, Pedro L.

Subjects
*MALARIA, *PLASMODIUM falciparum, *VACCINATION, *ANTIGENS
Abstract

Summary: RTS,S/AS02A is a pre-erythrocytic vaccine candidate based on the Plasmodium falciparum circumsporozoite surface antigen and is currently the most advanced malaria vaccine candidate in development. A proof of concept phase IIb trial of the RTS,S/AS02A in Mozambican children aged 1–4 years determined a vaccine efficacy against risk of clinical malaria of 35.3% (95% CI 21.6–46.6; p <0.0001) and against severe malaria of 48.6% (95% CI 12.3–71.0; p =0.02). We evaluated the safety of the RTS,S/AS02A vaccine. 2022 children that received at least one vaccine dose of RTS,S/AS02A or control vaccines were included in the intention to treat safety analysis. Vaccine safety was evaluated using active and passive follow-up. Participants were observed for at least 1h after each dose. Trained field workers visited children at home daily for the next 3 days to record solicited and unsolicited local and general symptoms. Investigators followed-up participants with severe adverse events until month 21. Overall, we recorded 1712 unsolicited adverse events after vaccination, 53% in the intervention and 47% in the control group. Most unsolicited adverse events reported with RTS,S/AS02A were self-limited, and participants recovered without sequelae. Local reactogenicity increased with the number of doses. The proportion of children experiencing serious adverse events was lower in the RTS,S/AS02A recipients compared to the control group (Engerix-B™ or Prevnar™ and Hiberix™). Overall, these results indicate that the RTS,S/AS02A vaccine has a good safety profile and well tolerated when given in three doses to semi-immune children living in malaria-endemic areas. [Copyright &y& Elsevier]

Published
2008
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2. Safety and immunogenicty of RTS,S/AS02A candidate malaria vaccine in Gambian children

Author

Bojang, Kalifa A., Olodude, Folasade, Pinder, Margaret, Ofori-Anyinam, Opokua, Vigneron, Laurence, Fitzpatrick, Steve, Njie, Fanta, Kassanga, Adams, Leach, Amanda, Milman, Jessica, Rabinovich, Regina, McAdam, Keith P.W.J., Kester, Kent E., Heppner, D. Gray, Cohen, Joe D., Tornieporth, Nadia, and Milligan, Paul J.M.

Subjects
*IMMUNIZATION of children, *PREVENTIVE medicine, *PROTOZOAN diseases, *MALARIA vaccines
Abstract

Abstract: RTS,S/AS02A is a pre-erythrocytic malaria vaccine candidate in which a portion of the circumsporozoite surface protein (CSP) of Plasmodium falciparum is genetically linked to hepatitis B surface antigen (HBsAg) coexpressed in yeast with unfused HBsAg. The resulting particulate antigen is formulated with the adjuvant system AS02A. We have initiated the paediatric clinical development of this vaccine by conducting two sequential Phase I studies in children: a study in older children (6–11 years), followed by a second study in younger children (1–5 years). In each study, a double-blind, randomised controlled, staggered, dose-escalation design was used to evaluate 10μg RTS,S dose (10μg RTS,S in 0.1mL AS02A), 25μg dose (25μg RTS,S in 0.25mL AS02A) and finally a 50μg dose (50μg RTS,S in 0.5mL AS02A) of the RTS,S/AS02A candidate malaria vaccine administered according to a 0-, 1- and 3-month vaccination schedule. Safety and reactogenicity were evaluated before moving to a higher dose level. The RTS,S/AS02A vaccine was safe at all dose levels, in both age groups. No serious adverse events related to vaccination were reported. The frequency of local Grade 3 symptoms was low but tended to increase with increasing dose level. Grade 3 general adverse events in the RTS,S/AS02A groups were infrequent and of short duration. The majority of local and general Grade 3 symptoms resolved or decreased in intensity within 48h. The pattern and intensity of reactogenicity seen in these studies are similar to those of previous studies with RTS,S/AS02A. All doses were highly immunogenic for anti-CSP and anti-HBsAg antibodies. The pooled anti-CSP antibody data from the two studies showed that the 25μg dose and 50μg dose anti-CSP antibody response were similar at both dose levels. However, the immunogenicity of the 10μg dose anti-CSP response was significantly lower than that of either the 50μg or 25μg dose. The 25μg dose was selected for future studies of RTS,S/AS02A in paediatric populations. [Copyright &y& Elsevier]

Published
2005
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3. Safety and efficacy of novel malaria vaccine regimens of RTS, S/AS01B alone, or with concomitant ChAd63-MVA-vectored vaccines expressing ME-TRAP

Author

Rampling, T, Ewer, KJ, Bowyer, G, Edwards, NJ, Wright, D, Sridhar, S, Payne, R, Powlson, J, Bliss, C, Venkatraman, N, Poulton, ID, De Graaf, H, Gbesemete, D, Grobbelaar, A, Davies, H, Roberts, R, Angus, B, Ivinson, K, Weltzin, R, Rajkumar, B-Y, Wille-Reece, U, Lee, C, Ockenhouse, C, Sinden, R, Gerry, SC, Lawrie, A, Vekemans, J, Morelle, D, Lievens, M, Ballou, RW, Lewis, DJM, Cooke, GS, Faust, SN, and Hill, AV

Subjects
Science & Technology, CIRCUMSPOROZOITE PROTEIN, ANTIBODY-RESPONSES, Immunology, RTS,S/AS02A, Research & Experimental Medicine, IMMUNOGENICITY, IMMUNIZATION, Medicine, Research & Experimental, FALCIPARUM-MALARIA, MULTISTAGE, TRIAL, PROTECTION, COMBINATION, Life Sciences & Biomedicine
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.

Published
2018

4. A combined analysis of immunogenicity, antibody kinetics and vaccine efficacy from phase 2 trials of the RTS,S malaria vaccine

Author

Seth Owusu-Agyei, Jahit Sacarlal, Kalifa Bojang, Emmanuel Mahama, John Lusingu, Michael T. White, Nekoye Otsyula, Nahya Salim, Ally Olotu, John J. Aponte, Selidji T Agnandji, Kwaku Poku Asante, Jamie T. Griffin, Tsiri Agbenyega, Philip Bejon, Salim Abdulla, Azra C. Ghani, Bertrand Lell, and Daniel Ansong

Subjects
Male, Protozoan Proteins, Antibodies, Protozoan, PLASMODIUM-FALCIPARUM INFECTION, INFANTS, Circumsporozoite protein, DOUBLE-BLIND, 0302 clinical medicine, Mathematical model, RTS,S, PROTECTION, Malaria, Falciparum, Child, Medicine(all), 0303 health sciences, Vaccines, Malaria vaccine, Immunogenicity, Vaccination, General Medicine, IMMUNIZATION, 3. Good health, Treatment Outcome, Child, Preschool, SAFETY, Female, Life Sciences & Biomedicine, CONJUGATE VACCINE, Research Article, Adult, AFRICAN CHILDREN, 030231 tropical medicine, RTS,S/AS02A, 03 medical and health sciences, Clinical Trials, Phase II as Topic, Medicine, General & Internal, Clinical immunity, Conjugate vaccine, General & Internal Medicine, Malaria Vaccines, parasitic diseases, medicine, Humans, Africa South of the Sahara, Antibody, 030304 developmental biology, Phase 2 clinical trials, Science & Technology, business.industry, Infant, Bayes Theorem, medicine.disease, Vaccine efficacy, Virology, RANDOMIZED-TRIAL, Malaria, Immunology, business, Vaccine
Abstract

Background: The RTS,S malaria vaccine is currently undergoing phase 3 trials. High vaccine-induced antibody titres to the circumsporozoite protein (CSP) antigen have been associated with protection from infection and episodes of clinical malaria. Methods: Using data from 5,144 participants in nine phase 2 trials, we explore predictors of vaccine immunogenicity (anti-CSP antibody titres), decay in antibody titres, and the association between antibody titres and clinical outcomes. We use empirically-observed relationships between these factors to predict vaccine efficacy in a range of scenarios.Results: Vaccine-induced anti-CSP antibody titres were significantly associated with age (P = 0.04), adjuvant (P and#60;0.001), pre-vaccination anti-hepatitis B surface antigen titres (P = 0.005) and pre-vaccination anti-CSP titres (P and#60;0.001). Co-administration with other vaccines reduced anti-CSP antibody titres although not significantly (P = 0.095). Antibody titres showed a bi-phasic decay over time with an initial rapid decay in the first three months and a second slower decay over the next three to four years. Antibody titres were significantly associated with protection, with a titre of 51 (95% Credible Interval (CrI): 29 to 85) ELISA units/ml (EU/mL) predicted to prevent 50% of infections in children. Vaccine efficacy was predicted to decline to zero over four years in a setting with entomological inoculation rate (EIR) = 20 infectious bites per year (ibpy). Over a five-year follow-up period at an EIR = 20 ibpy, we predict RTS,S will avert 1,782 cases per 1,000 vaccinated children, 1,452 cases per 1,000 vaccinated infants, and 887 cases per 1,000 infants when co-administered with expanded programme on immunisation (EPI) vaccines. Our main study limitations include an absence of vaccine-induced cellular immune responses and short duration of follow-up in some individuals. Conclusions: Vaccine-induced anti-CSP antibody titres and transmission intensity can explain variations in observed vaccine efficacy.

Published
2016
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5. Safety of the RTS,S/AS02A malaria vaccine in Mozambican children during a Phase IIb trial

Author

Sacaral, Jahit, Aponte, John J., Aide, Pedro, Mandomando, Inacio, Bassat, Quique, Guinovart, Caterina, Leach, Amanda J., Milman, Jessica, Macete, Eusebio, Ofori-Anyiname, Opokua, Thonnard, Joelle, Corachan, Sabine, Dubois, Marie-Claude, Lievens, Marc, Dubovsky, Filip, Ballou, W. Ripley, Cohen, Joe, Alonso, Pedro L., Sacaral, Jahit, Aponte, John J., Aide, Pedro, Mandomando, Inacio, Bassat, Quique, Guinovart, Caterina, Leach, Amanda J., Milman, Jessica, Macete, Eusebio, Ofori-Anyiname, Opokua, Thonnard, Joelle, Corachan, Sabine, Dubois, Marie-Claude, Lievens, Marc, Dubovsky, Filip, Ballou, W. Ripley, Cohen, Joe, and Alonso, Pedro L.

Abstract

RTS,S/AS02A is a pre-erythrocytic vaccine candidate based on the Plasmodium falciparum circumsporozoite surface antigen and is currently the most advanced malaria vaccine candidate in development. A proof of concept phase IIb trial of the RTS,S/AS02A in Mozambican children aged 1-4 years determined a vaccine efficacy against risk of clinical malaria of 35.3% (95% CI 21.6-46.6; p<0.0001) and against severe malaria of 48.6% (95% CI 12.3-71.0; p=0.02). We evaluated the safety of the RTS,S/AS02A vaccine. 2022 children that received at least one vaccine dose of RTS,S/AS02A or control vaccines were included in the intention to treat safety analysis. Vaccine safety was evaluated using active and passive follow-up. Participants were observed for at least 1h after each dose. Trained field workers visited children at home daily for the next 3 days to record solicited and unsolicited local and general symptoms. Investigators followed-up participants with severe adverse events until month 21. Overall, we recorded 1712 unsolicited adverse events after vaccination, 53% in the intervention and 47% in the control group. Most unsolicited adverse events reported with RTS,S/AS02A were self-limited, and participants recovered without sequelae. Local reactogenicity increased with the number of doses. The proportion of children experiencing serious adverse events was lower in the RTS,S/AS02A recipients compared to the control group (Engerix-Btrade mark or Prevnartrade mark and Hiberixtrade mark). Overall, these results indicate that the RTS,S/AS02A vaccine has a good safety profile and well tolerated when given in three doses to semi-immune children living in malaria-endemic areas.

Published
2008

6. Vaccine approaches to malaria control and elimination: Insights from mathematical models

Author

Robert Verity, Azra C. Ghani, Thomas S. Churcher, Michael T. White, PATH-Program for Appropriate Technology in Health, and Bill & Melinda Gates Foundation

Subjects
PLASMODIUM-FALCIPARUM INFECTION, Research & Experimental Medicine, law.invention, DOUBLE-BLIND, Mathematical model, Randomized controlled trial, law, Malaria, Falciparum, Clinical Trials as Topic, biology, Malaria vaccine, Vaccination, 11 Medical And Health Sciences, IMMUNIZATION, Infectious Diseases, Medicine, Research & Experimental, Molecular Medicine, Public Health, Life Sciences & Biomedicine, AFRICAN CHILDREN, Trial design, medicine.medical_specialty, Immunology, Plasmodium falciparum, MOSQUITO TRANSMISSION, RTS,S/AS02A, CONTROLLED-TRIAL, Virology, Immunology and Microbiology(all), Malaria Vaccines, parasitic diseases, medicine, Humans, Transmission, Intensive care medicine, Science & Technology, Models, Statistical, PHASE-3 TRIAL, General Veterinary, General Immunology and Microbiology, business.industry, Public Health, Environmental and Occupational Health, 06 Biological Sciences, EFFICACY, medicine.disease, biology.organism_classification, Vaccine efficacy, veterinary(all), Malaria, Clinical trial, Immunization, 07 Agricultural And Veterinary Sciences, FOLLOW-UP, business, Vaccine
Abstract

A licensed malaria vaccine would provide a valuable new tool for malaria control and elimination efforts. Several candidate vaccines targeting different stages of the malaria parasite's lifecycle are currently under development, with one candidate, RTS,S/AS01 for the prevention of Plasmodium falciparum infection, having recently completed Phase III trials. Predicting the public health impact of a candidate malaria vaccine requires using clinical trial data to estimate the vaccine's efficacy profile—the initial efficacy following vaccination and the pattern of waning of efficacy over time. With an estimated vaccine efficacy profile, the effects of vaccination on malaria transmission can be simulated with the aid of mathematical models.Here, we provide an overview of methods for estimating the vaccine efficacy profiles of pre-erythrocytic vaccines and transmission-blocking vaccines from clinical trial data. In the case of RTS,S/AS01, model estimates from Phase II clinical trial data indicate a bi-phasic exponential profile of efficacy against infection, with efficacy waning rapidly in the first 6 months after vaccination followed by a slower rate of waning over the next 4 years. Transmission-blocking vaccines have yet to be tested in large-scale Phase II or Phase III clinical trials so we review ongoing work investigating how a clinical trial might be designed to ensure that vaccine efficacy can be estimated with sufficient statistical power. Finally, we demonstrate how parameters estimated from clinical trials can be used to predict the impact of vaccination campaigns on malaria using a mathematical model of malaria transmission.

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