Joe Cohen | Graduate Center of the City University of New York (original) (raw)

Papers by Joe Cohen

Research paper thumbnail of Safety and Immunogenicity of RTS,S+Trap Malaria Vaccine, Formulated in the AS02A Adjuvant System, in Infant Rhesus Monkeys

The American Journal of Tropical Medicine and Hygiene, 2004

Malaria vaccine RTS,S combined with thrombospondin-related anonymous protein (TRAP) and formulate... more Malaria vaccine RTS,S combined with thrombospondin-related anonymous protein (TRAP) and formulated with AS02A (RTS,S+TRAP/AS02A) is safe and immunogenic in adult humans and rhesus monkeys (Macaca mulatta). Here, RTS,S+TRAP/AS02A was administered on a 0-, 1-, and 3-month schedule to three cohorts of infant monkeys, along with adult comparators. Cohort 1 evaluated 1/5, 1/2, and full adult doses, with the first dose administration at one month of age; cohort 2 monkeys received full adult doses, with the first dose administration at one versus three months of age; and, cohort 3 compared infants gestated in mothers with or without previous RTS,S/AS02A immunization. Immunization site reactogenicity was mild. Some infants, including the phosphate-buffered saline only recipient, developed transient iron-deficiency anemia, which is considered a result of repeated phlebotomies. All RTS,S+TRAP/AS02A regimens induced vigorous antibody responses that persisted through 12 weeks after the last vaccine dose. Modest lymphoproliferative and ELISPOT (interferon-␥ and interleukin-5) responses, particularly to TRAP, approximated adult comparators. RTS,S+TRAP/AS02A was safe and well tolerated. Vigorous antibody production and modest, selective cell-mediated immune responses suggest that RTS,S+TRAP/AS02A may be immunogenic in human infants.

Research paper thumbnail of Update on the Clinical Development of Candidate Malaria Vaccines

The American Journal of Tropical Medicine and Hygiene, 2004

The recent availability of significantly increased levels of funding for unmet medical needs in t... more The recent availability of significantly increased levels of funding for unmet medical needs in the developing world, made available by newly created public-private-partnerships, has proven to be a powerful driver for stimulating clinical development of candidate vaccines for malaria. This new way forward promises to greatly increase the likelihood of bringing a safe and effective vaccine to licensure. The investigators bring together important published and unpublished information that illuminates the status of malaria vaccine development. They focus their comments on those candidate vaccines that are currently in or expected to enter clinical trials in the next 12 months.

Research paper thumbnail of Fractional third and fourth dose of RTS,S/AS01 malaria candidate vaccine: a phase 2a controlled human malaria infection and immunogenicity study

The Journal of infectious diseases, Jan 13, 2016

Three full doses of RTS,S/AS01 malaria vaccine provides partial protection against controlled hu... more Three full doses of RTS,S/AS01 malaria vaccine provides partial protection against controlled human malaria infection (CHMI) and natural exposure. Immunization regimens including a delayed fractional third dose were assessed for potential increased protection against malaria and immunologic responses. In a Phase IIa, controlled, open-label, study of healthy malaria-naïve adults, 16 subjects vaccinated with a 0, 1, 2-month full dose regimen (012M) and 30 subjects with a 0, 1, 7-month regimen including a fractional third dose (Fx017M) underwent CHMI three weeks after last dose. Plasmablast heavy and light chain immunoglobulin mRNA sequencing and antibody avidity were evaluated. Protection against repeat CHMI was evaluated post-8 months (Clinical Trials.gov: NCT01857869). 26/30 subjects in the Fx017M group (vaccine efficacy [VE] 86·7% [95% CI: 66·8, 94·6]; p<0·0001), and 10/16 in the 012M group (VE 62·5% [95% CI: 29·4, 80·1]; p=0·0009) were protected against infection and protect...

Research paper thumbnail of Phase 1/2a Trial of Plasmodium vivax Malaria Vaccine Candidate VMP001/AS01B in Malaria-Naive Adults: Safety, Immunogenicity, and Efficacy

PLOS Neglected Tropical Diseases, 2016

Background A vaccine to prevent infection and disease caused by Plasmodium vivax is needed both t... more Background A vaccine to prevent infection and disease caused by Plasmodium vivax is needed both to reduce the morbidity caused by this parasite and as a key component in efforts to eradicate malaria worldwide. Vivax malaria protein 1 (VMP001), a novel chimeric protein that incorporates the amino-and carboxy-terminal regions of the circumsporozoite protein (CSP) and a truncated repeat region that contains repeat sequences from both the VK210 (type 1) and the VK247 (type 2) parasites, was developed as a vaccine candidate for global use. Methods We conducted a first-inhuman Phase 1 dose escalation vaccine study with controlled human malaria infection (CHMI) of VMP001 formulated in the GSK Adjuvant System AS01 B. A total of 30 volunteers divided into 3 groups (10 per group) were given 3 intramuscular injections of 15μg, 30μg, or 60μg respectively of VMP001, all formulated in 500μL of AS01 B at each immunization. All vaccinated volunteers participated in a P. vivax CHMI 14 days following the third immunization. Six non-vaccinated subjects served as infectivity controls. Results The vaccine was shown to be well tolerated and immunogenic. All volunteers generated robust humoral and cellular immune responses to the vaccine antigen. Vaccination did not

Research paper thumbnail of Sequential Phase 1 and Phase 2 randomized, controlled trials of the safety, immunogenicity and efficacy of combined pre-erythrocytic vaccine antigens RTS,S and TRAP formulated with AS02 Adjuvant System in healthy, malaria naïve adults

Research paper thumbnail of Evaluation of the immune response to RTS,S/AS01 and RTS,S/AS02 adjuvanted vaccines

Human Vaccines & Immunotherapeutics, 2014

This phase II, randomized, double-blind study evaluated the immune responses elicited by RTS,S va... more This phase II, randomized, double-blind study evaluated the immune responses elicited by RTS,S vaccines containing adjuvant system AS01 or AS02 as compared to nonadjuvanted RTS,S in healthy, malaria-naïve adults (ClinicalTrials.gov identifier: NCT00443131). Thirty-six subjects were randomized (1:1:1

Research paper thumbnail of Evaluation of RTS,S/AS02A and RTS,S/AS01B in Adults in a High Malaria Transmission Area

PLoS ONE, 2009

Background: This study advances the clinical development of the RTS,S/AS01B candidate malaria vac... more Background: This study advances the clinical development of the RTS,S/AS01B candidate malaria vaccine to malaria endemic populations. As a primary objective it compares the safety and reactogenicity of RTS,S/AS01B to the more extensively evaluated RTS,S/AS02A vaccine. Methodology: A Phase IIb, single centre, double-blind, controlled trial of 6 months duration with a subsequent 6 month single-blind follow-up conducted in Kisumu West District, Kenya between August 2005 and August 2006. 255 healthy adults aged 18 to 35 years were randomized (1:1:1) to receive 3 doses of RTS,S/AS02A, RTS,S/AS01B or rabies vaccine (RabipurH; Chiron Behring GmbH) at months 0, 1, 2. The primary objective was the occurrence of severe (grade 3) solicited or unsolicited general (i.e. systemic) adverse events (AEs) during 7 days follow up after each vaccination.

Research paper thumbnail of Phase 2a trial of 0, 1, and 3 month and 0, 7, and 28 day immunization schedules of malaria vaccine RTS,S/AS02 in malaria-naïve adults at the Walter Reed Army Institute of Research

Vaccine, 2008

Background: Immunization with RTS,S/AS02 consistently protects some vaccinees against malaria inf... more Background: Immunization with RTS,S/AS02 consistently protects some vaccinees against malaria infection in experimental challenges and in field trials. A brief immunization schedule ଝ The opinions expressed herein are the private views of the authors and are not to be construed as official or as reflecting the views of the United States Army, the Department of Defense, the Centers for Disease Control and Prevention, or the Department of Health and Human Services.

Research paper thumbnail of Towards an RTS,S-based, multi-stage, multi-antigen vaccine against falciparum malaria: progress at the Walter Reed Army Institute of Research

Vaccine, 2005

The goal of the Malaria Vaccine Program at the Walter Reed Army Institute of Research (WRAIR) is ... more The goal of the Malaria Vaccine Program at the Walter Reed Army Institute of Research (WRAIR) is to develop a licensed multi-antigen, multi-stage vaccine against Plasmodium falciparum able to prevent all symptomatic manifestations of malaria by preventing parasitemia. A secondary goal is to limit disease in vaccinees that do develop malaria. Malaria prevention will be achieved by inducing humoral and cellular immunity against the pre-erythrocytic circumsporozoite protein (CSP) and the liver stage antigen-1 (LSA-1). The strategy to limit disease will target immune responses against one or more blood stage antigens, merozoite surface protein-1 (MSP-1) and apical merozoite antigen-1 (AMA-1). The induction of T-and B-cell memory to achieve a sustained vaccine response may additionally require immunization with an adenovirus vector such as adenovirus serotype 35. RTS,S, a CSP-derived antigen developed by GlaxoSmithKline Biologicals in collaboration with the Walter Reed Army Institute of Research over the past 17 years, is the cornerstone of our program. RTS,S formulated in AS02A (a GSK proprietary formulation) is the only vaccine candidate shown in field trials to prevent malaria and, in one instance, to limit disease severity. Our vaccine development plan requires proof of an individual antigen's efficacy in a Phase 2 laboratory challenge or field trial prior to its integration into an RTS,S-based, multi-antigen vaccine. Progress has been accelerated through extensive partnerships with industrial,

Research paper thumbnail of Phase I dose escalation safety and immunogenicity trial of Plasmodium falciparum apical membrane protein (AMA-1) FMP2.1, adjuvanted with AS02A, in malaria-naïve adults at the Walter Reed Army Institute of Research

Vaccine, 2007

We report the first safety and immunogenicity trial of the Plasmodium falciparum vaccine candidat... more We report the first safety and immunogenicity trial of the Plasmodium falciparum vaccine candidate FMP2.1/AS02A, a recombinant E. coli-expressed protein based upon the apical membrane antigen-1 (AMA-1) of the 3D7 clone formulated with the AS02A adjuvant. We conducted an open-label, staggered-start, dose-escalating Phase I trial in 23 malaria-naïve volunteers who received 8, 20 or 40 g of FMP2.1 in a fixed volume of 0.5 mL of AS02A on a 0, 1, and 2 month schedule. Nineteen of 23 volunteers received all three scheduled immunizations. The most frequent solicited local and systemic adverse events associated with immunization were injection site pain (68%) and headache (29%). There were no significant laboratory abnormalities or vaccine-related serious adverse events. All volunteers seroconverted after second immunization as determined by ELISA. Immune sera recognized sporozoites and merozoites by immunofluorescence assay (IFA), and exhibited both growth inhibition and processing inhibition activity against homologous (3D7) asexual stage parasites. Post-immunization, peripheral blood mononuculear cells exhibited FMP2.1-specific lymphoproliferation and IFN-␥ and IL-5 ELISPOT assay responses. This is the first PfAMA-1-based vaccine shown to elicit both potent humoral and cellular immunity in humans. Encouraged by the potential of FMP1/AS02A to target host immunity against PfAMA-1 that is known to be expressed by sporozoite, hepatic and erythrocytic stages, we have initiated field trials of FMP2.1/AS02A in an endemic population in the Republic of Mali.

Research paper thumbnail of T Cell Responses to the RTS,S/AS01E and RTS,S/AS02D Malaria Candidate Vaccines Administered According to Different Schedules to Ghanaian Children

PLoS ONE, 2011

Background: The Plasmodium falciparum pre-erythrocytic stage candidate vaccine RTS,S is being dev... more Background: The Plasmodium falciparum pre-erythrocytic stage candidate vaccine RTS,S is being developed for protection of young children against malaria in sub-Saharan Africa. RTS,S formulated with the liposome based adjuvant AS01 E or the oil-in-water based adjuvant AS02 D induces P. falciparum circumsporozoite (CSP) antigen-specific antibody and T cell responses which have been associated with protection in the experimental malaria challenge model in adults. Methods: This study was designed to evaluate the safety and immunogenicity induced over a 19 month period by three vaccination schedules (0,1-, 0,1,2-and 0,1,7-month) of RTS,S/AS01 E and RTS,S/AS02 D in children aged 5-17 months in two research centers in Ghana. Control Rabies vaccine using the 0,1,2-month schedule was used in one of two study sites. Results: Whole blood antigen stimulation followed by intra-cellular cytokine staining showed RTS,S/AS01 E induced CSP specific CD4 T cells producing IL-2, TNF-a, and IFN-c. Higher T cell responses were induced by a 0,1,7-month immunization schedule as compared with a 0,1-or 0,1,2-month schedule. RTS,S/AS01 E induced higher CD4 T cell responses as compared to RTS,S/AS02 D when given on a 0,1,7-month schedule. Conclusions: These findings support further Phase III evaluation of RTS,S/AS01 E. The role of immune effectors and immunization schedules on vaccine protection are currently under evaluation.

Research paper thumbnail of Circumsporozoite-Specific T Cell Responses in Children Vaccinated with RTS,S/AS01E and Protection against P falciparum Clinical Malaria

PLoS ONE, 2011

Background: RTS,S/AS01 E is the lead candidate pre-erythrocytic malaria vaccine. In Phase IIb fie... more Background: RTS,S/AS01 E is the lead candidate pre-erythrocytic malaria vaccine. In Phase IIb field trials the safety profile was acceptable and the efficacy was 53% (95%CI 31%-72%) for protecting children against clinical malaria caused by P. falciparum. We studied CS-specific T cell responses in order to identify correlates of protection. Methods and Findings: We used intracellular cytokine staining (for IL2, IFNc, and TNFa), ex-vivo ELISPOTs (IFNc and IL2) and IFNc cultured ELISPOT assays to characterize the CS-specific cellular responses in 407 children (5-17 months of age) in a phase IIb randomized controlled trial of RTS,S/AS01 E (NCT00380393). RTS,S/ AS01 E vaccinees had higher frequencies of CSspecific CD4+ T cells producing IFNc, TNFa or IL2 compared to control vaccinees. In a multivariable analysis TNFa + CD4 + T cells were independently associated with a reduced risk for clinical malaria among RTS,S/AS01 E vaccinees (HR = 0.64, 95%CI 0.49-0.86, p = 0.002). There was a non-significant tendency towards reduced risk among control vaccinees (HR = 0.80, 95%CI 0.62-1.03, p = 0.084), albeit with lower CS-specific T cell frequencies and higher rates of clinical malaria. When data from both RTS,S/AS01 E vaccinees and control vaccinees were combined (with adjusting for vaccination group), the HR was 0.74 (95%CI 0.62-0.89, p = 0.001). After a Bonferroni correction for multiple comparisons (n-18), the finding was still significant at p = 0.018. There was no significant correlation between cultured or ex vivo ELISPOT data and protection from clinical malaria. The combination of TNFa + CD4 + T cells and anti-CS antibody statistically accounted for the protective effect of vaccination in a Cox regression model. Conclusions: RTS,S/AS01 E induces CS-specific Th1 T cell responses in young children living in a malaria endemic area. The combination of anti-CS antibody concentrations titers and CS-specific TNFa + CD4 + T cells could account for the level of protection conferred by RTS,S/AS01 E. The correlation between CS-specific TNFa + CD4 + T cells and protection needs confirmation in other datasets.

Research paper thumbnail of Impact of RTS,S/AS02A and RTS,S/AS01B on Genotypes of P. falciparum in Adults Participating in a Malaria Vaccine Clinical Trial

PLoS ONE, 2009

Objective: RTS,S, a candidate vaccine for malaria, is a recombinant protein expressed in yeast co... more Objective: RTS,S, a candidate vaccine for malaria, is a recombinant protein expressed in yeast containing part of the circumsporozoite protein (CSP) sequence of 3D7 strain of Plasmodium falciparum linked to the hepatitis B surface antigen in a hybrid protein. The RTS,S antigen is formulated with GSK Biologicals' proprietary Adjuvant Systems AS02 A or AS01 B. A recent trial of the RTS,S/AS02 A and RTS,S/AS01 B vaccines evaluated safety, immunogenicity and impact on the development of parasitemia of the two formulations. Parasite isolates from this study were used to determine the molecular impact of RTS,S/AS02 A and RTS,S/AS01 B on the multiplicity of infection (MOI) and the csp allelic characteristics of subsequent parasitemias. Design: The distribution of csp sequences and the MOI of the infecting strains were examined at baseline and in breakthrough infections from vaccinated individuals and from those receiving a non-malarial vaccine. Setting: The study was conducted in Kombewa District, western Kenya. Participants: Semi-immune adults from the three study arms provided isolates at baseline and during breakthrough infections. Outcome: Parasite isolates used for determining MOI and divergence of csp T cell-epitopes were 191 at baseline and 87 from breakthrough infections. Results: Grouping recipients of RTS,S/AS01 A and RTS,S/AS02 B together, vaccine recipients identified as parasite-positive by microscopy contained significantly fewer parasite genotypes than recipients of the rabies vaccine comparator (median in pooled RTS,S groups: 3 versus 4 in controls, P = 0.0313). When analyzed separately, parasitaemic individuals in the RTS,S/ AS01 B group, but not the RTS,S/AS02 A group, were found to have significantly fewer genotypes than the comparator group. Two individual amino acids found in the vaccine construct (Q339 in Th2R and D371 in Th3R) were observed to differ in incidence between vaccine and comparator groups but in different directions; parasites harboring Q339 were less common among pooled RTS,S/AS vaccine recipients than among recipients of rabies vaccine, whereas parasites with D371 were more common among the RTS,S/AS groups. Conclusions: It is concluded that both RTS,S/AS vaccines reduce multiplicity of infection. Our results do not support the hypothesis that RTS,S/AS vaccines elicit preferential effects against pfcsp alleles with sequence similarity to the 3D7 pfcsp sequence employed in the vaccine construct.

Research paper thumbnail of A Randomized Trial Assessing the Safety and Immunogenicity of AS01 and AS02 Adjuvanted RTS,S Malaria Vaccine Candidates in Children in Gabon

PLoS ONE, 2009

Background: The malaria vaccine candidate antigen RTS,S includes parts of the pre-erythrocytic st... more Background: The malaria vaccine candidate antigen RTS,S includes parts of the pre-erythrocytic stage circumsporozoite protein fused to the Hepatitis B surface antigen. Two Adjuvant Systems are in development for this vaccine, an oil-in water emulsion-based formulation (AS02) and a formulation based on liposomes (AS01). Methods & Principal Findings: In this Phase II, double-blind study (NCT00307021), 180 healthy Gabonese children aged 18 months to 4 years were randomized to receive either RTS,S/AS01 E or RTS,S/AS02 D , on a 0-1-2 month vaccination schedule. The children were followed-up daily for six days after each vaccination and monthly for 14 months. Blood samples were collected at 4 time-points. Both vaccines were well tolerated. Safety parameters were distributed similarly between the two groups. Both vaccines elicited a strong specific immune response after Doses 2 and 3 with a ratio of anti-CS GMT titers (AS02 D /AS01 E) of 0.88 (95% CI: 0.68-1.15) post-Dose 3. After Doses 2 and 3 of experimental vaccines, anti-CS and anti-HBs antibody GMTs were higher in children who had been previously vaccinated with at least one dose of hepatitis B vaccine compared to those not previously vaccinated. Conclusions: RTS,S/AS01 E proved similarly as well tolerated and immunogenic as RTS,S/AS02 D , completing an essential step in the age de-escalation process within the RTS,S clinical development plan.

Research paper thumbnail of Randomized Controlled Trial of RTS,S/AS02D and RTS,S/AS01E Malaria Candidate Vaccines Given According to Different Schedules in Ghanaian Children

PLoS ONE, 2009

Background: The target delivery channel of RTS,S candidate malaria vaccines in malaria-endemic co... more Background: The target delivery channel of RTS,S candidate malaria vaccines in malaria-endemic countries in Africa is the World Health Organisation Expanded Program on Immunization. As an Adjuvant System, age de-escalation and schedule selection step, this study assessed 3 schedules of RTS,S/AS01 E and RTS,S/AS02 D in infants and young children 5-17 months of age in Ghana. Methodology: A Phase II, partially-blind randomized controlled study (blind to vaccine, not to schedule), of 19 months duration was conducted in two (2) centres in Ghana

Research paper thumbnail of A Phase 3 Trial of RTS,S/AS01 Malaria Vaccine in African Infants

New England Journal of Medicine, 2012

Background The candidate malaria vaccine RTS,S/AS01 reduced episodes of both clinical and severe ... more Background The candidate malaria vaccine RTS,S/AS01 reduced episodes of both clinical and severe malaria in children 5 to 17 months of age by approximately 50% in an ongoing phase 3 trial. We studied infants 6 to 12 weeks of age recruited for the same trial. Methods We administered RTS,S/AS01 or a comparator vaccine to 6537 infants who were 6 to 12 weeks of age at the time of the first vaccination in conjunction with Expanded Program on Immunization (EPI) vaccines in a three-dose monthly schedule. Vaccine efficacy against the first or only episode of clinical malaria during the 12 months after vaccination, a coprimary end point, was analyzed with the use of Cox regression. Vaccine efficacy against all malaria episodes, vaccine efficacy against severe malaria, safety, and immunogenicity were also assessed. Results The incidence of the first or only episode of clinical malaria in the intention-to-treat population during the 14 months after the first dose of vaccine was 0.31 per personyear in the RTS,S/AS01 group and 0.40 per person-year in the control group, for a vaccine efficacy of 30.1% (95% confidence interval [CI], 23.6 to 36.1). Vaccine efficacy in the per-protocol population was 31.3% (97.5% CI, 23.6 to 38.3). Vaccine efficacy against severe malaria was 26.0% (95% CI, −7.4 to 48.6) in the intention-totreat population and 36.6% (95% CI, 4.6 to 57.7) in the per-protocol population. Serious adverse events occurred with a similar frequency in the two study groups. One month after administration of the third dose of RTS,S/AS01, 99.7% of children were positive for anti-circumsporozoite antibodies, with a geometric mean titer of 209 EU per milliliter (95% CI, 197 to 222). Conclusions The RTS,S/AS01 vaccine coadministered with EPI vaccines provided modest protection against both clinical and severe malaria in young infants. (Funded by Glaxo SmithKline Biologicals and the PATH Malaria Vaccine Initiative; RTS,S ClinicalTrials.gov number, NCT00866619.

Research paper thumbnail of Safety and efficacy of the RTS,S/AS01 E candidate malaria vaccine given with expanded-programme-on-immunisation vaccines: 19 month follow-up of a randomised, open-label, phase 2 trial

The Lancet Infectious Diseases, 2011

Background The RTS,S/AS01 E candidate malaria vaccine is being developed for immunisation of infa... more Background The RTS,S/AS01 E candidate malaria vaccine is being developed for immunisation of infants in Africa through the expanded programme on immunisation (EPI). 8 month follow-up data have been reported for safety and immunogenicity of RTS,S/AS01 E when integrated into the EPI. We report extended follow-up to 19 months, including effi cacy results. Methods We did a randomised, open-label, phase 2 trial of safety and effi cacy of the RTS,S/AS01 E candidate malaria vaccine given with EPI vaccines between April 30, 2007, and Oct 7, 2009, in Ghana, Tanzania, and Gabon. Eligible children were 6-10 weeks of age at fi rst vaccination, without serious acute or chronic illness. All children received the EPI diphtheria, tetanus, pertussis (inactivated whole-cell), and hepatitis-B vaccines, Haemophilus infl uenzae type b vaccine, and oral polio vaccine at study months 0, 1, and 2, and measles vaccine and yellow fever vaccines at study month 7. Participants were randomly assigned (1:1:1) to receive three doses of RTS,S/AS01 E at 6, 10, and 14 weeks (0, 1, 2 month schedule) or at 6 weeks, 10 weeks, and 9 months (0, 2, 7 month schedule) or placebo. Randomisation was according to a predefi ned block list with a computer-generated randomisation code. Detection of serious adverse events and malaria was by passive case detection. Antibodies against Plasmodium falciparum circumsporozoite protein and HBsAg were monitored for 19 months. This study is registered with ClinicalTrials.gov, number NCT00436007. Findings 511 children were enrolled. Serious adverse events occurred in 57 participants in the RTS,S/AS01 E 0, 1, 2 month group (34%, 95% CI 27-41), 47 in the 0, 1, 7 month group (28%, 21-35), and 49 (29%, 22-36) in the control group; none were judged to be related to study vaccination. At month 19, anticircumsporozoite immune responses were signifi cantly higher in the RTS,S/AS01 E groups than in the control group. Vaccine effi cacy for the 0, 1, 2 month schedule (2 weeks after dose three to month 19, site-adjusted according-to-protocol analysis) was 53% (95% CI 26-70; p=0•0012) against fi rst malaria episodes and 59% (36-74; p=0•0001) against all malaria episodes. For the entire study period, (total vaccinated cohort) vaccine effi cacy against all malaria episodes was higher with the 0, 1, 2 month schedule (57%, 95% CI 33-73; p=0•0002) than with the 0, 1, 7 month schedule (32% CI 16-45; p=0•0003). 1 year after dose three, vaccine effi cacy against fi rst malaria episodes was similar for both schedules (0, 1, 2 month group, 61•6% [95% CI 35•6-77•1], p<0•001; 0, 1, 7 month group, 63•8% [40•4-78•0], p<0•001, according-to-protocol cohort). Interpretation Vaccine effi cacy was consistent with the target put forward by the WHO-sponsored malaria vaccine technology roadmap for a fi rst-generation malaria vaccine. The 0, 1, 2 month vaccine schedule has been selected for phase 3 candidate vaccine assessment. Funding Program for Appropriate Technology in Health Malaria Vaccine Initiative; GlaxoSmithKline Biologicals.

Research paper thumbnail of Efficacy of RTS,S/AS01E malaria vaccine and exploratory analysis on anti-circumsporozoite antibody titres and protection in children aged 5–17 months in Kenya and Tanzania: a randomised controlled trial

The Lancet Infectious Diseases, 2011

Research paper thumbnail of Randomized, Double‐Blind, Phase 2a Trial of Falciparum Malaria Vaccines RTS,S/AS01B and RTS,S/AS02A in Malaria‐Naive Adults: Safety, Efficacy, and Immunologic Associates of Protection

The Journal of Infectious Diseases, 2009

See the editorial commentary by Bremen and Plowe, on pages 317-20, and the article by Sacarlal et... more See the editorial commentary by Bremen and Plowe, on pages 317-20, and the article by Sacarlal et al, on pages 329-36.) Background. To further increase the eff cacy of malaria vaccine RTS,S/AS02A, we tested the RTS,S antigen formulated using the AS01B Adjuvant System (GlaxoSmithKline Biologicals). Methods. In a double-blind, randomized trial, 102 healthy volunteers were evenly allocated to receive RTS,S/ AS01B or RTS,S/AS02A vaccine at months 0, 1, and 2 of the study, followed by malaria challenge. Protected vaccine recipients were rechallenged 5 months later. Results. RTS,S/AS01B and RTS,S/AS02A were well tolerated and were safe. The efficac of RTS,S/AS01B and RTS,S/AS02A was 50% (95% confidenc interval [CI], 32.9%-67.1%) and 32% (95% CI, 17.6%-47.6%), respectively. At the time of initial challenge, the RTS,S/AS01B group had greater circumsporozoite protein (CSP)-specifi immune responses, including higher immunoglobulin (Ig) G titers, higher numbers of CSP-specifi CD4 + T cells expressing у2 activation markers (interleukin-2, interferon [IFN]-g, tumor necrosis factor-a, or CD40L), and more ex vivo IFN-g enzyme-linked immunospots (ELISPOTs) than did the RTS,S/AS02A group. Protected vaccine recipients had a higher CSP-specifi IgG titer (geometric mean titer, 188 vs 73 mg/mL;

Research paper thumbnail of Evaluation of the Safety and Immunogenicity of the RTS,S/AS01EMalaria Candidate Vaccine When Integrated in the Expanded Program of Immunization

The Journal of Infectious Diseases, 2010

Background. The RTS,S/AS01 E malaria candidate vaccine is being developed for immunization of Afr... more Background. The RTS,S/AS01 E malaria candidate vaccine is being developed for immunization of African infants through the Expanded Program of Immunization (EPI). Methods. This phase 2, randomized, open, controlled trial conducted in Ghana, Tanzania, and Gabon evaluated the safety and immunogenicity of RTS,S/AS01 E when coadministered with EPI vaccines. Five hundred eleven infants were randomized to receive RTS,S/AS01 E at 0, 1, and 2 months (in 3 doses with diphtheria, tetanus, and wholecell pertussis conjugate [DTPw]; hepatitis B [HepB]; Haemophilus influenzae type b [Hib]; and oral polio vaccine [OPV]), RTS,S/AS01 E at 0, 1, and 7 months (2 doses with DTPwHepB/Hib+OPV and 1 dose with measles and yellow fever), or EPI vaccines only. Results. The occurrences of serious adverse events were balanced across groups; none were vaccine-related. One child from the control group died. Mild to moderate fever and diaper dermatitis occurred more frequently in the RTS,S/AS01 E coadministration groups. RTS,S/AS01 E generated high anti-circumsporozoite protein and antihepatitis B surface antigen antibody levels. Regarding EPI vaccine responses upon coadministration when considering both immunization schedules, despite a tendency toward lower geometric mean titers to some EPI antigens, predefined noninferiority criteria were met for all EPI antigens except for polio 3 when EPI vaccines were given with RTS,S/AS01 E at 0, 1, and 2 months. However, when antibody levels at screening were taken into account, the rates of response to polio 3 antigens were comparable between groups. Conclusion. RTS,S/AS01 E integrated in the EPI showed a favorable safety and immunogenicity evaluation. Trial registration. ClinicalTrials.gov identifier: NCT00436007. GlaxoSmithKline study ID number: 106369 (Malaria-050). The development of a malaria vaccine has been identified as a key component of future integrated malaria control programs and an important step toward sus

Research paper thumbnail of Safety and Immunogenicity of RTS,S+Trap Malaria Vaccine, Formulated in the AS02A Adjuvant System, in Infant Rhesus Monkeys

The American Journal of Tropical Medicine and Hygiene, 2004

Malaria vaccine RTS,S combined with thrombospondin-related anonymous protein (TRAP) and formulate... more Malaria vaccine RTS,S combined with thrombospondin-related anonymous protein (TRAP) and formulated with AS02A (RTS,S+TRAP/AS02A) is safe and immunogenic in adult humans and rhesus monkeys (Macaca mulatta). Here, RTS,S+TRAP/AS02A was administered on a 0-, 1-, and 3-month schedule to three cohorts of infant monkeys, along with adult comparators. Cohort 1 evaluated 1/5, 1/2, and full adult doses, with the first dose administration at one month of age; cohort 2 monkeys received full adult doses, with the first dose administration at one versus three months of age; and, cohort 3 compared infants gestated in mothers with or without previous RTS,S/AS02A immunization. Immunization site reactogenicity was mild. Some infants, including the phosphate-buffered saline only recipient, developed transient iron-deficiency anemia, which is considered a result of repeated phlebotomies. All RTS,S+TRAP/AS02A regimens induced vigorous antibody responses that persisted through 12 weeks after the last vaccine dose. Modest lymphoproliferative and ELISPOT (interferon-␥ and interleukin-5) responses, particularly to TRAP, approximated adult comparators. RTS,S+TRAP/AS02A was safe and well tolerated. Vigorous antibody production and modest, selective cell-mediated immune responses suggest that RTS,S+TRAP/AS02A may be immunogenic in human infants.

Research paper thumbnail of Update on the Clinical Development of Candidate Malaria Vaccines

The American Journal of Tropical Medicine and Hygiene, 2004

The recent availability of significantly increased levels of funding for unmet medical needs in t... more The recent availability of significantly increased levels of funding for unmet medical needs in the developing world, made available by newly created public-private-partnerships, has proven to be a powerful driver for stimulating clinical development of candidate vaccines for malaria. This new way forward promises to greatly increase the likelihood of bringing a safe and effective vaccine to licensure. The investigators bring together important published and unpublished information that illuminates the status of malaria vaccine development. They focus their comments on those candidate vaccines that are currently in or expected to enter clinical trials in the next 12 months.

Research paper thumbnail of Fractional third and fourth dose of RTS,S/AS01 malaria candidate vaccine: a phase 2a controlled human malaria infection and immunogenicity study

The Journal of infectious diseases, Jan 13, 2016

Three full doses of RTS,S/AS01 malaria vaccine provides partial protection against controlled hu... more Three full doses of RTS,S/AS01 malaria vaccine provides partial protection against controlled human malaria infection (CHMI) and natural exposure. Immunization regimens including a delayed fractional third dose were assessed for potential increased protection against malaria and immunologic responses. In a Phase IIa, controlled, open-label, study of healthy malaria-naïve adults, 16 subjects vaccinated with a 0, 1, 2-month full dose regimen (012M) and 30 subjects with a 0, 1, 7-month regimen including a fractional third dose (Fx017M) underwent CHMI three weeks after last dose. Plasmablast heavy and light chain immunoglobulin mRNA sequencing and antibody avidity were evaluated. Protection against repeat CHMI was evaluated post-8 months (Clinical Trials.gov: NCT01857869). 26/30 subjects in the Fx017M group (vaccine efficacy [VE] 86·7% [95% CI: 66·8, 94·6]; p<0·0001), and 10/16 in the 012M group (VE 62·5% [95% CI: 29·4, 80·1]; p=0·0009) were protected against infection and protect...

Research paper thumbnail of Phase 1/2a Trial of Plasmodium vivax Malaria Vaccine Candidate VMP001/AS01B in Malaria-Naive Adults: Safety, Immunogenicity, and Efficacy

PLOS Neglected Tropical Diseases, 2016

Background A vaccine to prevent infection and disease caused by Plasmodium vivax is needed both t... more Background A vaccine to prevent infection and disease caused by Plasmodium vivax is needed both to reduce the morbidity caused by this parasite and as a key component in efforts to eradicate malaria worldwide. Vivax malaria protein 1 (VMP001), a novel chimeric protein that incorporates the amino-and carboxy-terminal regions of the circumsporozoite protein (CSP) and a truncated repeat region that contains repeat sequences from both the VK210 (type 1) and the VK247 (type 2) parasites, was developed as a vaccine candidate for global use. Methods We conducted a first-inhuman Phase 1 dose escalation vaccine study with controlled human malaria infection (CHMI) of VMP001 formulated in the GSK Adjuvant System AS01 B. A total of 30 volunteers divided into 3 groups (10 per group) were given 3 intramuscular injections of 15μg, 30μg, or 60μg respectively of VMP001, all formulated in 500μL of AS01 B at each immunization. All vaccinated volunteers participated in a P. vivax CHMI 14 days following the third immunization. Six non-vaccinated subjects served as infectivity controls. Results The vaccine was shown to be well tolerated and immunogenic. All volunteers generated robust humoral and cellular immune responses to the vaccine antigen. Vaccination did not

Research paper thumbnail of Sequential Phase 1 and Phase 2 randomized, controlled trials of the safety, immunogenicity and efficacy of combined pre-erythrocytic vaccine antigens RTS,S and TRAP formulated with AS02 Adjuvant System in healthy, malaria naïve adults

Research paper thumbnail of Evaluation of the immune response to RTS,S/AS01 and RTS,S/AS02 adjuvanted vaccines

Human Vaccines & Immunotherapeutics, 2014

This phase II, randomized, double-blind study evaluated the immune responses elicited by RTS,S va... more This phase II, randomized, double-blind study evaluated the immune responses elicited by RTS,S vaccines containing adjuvant system AS01 or AS02 as compared to nonadjuvanted RTS,S in healthy, malaria-naïve adults (ClinicalTrials.gov identifier: NCT00443131). Thirty-six subjects were randomized (1:1:1

Research paper thumbnail of Evaluation of RTS,S/AS02A and RTS,S/AS01B in Adults in a High Malaria Transmission Area

PLoS ONE, 2009

Background: This study advances the clinical development of the RTS,S/AS01B candidate malaria vac... more Background: This study advances the clinical development of the RTS,S/AS01B candidate malaria vaccine to malaria endemic populations. As a primary objective it compares the safety and reactogenicity of RTS,S/AS01B to the more extensively evaluated RTS,S/AS02A vaccine. Methodology: A Phase IIb, single centre, double-blind, controlled trial of 6 months duration with a subsequent 6 month single-blind follow-up conducted in Kisumu West District, Kenya between August 2005 and August 2006. 255 healthy adults aged 18 to 35 years were randomized (1:1:1) to receive 3 doses of RTS,S/AS02A, RTS,S/AS01B or rabies vaccine (RabipurH; Chiron Behring GmbH) at months 0, 1, 2. The primary objective was the occurrence of severe (grade 3) solicited or unsolicited general (i.e. systemic) adverse events (AEs) during 7 days follow up after each vaccination.

Research paper thumbnail of Phase 2a trial of 0, 1, and 3 month and 0, 7, and 28 day immunization schedules of malaria vaccine RTS,S/AS02 in malaria-naïve adults at the Walter Reed Army Institute of Research

Vaccine, 2008

Background: Immunization with RTS,S/AS02 consistently protects some vaccinees against malaria inf... more Background: Immunization with RTS,S/AS02 consistently protects some vaccinees against malaria infection in experimental challenges and in field trials. A brief immunization schedule ଝ The opinions expressed herein are the private views of the authors and are not to be construed as official or as reflecting the views of the United States Army, the Department of Defense, the Centers for Disease Control and Prevention, or the Department of Health and Human Services.

Research paper thumbnail of Towards an RTS,S-based, multi-stage, multi-antigen vaccine against falciparum malaria: progress at the Walter Reed Army Institute of Research

Vaccine, 2005

The goal of the Malaria Vaccine Program at the Walter Reed Army Institute of Research (WRAIR) is ... more The goal of the Malaria Vaccine Program at the Walter Reed Army Institute of Research (WRAIR) is to develop a licensed multi-antigen, multi-stage vaccine against Plasmodium falciparum able to prevent all symptomatic manifestations of malaria by preventing parasitemia. A secondary goal is to limit disease in vaccinees that do develop malaria. Malaria prevention will be achieved by inducing humoral and cellular immunity against the pre-erythrocytic circumsporozoite protein (CSP) and the liver stage antigen-1 (LSA-1). The strategy to limit disease will target immune responses against one or more blood stage antigens, merozoite surface protein-1 (MSP-1) and apical merozoite antigen-1 (AMA-1). The induction of T-and B-cell memory to achieve a sustained vaccine response may additionally require immunization with an adenovirus vector such as adenovirus serotype 35. RTS,S, a CSP-derived antigen developed by GlaxoSmithKline Biologicals in collaboration with the Walter Reed Army Institute of Research over the past 17 years, is the cornerstone of our program. RTS,S formulated in AS02A (a GSK proprietary formulation) is the only vaccine candidate shown in field trials to prevent malaria and, in one instance, to limit disease severity. Our vaccine development plan requires proof of an individual antigen's efficacy in a Phase 2 laboratory challenge or field trial prior to its integration into an RTS,S-based, multi-antigen vaccine. Progress has been accelerated through extensive partnerships with industrial,

Research paper thumbnail of Phase I dose escalation safety and immunogenicity trial of Plasmodium falciparum apical membrane protein (AMA-1) FMP2.1, adjuvanted with AS02A, in malaria-naïve adults at the Walter Reed Army Institute of Research

Vaccine, 2007

We report the first safety and immunogenicity trial of the Plasmodium falciparum vaccine candidat... more We report the first safety and immunogenicity trial of the Plasmodium falciparum vaccine candidate FMP2.1/AS02A, a recombinant E. coli-expressed protein based upon the apical membrane antigen-1 (AMA-1) of the 3D7 clone formulated with the AS02A adjuvant. We conducted an open-label, staggered-start, dose-escalating Phase I trial in 23 malaria-naïve volunteers who received 8, 20 or 40 g of FMP2.1 in a fixed volume of 0.5 mL of AS02A on a 0, 1, and 2 month schedule. Nineteen of 23 volunteers received all three scheduled immunizations. The most frequent solicited local and systemic adverse events associated with immunization were injection site pain (68%) and headache (29%). There were no significant laboratory abnormalities or vaccine-related serious adverse events. All volunteers seroconverted after second immunization as determined by ELISA. Immune sera recognized sporozoites and merozoites by immunofluorescence assay (IFA), and exhibited both growth inhibition and processing inhibition activity against homologous (3D7) asexual stage parasites. Post-immunization, peripheral blood mononuculear cells exhibited FMP2.1-specific lymphoproliferation and IFN-␥ and IL-5 ELISPOT assay responses. This is the first PfAMA-1-based vaccine shown to elicit both potent humoral and cellular immunity in humans. Encouraged by the potential of FMP1/AS02A to target host immunity against PfAMA-1 that is known to be expressed by sporozoite, hepatic and erythrocytic stages, we have initiated field trials of FMP2.1/AS02A in an endemic population in the Republic of Mali.

Research paper thumbnail of T Cell Responses to the RTS,S/AS01E and RTS,S/AS02D Malaria Candidate Vaccines Administered According to Different Schedules to Ghanaian Children

PLoS ONE, 2011

Background: The Plasmodium falciparum pre-erythrocytic stage candidate vaccine RTS,S is being dev... more Background: The Plasmodium falciparum pre-erythrocytic stage candidate vaccine RTS,S is being developed for protection of young children against malaria in sub-Saharan Africa. RTS,S formulated with the liposome based adjuvant AS01 E or the oil-in-water based adjuvant AS02 D induces P. falciparum circumsporozoite (CSP) antigen-specific antibody and T cell responses which have been associated with protection in the experimental malaria challenge model in adults. Methods: This study was designed to evaluate the safety and immunogenicity induced over a 19 month period by three vaccination schedules (0,1-, 0,1,2-and 0,1,7-month) of RTS,S/AS01 E and RTS,S/AS02 D in children aged 5-17 months in two research centers in Ghana. Control Rabies vaccine using the 0,1,2-month schedule was used in one of two study sites. Results: Whole blood antigen stimulation followed by intra-cellular cytokine staining showed RTS,S/AS01 E induced CSP specific CD4 T cells producing IL-2, TNF-a, and IFN-c. Higher T cell responses were induced by a 0,1,7-month immunization schedule as compared with a 0,1-or 0,1,2-month schedule. RTS,S/AS01 E induced higher CD4 T cell responses as compared to RTS,S/AS02 D when given on a 0,1,7-month schedule. Conclusions: These findings support further Phase III evaluation of RTS,S/AS01 E. The role of immune effectors and immunization schedules on vaccine protection are currently under evaluation.

Research paper thumbnail of Circumsporozoite-Specific T Cell Responses in Children Vaccinated with RTS,S/AS01E and Protection against P falciparum Clinical Malaria

PLoS ONE, 2011

Background: RTS,S/AS01 E is the lead candidate pre-erythrocytic malaria vaccine. In Phase IIb fie... more Background: RTS,S/AS01 E is the lead candidate pre-erythrocytic malaria vaccine. In Phase IIb field trials the safety profile was acceptable and the efficacy was 53% (95%CI 31%-72%) for protecting children against clinical malaria caused by P. falciparum. We studied CS-specific T cell responses in order to identify correlates of protection. Methods and Findings: We used intracellular cytokine staining (for IL2, IFNc, and TNFa), ex-vivo ELISPOTs (IFNc and IL2) and IFNc cultured ELISPOT assays to characterize the CS-specific cellular responses in 407 children (5-17 months of age) in a phase IIb randomized controlled trial of RTS,S/AS01 E (NCT00380393). RTS,S/ AS01 E vaccinees had higher frequencies of CSspecific CD4+ T cells producing IFNc, TNFa or IL2 compared to control vaccinees. In a multivariable analysis TNFa + CD4 + T cells were independently associated with a reduced risk for clinical malaria among RTS,S/AS01 E vaccinees (HR = 0.64, 95%CI 0.49-0.86, p = 0.002). There was a non-significant tendency towards reduced risk among control vaccinees (HR = 0.80, 95%CI 0.62-1.03, p = 0.084), albeit with lower CS-specific T cell frequencies and higher rates of clinical malaria. When data from both RTS,S/AS01 E vaccinees and control vaccinees were combined (with adjusting for vaccination group), the HR was 0.74 (95%CI 0.62-0.89, p = 0.001). After a Bonferroni correction for multiple comparisons (n-18), the finding was still significant at p = 0.018. There was no significant correlation between cultured or ex vivo ELISPOT data and protection from clinical malaria. The combination of TNFa + CD4 + T cells and anti-CS antibody statistically accounted for the protective effect of vaccination in a Cox regression model. Conclusions: RTS,S/AS01 E induces CS-specific Th1 T cell responses in young children living in a malaria endemic area. The combination of anti-CS antibody concentrations titers and CS-specific TNFa + CD4 + T cells could account for the level of protection conferred by RTS,S/AS01 E. The correlation between CS-specific TNFa + CD4 + T cells and protection needs confirmation in other datasets.

Research paper thumbnail of Impact of RTS,S/AS02A and RTS,S/AS01B on Genotypes of P. falciparum in Adults Participating in a Malaria Vaccine Clinical Trial

PLoS ONE, 2009

Objective: RTS,S, a candidate vaccine for malaria, is a recombinant protein expressed in yeast co... more Objective: RTS,S, a candidate vaccine for malaria, is a recombinant protein expressed in yeast containing part of the circumsporozoite protein (CSP) sequence of 3D7 strain of Plasmodium falciparum linked to the hepatitis B surface antigen in a hybrid protein. The RTS,S antigen is formulated with GSK Biologicals' proprietary Adjuvant Systems AS02 A or AS01 B. A recent trial of the RTS,S/AS02 A and RTS,S/AS01 B vaccines evaluated safety, immunogenicity and impact on the development of parasitemia of the two formulations. Parasite isolates from this study were used to determine the molecular impact of RTS,S/AS02 A and RTS,S/AS01 B on the multiplicity of infection (MOI) and the csp allelic characteristics of subsequent parasitemias. Design: The distribution of csp sequences and the MOI of the infecting strains were examined at baseline and in breakthrough infections from vaccinated individuals and from those receiving a non-malarial vaccine. Setting: The study was conducted in Kombewa District, western Kenya. Participants: Semi-immune adults from the three study arms provided isolates at baseline and during breakthrough infections. Outcome: Parasite isolates used for determining MOI and divergence of csp T cell-epitopes were 191 at baseline and 87 from breakthrough infections. Results: Grouping recipients of RTS,S/AS01 A and RTS,S/AS02 B together, vaccine recipients identified as parasite-positive by microscopy contained significantly fewer parasite genotypes than recipients of the rabies vaccine comparator (median in pooled RTS,S groups: 3 versus 4 in controls, P = 0.0313). When analyzed separately, parasitaemic individuals in the RTS,S/ AS01 B group, but not the RTS,S/AS02 A group, were found to have significantly fewer genotypes than the comparator group. Two individual amino acids found in the vaccine construct (Q339 in Th2R and D371 in Th3R) were observed to differ in incidence between vaccine and comparator groups but in different directions; parasites harboring Q339 were less common among pooled RTS,S/AS vaccine recipients than among recipients of rabies vaccine, whereas parasites with D371 were more common among the RTS,S/AS groups. Conclusions: It is concluded that both RTS,S/AS vaccines reduce multiplicity of infection. Our results do not support the hypothesis that RTS,S/AS vaccines elicit preferential effects against pfcsp alleles with sequence similarity to the 3D7 pfcsp sequence employed in the vaccine construct.

Research paper thumbnail of A Randomized Trial Assessing the Safety and Immunogenicity of AS01 and AS02 Adjuvanted RTS,S Malaria Vaccine Candidates in Children in Gabon

PLoS ONE, 2009

Background: The malaria vaccine candidate antigen RTS,S includes parts of the pre-erythrocytic st... more Background: The malaria vaccine candidate antigen RTS,S includes parts of the pre-erythrocytic stage circumsporozoite protein fused to the Hepatitis B surface antigen. Two Adjuvant Systems are in development for this vaccine, an oil-in water emulsion-based formulation (AS02) and a formulation based on liposomes (AS01). Methods & Principal Findings: In this Phase II, double-blind study (NCT00307021), 180 healthy Gabonese children aged 18 months to 4 years were randomized to receive either RTS,S/AS01 E or RTS,S/AS02 D , on a 0-1-2 month vaccination schedule. The children were followed-up daily for six days after each vaccination and monthly for 14 months. Blood samples were collected at 4 time-points. Both vaccines were well tolerated. Safety parameters were distributed similarly between the two groups. Both vaccines elicited a strong specific immune response after Doses 2 and 3 with a ratio of anti-CS GMT titers (AS02 D /AS01 E) of 0.88 (95% CI: 0.68-1.15) post-Dose 3. After Doses 2 and 3 of experimental vaccines, anti-CS and anti-HBs antibody GMTs were higher in children who had been previously vaccinated with at least one dose of hepatitis B vaccine compared to those not previously vaccinated. Conclusions: RTS,S/AS01 E proved similarly as well tolerated and immunogenic as RTS,S/AS02 D , completing an essential step in the age de-escalation process within the RTS,S clinical development plan.

Research paper thumbnail of Randomized Controlled Trial of RTS,S/AS02D and RTS,S/AS01E Malaria Candidate Vaccines Given According to Different Schedules in Ghanaian Children

PLoS ONE, 2009

Background: The target delivery channel of RTS,S candidate malaria vaccines in malaria-endemic co... more Background: The target delivery channel of RTS,S candidate malaria vaccines in malaria-endemic countries in Africa is the World Health Organisation Expanded Program on Immunization. As an Adjuvant System, age de-escalation and schedule selection step, this study assessed 3 schedules of RTS,S/AS01 E and RTS,S/AS02 D in infants and young children 5-17 months of age in Ghana. Methodology: A Phase II, partially-blind randomized controlled study (blind to vaccine, not to schedule), of 19 months duration was conducted in two (2) centres in Ghana

Research paper thumbnail of A Phase 3 Trial of RTS,S/AS01 Malaria Vaccine in African Infants

New England Journal of Medicine, 2012

Background The candidate malaria vaccine RTS,S/AS01 reduced episodes of both clinical and severe ... more Background The candidate malaria vaccine RTS,S/AS01 reduced episodes of both clinical and severe malaria in children 5 to 17 months of age by approximately 50% in an ongoing phase 3 trial. We studied infants 6 to 12 weeks of age recruited for the same trial. Methods We administered RTS,S/AS01 or a comparator vaccine to 6537 infants who were 6 to 12 weeks of age at the time of the first vaccination in conjunction with Expanded Program on Immunization (EPI) vaccines in a three-dose monthly schedule. Vaccine efficacy against the first or only episode of clinical malaria during the 12 months after vaccination, a coprimary end point, was analyzed with the use of Cox regression. Vaccine efficacy against all malaria episodes, vaccine efficacy against severe malaria, safety, and immunogenicity were also assessed. Results The incidence of the first or only episode of clinical malaria in the intention-to-treat population during the 14 months after the first dose of vaccine was 0.31 per personyear in the RTS,S/AS01 group and 0.40 per person-year in the control group, for a vaccine efficacy of 30.1% (95% confidence interval [CI], 23.6 to 36.1). Vaccine efficacy in the per-protocol population was 31.3% (97.5% CI, 23.6 to 38.3). Vaccine efficacy against severe malaria was 26.0% (95% CI, −7.4 to 48.6) in the intention-totreat population and 36.6% (95% CI, 4.6 to 57.7) in the per-protocol population. Serious adverse events occurred with a similar frequency in the two study groups. One month after administration of the third dose of RTS,S/AS01, 99.7% of children were positive for anti-circumsporozoite antibodies, with a geometric mean titer of 209 EU per milliliter (95% CI, 197 to 222). Conclusions The RTS,S/AS01 vaccine coadministered with EPI vaccines provided modest protection against both clinical and severe malaria in young infants. (Funded by Glaxo SmithKline Biologicals and the PATH Malaria Vaccine Initiative; RTS,S ClinicalTrials.gov number, NCT00866619.

Research paper thumbnail of Safety and efficacy of the RTS,S/AS01 E candidate malaria vaccine given with expanded-programme-on-immunisation vaccines: 19 month follow-up of a randomised, open-label, phase 2 trial

The Lancet Infectious Diseases, 2011

Background The RTS,S/AS01 E candidate malaria vaccine is being developed for immunisation of infa... more Background The RTS,S/AS01 E candidate malaria vaccine is being developed for immunisation of infants in Africa through the expanded programme on immunisation (EPI). 8 month follow-up data have been reported for safety and immunogenicity of RTS,S/AS01 E when integrated into the EPI. We report extended follow-up to 19 months, including effi cacy results. Methods We did a randomised, open-label, phase 2 trial of safety and effi cacy of the RTS,S/AS01 E candidate malaria vaccine given with EPI vaccines between April 30, 2007, and Oct 7, 2009, in Ghana, Tanzania, and Gabon. Eligible children were 6-10 weeks of age at fi rst vaccination, without serious acute or chronic illness. All children received the EPI diphtheria, tetanus, pertussis (inactivated whole-cell), and hepatitis-B vaccines, Haemophilus infl uenzae type b vaccine, and oral polio vaccine at study months 0, 1, and 2, and measles vaccine and yellow fever vaccines at study month 7. Participants were randomly assigned (1:1:1) to receive three doses of RTS,S/AS01 E at 6, 10, and 14 weeks (0, 1, 2 month schedule) or at 6 weeks, 10 weeks, and 9 months (0, 2, 7 month schedule) or placebo. Randomisation was according to a predefi ned block list with a computer-generated randomisation code. Detection of serious adverse events and malaria was by passive case detection. Antibodies against Plasmodium falciparum circumsporozoite protein and HBsAg were monitored for 19 months. This study is registered with ClinicalTrials.gov, number NCT00436007. Findings 511 children were enrolled. Serious adverse events occurred in 57 participants in the RTS,S/AS01 E 0, 1, 2 month group (34%, 95% CI 27-41), 47 in the 0, 1, 7 month group (28%, 21-35), and 49 (29%, 22-36) in the control group; none were judged to be related to study vaccination. At month 19, anticircumsporozoite immune responses were signifi cantly higher in the RTS,S/AS01 E groups than in the control group. Vaccine effi cacy for the 0, 1, 2 month schedule (2 weeks after dose three to month 19, site-adjusted according-to-protocol analysis) was 53% (95% CI 26-70; p=0•0012) against fi rst malaria episodes and 59% (36-74; p=0•0001) against all malaria episodes. For the entire study period, (total vaccinated cohort) vaccine effi cacy against all malaria episodes was higher with the 0, 1, 2 month schedule (57%, 95% CI 33-73; p=0•0002) than with the 0, 1, 7 month schedule (32% CI 16-45; p=0•0003). 1 year after dose three, vaccine effi cacy against fi rst malaria episodes was similar for both schedules (0, 1, 2 month group, 61•6% [95% CI 35•6-77•1], p<0•001; 0, 1, 7 month group, 63•8% [40•4-78•0], p<0•001, according-to-protocol cohort). Interpretation Vaccine effi cacy was consistent with the target put forward by the WHO-sponsored malaria vaccine technology roadmap for a fi rst-generation malaria vaccine. The 0, 1, 2 month vaccine schedule has been selected for phase 3 candidate vaccine assessment. Funding Program for Appropriate Technology in Health Malaria Vaccine Initiative; GlaxoSmithKline Biologicals.

Research paper thumbnail of Efficacy of RTS,S/AS01E malaria vaccine and exploratory analysis on anti-circumsporozoite antibody titres and protection in children aged 5–17 months in Kenya and Tanzania: a randomised controlled trial

The Lancet Infectious Diseases, 2011

Research paper thumbnail of Randomized, Double‐Blind, Phase 2a Trial of Falciparum Malaria Vaccines RTS,S/AS01B and RTS,S/AS02A in Malaria‐Naive Adults: Safety, Efficacy, and Immunologic Associates of Protection

The Journal of Infectious Diseases, 2009

See the editorial commentary by Bremen and Plowe, on pages 317-20, and the article by Sacarlal et... more See the editorial commentary by Bremen and Plowe, on pages 317-20, and the article by Sacarlal et al, on pages 329-36.) Background. To further increase the eff cacy of malaria vaccine RTS,S/AS02A, we tested the RTS,S antigen formulated using the AS01B Adjuvant System (GlaxoSmithKline Biologicals). Methods. In a double-blind, randomized trial, 102 healthy volunteers were evenly allocated to receive RTS,S/ AS01B or RTS,S/AS02A vaccine at months 0, 1, and 2 of the study, followed by malaria challenge. Protected vaccine recipients were rechallenged 5 months later. Results. RTS,S/AS01B and RTS,S/AS02A were well tolerated and were safe. The efficac of RTS,S/AS01B and RTS,S/AS02A was 50% (95% confidenc interval [CI], 32.9%-67.1%) and 32% (95% CI, 17.6%-47.6%), respectively. At the time of initial challenge, the RTS,S/AS01B group had greater circumsporozoite protein (CSP)-specifi immune responses, including higher immunoglobulin (Ig) G titers, higher numbers of CSP-specifi CD4 + T cells expressing у2 activation markers (interleukin-2, interferon [IFN]-g, tumor necrosis factor-a, or CD40L), and more ex vivo IFN-g enzyme-linked immunospots (ELISPOTs) than did the RTS,S/AS02A group. Protected vaccine recipients had a higher CSP-specifi IgG titer (geometric mean titer, 188 vs 73 mg/mL;

Research paper thumbnail of Evaluation of the Safety and Immunogenicity of the RTS,S/AS01EMalaria Candidate Vaccine When Integrated in the Expanded Program of Immunization

The Journal of Infectious Diseases, 2010

Background. The RTS,S/AS01 E malaria candidate vaccine is being developed for immunization of Afr... more Background. The RTS,S/AS01 E malaria candidate vaccine is being developed for immunization of African infants through the Expanded Program of Immunization (EPI). Methods. This phase 2, randomized, open, controlled trial conducted in Ghana, Tanzania, and Gabon evaluated the safety and immunogenicity of RTS,S/AS01 E when coadministered with EPI vaccines. Five hundred eleven infants were randomized to receive RTS,S/AS01 E at 0, 1, and 2 months (in 3 doses with diphtheria, tetanus, and wholecell pertussis conjugate [DTPw]; hepatitis B [HepB]; Haemophilus influenzae type b [Hib]; and oral polio vaccine [OPV]), RTS,S/AS01 E at 0, 1, and 7 months (2 doses with DTPwHepB/Hib+OPV and 1 dose with measles and yellow fever), or EPI vaccines only. Results. The occurrences of serious adverse events were balanced across groups; none were vaccine-related. One child from the control group died. Mild to moderate fever and diaper dermatitis occurred more frequently in the RTS,S/AS01 E coadministration groups. RTS,S/AS01 E generated high anti-circumsporozoite protein and antihepatitis B surface antigen antibody levels. Regarding EPI vaccine responses upon coadministration when considering both immunization schedules, despite a tendency toward lower geometric mean titers to some EPI antigens, predefined noninferiority criteria were met for all EPI antigens except for polio 3 when EPI vaccines were given with RTS,S/AS01 E at 0, 1, and 2 months. However, when antibody levels at screening were taken into account, the rates of response to polio 3 antigens were comparable between groups. Conclusion. RTS,S/AS01 E integrated in the EPI showed a favorable safety and immunogenicity evaluation. Trial registration. ClinicalTrials.gov identifier: NCT00436007. GlaxoSmithKline study ID number: 106369 (Malaria-050). The development of a malaria vaccine has been identified as a key component of future integrated malaria control programs and an important step toward sus