Prof. Marcel Tanner
Professor of Epidemiology and Medical Parasitology
University of Basel
Swiss Tropical and Public Health Institute
Professor of Epidemiology and Medical Parasitology
University of Basel
 
Swiss Tropical and Public Health Institute


MAJOR SCIENTIFIC PUBLICATIONS

  • 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

    Asante-Poku A, Abdulla S, Agnandji S, Lyimo J, Vekemans J, Soulanoudjingar S, Owusu R, Shomari M, Leach A, Jongert E, Salim N, Fernandes JF, Dosoo D, Chikawe M, Issifou S, Osei-Kwakye K, Lievens M, Paricek M, Moller T, Apanga S, Mwangoka G, Lancet Infect Dis 2011; 11: 741-749
    Abstract
     
    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 efficacy results.
     
    METHODS:
    We did a randomised, open-label, phase 2 trial of safety and efficacy 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 first vaccination, without serious acute or chronic illness. All children received the EPI diphtheria, tetanus, pertussis (inactivated whole-cell), and hepatitis-B vaccines, Haemophilus influenzae 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 predefined 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 significantly higher in the RTS,S/AS01(E) groups than in the control group. Vaccine efficacy 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 first malaria episodes and 59% (36-74; p=0.0001) against all malaria episodes. For the entire study period, (total vaccinated cohort) vaccine efficacy 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 efficacy against first 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 efficacy was consistent with the target put forward by the WHO-sponsored malaria vaccine technology roadmap for a first-generation malaria vaccine. The 0, 1, 2 month vaccine schedule has been selected for phase 3 candidate vaccine assessment.
     

  • Virosome-Formulated Plasmodium Falciparum AMA-1 & CSP Derived Peptides as Malaria Vaccine: Randomized Phase 1b Trial in Semi-Immune Adults & Children

    Cech PG, Aebi T, Abdallah MS, Mpina M, Machunda EB, Westerfeld N, Stoffel SA, Zurbriggen R, Pluschke G, Tanner M, Daubenberger C, Genton B & Abdulla SPLoS One 2011; 6(7): e22273
    Abstract
     
    BACKGROUND:
    This trial was conducted to evaluate the safety and immunogenicity of two virosome formulated malaria peptidomimetics derived from Plasmodium falciparum AMA-1 and CSP in malariasemi-immune adults and children.
     
    METHODS:
    The design was a prospective randomized, double-blind, controlled, age-deescalating study with two immunizations. 10 adults and 40 children (aged 5-9 years) living in a malaria endemic area were immunized with PEV3B or virosomal influenza vaccine Inflexal®V on day 0 and 90.
     
    RESULTS:
    No serious or severe adverse events (AEs) related to the vaccines were observed. The only local solicited AE reported was pain at injection site, which affected more children in the Inflexal®V group compared to the PEV3B group (p = 0.014). In the PEV3B group, IgG ELISA endpoint titers specific for the AMA-1 and CSP peptide antigens were significantly higher for most time points compared to the Inflexal®V control group. Across all time points after first immunization the average ratio of endpoint titers to baseline values in PEV3B subjects ranged from 4 to 15 in adults and from 4 to 66 in children. As an exploratory outcome, we found that the incidence rate of clinical malariaepisodes in children vaccinees was half the rate of the control children between study days 30 and 365 (0.0035 episodes per day at risk for PEV3B vs. 0.0069 for Inflexal®V; RR = 0.50 [95%-CI: 0.29-0.88], p = 0.02).
     
    CONCLUSION:
    These findings provide a strong basis for the further development of multivalent virosomal malaria peptide vaccines.
     

  • Uses of Mosquito-Stage Transmission-Blocking Vaccines against Plasmodium Falciparum

    Smith TA, Chitnis N, Briët OJ & Tanner MTrends Parasitol 2011; 27(5): 190-196
    Abstract
     
    A quantitative framework is used to explore the potential applications and probable effects of sexual stage or mosquito stage transmission blocking vaccines (TBVs) against malaria. The combination of TBVs with biocides or other malaria vaccines will increase chances of interrupting transmission, whereas the value of TBVs for morbidity control will be limited. Vaccine combination will also protect against selection of insensitive parasites. Simulations indicate that TBVs will reduce risks of reestablishment of transmission when vector control is withdrawn. Simple mathematical analysis shows that efficacy and coverage are equally important, implying that a vaccine that requires a small number of doses (ideally one) is preferable to one that is difficult to deliver, even if this entails accepting a lower efficacy.
     

  • First Results of Phase 3 Trial of RTS, S/AS01 Malaria Vaccine in African Children

    RTS, S Clinical Trials PartnershipN Engl J Med 2011; 365(20): 1863-1875
    Abstract
     
    BACKGROUND:
    An ongoing phase 3 study of the efficacy, safety, and immunogenicity of candidatemalaria vaccine RTS,S/AS01 is being conducted in seven African countries.
     
    METHODS:
    From March 2009 through January 2011, we enrolled 15,460 children in two age categories--6 to 12 weeks of age and 5 to 17 months of age--for vaccination with either RTS,S/AS01or a non-malaria comparator vaccine. The primary end point of the analysis was vaccine efficacy against clinical malaria during the 12 months after vaccination in the first 6000 children 5 to 17 months of age at enrollment who received all three doses of vaccine according to protocol. After 250 childrenhad an episode of severe malaria, we evaluated vaccine efficacy against severe malaria in both age categories.
     
    RESULTS:
    In the 14 months after the first dose of vaccine, the incidence of first episodes of clinicalmalaria in the first 6000 children in the older age category was 0.32 episodes per person-year in theRTS,S/AS01 group and 0.55 episodes per person-year in the control group, for an efficacy of 50.4% (95% confidence interval [CI], 45.8 to 54.6) in the intention-to-treat population and 55.8% (97.5% CI, 50.6 to 60.4) in the per-protocol population. Vaccine efficacy against severe malaria was 45.1% (95% CI, 23.8 to 60.5) in the intention-to-treat population and 47.3% (95% CI, 22.4 to 64.2) in the per-protocol population. Vaccine efficacy against severe malaria in the combined age categories was 34.8% (95% CI, 16.2 to 49.2) in the per-protocol population during an average follow-up of 11 months. Serious adverse events occurred with a similar frequency in the two study groups. Among children in the older age category, the rate of generalized convulsive seizures after RTS,S/AS01 vaccination was 1.04 per 1000 doses (95% CI, 0.62 to 1.64).
     
    CONCLUSIONS:
    The RTS,S/AS01 vaccine provided protection against both clinical and severemalaria in African children. (Funded by GlaxoSmithKline Biologicals and the PATH Malaria VaccineInitiative; RTS,S ClinicalTrials.gov number, NCT00866619 .).

     


  • Ensemble Modeling of the Likely Public Health Impact of a Pre-erythrocytic Malaria Vaccine

    Smith T, Ross A, Maire N, Chitnis N, Studer A, Hardy D, Brooks A, Penny M & Tanner MPLoS Medicine 2012; 9: e1001157
    Abstract
     
    BACKGROUND:
    The RTS,S malaria vaccine may soon be licensed. Models of impact of such vaccines have mainly considered deployment via the World Health Organization's Expanded Programme on Immunization (EPI) in areas of stable endemic transmission of Plasmodium falciparum, and have been calibrated for such settings. Their applicability to low transmission settings is unclear. Evaluations of the efficiency of different deployment strategies in diverse settings should consider uncertainties in model structure.
     
    METHODS AND FINDINGS:
    An ensemble of 14 individual-based stochastic simulation models of P. falciparum dynamics, with differing assumptions about immune decay, transmission heterogeneity, and treatment access, was constructed. After fitting to an extensive library of field data, each model was used to predict the likely health benefits of RTS,S deployment, via EPI (with or without catch-up vaccinations), supplementary vaccination of school-age children, or mass vaccination every 5 y. Settings with seasonally varying transmission, with overall pre-intervention entomological inoculation rates (EIRs) of two, 11, and 20 infectious bites per person per annum, were considered. Predicted benefits of EPI vaccination programs over the simulated 14-y time horizon were dependent on duration of protection. Nevertheless, EPI strategies (with an initial catch-up phase) averted the most deaths per dose at the higher EIRs, although model uncertainty increased with EIR. At two infectious bites per person per annum, mass vaccination strategies substantially reduced transmission, leading to much greater health effects per dose, even at modest coverage.
     
    CONCLUSIONS:
    In higher transmission settings, EPI strategies will be most efficient, but vaccination additional to the EPI in targeted low transmission settings, even at modest coverage, might be more efficient than national-level vaccination of infants. The feasibility and economics of mass vaccination, and the circumstances under which vaccination will avert epidemics, remain unclear. The approach of using an ensemble of models provides more secure conclusions than a single-model approach, and suggests greater confidence in predictions of health effects for lower transmission settings than for higher ones.
     

  • A Phase 3 Trial of RTS, S/AS01 Malaria Vaccine in African Infants

    RTS, S Clinical Trials PartnershipN Engl J Med 2012; 367(24): 2284-2295
    Abstract
     
    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 ofclinical 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 severemalaria, 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 person-year in theRTS,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-to-treat 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 GlaxoSmithKline Biologicals and the PATH Malaria Vaccine Initiative; RTS, S ClinicalTrials.gov number,NCT00866619.).

  • Genetic Diversity and Protective Efficacy of the RTS, S/AS01 Malaria Vaccine

    Neafsey DE, Juraska M, Bedford T, Benkeser D, Valim C, Griggs A, Lievens M, Abdulla S, Adjei S, Agbenyega T, Agnandji ST, Aide P, Anderson S, Ansong D, Aponte JJ, Asante KP, Bejon P, Birkett AJ, Bruls M, Connolly KM, D'Alessandro U, Dobaño N Engl J Med 2015; 373(21): 2025–2037
    Abstract
     
    BACKGROUND:
    The RTS, S/AS01 vaccine targets the circumsporozoite protein of Plasmodium falciparum and has partial protective efficacy against clinical and severe malaria disease in infants and children. We investigated whether the vaccine efficacy was specific to certain parasite genotypes at the circumsporozoite protein locus.
     
    METHODS:
    We used polymerase chain reaction-based next-generation sequencing of DNA extracted from samples from 4985 participants to survey circumsporozoite protein polymorphisms. We evaluated the effect that polymorphic positions and haplotypic regions within the circumsporozoite protein had on vaccine efficacy against first episodes of clinical malaria within 1 year after vaccination.
     
    RESULTS:
    In the per-protocol group of 4577 RTS,S/AS01-vaccinated participants and 2335 control-vaccinated participants who were 5 to 17 months of age, the 1-year cumulative vaccine efficacy was 50.3% (95% confidence interval [CI], 34.6 to 62.3) against clinical malaria in which parasites matched the vaccine in the entire circumsporozoite protein C-terminal (139 infections), as compared with 33.4% (95% CI, 29.3 to 37.2) against mismatched malaria (1951 infections) (P=0.04 for differential vaccineefficacy). The vaccine efficacy based on the hazard ratio was 62.7% (95% CI, 51.6 to 71.3) against matched infections versus 54.2% (95% CI, 49.9 to 58.1) against mismatched infections (P=0.06). In the group of infants 6 to 12 weeks of age, there was no evidence of differential allele-specific vaccineefficacy.
     
    CONCLUSIONS:
    These results suggest that among children 5 to 17 months of age, the RTS, Svaccine has greater activity against malaria parasites with the matched circumsporozoite protein allele than against mismatched malaria. The overall vaccine efficacy in this age category will depend on the proportion of matched alleles in the local parasite population; in this trial, less than 10% of parasites had matched alleles.

  • The Public Health Impact of Malaria Vaccine RTS, S in Malaria Endemic Africa: Country-Specific Predictions Using 18 Month Follow-up Phase III Data and Simulation Models

    Penny MA, Galactionova K, Tarantino M, Tanner M & Smith TABMC Med 2015; 13: 170
    Abstract
     
    BACKGROUND:
    The RTS, S/AS01 malaria vaccine candidate recently completed Phase III trials in 11 African sites. Recommendations for its deployment will partly depend on predictions of public healthimpact in endemic countries.Previous predictions of these used only limited information on underlyingvaccine properties and have not considered country-specific contextual data.
     
    METHODS:
    Each Phase III trial cohort was simulated explicitly using an ensemble of individual-based stochastic models, and many hypothetical vaccine profiles. The true profile was estimated by Bayesian fitting of these models to the site- and time-specific incidence of clinical malaria in both trial arms over18 months of follow-up. Health impacts of implementation via two vaccine schedules in 43 endemicsub-Saharan African countries, using country-specific prevalence, access to care, immunisation coverage and demography data, were predicted via weighted averaging over many simulations.
     
    RESULTS:
    The efficacy against infection of three doses of vaccine was initially approximately 65 % (when immunising 6-12 week old infants) and 80 % (children 5-17 months old), with a 1 year half-life (exponential decay). Either schedule will avert substantial disease, but predicted impact strongly depends on the decay rate of vaccine effects and average transmission intensity.
     
    CONCLUSIONS:
    For the first time Phase III site- and time-specific data were available to estimate both the underlying profile of RTS, S/AS01 and likely country-specific health impacts. Initial efficacy will probably be high, but decay rapidly. Adding RTS, S to existing control programs, assuming continuation of current levels of malaria exposure and of health system performance, will potentially avert 100-580malaria deaths and 45,000 to 80,000 clinical episodes per 100,000 fully vaccinated children over an initial 10-year phase.
     

     


  • Progress with Plasmodium Falciparum Sporozoite (PfSPZ) - Based Malaria Vaccines

    Richie TL, Billingsley PF, Sim BK, Epstein JE, Lyke KE, Mordmüller B, Alonso P, Duffy PE, Doumbo OK, Sauerwein RW, Tanner M, Abdulla S, Kremsner PG, Seder RA & Hoffman SLVaccine 2015; 33(52): 7452–7461
    Abstract
     
    Sanaria Inc. has developed methods to manufacture, purify and cryopreserve aseptic Plasmodium falciparum (Pf) sporozoites (SPZ), and is using this platform technology to develop an injectablePfSPZ-based vaccine that provides high-grade, durable protection against infection with Pf malaria. Several candidate vaccines are being developed and tested, including PfSPZ Vaccine, in which thePfSPZ are attenuated by irradiation, PfSPZ-CVac, in which fully infectious PfSPZ are attenuated in vivo by concomitant administration of an anti-malarial drug, and PfSPZ-GA1, in which the PfSPZ are attenuated by gene knockout. Forty-three research groups in 15 countries, organized as the International PfSPZ Consortium (I-PfSPZ-C), are collaborating to advance this program by providing intellectual, clinical, and financial support. Fourteen clinical trials of these products have been completed in the USA, Europe and Africa, two are underway and at least 12 more are planned for 2015-2016 in the US (four trials), Germany (2 trials), Tanzania, Kenya, Mali, Burkina Faso, Ghana and Equatorial Guinea. Sanaria anticipates application to license a first generation product as early as late 2017, initially to protect adults, and a year later to protect all persons >6 months of age for at least six months. Improved vaccine candidates will be advanced as needed until the following requirements have been met: long-term protection against natural transmission, excellent safety and tolerability, and operational feasibility for population-wide administration. Here we describe the three most developed whole PfSPZ vaccine candidates, associated clinical trials, initial plans for licensure and deployment, and long-term objectives for a final product suitable for mass administration to achieve regionalmalaria elimination and eventual global eradication.
     

  • Ecacy and Safety of RTS, S/AS01 Malaria Vaccine with or without a Booster Dose in Infants and Children in Africa: Final Results of a Phase 3, Individually Randomised, Controlled Trial

    RTS, S Clinical Trials PartnershipLancet 2015; 386(9988): 31–45
    Abstract
     
    BACKGROUND:
    The efficacy and safety of the RTS, S/AS01 candidate malaria vaccine during 18 months of follow-up have been published previously. Herein, we report the final results from the same trial, including the efficacy of a booster dose.
     
    METHODS:
    From March 27, 2009, until Jan 31, 2011, children (age 5-17 months) and younginfants (age 6-12 weeks) were enrolled at 11 centres in seven countries in sub-Saharan Africa. Participants were randomly assigned (1:1:1) at first vaccination by block randomisation with minimisation by centre to receive three doses of RTS,S/AS01 at months 0, 1, and 2 and abooster dose at month 20 (R3R group); three doses of RTS,S/AS01 and a dose of comparatorvaccine at month 20 (R3C group); or a comparator vaccine at months 0, 1, 2, and 20 (C3C [control group]). Participants were followed up until Jan 31, 2014. Cases of clinical and severemalaria were captured through passive case detection. Serious adverse events (SAEs) were recorded. Analyses were by modified intention to treat and per protocol. The coprimary endpoints were the occurrence of malaria over 12 months after dose 3 in each age category. In this final analysis, we present data for the efficacy of the booster on the occurrence of malaria.Vaccine efficacy (VE) against clinical malaria was analysed by negative binomial regression and against severe malaria by relative risk reduction. This trial is registered with ClinicalTrials.gov, number NCT00866619.
     
    FINDINGS:
    8922 children and 6537 young infants were included in the modified intention-to-treat analyses. Children were followed up for a median of 48 months (IQR 39-50) and young infantsfor 38 months (34-41) after dose 1. From month 0 until study end, compared with 9585 episodes of clinical malaria that met the primary case definition in children in the C3C group, 6616 episodes occurred in the R3R group (VE 36.3%, 95% CI 31.8-40.5) and 7396 occurred in the R3C group (28.3%, 23.3-32.9); compared with 171 children who experienced at least one episode of severe malaria in the C3C group, 116 children experienced at least one episode of severe malaria in the R3R group (32.2%, 13.7 to 46.9) and 169 in the R3C group (1.1%, -23.0 to 20.5). In young infants, compared with 6170 episodes of clinical malaria that met the primary case definition in the C3C group, 4993 episodes occurred in the R3R group (VE 25.9%, 95% CI 19.9-31.5) and 5444 occurred in the R3C group (18.3%, 11.7-24.4); and compared with 116infants who experienced at least one episode of severe malaria in the C3C group, 96 infantsexperienced at least one episode of severe malaria in the R3R group (17.3%, 95% CI -9.4 to 37.5) and 104 in the R3C group (10.3%, -17.9 to 31.8). In children, 1774 cases of clinicalmalaria were averted per 1000 children (95% CI 1387-2186) in the R3R group and 1363 per 1000 children (995-1797) in the R3C group. The numbers of cases averted per 1000 younginfants were 983 (95% CI 592-1337) in the R3R group and 558 (158-926) in the R3C group. The frequency of SAEs overall was balanced between groups. However, meningitis was reported as a SAE in 22 children: 11 in the R3R group, ten in the R3C group, and one in the C3C group. The incidence of generalised convulsive seizures within 7 days of RTS,S/AS01 booster was 2.2 per 1000 doses in young infants and 2.5 per 1000 doses in children.
     
    INTERPRETATION:
    RTS, S/AS01 prevented a substantial number of cases of clinical malariaover a 3-4 year period in young infants and children when administered with or without a boosterdose. Efficacy was enhanced by the administration of a booster dose in both age categories. Thus, the vaccine has the potential to make a substantial contribution to malaria control when used in combination with other effective control measures, especially in areas of high transmission.

     


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