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Purpose: The aim of this study was to characterize W' recovery kinetics in response to a partial W' depletion. We hypothesized that W' recovery following a partial depletion would be better described by a biexponential than by a monoexponential model., Methods: Nine healthy men performed a ramp incremental exercise test, three to five constant load trials to determine critical power and W', and 10 experimental trials to quantify W' depletion. Each experimental trial consisted of two constant load work bouts (WB1 and WB2) interspersed by a recovery interval. WB1 was designed to evoke a 25% or 75% W' depletion (DEP 25% and DEP 75% ). Subsequently, participants recovered for 30, 60, 120, 300, or 600 s and then performed WB2 to exhaustion to calculate the observed W' recovery (W' OBS ). W' OBS data were fitted using monoexponential and biexponential models, both with a variable and with a fixed model amplitude. Root mean square error and Akaike information criterion (AIC c ) were calculated to evaluate the models' goodness-of-fit., Results: The biexponential model fits were associated with overall lower root mean square error values (0.4% to 5.0%) when compared with the monoexponential models (2.9% to 8.0%). However, ΔAIC c resulted in negative values (-15.5 and -23.3) for the model fits where the amplitude was kept free, thereby favoring the use of a monoexponential model for both depletion conditions. For the model fits where the amplitude was fixed at 100%, ΔAIC c was negative for DEP 25% (-15.0) but positive for DEP 75% (11.2). W' OBS values were strongly correlated between both depletion conditions ( r = 0.92) and positively associated with V̇O 2peak , critical power, and gas exchange threshold ( r = 0.67 to 0.77)., Conclusions: The present study results did not provide evidence in favor of a biexponential modeling technique to characterize W' recovery following a partial depletion. Moreover, we demonstrated that fixed time constants were insufficient to model W' recovery across different depletion levels, and that W' recovery was positively associated with aerobic fitness. These findings underline the importance of employing variable and individualized time constants in future predictive W' models., (Copyright © 2024 by the American College of Sports Medicine.)

Background: The first licensed malaria vaccine, RTS,S/AS01 E , confers moderate protection against symptomatic disease. Because many malaria infections are asymptomatic, we conducted a large-scale longitudinal parasite genotyping study of samples from a clinical trial exploring how vaccine dosing regimen affects vaccine efficacy., Methods: Between Sept 28, 2017, and Sept 25, 2018, 1500 children aged 5-17 months were randomly assigned (1:1:1:1:1) to receive four different RTS,S/AS01 E regimens or a rabies control vaccine in a phase 2b open-label clinical trial in Ghana and Kenya. Participants in the four RTS,S groups received two full doses at month 0 and month 1 and either full doses at month 2 and month 20 (group R012-20); full doses at month 2, month 14, month 26, and month 38 (group R012-14); fractional doses at month 2, month 14, month 26, and month 38 (group Fx012-14; early fourth dose); or fractional doses at month 7, month 20, and month 32 (group Fx017-20; delayed third dose). We evaluated the time to the first new genotypically detected infection and the total number of new infections during two follow-up periods (12 months and 20 months) in more than 36 000 dried blood spot specimens from 1500 participants. To study vaccine effects on time to the first new infection, we defined vaccine efficacy as one minus the hazard ratio (HR; RTS,S vs control) of the first new infection. We performed a post-hoc analysis of vaccine efficacy based on malaria infection status at first vaccination and force of infection by month 2. This trial (MAL-095) is registered with ClinicalTrials.gov, NCT03281291., Findings: We observed significant and similar vaccine efficacy (25-43%; 95% CI union 9-53) against first new infection for all four RTS,S/AS01 E regimens across both follow-up periods (12 months and 20 months). Each RTS,S/AS01 E regimen significantly reduced the mean number of new infections in the 20-month follow-up period by 1·1-1·6 infections (95% CI union 0·6-2·1). Vaccine efficacy against first new infection was significantly higher in participants who were infected with malaria (68%; 95% CI 50-80) than in those who were uninfected (37%; 23-48) at the first vaccination (p=0·0053)., Interpretation: All tested dosing regimens blocked some infections to a similar degree. Improved vaccine efficacy in participants infected during vaccination could suggest new strategies for highly efficacious malaria vaccine development and implementation., Funding: GlaxoSmithKline Biologicals SA, PATH, Bill & Melinda Gates Foundation, and the German Federal Ministry of Education and Research., Competing Interests: Declaration of interests The findings and conclusions in this article are those of the authors and do not necessarily represent the views of the US Centers for Disease Control and Prevention or the US Department of Health and Human Services. LDM received grants from the Bill and Melinda Gates Foundation and the German Federal Ministry of Education and Research through the KfW Development Bank through her institution. CKL received a grant from the German Federal Ministry of Education and Research through the KfW Development Bank and a grant from the Bill and Melinda Gates Foundation. DFW acted as a principal investigator on the MAL-095 study funded by a PATH grant paid to Harvard University, which also supported DEN, AME, BLM, SFS, and AK. DFW is also Chair of the Malaria Policy Advisory Group that advises the WHO on all malaria policy. PBG discloses a PATH subaward from Harvard for statistical analysis contributing to salary support for PBG, MJ, and LL. AME, LL, AK, BS, NSH, DB, SaA, TA, ScA, DA, DKB, PBYB, SE, NF, JG, SKK, KO, AMS, NW, and CFO declare no conflict of interest. ML, FR, OO-A are employees of GSK. ML, FR, and OO-A own shares in GSK., (Copyright © 2024 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Background: The RTS,S/AS01E (RTS,S) malaria vaccine is recommended for children in malaria endemic areas. This phase 2b trial evaluates RTS,S fractional- and full-dose regimens in Ghana and Kenya., Methods: In total, 1500 children aged 5-17 months were randomized (1:1:1:1:1) to receive RTS,S or rabies control vaccine. RTS,S groups received 2 full RTS,S doses at months 0 and 1 and either full (groups R012-20, R012-14-26) or fractional doses (one-fifth; groups Fx012-14-26, Fx017-20-32)., Results: At month 32 post-dose 1, vaccine efficacy against clinical malaria (all episodes) ranged from 38% (R012-20; 95% confidence interval [CI]: 24%-49%) to 53% (R012-14-26; 95% CI: 42%-62%). Vaccine impact (cumulative number of cases averted/1000 children vaccinated) was 1344 (R012-20), 2450 (R012-14-26), 2273 (Fx012-14-26), and 2112 (Fx017-20-32). To account for differences in vaccine volume (fractional vs full dose; post hoc analysis), we estimated cases averted/1000 RTS,S full-dose equivalents: 336 (R012-20), 490 (R012-14-26), 874 (Fx012-14-26), and 880 (Fx017-20-32)., Conclusions: Vaccine efficacy was similar across RTS,S groups. Vaccine impact accounting for full-dose equivalence suggests that using fractional-dose regimens could be a viable dose-sparing strategy. If maintained through trial end, these observations underscore the means to reduce cost per regimen thus maximizing impact and optimizing supply., Clinical Trials Registration: NCT03276962 (ClinicalTrials.gov)., Competing Interests: Potential conflicts of interest. L. S., A. Bo., M. L., F. R., and O. O.-A. are GSK employees. L. S., F. R., and O. O.-A. have restricted shares in GSK. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Background: The recently approved AS01E-adjuvanted respiratory syncytial virus (RSV) prefusion F protein-based vaccine for older adults (RSVPreF3 OA) demonstrated high efficacy against RSV-related disease in ≥60-year-olds., Methods: This ongoing phase 3 study in ≥60-year-olds evaluates immune persistence until 3 years after RSVPreF3 OA vaccination. Here, we describe interim results on humoral and cell-mediated immunogenicity, reactogenicity, and safety until 1 year post-dose 1., Results: In total, 1653 participants were vaccinated. One month post-dose 1, neutralization titers increased 10.5-fold (RSV-A) and 7.8-fold (RSV-B) vs pre-dose 1. Titers then declined to levels 4.4-fold (RSV-A) and 3.5-fold (RSV-B) above pre-dose 1 at month 6 and remained 3.1-fold (RSV-A) and 2.3-fold (RSV-B) above pre-dose 1 levels after 1 year. RSVPreF3-binding immunoglobulin G levels and CD4+ T-cell frequencies showed similar kinetics. Solicited administration-site and systemic adverse events (mostly mild to moderate and transient) were reported by 62.2% and 49.5% of participants. Serious adverse events were reported by 3.9% of participants within 6 months post-dose 1; 1 case was considered vaccine related., Conclusions: One RSVPreF3 OA dose elicited cell-mediated and RSV-A- and RSV-B-specific humoral immune responses that declined over time but remained above pre-dose 1 levels for at least 1 year. The vaccine was well tolerated with an acceptable safety profile. Clinical Trials Registration. NCT04732871 (ClinicalTrials.gov)., Competing Interests: Potential conflicts of interest. T. F. S. reports having received payment or honoraria for lecturing or advisory boards from GSK, AstraZeneca, Bavarian Nordic, Biogen, BioNTech, Janssen-Cilag, Merck-Serono, Moderna, MSD, Pfizer, Roche, Sanofi-Aventis, Seqirus, Takeda, and for conducting clinical vaccine trials from GSK, Pfizer, and Serum Institute of India. S.-J. H. received research support and consultation fees from GSK. P. Y. assisted as Site Principal Investigator for the current study. C. P. A. was a paid Site Principal Investigator for the study and has received consulting fees from Merck and Boehringer Ingelheim. D. C., M. d. H., N. D. S., B. S., A. L., C. M., A. O., P. N., M. L., and V. H. were employees of GSK at the time the study was designed, initiated, and/or conducted. D. C., M. d. H., N. D. S., B. S., C.M., A. O., M. L., and V. H. hold shares of stock in the company as part of their employee remuneration. A. O. is a co-applicant on a pending patent filed by GSK. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Purpose: To analyze the physical profile and training program of a world-class lightweight double sculls rowing crew toward the Tokyo 2020 Olympics., Method: A case study in which both rowers performed physical testing in November 2020 and April 2021 (anthropometrics, incremental rowing test, and power profiling). The training program (38 wk) in the buildup to the Olympics was analyzed, providing insight into training characteristics (volume; contribution of rowing, alternative, and strength training; prescribed and recorded [heart rate] training-intensity distribution). The entire period was split into 3 phases: preparation period (8 wk), competition period 1 (11 wk), and competition period 2 (9 wk), and training characteristics were compared., Results: In the April 2021 testing, rower A (1.89 m, 74.6 kg, 4.4% body fat) had a peak oxygen uptake of 5.8 L·min-1 (77.8 mL·min-1·kg-1) and a peak power output of 491 W. Rower B (1.82 m, 70.6 kg, 7.8% body fat) had a peak oxygen uptake of 5.5 L·min-1 (77.9 mL·min-1·kg-1) and a peak power output of 482 W. The mean weekly training volume was 14 hours 47 minutes (4 h 5 min), of which 58.5% (14.6%) consisted of rowing, 13.4% (6.8%) strength training, and 28.1% (2.6%) alternative training. Heart-rate training-intensity distribution was 77.8% (4.2%) in zone 1, 16.6% (3.7%) in zone 2, and 5.6% (2.8%) in zone 3 with a lower contribution of zone 1 in competition period 1 (P = .029) and competition period 2 (P = .023) compared with the preparation period, and a higher contribution of zone 3 in competition period 1 (P = .018) and competition period 2 (P = .011) compared with the preparation period., Conclusion: The crew combined a high volume of rowing, alternative, and strength training in a pyramidal heart-rate training-intensity distribution throughout the year.

Background: Controlled infection studies in malaria-naive adults suggest increased vaccine efficacy for fractional-dose versus full-dose regimens of RTS,S/AS01. We report first results of an ongoing trial assessing different fractional-dose regimens in children, in natural exposure settings., Methods: This open-label, phase 2b, randomised controlled trial is conducted at the Malaria Research Center, Agogo, Ashanti Region (Ghana), and the Kenya Medical Research Institute and the US Centers for Disease Control and Prevention site in Siaya County (Kenya). We enrolled children aged 5-17 months without serious acute or chronic illness who had previously received three doses of diphtheria, tetanus, pertussis, and hepatitis B vaccine and at least three doses of oral polio vaccine. Children were randomly assigned (1:1:1:1:1) using a web-based randomisation system with a minimisation procedure accounting for centre to receive rabies control vaccine (M012 schedule) or two full doses of RTS,S/AS01 E at month 0 and month 1, followed by either full doses at months 2 and 20 (group R012-20 [standard regimen]), full doses at months 2, 14, 26, and 38 (R012-14), fractional doses at months 2, 14, 26, and 38 (Fx012-14), or fractional doses at months 7, 20, and 32 (Fx017-20). The fractional doses were administered as one fifth (0·1 mL) of the full RTS,S dose (0·5 mL) after reconstitution. All vaccines were administered by intramuscular injection in the left deltoid. The primary outcome was occurrence of clinical malaria cases from month 2·5 until month 14 for the Fx012-14 group versus the pooled R012-14 and R012-20 groups in the per-protocol set. We assessed incremental vaccine efficacy of the Fx012-14 group versus the pooled R012-14 and R012-20 group over 12 months after dose three. Safety was assessed in all children who received at least one vaccine dose. This trial is registered with ClinicalTrials.gov, NCT03276962., Findings: Between Sept 28, 2017, and Sept 25, 2018, 2157 children were enrolled, of whom 1609 were randomly assigned to a treatment group (322 to each RTS,S/AS01 E group and 321 to the rabies vaccine control group). 1500 children received at least one study vaccine dose and the per-protocol set comprised 1332 children. Over 12 months after dose three, the incremental vaccine efficacy in the Fx012-14 group versus the pooled R012-14 and R12-20 groups was -21% (95% CI -57 to 7; p=0·15). Up to month 21, serious adverse events occurred in 48 (16%) of 298 children in the R012-20 group, 45 (15%) of 294 in the R012-14 group, 47 (15%) of 304 in the Fx012-14 group, 62 (20%) of 311 in the Fx017-20 group, and 71 (24%) of 293 in the control group, with no safety signals observed., Interpretation: The Fx012-14 regimen was not superior to the standard regimen over 12 months after dose three. All RTS,S/AS01 E regimens provided substantial, similar protection against clinical malaria, suggesting potential flexibility in the recommended dosing regimen and schedule. This, and the effect of annual boosters, will be further evaluated through 50 months of follow-up., Funding: GlaxoSmithKline Biologicals; PATH's Malaria Vaccine Initiative., Competing Interests: Declaration of interests The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the US Centers for Disease Control and Prevention. OO-A, LS, ML, DM, ABo, FR, and EJ are employees of the GSK group of companies. OO-A, LS, DM, FR, and EJ have restricted shares in the GSK group of companies. All other authors declare no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Abstract: Vermeire, KM, Vandewiele, G, Caen, K, Lievens, M, Bourgois, JG, and Boone, J. Training progression in recreational cyclists: no linear dose-response relationship with training load. J Strength Cond Res 35(12): 3500-3505, 2021-The purpose of the study was to assess the relationship between training load (TL) and performance improvement in a homogeneous group of recreational cyclists, training with a self-oriented training plan. Training data from 11 recreational cyclists were collected over a 12-week period. Before and after the training period, subjects underwent a laboratory incremental exercise test with blood lactate measurements to determine the power output associated with the aerobic threshold (PAT) and the anaerobic threshold (PANT), and the maximal power output (PMAX) was also determined. Mean weekly TL (calculated using the training impulse (TRIMP) of Banister, Edwards TRIMP, Lucia TRIMP and the individualized TRIMP) were correlated to the progression in fitness parameters using Pearson Correlation. Training intensity distribution (TID) was also determined (% in zone 1 as ANT). No significant correlations between mean weekly TRIMP values and the improvement on PMAX (r = -0.22 to 0.08), PANT (r = -0.56 to -0.31) and PAT (r = -0.08 to 0.41) were found. The TID was significant in a multiple regression with PANT as dependent variable (y = 0.0088 + 0.1094 × Z1 - 0.2704 × Z2 + 1.0416 × Z3; p = 0.02; R2 = 0.62). In conclusion, this study shows that the commonly used TRIMP methods to quantify TL do not show a linear dose-response relationship with performance improvement in recreational cyclists. Furthermore, the study shows that TID might be a key factor to establish a relationship with performance improvement., (Copyright © 2019 National Strength and Conditioning Association.)

Background: We previously demonstrated that RTS,S/AS01 B and RTS,S/AS01 E vaccination regimens including at least one delayed fractional dose can protect against Plasmodium falciparum malaria in a controlled human malaria infection (CHMI) model, and showed inferiority of a two-dose versus three-dose regimen. In this follow-on trial, we evaluated whether fractional booster vaccination extended or induced protection in previously protected (P-Fx) or non-protected (NP-Fx) participants., Methods: 49 participants (P-Fx: 25; NP-Fx: 24) received a fractional (1/5th dose-volume) RTS,S/AS01 E booster 12 months post-primary regimen. They underwent P. falciparum CHMI three weeks later and were then followed for six months for safety and immunogenicity., Results: Overall vaccine efficacy against re-challenge was 53% (95% CI: 37-65%), and similar for P-Fx (52% [95% CI: 28-68%]) and NP-Fx (54% [95% CI: 29-70%]). Efficacy appeared unaffected by primary regimen or previous protection status. Anti-CS (repeat region) antibody geometric mean concentrations (GMCs) increased post-booster vaccination. GMCs were maintained over time in primary three-dose groups but declined in the two-dose group. Protection after re-challenge was associated with higher anti-CS antibody responses. The booster was well-tolerated., Conclusions: A fractional RTS,S/AS01 E booster given one year after completion of a primary two- or three-dose RTS,S/AS01 delayed fractional dose regimen can extend or induce protection against CHMI., Clinical Trial Registration: NCT03824236. linked to this article can be found on the Research Data as well as Figshare https://figshare.com/s/ee025150f9d1ac739361., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Lievens, Marc; Morelle, Danielle; Debois, Muriel and Ofori-Anyinam, Opokua; are employees of the GSK group of companies. Debois, Muriel; Morelle, Danielle; Lievens, Marc; Ofori-Anyinam, Opokua have restricted shares in the GSK group of companies. Greenleaf, Melissa; Duncan, Elizabeth; Chuang, Ilin; Angov, Evelina; Ivinson, Karen; Komisar, Jack; Lee, Cynthia; Moon, James; Ockenhouse, Christian; Regules, Jason; Garver, Lindsey; Sedegah, Martha; Sikaffy, April K; Ngauy, Viseth declare no competing interests., (Copyright © 2021 GlaxoSmithKline Biologicals S.A. Published by Elsevier Ltd.. All rights reserved.)

Abstract: Lievens, M, Bourgois, JG, and Boone, J. Periodization of plyometrics: Is there an optimal overload principle? J Strength Cond Res 35(10): 2669-2676, 2021-This study investigated the acute and chronic effects of 3 plyometric training (PT) programs with equal training loads (intensity × volume × frequency) on speed, agility, and jumping performance. Forty-four male recreational team sport athletes were either assigned to a program that increased training volume with exercises of mixed intensity (Mix), kept training volume equal and increased exercise intensity (LowHi), increased training volume and kept exercise intensity low (Low), or to a control group (Control). Subjects were trained twice a week for 8 weeks and were tested for 5- (5 m) and 10-m sprint (10 m), 5 × 10-m shuttle run (5 × 10 m), squat jump (SJ), countermovement jump without and with arm swing, and standing broad jump. Five-, 10- and 5 × 10-m performance did not change (p > 0.05) after the PT program. Jumping performance, except for SJ (p = 0.114), improved significantly (p < 0.05) in the PT groups compared with the control group. However, no mutual differences (p < 0.05) were established between plyometric groups. In addition, it was shown that a PT of high intensity was more likely to affect performance and blood inflammation markers in the following days. To conclude, PT programs following a different overload pattern, i.e., different combination of volume and intensity, but equal training load showed similar performance effects in recreationally trained men. However, before competition, a PT of low intensity is preferred over a PT of high intensity to avoid a decline in performance., (Copyright © 2019 National Strength and Conditioning Association.)

Purpose: To determine if there is a link between the demands of competitive game activity and performance profiles of elite female field hockey players., Methods: Global positioning systems (GPS) were used to quantify running performance of elite female field hockey players (N = 20) during 26 competitive games. Performance profiles were assessed at 2 time points (preseason and midseason) for 2 competitive seasons. A battery of anthropometric and performance field-based tests (30-15 intermittent fitness test, incremental run test, 10-30-m speed test, T test, and vertical jump test) were used to determine the performance profiles of the players., Results: Players covered a mean total distance of 5384 (835) m, of which 19% was spent at high intensities (zone 5: 796 [221] m; zone 6: 274 [105] m). Forwards covered the lowest mean total distance (estimated marginal means 4586 m; 95% confidence interval, 4275-4897), whereas work rate was higher in forwards compared with midfielders (P = .006, d = 0.43) and central defenders (P = .001, d = 1.41). Players showed an improvement in body composition and anaerobic performance from preseason to midseason. Aerobic performance capacity (maximal oxygen uptake and speed at the 4-mM lactate threshold) was positively correlated with high-intensity activities., Conclusions: There is a clear relationship between running performance and aerobic performance profiles in elite female hockey players. These results highlight the importance of a well-developed aerobic performance capacity in order to maintain a high performance level during hockey games.

Purpose: The aims of this study were (1) to investigate if the respiratory compensation point (RCP) as derived from ramp incremental (RI) exercise could accurately predict the power output (PO) at the maximal lactate steady state (MLSS), and (2) to compare its accuracy with the second lactate threshold (LT 2 ) obtained from step incremental (SI) exercise., Methods: Nineteen participants performed a RI test (30 W·min -1 ) to determine RCP, a SI test (30 or 40 W·3 min -1 ) to determine LT 2 , and two or more constant work rate (CWR) tests to determine MLSS. For each participant, the [Formula: see text]O 2 /PO relationship for RI and CWR exercise was established. The ramp-identified PO at RCP was corrected by accounting for the gap between these relationships using the individually determined [Formula: see text] O 2 /PO regression above GET (RCP corr-1 ) or using a fixed regression slope (RCP corr-2 ). LT 2 was determined using four methods: D max , modified D max (ModD max ), 4-mM threshold (LT 4mM ) and an expert-determined LT 2 (LT 2-expert )., Results: RCP corr-1 (235 ± 69 W), RCP corr-2 (228 ± 58 W) and LT 2-expert (227 ± 61 W) were not different from MLSS (225 ± 60 W). D max (203 ± 53 W) underestimated MLSS, while RCP (280 ± 60 W), ModD max (235 ± 67 W) and LT 4mM (234 ± 68 W) overestimated MLSS. The [Formula: see text]O 2 at RCP (3.13 ± 0.79L·min -1 ) and LT 2-expert (2.99 ± 0.19L·min -1 ) did not differ from MLSS (3.05 ± 0.72 L·min -1 )., Conclusion: This study demonstrated that RCP as derived from RI exercise and LT 2 as derived from SI exercise can be equally accurate to determine the PO associated with MLSS. Although these results confirmed the suitability of RI and SI tests for this purpose, they also highlighted the importance of an appropriate threshold method selection and the eye of the expert.

Introduction: The purpose of this study was to investigate the effect of the recovery intensity domain on W' reconstitution. We used the W'BAL model as a framework and tested its predictive capabilities (W'PRED) across the different intensity domains., Methods: Twelve young men (51.7 ± 5.9 mL·kg-1·min-1) completed a ramp incremental test, three to five constant power output (PO) tests to determine critical power (CP) and W', and minimally two trials to verify the maximal lactate (La-) steady state. During four experimental trials, subjects performed two work bouts (WB1 and WB2) at P6 (i.e., PO that predicts exhaustion within 6 min) separated by a recovery interval at CP-10 W, Δgas exchange threshold (GET)-CP, GET, and 50% GET, respectively. WB1 was designed to deplete 75% W', and the recovery time varied to replenish 50% W'. WB2 was performed to exhaustion (W'ACT). W'PRED was compared with W'ACT to evaluate the accuracy of the W'BAL model. Excess postexercise oxygen consumption was calculated as the difference between the measured and the predicted oxygen uptake during recovery., Results: W'ACT averaged 49% ± 24%, 69% ± 24%, 81% ± 28%, and 93% ± 21% for CP-10 W, ΔGET-CP, GET, and 50% GET, respectively (P = 0.002). W'PRED overestimated W'ACT in CP-10 W (34% ± 32%, P = 0.004) and underestimated W'ACT in 50% GET (24% ± 28%, P = 0.013). Excess postexercise oxygen consumption was lowest in CP-10 W (P < 0.01) and higher in GET compared with ΔGET-CP (P = 0.01)., Conclusion: We demonstrated that W'PRED overestimated and underestimated W'ACT in the heavy- and moderate-intensity domain, respectively. Therefore, the practical applicability of a single recovery time constant, which only relies on the difference between the recovery PO and the CP, is questionable., (Copyright © 2020 by the American College of Sports Medicine.)

Purpose: To determine the start exercise prescription dose in metastatic castrate-resistant prostate cancer (mCRPC) patients receiving second-line hormone treatment and recommended phase II exercise prescription., Methods: Patients were enrolled in a 3 + 3 dose escalation phase I trial of aerobic, resistance, and flexibility exercises to evaluate dose-limiting tolerance and safety. Tolerance was defined as Borg score ≤ 16 and safety (pain) as a visual analogue scale score (VAS) ≤ 3 and CTCAE grade < 2. Dose level 1 (escalation start dose) was set at 15 min. Aerobic training (50-80% HRmax warm-up and cooling-down; and 65-80% HRmax. core), 1 set with 8-10 repetitions (reps.) resistance training (50-60% 1-RM, 8 exercises), and 1 set (30s) with 2 reps flexibility training (5 exercises). The prescription dose escalation was designed in four levels (from dose -1 to 3), with a dose escalation in volume and intensity of the exercises., Results: Nine patients were included in two dosing cohorts and were under active treatment (n = 4 abiraterone acetate and n = 5 enzalutamide). Dose limiting safety concerns were observed in 2 out of 3 patients in dose level 2 and 1 patient out of 6 in dose level 1 due to VAS > 3 during resistance training and/or flexibility training. No tolerance issues were observed in the two dosing cohorts. The optimal start exercise prescription dose was set at dose level 1 due to safety issues at dose level 2., Conclusion: Our findings suggest that exercise is perceived tolerable in mCRPC patients receiving second-line hormone therapy. Caution is indicated on safety during performance of the exercises.

Objectives: This study aimed at proposing a new heart rate (HR) method to track aerobic metabolism in soccer by: (i) validating a recently developed HR index (HR index ) in professional soccer players, (ii) comparing HR index vs the most common HR parameters and (iii) testing the agreement between measured and estimated VO 2 values using HR index ., Design: cross-sectional., Methods: 184 professional soccer players performed a step incremental running test on a treadmill while VO 2 and HR were recorded. HR index was calculated (actual HR/resting HR) and its relationship with VO 2 was compared with the relationships with the metabolism of actual HR, net HR, and % of HR reserve. Finally, HR index was used to predict VO 2 =((HR index ·6)-5)·3.5) and measured and estimated VO 2 were compared by 2W RM-ANOVA and Bland-Altman analysis., Results: HR index /VO 2 relationship explained 85% of the variability in data, showing a higher performance than actual HR (77%) and similar values to the other parameters. Measured and estimated VO 2 were not significantly different ≤14kmh -1 , whereas at speeds ≥14kmh -1 measured VO 2 was higher than estimated VO 2 . Finally, measured and estimated VO 2 were highly correlated (R 2 =0.85, p=0.000), and showed no significant bias (bias=-1.03, z=-0.69, precision=3.75mlkgmin -1 )., Conclusions: We validated the HR index /VO 2 relationship in professional soccer players. HR index showed better agreement with metabolism than actual HR and similar agreement to the other HR parameters. HR index allowed to estimate VO 2 , but at very high-intensity HR index underestimated VO 2 . Future studies should test this in real game conditions. HR index could offer a time-efficient and easy-to-use "field" method to monitor aerobic metabolism in soccer., (Copyright © 2020 Sports Medicine Australia. Published by Elsevier Ltd. All rights reserved.)

Background: A previous RTS,S/AS01B vaccine challenge trial demonstrated that a 3-dose (0-1-7-month) regimen with a fractional third dose can produce high vaccine efficacy (VE) in adults challenged 3 weeks after vaccination. This study explored the VE of different delayed fractional dose regimens of adult and pediatric RTS,S/AS01 formulations., Methods: A total of 130 participants were randomized into 5 groups. Four groups received 3 doses of RTS,S/AS01B or RTS,S/AS01E on a 0-1-7-month schedule, with the final 1 or 2 doses being fractional (one-fifth dose volume). One group received 1 full (month 0) and 1 fractional (month 7) dose of RTS,S/AS01E. Immunized and unvaccinated control participants underwent Plasmodium falciparum-infected mosquito challenge (controlled human malaria infection) 3 months after immunization, a timing chosen to potentially discriminate VEs between groups., Results: The VE of 3-dose formulations ranged from 55% (95% confidence interval, 27%-72%) to 76% (48%-89%). Groups administered equivalent formulations of RTS,S/AS01E and RTS,S/AS01B demonstrated comparable VE. The 2-dose group demonstrated lower VE (29% [95% confidence interval, 6%-46%]). All regimens were well tolerated and immunogenic, with trends toward higher anti-circumsporozoite antibody titers in participants protected against infection., Conclusions: RTS,S/AS01E can provide VE comparable to an equivalent RTS,S/AS01B regimen in adults, suggesting a universal formulation may be considered. Results also suggest that the 2-dose regimen is inferior to the 3-dose regimens evaluated., Clinical Trial Registration: NCT03162614., (© The Author(s) 2020. Published by Oxford University Press for the Infectious Diseases Society of America.)

Background: RTS,S/AS01 is the first vaccine against malaria to undergo pilot implementation, beginning in 2019 and vaccinating 360,000 children per year in Malawi, Ghana, and Kenya. The four-dose vaccine is given as a primary three-dose series with a fourth dose given approximately 18 months later. The efficacy of RTS,S/AS01 was variable among the 11 sites participating in the 2009-2014 phase III trial (MALARIA-055, NCT00866619), possibly due to differences in transmission intensity. However, a within-site examination of environmental factors related to transmission intensity and their impact on vaccine efficacy has yet to be conducted., Methods: We implemented the phase III RTS,S/AS01 trial at the Malawi site, which enrolled 1578 infants (6-12 weeks) and children (5-17 months) living in the Lilongwe District in Central Malawi and followed them for 3 years between 2009 and 2014. A global positioning system survey and an ecological questionnaire were conducted to collect participant household locations and characteristics, while additional data on background malaria prevalence were obtained from a concurrent Malaria Transmission Intensity (MTI) survey. Negative binomial regression models were used to assess whether the efficacy of the vaccine varied by estimated background malaria prevalence, household roof type, or amount of nearby vegetation., Results: Vaccine efficacy did not significantly vary by estimated malaria prevalence or by roof type. However, increased vegetation cover was associated with an increase in the efficacy of the three-dose primary RTS,S/AS01 series in the 18 months before the fourth dose and a decrease in the efficacy of the primary vaccine series in the second 18 months following, if the fourth dose was not given. Vegetation cover did not alter the efficacy of the fourth dose in a statistically or practically significant manner., Conclusions: Vegetation coverage in this study site might be a proxy for nearness to rivers or branching, shallow wetlands called "dambos" which could serve as breeding sites for mosquitoes. We observed statistically significant modification of the efficacy of RTS,S/AS01 by forest cover, suggesting that initial vaccine efficacy and the importance of the fourth dose varies based on ecological context., Trial Registration: Efficacy of GSK Biologicals' Candidate Malaria Vaccine (257049) Against Malaria Disease Caused by P. falciparum Infection in Infants and Children in Africa. NCT00866619 prospectively registered 20 March 2009.

RTS,S/AS01 E malaria vaccine contains the hepatitis B virus surface antigen and may thus serve as a potential hepatitis B vaccine. To evaluate the impact of RTS,S/AS01 E when implemented in the Expanded Program of Immunization, infants 8-12 weeks old were randomized to receive either RTS,S/AS01 E or a licensed hepatitis B control vaccine (HepB), both co-administered with various combinations of the following childhood vaccines: diphtheria-tetanus-acellular pertussis- Haemophilus influenzae type b, trivalent oral poliovirus, pneumococcal non-typeable Haemophilus influenzae protein D conjugate and human rotavirus vaccine. Long-term persistence of antibodies against the circumsporozoite (CS) protein and hepatitis B surface antigen (HBsAg) were assessed, together with the immune memory response to the HB antigen following a booster dose of HepB vaccine. Subgroups receiving RTS,S or the HepB control vaccine were pooled into RTS,S groups and HepB groups, respectively. One month post-HepB booster vaccination, 100% of participants in the RTS,S groups and 98.3% in the control groups had anti-HBs antibody concentrations ≥10 mIU/mL with the geometric mean concentrations (GMCs) at 46634.7 mIU/mL (95% CI: 40561.3; 53617.6) and 9258.2 mIU/mL (95% CI: 6925.3; 12377.0), respectively. Forty-eight months post-primary vaccination anti-CS antibody GMCs ranged from 2.3 EU/mL to 2.7 EU/mL in the RTS,S groups compared to 1.1 EU/mL in the control groups. Hepatitis B priming with the RTS,S/AS01 E vaccine was effective and resulted in a memory response to HBsAg as shown by the robust booster response following an additional dose of HepB vaccine. RTS,S/AS01E when co-administered with PHiD-CV, HRV and other childhood vaccines, had an acceptable safety profile.

Background: To optimize vaccine implementation visits for young children, it could be efficient to administer the first RTS,S/AS01 malaria vaccine dose during the Expanded Programme on Immunization (EPI) visit at 6 months of age together with Vitamin A supplementation and the third RTS,S/AS01 dose on the same day as yellow fever (YF), measles and rubella vaccines at 9 months of age. We evaluated the safety and immunogenicity of RTS,S/AS01 when co-administered with YF and combined measles-rubella (MR) vaccines., Methods: In this phase 3b, open-label, controlled study (NCT02699099), 709 Ghanaian children were randomized (1:1:1) to receive RTS,S/AS01 at 6, 7.5 and 9 months of age, and YF and MR vaccines at 9 or 10.5 months of age (RTS,S coad and RTS,S alone groups, respectively). The third group received YF and MR vaccines at 9 months of age and will receive RTS,S/AS01 at 10.5, 11.5 and 12.5 months of age (Control group). All children received Vitamin A at 6 months of age. Non-inferiority of immune responses to the vaccine antigens was evaluated 1 month following co-administration versus RTS,S/AS01 or EPI vaccines (YF and MR vaccines) alone using pre-defined non-inferiority criteria. Safety was assessed until Study month 4.5., Results: Non-inferiority of antibody responses to the anti-circumsporozoite and anti-hepatitis B virus surface antigens when RTS,S/AS01 was co-administered with YF and MR vaccines versus RTS,S/AS01 alone was demonstrated. Non-inferiority of antibody responses to the measles, rubella, and YF antigens when RTS,S/AS01 was co-administered with YF and MR vaccines versus YF and MR vaccines alone was demonstrated. The safety profile of all vaccines was clinically acceptable in all groups., Conclusions: RTS,S/AS01 can be co-administered with Vitamin A at 6 months and with YF and MR vaccines at 9 months of age during EPI visits, without immune response impairment to any vaccine antigen or negative safety effect., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: LS, ML and OOA are employees of the GSK group of companies. The current affiliation of CA is Kemri-Wellcome Trust Research Programme and KWTRP played no role in the study, holds no responsibility relative to the data presented and the views expressed here do not represent KWTRP views. EG was an employee of GSK at the time of the study. LS, CA, PV, OOA have shares or stock options in the GSK group of companies. KPA, DA, SA, EG, HOB, SOA, TA, TR, DS, OB, DD, EA, LNB, FP, PBYB, JAA, SK, PAD, SBEH, EAW, AAD, YN, CA, FP declare no competing interests., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background: Manipulation of the endoscope during minimally invasive surgery is a major source of inconvenience and discomfort. This report elucidates the architecture of a novel one-hand controlled endoscope positioning device and presents a practicability evaluation., Methods and Materials: Setup time and total surgery time, number and duration of the manipulations, side effects of three-dimensional (3D) imaging, and ergonomic complaints were assessed by three surgeons during cadaveric and in vivo porcine trials., Results: Setup was accomplished in an average (SD) of 230 (120) seconds. The manipulation time was 3.87 (1.77) seconds for angular movements and 0.83 (0.24) seconds for zooming, with an average (SD) of 30.5 (16.3) manipulations per procedure. No side effects of 3D imaging or ergonomic complaints were reported., Conclusions: The integration of an active zoom into a passive endoscope holder delivers a convenient synergy between a human and a machine-controlled holding device. It is shown to be safe, simple, and intuitive to use and allows unrestrained autonomic control of the endoscope by the surgeon., (© 2019 John Wiley & Sons, Ltd.)

Background: We assessed the safety and immunogenicity of the RTS,S/AS01 malaria vaccine in a subset of children identified as HIV-infected during a large phase III randomized controlled trial conducted in seven sub-Saharan African countries., Methods: Infants 6-12 weeks and children 5-17 months old were randomized to receive 4 RTS,S/AS01 doses (R3R group), 3 RTS,S/AS01 doses plus 1 comparator vaccine dose (R3C group), or 4 comparator vaccine doses (C3C group) at study months 0, 1, 2 and 20. Infants and children with WHO stage III/IV HIV disease were excluded but HIV testing was not routinely performed on all participants; our analyses included children identified as HIV-infected based on medical history or clinical suspicion and confirmed by polymerase chain reaction or antibody testing. Serious adverse events (SAEs) and anti-circumsporozoite (CS) antibodies were assessed., Results: Of 15459 children enrolled in the trial, at least 1953 were tested for HIV and 153 were confirmed as HIV-infected (R3R: 51; R3C: 54; C3C: 48). Among these children, SAEs were reported for 92.2% (95% CI: 81.1-97.8) in the R3R, 85.2% (72.9-93.4) in the R3C and 87.5% (74.8-95.3) in the C3C group over a median follow-up of 39.3, 39.4 and 38.3 months, respectively. Fifteen HIV-infected participants in each group (R3R: 29.4%, R3C: 27.8%, C3C: 31.3%) died during the study. No deaths were considered vaccination-related. In a matched case-control analysis, 1 month post dose 3 anti-CS geometric mean antibody concentrations were 193.3 EU/mL in RTS,S/AS01-vaccinated HIV-infected children and 491.5 EU/mL in RTS,S/AS01-vaccinated immunogenicity controls with unknown or negative HIV status (p = 0.0001)., Conclusions: The safety profile of RTS,S/AS01 in HIV-infected children was comparable to that of the comparator (meningococcal or rabies) vaccines. RTS,S/AS01 was immunogenic in HIV-infected children but antibody concentrations were lower than in children with an unknown or negative HIV status., Clinical Trial Registration: ClinicalTrials.gov: NCT00866619., (Copyright © 2019 GlaxoSmithKline Biologicals S.A. Published by Elsevier Ltd.. All rights reserved.)

Background: Results from a previous phase 3 study showed efficacy of the RTS,S/AS01 vaccine against severe and clinical malaria in children (in 11 sites in Africa) during a 3-4-year follow-up. We aimed to investigate malaria incidence up to 7 years postvaccination in three of the sites of the initial study., Methods: In the initial phase 3 study, infants aged 6-12 weeks and children aged 5-17 months were randomly assigned (1:1:1) to receive four RTS,S/AS01 doses (four-dose group), three RTS,S/AS01 doses and a comparator dose (three-dose group), or four comparator doses (control group). In this open-label extension study in Korogwe (Tanzania), Kombewa (Kenya), and Nanoro (Burkina Faso), we assessed severe malaria incidences as the primary outcome for 3 additional years (January, 2014, to December, 2016), up to 6 years (younger children) or 7 years (older children) postprimary vaccination in the modified intention-to-treat population (ie, participants who received at least one dose of the study vaccine). As secondary outcomes, we evaluated clinical malaria incidences and serious adverse events. This trial is registered with ClinicalTrials.gov, number NCT02207816., Findings: We enrolled 1739 older children (aged 5-7 years) and 1345 younger children (aged 3-5 years). During the 3-year extension, 66 severe malaria cases were reported, resulting in severe malaria incidence of 0·004 cases per person-years at risk (PPY; 95% CI 0-0·033) in the four-dose group, 0·007 PPY (0·001-0·052) in the three-dose group, and 0·009 PPY (0·001-0·066) in the control group in the older children category and a vaccine efficacy against severe malaria that did not contribute significantly to the overall efficacy (four-dose group 53·7% [95% CI -13·7 to 81·1], p=0·093; three-dose group 23·3% [-67·1 to 64·8], p=0·50). In younger children, severe malaria incidences were 0·007 PPY (0·001-0·058) in the four-dose group, 0·007 PPY (0·001-0·054) in the three-dose group, and 0·011 PPY (0·001-0·083) in the control group. Vaccine efficacy against severe malaria also did not contribute significantly to the overall efficacy (four-dose group 32·1% [-53·1 to 69·9], p=0·35; three-dose group 37·6% [-44·4 to 73·0], p=0·27). Malaria transmission was still occurring as evidenced by an incidence of clinical malaria ranging from 0·165 PPY to 3·124 PPY across all study groups and sites. In older children, clinical malaria incidence was 1·079 PPY (95% CI 0·152-7·662) in the four-dose group, 1·108 PPY (0·156-7·868) in the three-dose group, and 1·016 PPY (0·14-7·213) in the control group. In younger children, malaria incidence was 1·632 PPY (0·23-11·59), 1·563 PPY (0·22-11·104), and 1·686 PPY (0·237-11·974), respectively. In the older age category in Nanoro, clinical malaria incidence was higher in the four-dose (2·444 PPY; p=0·011) and three-dose (2·411 PPY; p=0·034) groups compared with the control group (1·998 PPY). Three cerebral malaria episodes and five meningitis cases, but no vaccine-related severe adverse events, were reported., Interpretation: Overall, severe malaria incidence was low in all groups, with no evidence of rebound in RTS,S/AS01 recipients, despite an increased incidence of clinical malaria in older children who received RTS,S/AS01 compared with the comparator group in Nanoro. No safety signal was identified., Funding: GlaxoSmithKline Biologicals SA., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Purpose: To predict the session rating of perceived exertion (sRPE) in soccer and determine its main predictive indicators., Methods: A total of 70 external-load indicators (ELIs), internal-load indicators, individual characteristics, and supplementary variables were used to build a predictive model., Results: The analysis using gradient-boosting machines showed a mean absolute error of 0.67 (0.09) arbitrary units (AU) and a root-mean-square error of 0.93 (0.16) AU. ELIs were found to be the strongest predictors of the sRPE, accounting for 61.5% of the total normalized importance (NI), with total distance as the strongest predictor. The included internal-load indicators and individual characteristics accounted only for 1.0% and 4.5%, respectively, of the total NI. Predictive accuracy improved when including supplementary variables such as group-based sRPE predictions (10.5% of NI), individual deviation variables (5.8% of NI), and individual player markers (17.0% of NI)., Conclusions: The results showed that the sRPE can be predicted quite accurately using only a relatively limited number of training observations. ELIs are the strongest predictors of the sRPE. However, it is useful to include a broad range of variables other than ELIs, because the accumulated importance of these variables accounts for a reasonable component of the total NI. Applications resulting from predictive modeling of the sRPE can help coaching staff plan, monitor, and evaluate both the external and internal training load.

A phase III, double-blind, randomized, controlled trial (NCT00866619) in sub-Saharan Africa showed RTS,S/AS01 vaccine efficacy against malaria. We now present in-depth safety results from this study. 8922 children (enrolled at 5-17 months) and 6537 infants (enrolled at 6-12 weeks) were 1:1:1-randomized to receive 4 doses of RTS,S/AS01 (R3R) or non-malaria control vaccine (C3C), or 3 RTS,S/AS01 doses plus control (R3C). Aggregate safety data were reviewed by a multi-functional team. Severe malaria with Blantyre Coma Score ≤2 (cerebral malaria [CM]) and gender-specific mortality were assessed post-hoc . Serious adverse event (SAE) and fatal SAE incidences throughout the study were 24.2%-28.4% and 1.5%-2.5%, respectively across groups; 0.0%-0.3% of participants reported vaccination-related SAEs. The incidence of febrile convulsions in children was higher during the first 2-3 days post-vaccination with RTS,S/AS01 than with control vaccine, consistent with the time window of post-vaccination febrile reactions in this study (mostly the day after vaccination). A statistically significant numerical imbalance was observed for meningitis cases in children (R3R: 11, R3C: 10, C3C: 1) but not in infants. CM cases were more frequent in RTS,S/AS01-vaccinated children (R3R: 19, R3C: 24, C3C: 10) but not in infants. All-cause mortality was higher in RTS,S/AS01-vaccinated versus control girls (2.4% vs 1.3%, all ages) in our setting with low overall mortality. The observed meningitis and CM signals are considered likely chance findings, that - given their severity - warrant further evaluation in phase IV studies and WHO-led pilot implementation programs to establish the RTS,S/AS01 benefit-risk profile in real-life settings.

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., Competing Interests: A.V.S.H. and S.C.G. are named inventors on patent applications and patents relating to malaria vectored vaccines and immunization regimens. D.M., M.L., and R.W.B are employees of GSK, which is developing vaccines for malaria and other diseases. S.N.F. acts on behalf of the University of Southampton/University Hospital Southampton NHS Foundation trust as chief and principal investigator for clinical trials Sponsored by vaccine manufacturers including GSK, but receives no personal payments for the work. The other authors declare no competing interests.

The RTS,S/AS01 malaria vaccine (Mosquirix) reduces the incidence of Plasmodium falciparum malaria and is intended for routine administration to infants in Sub-Saharan Africa. We evaluated the immunogenicity and safety of 10-valent pneumococcal non-typeable Haemophilus influenzae protein D conjugate vaccine (PHiD-CV; Synflorix) and human rotavirus vaccine (HRV; Rotarix) when co-administered with RTS,S/AS01 ( www.clinicaltrials.gov NCT01345240) in African infants. 705 healthy infants aged 8-12 weeks were randomized to receive three doses of either RTS,S/AS01 or licensed hepatitis B (HBV; Engerix B) vaccine (control) co-administered with diphtheria-tetanus-acellular pertussis-Haemophilus influenzae type-b-conjugate vaccine (DTaP/Hib) and trivalent oral poliovirus vaccine at 8-12-16 weeks of age, because DTaP/Hib was not indicated before 8 weeks of age. The vaccination schedule can still be considered broadly applicable because it was within the age range recommended for EPI vaccination. PHiD-CV or HRV were either administered together with the study vaccines, or after a 2-week interval. Booster doses of PHiD-CV and DTaP/Hib were administered at age 18 months. Non-inferiority of anti-HBV surface antigen antibody seroprotection rates following co-administration with RTS,S/AS01 was demonstrated compared to the control group (primary objective). Pre-specified non-inferiority criteria were reached for PHiD-CV (for 9/10 vaccine serotypes), HRV, and aP antigens co-administered with RTS,S/AS01 as compared to HBV co-administration (secondary objectives). RTS,S/AS01 induced a response to circumsporozoite protein in all groups. Pain and low grade fever were reported more frequently in the PHiD-CV group co-administered with RTS,S/AS01 than PHiD-CV co-administered with HBV. No serious adverse events were considered to be vaccine-related. RTS,S/AS01 co-administered with pediatric vaccines had an acceptable safety profile. Immune responses to RTS,S/AS01 and to co-administered PHiD-CV, pertussis antigens and HRV were satisfactory.

Background: In a phase III trial, the RTS,S/AS01 malaria vaccine produced lower anti-circumsporozoite (CS) antibody titers when co-administered with Expanded Programme on Immunization vaccines (0-, 1- and 2-month schedule) at 6 to 12 weeks compared with 5 to 17 months at first vaccination. Alternative infant immunization schedules within the Expanded Programme on Immunization were investigated., Methods: This phase II, open, single-site (Blantyre, Malawi) trial was conducted in infants 1 to 7 days of age. Subjects were equally randomized across 7 groups to receive 3 doses of RTS,S/AS01E at time points that included ≤7 days, 6, 10, 14 and 26 weeks, and 9 months. All RTS,S/AS01E groups plus a control group (without RTS,S/AS01E) received Bacillus Calmette-Guérin + oral poliovirus vaccine at ≤7 days, diphtheria, tetanus, whole-cell pertussis, hepatitis B and Haemophilus influenzae type b vaccine + oral poliovirus vaccine at 6, 10, and 14 weeks and measles vaccine at 9 months; one RTS,S/AS01E group and the control additionally received hepatitis B vaccination at ≤7 days. Serum anti-CS antibody geometric mean concentration (GMC; enzyme-linked immunosorbent assay) and safety were assessed up to age 18 months., Results: Of the 480 infants enrolled, 391 completed the study. No causally related serious adverse event was reported. A higher frequency of fever within 7 days of RTS,S/AS01E vaccination compared with control was observed. Compared with the standard 6-, 10-, 14-week schedule, anti-CS antibody GMC ratios post-dose 3 were significantly higher in the 10-, 14- and 26-week group only (ratio 1.80; 95% confidence interval, 1.24-2.60); RTS,S/AS01E vaccination at ≤7 days and 10 and 14 weeks produced significantly lower anti-CS GMCs (ratio 0.59; 95% confidence interval, 0.38-0.92)., Conclusions: Initiation of RTS,S/AS01E vaccination above 6 weeks of age tended to improve anti-CS antibody responses. Neonatal vaccination was well tolerated but produced a comparatively lower immune response.

Host immunity exerts strong selective pressure on pathogens. Population-level genetic analysis can identify signatures of this selection, but these signatures reflect the net selective effect of all hosts and vectors in a population. In contrast, analysis of pathogen diversity within hosts provides information on individual, host-specific selection pressures. Here, we combine these complementary approaches in an analysis of the malaria parasite Plasmodium falciparum using haplotype sequences from thousands of natural infections in sub-Saharan Africa. We find that parasite genotypes show preferential clustering within multi-strain infections in young children, and identify individual amino acid positions that may contribute to strain-specific immunity. Our results demonstrate that natural host defenses to P. falciparum act in an allele-specific manner to block specific parasite haplotypes from establishing blood-stage infections. This selection partially explains the extreme amino acid diversity of many parasite antigens and suggests that vaccines targeting such proteins should account for allele-specific immunity.