Genotypic analysis of RTS,S/AS01E malaria vaccine efficacy against parasite infection as a function of dosage regimen and baseline malaria infection status in children aged 5-17 months in Ghana and Kenya: a longitudinal phase 2b randomised controlled trial.

BACKGROUND: The first licensed malaria vaccine, RTS,S/AS01E, 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/AS01E 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/AS01E regimens across both follow-up periods (12 months and 20 months). Each RTS,S/AS01E 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.

Could less be more? Accounting for fractional-dose regimens and different number of vaccine doses when measuring the impact of the RTS, S/AS01E malaria vaccine.

BACKGROUND: The RTS, S/AS01E malaria vaccine (RTS, S) is recommended for children in moderate-to-high Plasmodium falciparum malaria transmission areas. This phase 2b trial (NCT03276962) evaluates RTS, S fractional- and full-dose regimens in Ghana and Kenya. METHODS: 1500 children aged 5-17 months were randomised (1:1:1:1:1) to receive RTS, S or rabies control vaccine. RTS, S groups received two full RTS, S doses at month (M)0/M1 followed by either full (groups R012-20, R012-14-26) or fractional (1/5) doses (groups Fx012-14-26, Fx017-20-32). RESULTS: At M32 post-first dose, vaccine efficacy (VE) against clinical malaria (all episodes) ranged from 38% (R012-20; 95%CI: 24-49) to 53% (R012-14-26; 95%CI: 42-62). Vaccine impact estimates (cumulative number of malaria cases averted/1000 children vaccinated) were 1344 (R012-20), 2450 (R012-14-26), 2273 (Fx012-14-26), 2112 (Fx017-20-32). To account for differences in vaccine volume (fractional- versus full-dose), in a post-hoc analysis, we also estimated cases averted/1000 RTS, S full-dose equivalents: 336 (R012-20), 490 (R012-14-26), 874 (Fx012-14-26), 880 (Fx017-20-32). CONCLUSIONS: VE against clinical malaria was similar in all RTS, S groups. Vaccine impact accounting for full-dose equivalence suggests that using fractional-dose regimens could be a viable dose-sparing strategy. If borne out through trial end (M50), these observations underscore the means to reduce cost per regimen with a goal of maximising impact and optimising supply.

Baseline malaria infection status and RTS,S/AS01E malaria vaccine efficacy.

Background: The only 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 (VE). Methods: 1,500 children aged 5-17 months were randomized to receive four different RTS,S/AS01 E regimens or a rabies control vaccine in a phase 2b clinical trial in Ghana and Kenya. We evaluated the time to the first new genotypically detected infection and the total number of new infections during two follow-up periods in over 36K participant specimens. We performed a post hoc analysis of VE based on malaria infection status at first vaccination and force of infection. Results: We observed significant and comparable VE (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 and 20 months). Each RTS,S/AS01 E regimen significantly reduced the number of new infections in the 20-month follow-up period (control mean 4.1 vs. RTS,S/AS01 E mean 2.6-3.0). VE against first new infection was significantly higher in participants who were malaria-infected (68%; 95% CI, 50 to 80%) versus uninfected (37%; 95% CI, 23 to 48%) at the first vaccination (P=0.0053) and in participants experiencing greater force of infection between dose 1 and 3 (P=0.059). Conclusions: All tested dosing regimens blocked some infections to a similar degree. Improved VE in participants infected during vaccination could suggest new strategies for highly efficacious malaria vaccine development and implementation. ( ClinicalTrials.gov number, NCT03276962 ).

Immunogenicity and safety following one dose of AS01E-adjuvanted respiratory syncytial virus prefusion F protein vaccine in older adults: a phase 3 trial.

BACKGROUND: The recently approved AS01E-adjuvanted respiratory syncytial virus (RSV) prefusion F protein-based vaccine (RSVPreF3 OA) demonstrated high efficacy against RSV-related disease in ≥60-year-olds. METHODS: This ongoing phase 3 study in ≥60-year-olds evaluates the immune persistence until three years post-RSVPreF3 OA vaccination. Here, we describe interim results on humoral and cell-mediated immunogenicity, reactogenicity, and safety until one 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) versus 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 one 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; one 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 one year. The vaccine was well tolerated with an acceptable safety profile.Clinicaltrials.gov NCT04732871.

Respiratory syncytial virus (RSV) is a major cause of illness and hospitalization in older adults. An RSV vaccine for older adults developed by GSK was recently approved. The vaccine was well tolerated and provided protection against RSV disease in adults aged 60 years and older during at least one RSV season. In this ongoing study, we are evaluating the magnitude and durability of the immune response, as well as vaccine safety, until three years after vaccination of adults aged 60 years and older from five countries. Here, we report the results of an interim analysis until one year after vaccination with one dose. In total, 1653 participants were vaccinated. We found that the vaccine induced a strong immune response that was evident one month after vaccination, after which it declined, but persisted for at least one year. Study participants most often reported pain at the injection site, muscle pain, tiredness, and headache as adverse reactions, which were mostly mild to moderate and of short duration. One serious adverse reaction was considered related to the vaccine. The long-term immune response that was observed in this study is consistent with the vaccine providing protection during at least one RSV season.

Efficacy of RTS,S/AS01E malaria vaccine administered according to different full, fractional, and delayed third or early fourth dose regimens in children aged 5-17 months in Ghana and Kenya: an open-label, phase 2b, randomised controlled trial.

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/AS01E 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/AS01E 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/AS01E 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.

A phase IIA extension study evaluating the effect of booster vaccination with a fractional dose of RTS,S/AS01E in a controlled human malaria infection challenge.

BACKGROUND: We previously demonstrated that RTS,S/AS01B and RTS,S/AS01E 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/AS01E 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/AS01E 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.

A Phase IIa Controlled Human Malaria Infection and Immunogenicity Study of RTS,S/AS01E and RTS,S/AS01B Delayed Fractional Dose Regimens in Malaria-Naive Adults.

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.

Environmental modifiers of RTS,S/AS01 malaria vaccine efficacy in Lilongwe, Malawi.

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.

Immunogenicity and safety of the RTS,S/AS01 malaria vaccine co-administered with measles, rubella and yellow fever vaccines in Ghanaian children: A phase IIIb, multi-center, non-inferiority, randomized, open, controlled trial.

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.

Long-term immunogenicity and immune memory response to the hepatitis B antigen in the RTS,S/AS01E malaria vaccine in African children: a randomized trial.

RTS,S/AS01E 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/AS01E when implemented in the Expanded Program of Immunization, infants 8-12 weeks old were randomized to receive either RTS,S/AS01E 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/AS01E 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.

Safety and immunogenicity of the RTS,S/AS01 malaria vaccine in infants and children identified as HIV-infected during a randomized trial in sub-Saharan Africa.

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.

Long-term incidence of severe malaria following RTS,S/AS01 vaccination in children and infants in Africa: an open-label 3-year extension study of a phase 3 randomised controlled trial.

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.

Safety profile of the RTS,S/AS01 malaria vaccine in infants and children: additional data from a phase III randomized controlled trial in sub-Saharan Africa.

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.

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

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.

Host-mediated selection impacts the diversity of Plasmodium falciparum antigens within infections.

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.

Immune response to the hepatitis B antigen in the RTS,S/AS01 malaria vaccine, and co-administration with pneumococcal conjugate and rotavirus vaccines in African children: A randomized controlled trial.

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.

Safety and Immunogenicity of Seven Dosing Regimens of the Candidate RTS,S/AS01E Malaria Vaccine Integrated Within an Expanded Program on Immunization Regimen: A Phase II, Single-Center, Open, Controlled Trial in Infants in Malawi.

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.

RTS,S/AS01 Malaria Vaccine Efficacy is Not Modified by Seasonal Precipitation: Results from a Phase 3 Randomized Controlled Trial in Malawi.

The World Health Organization has selected Malawi as one of three sites to pilot the roll-out of RTS,S/AS01 in phase 4 trials. As policy discussions for the expanded use of RTS,S/AS01 continue, it will be critical to determine the performance of the vaccine according to seasonal patterns of malaria transmission in regions of Africa. Given waning vaccine efficacy over time, this secondary analysis demonstrates that administering the vaccine to children in the months prior to malaria season could maximize impact of the vaccine. We followed children (5-17 months) and infants (6-12 weeks) assigned to one of three groups: (1) vaccine with four doses; (2) vaccine with three doses; (3) control. The primary endpoint was defined as episodes of clinical malaria. During the 4-years of follow-up, 658 of 1544 (42.6%) children and infants had at least one episode of clinical malaria. With each 1-inch increase in rainfall per month there was an associated increase in the rate of malaria by 12.6% (95% CI 9.6%, 15.6%, P < 0.0001) among children and 15.9% (95% CI 12.8%, 18.9%, P < 0.0001) among infants. There was no evidence of effect modification of vaccine efficacy by precipitation (89% power).

Safety and immunogenicity of RTS,S/AS01 malaria vaccine in infants and children with WHO stage 1 or 2 HIV disease: a randomised, double-blind, controlled trial.

BACKGROUND: Malaria remains a major global public health concern, especially in sub-Saharan Africa. The RTS,S/AS01 malaria candidate vaccine was reviewed by the European Medicines Agency and received a positive scientific opinion; WHO subsequently recommended pilot implementation in sub-Saharan African countries. Because malaria and HIV overlap geographically, HIV-infected children should be considered for RTS,S/AS01 vaccination. We therefore aimed to assess the safety of RTS,S/AS01 in HIV-infected children at two sites in western Kenya. METHODS: We did a randomised, double-blind, controlled trial at the clinical trial sites of the Kenya Medical Research Institute (KEMRI)-Walter Reed Army Institute of research in Kisumu and the KEMRI/US Centers for Disease Control and Prevention in Siaya. Eligible participants were infants and children aged from 6 weeks to 17 months with WHO stage 1 or 2 HIV disease (documented positive by DNA PCR), whether or not they were receiving antiretroviral therapy (ART). We randomly assigned participants (1:1) to receive three doses of either RTS,S/AS01 or rabies vaccine (both 0·5 mL per dose by intramuscular injection), given once per month at 0, 1, and 2 months. We did the treatment allocation using a web-based central randomisation system stratified by age (6 weeks-4 months, 5-17 months), and by baseline CD4% (<10, 10-14, 15-19, and ≥20). Data were obtained in an observer-blind manner, and the vaccine recipient, their parent or carer, the funder, and investigators responsible for the assessment of endpoints were all masked to treatment allocation (only staff responsible for the preparation and administration of the vaccines were aware of the assignment and these individuals played no other role in the study). We provided ART, even if the participants were not receiving ART before the study, and daily co-trimoxazole for prevention of opportunistic infections. The primary outcome was the occurrence of serious adverse events until 14 months after dose 1 of the vaccine, assessed in the intention-to-treat population. This trial was registered at ClinicalTrials.gov, number NCT01148459. FINDINGS: Between July 30, 2010, and May 24, 2013, we enrolled 200 children to our study and randomly assigned 99 to receive RTS,S/AS01 and 101 to receive rabies vaccine. 177 (89%) of the 200 children enrolled completed 14 months of follow-up. Serious adverse events were noted in 41 (41·4%, 95% CI 31·6-51·8) of 99 RTS,S/AS01 recipients and 37 (36·6%, 27·3-46·8) of 101 rabies-vaccine recipients (relative risk 1·1, 95% CI 0·8-1·6). 20 (20·2%, 95% CI 12·8-29·5) of 99 RTS,S/AS01 recipients and 12 (11·9%, 6·3-19·8) of 101 rabies-vaccine recipients had at least one serious adverse event within 30 days after vaccination, mainly pneumonia, febrile convulsions, and salmonella sepsis. Five (5·1%, 95% CI 1·7-11·4) of 99 RTS,S/AS01 recipients and four (4·0%, 1·1-9·8) of 101 rabies-vaccine recipients died, but no deaths were deemed related to vaccination. Mortality was associated with five cases of pneumonia (1% RTS,S/AS01 recipients vs 3% rabies-vaccine recipients), five cases of gastroenteritis (3% RTS,S/AS01 recipients vs 2% rabies-vaccine recipients), five cases of malnutrition (2% RTS,S/AS01 recipients vs 3% rabies-vaccine recipients), one case of sepsis (1% rabies-vaccine recipients), one case of Haemophilus influenza meningitis (1% rabies-vaccine recipients), and one case of tuberculosis (1% RTS,S/AS01 recipients). INTERPRETATION: RTS, S/AS01 was well tolerated when given to children with WHO clinical stage 1 or 2 HIV disease along with high antiretroviral and co-trimoxazole use. Children with HIV disease could be included in future RTS,S/AS01 vaccination programmes. FUNDING: GlaxoSmithKline Biologicals SA and PATH Malaria Vaccine Initiative.

Seven-Year Efficacy of RTS,S/AS01 Malaria Vaccine among Young African Children.

BACKGROUND: The candidate malaria vaccine RTS,S/AS01 is being evaluated in order to inform a decision regarding its inclusion in routine vaccination schedules. METHODS: We conducted 7 years of follow-up in children who had been randomly assigned, at 5 to 17 months of age, to receive three doses of either the RTS,S/AS01 vaccine or a rabies (control) vaccine. The end point was clinical malaria (temperature of ≥37.5°C and infection with Plasmodium falciparum of >2500 parasites per cubic millimeter). In an analysis that was not prespecified, the malaria exposure of each child was estimated with the use of information on the prevalence of malaria among residents within a 1-km radius of the child's home. Vaccine efficacy was defined as 1 minus the hazard ratio or the incidence-rate ratio, multiplied by 100, in the RTS,S/AS01 group versus the control group. RESULTS: Over 7 years of follow-up, we identified 1002 episodes of clinical malaria among 223 children randomly assigned to the RTS,S/AS01 group and 992 episodes among 224 children randomly assigned to the control group. The vaccine efficacy, as assessed by negative binomial regression, was 4.4% (95% confidence interval [CI], -17.0 to 21.9; P=0.66) in the intention-to-treat analysis and 7.0% (95% CI, -14.5 to 24.6; P=0.52) in the per-protocol analysis. Vaccine efficacy waned over time (P=0.006 for the interaction between vaccination and time), including negative efficacy during the fifth year among children with higher-than-average exposure to malaria parasites (intention-to-treat analysis: -43.5%; 95% CI, -100.3 to -2.8 [P=0.03]; per-protocol analysis: -56.8%; 95% CI, -118.7 to -12.3 [P=0.008]). CONCLUSIONS: A three-dose vaccination with RTS,S/AS01 was initially protective against clinical malaria, but this result was offset by rebound in later years in areas with higher-than-average exposure to malaria parasites. (Funded by the PATH Malaria Vaccine Initiative and others; ClinicalTrials.gov number, NCT00872963.).