Efficacy and immunogenicity of R21/Matrix-M vaccine against clinical malaria after 2 years' follow-up in children in Burkina Faso: a phase 1/2b randomised controlled trial

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Efficacy and immunogenicity of R21/Matrix-M vaccine against clinical malaria after 2 years' follow-up in children in Burkina Faso: a phase 1/2b randomised controlled trial

Malaria is a leading cause of morbidity and mortality worldwide. We previously reported the efficacy of the R21/Matrix-M malaria vaccine, which reached the WHO-specified goal of 75% or greater efficacy over 12 months in the target population of African children. Here, we report the safety, immunogenicity, and efficacy results at 12 months following administration of a booster vaccination.
This double-blind phase 1/2b randomised controlled trial was done in children aged 5–17 months in Nanoro, Burkina Faso. Eligible children were enrolled and randomly assigned (1:1:1) to receive three vaccinations of either 5 μg R21/25 μg Matrix-M, 5 μg R21/50 μg Matrix-M, or a control vaccine (the Rabivax-S rabies vaccine) before the malaria season, with a booster dose 12 months later. Children were eligible for inclusion if written informed consent could be provided by a parent or guardian. Exclusion criteria included any existing clinically significant comorbidity or receipt of other investigational products. A random allocation list was generated by an independent statistician by use of block randomisation with variable block sizes. A research assistant from the University of Oxford, independent of the trial team, prepared sealed envelopes using this list, which was then provided to the study pharmacists to assign participants. All vaccines were prepared by the study pharmacists by use of the same type of syringe, and the contents were covered with an opaque label. Vaccine safety, efficacy, and a potential correlate of efficacy with immunogenicity, measured as anti-NANP antibody titres, were evaluated over 1 year following the first booster vaccination. The population in which the efficacy analyses were done comprised all participants who received the primary series of vaccinations and a booster vaccination. Participants were excluded from the efficacy analysis if they withdrew from the trial within the first 2 weeks of receiving the booster vaccine. This trial is registered with ClinicalTrials.gov (NCT03896724), and is continuing for a further 2 years to assess both the potential value of additional booster vaccine doses and longer-term safety.
Between June 2, and July 2, 2020, 409 children returned to receive a booster vaccine. Each child received the same vaccination for the booster as they received in the primary series of vaccinations; 132 participants received 5 μg R21 adjuvanted with 25 μg Matrix-M, 137 received 5 μg R21 adjuvanted with 50 μg Matrix-M, and 140 received the control vaccine. R21/Matrix-M had a favourable safety profile and was well tolerated. Vaccine efficacy remained high in the high adjuvant dose (50 μg) group, similar to previous findings at 1 year after the primary series of vaccinations. Following the booster vaccination, 67 (51%) of 132 children who received R21/Matrix-M with low-dose adjuvant, 54 (39%) of 137 children who received R21/Matrix-M with high-dose adjuvant, and 121 (86%) of 140 children who received the rabies vaccine developed clinical malaria by 12 months. Vaccine efficacy was 71% (95% CI 60 to 78) in the low-dose adjuvant group and 80% (72 to 85) in the high-dose adjuvant group. In the high-dose adjuvant group, vaccine efficacy against multiple episodes of malaria was 78% (95% CI 71 to 83), and 2285 (95% CI 1911 to 2568) cases of malaria were averted per 1000 child-years at risk among vaccinated children in the second year of follow-up. Among these participants, at 28 days following their last R21/Matrix-M vaccination, titres of malaria-specific anti-NANP antibodies correlated positively with protection against malaria in both the first year of follow-up (Spearman's ρ –0·32 [95% CI –0·45 to –0·19]; p=0·0001) and second year of follow-up (–0·20 [–0·34 to –0·06]; p=0·02).
A booster dose of R21/Matrix-M at 1 year following the primary three-dose regimen maintained high efficacy against first and multiple episodes of clinical malaria. Furthermore, the booster vaccine induced antibody concentrations that correlated with vaccine efficacy. The trial is ongoing to assess long-term follow-up of these participants and the value of further booster vaccinations.
European and Developing Countries Clinical Trials Partnership 2 (EDCTP2), Wellcome Trust, and NIHR Oxford Biomedical Research Centre.
For the French translation of the abstract see Supplementary Materials section.
RTS,S/AS01 (Mosquirix; GlaxoSmithKline) is the first malaria vaccine recommended by WHO for use in children in moderate-to-high transmission settings following pilot implementation trials in Ghana, Kenya, and Malawi. We searched PubMed from database inception to March 11, 2022, for published articles using the search terms “malaria vaccine” AND “clinical trial” AND “phase III” AND “efficacy”. No language restrictions were applied. In a large phase 3 trial, RTS,S/AS01 had a vaccine efficacy of 68% over a period of 6 months following administration of the initial three doses, but this efficacy waned over time. At 6 months after a fourth dose, administered 18 months following the third dose, vaccine efficacy was 44% (95% CI 40–48). The most recent update to the Malaria Vaccine Technology Roadmap highlights that, by 2030, one of the goals should be to license malaria vaccines targeting Plasmodium falciparum that have a protective efficacy of at least 75% against clinical malaria for more than 2 years, in at-risk groups in malaria-endemic areas.
This phase 1/2b randomised controlled trial reports the safety, immunogenicity, and efficacy of the R21/Matrix-M malaria vaccine at 12 months following administration of a booster dose in children aged 5–17 months in Nanoro, Burkina Faso. These findings further support our previously published efficacy data for R21/Matrix-M in the same cohort of children. We previously reported high-level efficacy of R21 adjuvanted with 50 μg of Matrix-M, administered before the malaria season, reaching the WHO-specified goal of at least 75% efficacy over 1 year in the target population of African children. The administration of a booster dose 12 months following the primary series of R21/Matrix-M vaccinations shows the added benefit of a fourth dose when administered before the malaria season. Vaccine efficacy was maintained in the high-dose adjuvant group, at 80% following the booster vaccine over 12 months, and 75% over 24 months after the primary three-dose regimen. Furthermore, vaccine efficacy against multiple episodes of clinical malaria was similar (78%) over 2 years of follow-up. R21/Matrix-M has a favourable safety profile and also induces high levels of malaria-specific anti-NANP antibodies that correlate with the observed protection against clinical malaria.
These findings demonstrate the potential of a booster dose of R21/Matrix-M to maintain the high efficacy seen after the primary vaccination series. Pre-season dosing with this promising malaria vaccine candidate could provide durable protection to children living in highly seasonal malaria transmission settings. This phase 1/2b trial has now progressed to a fully enrolled phase 3 trial, with 4800 participants, aiming for licensure of the R21/Matrix-M vaccine in 2023.
The R21/Matrix-M pre-erythrocytic malaria vaccine candidate was developed at the University of Oxford (Oxford, UK) and is currently manufactured by the Serum Institute of India (Pune, India).
Here, we report the ongoing safety, immunogenicity, and efficacy of R21/Matrix-M, and the number of malaria cases averted by this vaccine over 2 years of follow-up, following administration of the first booster dose.
The trial was approved by the Comité d'Ethique pour la Recherche en Santé, Burkina Faso (CERS; reference number 2019-01-012), and by the national regulatory authority, Agence National de Régulation Pharmaceutique, Burkina Faso (ANRP; reference number 5005420193EC0000). Ethical approval was also granted in the UK by the Oxford Tropical Research Ethics Committee (OxTREC; reference number 19-19).
Children aged 5–17 months were randomly assigned (1:1:1) to three groups at the start of the trial from a random allocation list, by use of block randomisation with variable block sizes. Thereafter, a research assistant from the University of Oxford, independent of the trial team, prepared sealed envelopes using this list, which was then provided to the study pharmacists to assign participants, once all the eligibility criteria had been met. All vaccines were prepared by the study pharmacists using the same type of syringe, and the contents of the syringe were covered with an opaque label. Each child received the same vaccination for the booster as they received in the primary series of vaccinations. Group 1 received 5 μg R21 adjuvanted with 25 μg Matrix-M, group 2 received 5 μg R21 adjuvanted with 50 μg Matrix-M, and group 3 was the control group and received the Rabivax-S rabies vaccine. The trial was double-blinded: participants, their caregivers, and the local study team were all masked to group allocation. Only the study pharmacists preparing the vaccine had access to group allocation.
Cox regression models were used to analyse time to first episodes of clinical malaria from 14 days following the booster vaccination to 12 months. For participants without an episode of clinical malaria, their time was censored at the date of their withdrawal from the study or the date of their 12-month post-booster blood sampling. The primary comparisons were prespecified as being between groups 1 and 3 and groups 2 and 3, with comparison of groups 1 and 2 combined with group 3 only considered if no significant difference was found between groups 1 and 2. A secondary analysis adjusted for confounding factors of sex, age at randomisation (categorised as 5–9 months, 10–12 months, and >12 months), and bednet use (adequate or not) during the malaria season. Vaccine efficacy was calculated as 1 minus the hazard ratio (HR).
Analyses of vaccine efficacy included all participants who received a booster vaccination. Outcomes of asymptomatic malaria infection at 12 months following the booster vaccination were analysed by use of a log binomial model, including randomised group as a covariate. Relative risks and 95% CIs were reported, comparing groups 1 and 3 and groups 2 and 3.
To assess for an immunological correlate of protection, a Spearman's rank correlation between the number of malaria episodes and the anti-NANP immune response was done for groups 1 and 2 combined, and for each group and each year of follow-up separately. A linear regression model was used to estimate the difference in mean log(ELISA) between those with and without at least one episode of malaria. Additionally, HRs for log(ELISA) were calculated when included in the Cox model for time to first episode of malaria for the same groups and for each year. Finally, a reverse cumulative distribution of antibody titres was plotted and used to calculate a threshold level of anti-NANP antibodies for the efficacy observed in groups 1 and 2 in each year of follow-up.
To facilitate blinding, analyses were done by statisticians external to the investigator teams.
The funders of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report.
Data are n (%) or mean (SD); percentages do not always sum to 100 due to rounding. This table includes all participants who received the booster vaccination dose at 12 months following the primary series of vaccinations. Group 1 received 5 μg R21/25 μg Matrix-M, group 2 received 5 μg R21/50 μg Matrix-M, and group 3 (the control group) received the Rabivax-S rabies vaccine. ITN=insecticide-treated net. SMC=seasonal malaria chemoprevention.
One round of seasonal malaria chemoprevention corresponds to three doses of treatment received per month.
Adequate use of insecticide-treated nets before the second malaria season was 89% (365 of 409) overall and indoor residual spraying was done in 176 (43%) of 409 households. 379 (93%) of 409 participants had at least one round of seasonal malaria chemoprevention ().
Cox proportional hazards model, adjusted for sex, age category (5–9 months, 10–12 months, and >12 months), and adequate insecticide-treated net use.
Analysis of multiple episodes of clinical malaria meeting the primary case definition from 14 days after the booster vaccination to 12 months, and from 14 days to 24 months following the primary series of vaccinations
Group 1 received 5 μg R21/25 μg Matrix-M, group 2 received 5 μg R21/50 μg Matrix-M, and group 3 received Rabivax-S. The primary case definition of clinical malaria was presence of axillary temperature 37·5°C or greater and Plasmodium falciparum parasite density greater 5000 asexual forms per μL. Attendance at clinic within 7 days of a previous episode was not counted. Negative binomial regression models were used to calculate vaccine efficacy when analysing multiple episodes. Wald test was used to calculate p value. Incidence rate differences were calculated per 1000 child-years at risk with ordinary least squares regression of transformed variables.
Protective efficacy adjusted for sex, age category (5–9 months, 10–12 months, and >12 months), and adequate insecticide-treated net use.
The primary analysis was repeated, adjusting for the potential confounding factors of sex, age at randomisation (5–9 months, 10–12 months, and >12 months), and adequate bednet use. Vaccine efficacy according to the primary case definition from 14 days following booster vaccination to 12 months was 70% (95% CI 59–78; p<0·0001) in group 1 and 80% (72–85; p<0·0001) in group 2 (). Further adjustment for use of seasonal malaria chemoprevention (at least one monthly course of three doses) resulted in a vaccine efficacy of 81% (95% CI 74–87; p<0·0001) in group 2.
Efficacy was further assessed at 24 months (range 660–731 days) following the primary series of vaccinations, where 280 participants had at least one episode of clinical malaria. All of these participants received a booster dose before the second malaria season, approximately 12 months following the primary series of vaccinations. These malaria episodes were recorded in 82 of 132 participants in group 1, 70 of 137 in group 2, and 128 of 140 participants in group 3 (the control group). Cox regression analysis showed a vaccine efficacy of 66% (95% CI 55–74; p<0·0001) for group 1 and 75% (66–81; p<0·0001) for group 2 (, ). When assessing multiple episodes of malaria over this time period, 978 cases were recorded and vaccine efficacy was similar to the analysis of a first or only event: 63% (95% CI 55–71; p<0·0001) in group 1 and 77% (69–83; p<0·0001) in group 2 ().
Cross-sectional blood films were done at 12 months following the booster vaccination. In group 1, two (2%) of 122 children had asymptomatic parasitaemia, as did two (2%) of 125 in group 2. In group 3, seven (5%) of 129 children had asymptomatic parasitaemia (). When compared with the control group (group 3), the risk ratios were not significant for group 1 (0·3 [95% CI 0·06–1·40]; p=0·125) or for group 2 (0·29 [0·06–1·39]; p=0·123).
Three serious adverse events were reported in participants () after the booster vaccination up to 12 months follow-up. All were deemed unrelated to vaccination. These serious adverse events all resolved and comprised severe malaria with pneumonia, severe malnutrition with anaemia, and bacterial meningitis.
For year 1, antibody responses were measured by ELISA at 28 days following the primary series of vaccinations (three vaccinations, 4 weeks apart) and an episode of malaria according to the primary case definition from 28 days after the third vaccination to 12 months. For year 2, antibody responses were measured by ELISA at 28 days following the booster vaccination and an episode of malaria according to the primary case definition from 28 days after the booster vaccination to 12 months.
p value for Spearman's rank correlation between number of malaria episodes and immune response. HR for log (ELISA) when included in Cox model for time to first episode of malaria in year 1 and in Cox model for year 2; group also included in model.
For participants in group 2, NANP antibodies were significantly higher in those who did not have any clinical malaria episodes during both the first year of follow-up (mean difference 0·21 [95% CI 0·10–0·33]; p=0·0004) and second year of follow-up (0·12 [0·01–0·22]; p=0·032). Cumulative distribution curves were used to identify a threshold correlate of vaccine efficacy for group 2 vaccinees: 6618 ELISA units (95% CI 5565–8397) in the first year of follow-up and 6130 ELISA units (5347–7179) in the second year of follow-up ().
Limitations of this study include the small sample size, which restricts identification of less common adverse events, and reduces the power to identify a potential correlate of protection. Furthermore, this study assessed the efficacy of the R21/Matrix-M vaccine in an area of highly seasonal malaria transmission, with vaccines administered before or at the start of the peak malaria season. Data are needed on vaccine efficacy in areas with different transmission patterns.
AVSH, HT, and MSD conceived and designed the trial, and AVSH was the chief investigator. AVSH, HT, MSD, KJE, HMN, HS, and AS contributed to the protocol and design of the study. HT and HS were the study site principal investigators. KJE and DB were responsible for laboratory studies of immune responses and assay development. NW, MC, and KJE did the statistical analysis. US, GG, and LF were responsible for vaccine and adjuvant manufacturing and provision. MSD, HMN, AVSH, and HT contributed to the preparation of the report. HMN, HT, HS, AS, FO, TR, MSD, AVSH, KJE, and RR contributed to the implementation of the study. HMN, HT, TR, SS, NW, MC, MSD, and AVSH have accessed and verified the data. HMN, MSD, AVSH, and HT were responsible for the decision to submit the manuscript for publication. All other authors contributed to the implementation of the study and data collection. All authors critically reviewed and approved the final version. All authors had full access to all the data in the study and had final responsibility for the decision to submit for publication.
The study protocol is provided in ). Anonymised participant data will be made available when the trial is complete, upon requests directed to the corresponding authors. Proposals will be reviewed and approved by the sponsor, investigators, and collaborators on the basis of scientific merit. After approval of a proposal, data can be shared through a secure online platform after signing a data access agreement. All data will be made available for a minimum of 5 years from the end of the trial.
AVSH and KJE are named as co-inventors on patent applications related to R21. GG, LF, and JR are employees of Novavax, developers of the Matrix-M adjuvant. US is an employee of the Serum Institute of India, a co-developer of the R21/Matrix-M vaccine. All other authors declare no competing interests.
We thank all the participants in the trial and their parents, the Nanoro Health District authorities, the CMA Saint Camille de Nanoro hospital and all the research staff at the Clinical Research Unit of Nanoro (CRUN). We are grateful to the members of the data and safety monitoring board (Greg Fegan, William Macharia, Brian Angus, and Kwaku Poku Asante) and the local safety monitor in Burkina Faso (William P M F Kaboré) for overseeing the trial, Patty Price-Abbott for the safety monitoring at Novavax, the Clinical Biomanufacturing Facility, University of Oxford, for qualified person (QP) services, and Ian Poulton at the Jenner Institute, University of Oxford, for facilitation. The trial was mainly funded by a European and Developing Countries Clinical Trials Partnership (EDCTP2) grant (funded in turn by the European Union) to the Multi-Stage Malaria Vaccine Consortium (grant agreement RIA2016V-1649), with additional support from the Wellcome Trust through Translation Award 205981/Z/17/Z, and from the UK National Institute for Health Research to the Oxford Biomedical Research Centre's Vaccines for Emerging and Endemic Diseases theme. Vaccine manufacture and supply was supported and undertaken by the Serum Institute of India, and the Matrix-M adjuvant was provided by Novavax.
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