Jahit Sacarlal

Efficacy of the RTS,S/AS02A vaccine against Plasmodium falciparum infection and disease in young African children: randomised controlled trial

BACKGROUND Development of an effective malaria vaccine could greatly contribute to disease control. RTS,S/AS02A is a pre-erythrocytic vaccine candidate based on Plasmodium falciparum circumsporozoite surface antigen. We aimed to assess vaccine efficacy, immunogenicity, and safety in young African children. METHODS We did a double-blind, phase IIb, randomised controlled trial in Mozambique in 2022 children aged 1-4 years. The study included two cohorts of children living in two separate areas which underwent different follow-up schemes. Participants were randomly allocated three doses of either RTS,S/AS02A candidate malaria vaccine or control vaccines. The primary endpoint, determined in cohort 1 (n=1605), was time to first clinical episode of P falciparum malaria (axillary temperature > or =37.5 degrees C and P falciparum asexual parasitaemia >2500 per microL) over a 6-month surveillance period. Efficacy for prevention of new infections was determined in cohort 2 (n=417). Analysis was per protocol. FINDINGS 115 children in cohort 1 and 50 in cohort 2 did not receive all three doses and were excluded from the per-protocol analysis. Vaccine efficacy for the first clinical episodes was 29.9% (95% CI 11.0-44.8; p=0.004). At the end of the 6-month observation period, prevalence of P falciparum infection was 37% lower in the RTS,S/AS02A group compared with the control group (11.9% vs 18.9%; p=0.0003). Vaccine efficacy for severe malaria was 57.7% (95% CI 16.2-80.6; p=0.019). In cohort 2, vaccine efficacy for extending time to first infection was 45.0% (31.4-55.9; p<0.0001). INTERPRETATION The RTS,S/AS02A vaccine was safe, well tolerated, and immunogenic. Our results show development of an effective vaccine against malaria is feasible.

Duration of protection with RTS,S/AS02A malaria vaccine in prevention of Plasmodium falciparum disease in Mozambican children: single-blind extended follow-up of a randomised controlled trial

BACKGROUND RTS,S/AS02A is a pre-erythrocytic stage malaria vaccine that provides partial protection against infection in malaria-naive adult volunteers and hyperimmune adults. A previous report showed that this vaccine reduced risk of clinical malaria, delayed time to new infection, and reduced episodes of severe malaria over 6 months in African children. An important remaining issue is the durability of protection against clinical disease in these children. METHODS We did a randomised, controlled, phase IIb trial of RTS,S/AS02A given at 0, 1, and 2 months in 2022 Mozambican children aged 1-4 years. We previously determined vaccine efficacy (VE) against clinical malaria in a double-blind phase that included study months 2.5-8.5 (VE(2.5-8.5)). We now report VE in a single-blind phase up to month 21 (VE(8.5-21)). The primary endpoint was time to first or only clinical episode of Plasmodium falciparum malaria (axillary temperature 37.5 degrees C and P falciparum asexual parasitaemia >2500 per microL) detected through a passive case detection system. We also determined VE for other case definitions and for episodes of severe malaria. This study is registered with the ClinicalTrials.gov identifier NCT00197041. FINDINGS During the single-blind phase, VE(8.5-21) was 28.9% (95% CI 8.4-44.8; p=0.008). At month 21, prevalence of P falciparum infection was 29% lower in the RTS,S/AS02A group than in the control (p=0.017). Considering the entire study period, VE(2.5-21) was 35.3% (95% CI 21.6-46.6; p<0.0001) and VE(2.5-21) for severe malaria was 48.6% (95% CI 12.3-71.0; p=0.02). INTERPRETATION These results show that RTS,S/AS02A confers partial protection in African children aged 1-4 years living in rural endemic areas against a range of clinical disease caused by P falciparum for at least 18 months, and confirm the potential of malaria vaccines to become credible control tools for public-health use.

Safety of the RTS,S/AS02D candidate malaria vaccine in infants living in a highly endemic area of Mozambique: a double blind randomised controlled phase I/IIb trial

BACKGROUND Malaria remains a leading global health problem that requires the improved use of existing interventions and the accelerated development of new control methods. We aimed to assess the safety, immunogenicity, and initial efficacy of the malaria vaccine RTS,S/AS02D in infants in Africa. METHODS We did a phase I/IIb double-blind randomised trial of 214 infants in Mozambique. Infants were randomly assigned to receive three doses either of RTS,S/AS02D or the hepatitis B vaccine Engerix-B at ages 10 weeks, 14 weeks, and 18 weeks of age, as well as routine immunisation vaccines given at 8, 12, and 16 weeks of age. The primary endpoint was safety of the RTS,S/AS02D during the first 6 months of the study, and analysis was by intention to treat. Secondary endpoints included immunogenicity and analysis of new Plasmodium falciparum infections during a 3-month follow up after the third dose. Time to new infections in the per-protocol cohort were compared between groups using Cox regression models. This study is registered with ClinicalTrials.gov, number NCT00197028. FINDINGS There were 17 children (15.9%; 95% CI 9.5-24.2) with serious adverse events in each group. In the follow-up which ended on March 6, 2007, there were 31 serious adverse events in the RTS,S/AS02D group and 30 serious adverse events in the Engerix-B group, none of which were reported as related to vaccination. There were four deaths during this same follow-up period; all of them after the active detection of infection period had finished at study month 6 (two in RTSS/AS02D group and two in the Engerix-B group). RTS,S/AS02D induced high titres of anti-circumsporozoite antibodies. 68 first or only P falciparum infections were documented: 22 in the RTS,S/AS02D group and 46 in the control group. The adjusted vaccine efficacy was 65.9% (95% CI 42.6-79.8%, p<0.0001). INTERPRETATION The RTS,S/AS02D malaria vaccine was safe, well tolerated, and immunogenic in young infants. These findings set the stage for expanded phase III efficacy studies to confirm vaccine efficacy against clinical malaria disease.

Community-acquired bacteremia among children admitted to a rural hospital in Mozambique.

Background: Although community-acquired bacteremia is an important cause of childhood mortality in Africa, recognition of disease burden and potential impact of bacterial vaccines is limited. Methods: Blood cultures for bacterial pathogens were conducted systematically among children <15 years of age admitted to Manhiça District Hospital, from 2001 to 2006. Results: Blood-stream infections were identified in 8% (1550/19,896) of pediatric hospital admissions. Nontyphoidal Salmonella (NTS) and Pneumococcus were the most prevalent pathogens isolated (26% and 25% of 1550 cases, respectively). Until 28 days of life, Staphylococcus aureus (39%) and group B Streptococcus (20%) predominated. Incidence of community-acquired bacteremia per 100,000 child-years was 1730/105 in children <1 year old, 782/105 in 1–4 year oldd, and 49/105 in children 5 years and older. Case-fatality of bacteremia was 12%. Community-acquired bacteremia associated mortality accounted for 21% (162/788) of hospital deaths. Resistance to antibiotics commonly used in Mozambique was high among invasive isolates of Haemophilus influenzae, Escherichia coli, and NTS. Conclusions: Community-acquired bacteremia is an important cause of pediatric hospital admission and death in rural African hospitals. The high burden of disease, mortality, and pattern of antibiotic resistance associated with bacteremia underscore the need for prevention in Sub-Saharan Africa.

Cause-specific mortality rates in sub-Saharan Africa and Bangladesh.

OBJECTIVE To provide internationally comparable data on the frequencies of different causes of death. METHODS We analysed verbal autopsies obtained during 1999 -2002 from 12 demographic surveillance sites in sub-Saharan Africa and Bangladesh to find cause-specific and age-specific mortality rates. The cause-of-death codes used by the sites were harmonized to conform to the ICD-10 system, and summarized with the classification system of the Global Burden of Disease 2000 (Version 2). FINDINGS Causes of death in the African sites differ strongly from those in Bangladesh, where there is some evidence of a health transition from communicable to noncommunicable diseases, and little malaria. HIV dominates in causes of mortality in the South African sites, which contrast with those in highly malaria endemic sites elsewhere in sub-Saharan Africa (even in neighbouring Mozambique). The contributions of measles and diarrhoeal diseases to mortality in sub-Saharan Africa are lower than has been previously suggested, while malaria is of relatively greater importance. CONCLUSION The different patterns of mortality we identified may be a result of recent changes in the availability and effectiveness of health interventions against childhood cluster diseases.

Long-Term Safety and Efficacy of the RTS,S/AS02A Malaria Vaccine in Mozambican Children

BACKGROUND We previously reported that the RTS,S/AS02A vaccine had an acceptable safety profile, was immunogenic, and demonstrated efficacy against Plasmodium falciparum malaria disease for 21 months. METHODS We conducted a randomized, controlled, phase 2b trial of RTS,S/AS02A in 2022 Mozambican children aged 1-4 years. We now report safety results for all randomized subjects and vaccine efficacy (VE) findings for children in the Manhiça area over the 45-month surveillance period. RESULTS During the surveillance period, the VE((2.5-45)) (VE over months 2.5-45 of surveillance) against a first or only episode of clinical malaria disease was 30.5% (95% confidence interval [CI], 18.9%-40.4%; P < .001), and the VE((2.5-45)) against all episodes was 25.6% (95% CI, 11.9%-37.1%; P < .001). When the same period was considered, the VE((2.5-45)) for subjects protected against severe malaria was 38.3% (95% CI, 3.4%-61.3%; P = .045). At study month 45, the prevalence of P. falciparum was 34% lower in the RTS,S/AS02A group than in the control group (66 [12.2%] of 541 patients vs 101 [18.5%] of 547 patients) (P = .004). CONCLUSION These results show evidence that RTS,S/AS02A maintained protection during the 45-month surveillance period, and they highlight the feasibility of developing an effective vaccine against malaria. In combination with other malaria-control measures, such a vaccine could greatly contribute to reducing the intolerable global burden of this disease. Trial registration. ClinicalTrials.gov identifiers NCT00197041 and NCT00323622 .

Genetic diversity and protective efficacy of the RTS,S/AS01 malaria vaccine

BACKGROUND The RTS,S/AS01 vaccine targets the circumsporozoite protein of Plasmodium falciparum and has partial protective efficacy against clinical and severe malaria disease in infants and children. We investigated whether the vaccine efficacy was specific to certain parasite genotypes at the circumsporozoite protein locus. METHODS We used polymerase chain reaction-based next-generation sequencing of DNA extracted from samples from 4985 participants to survey circumsporozoite protein polymorphisms. We evaluated the effect that polymorphic positions and haplotypic regions within the circumsporozoite protein had on vaccine efficacy against first episodes of clinical malaria within 1 year after vaccination. RESULTS In the per-protocol group of 4577 RTS,S/AS01-vaccinated participants and 2335 control-vaccinated participants who were 5 to 17 months of age, the 1-year cumulative vaccine efficacy was 50.3% (95% confidence interval [CI], 34.6 to 62.3) against clinical malaria in which parasites matched the vaccine in the entire circumsporozoite protein C-terminal (139 infections), as compared with 33.4% (95% CI, 29.3 to 37.2) against mismatched malaria (1951 infections) (P=0.04 for differential vaccine efficacy). The vaccine efficacy based on the hazard ratio was 62.7% (95% CI, 51.6 to 71.3) against matched infections versus 54.2% (95% CI, 49.9 to 58.1) against mismatched infections (P=0.06). In the group of infants 6 to 12 weeks of age, there was no evidence of differential allele-specific vaccine efficacy. CONCLUSIONS These results suggest that among children 5 to 17 months of age, the RTS,S vaccine has greater activity against malaria parasites with the matched circumsporozoite protein allele than against mismatched malaria. The overall vaccine efficacy in this age category will depend on the proportion of matched alleles in the local parasite population; in this trial, less than 10% of parasites had matched alleles. (Funded by the National Institutes of Health and others.).

Severe malaria and concomitant bacteraemia in children admitted to a rural Mozambican hospital

Objectives  To describe the prevalence, aetiology and prognostic implications of coexisting invasive bacterial disease in children admitted with severe malaria in a rural Mozambican Hospital.

Immunogenicity of the RTS,S/AS01 malaria vaccine and implications for duration of vaccine efficacy: secondary analysis of data from a phase 3 randomised controlled trial

Summary Background The RTS,S/AS01 malaria vaccine targets the circumsporozoite protein, inducing antibodies associated with the prevention of Plasmodium falciparum infection. We assessed the association between anti-circumsporozoite antibody titres and the magnitude and duration of vaccine efficacy using data from a phase 3 trial done between 2009 and 2014. Methods Using data from 8922 African children aged 5–17 months and 6537 African infants aged 6–12 weeks at first vaccination, we analysed the determinants of immunogenicity after RTS,S/AS01 vaccination with or without a booster dose. We assessed the association between the incidence of clinical malaria and anti-circumsporozoite antibody titres using a model of anti-circumsporozoite antibody dynamics and the natural acquisition of protective immunity over time. Findings RTS,S/AS01-induced anti-circumsporozoite antibody titres were greater in children aged 5–17 months than in those aged 6–12 weeks. Pre-vaccination anti-circumsporozoite titres were associated with lower immunogenicity in children aged 6–12 weeks and higher immunogenicity in those aged 5–17 months. The immunogenicity of the booster dose was strongly associated with immunogenicity after primary vaccination. Anti-circumsporozoite titres wane according to a biphasic exponential distribution. In participants aged 5–17 months, the half-life of the short-lived component of the antibody response was 45 days (95% credible interval 42–48) and that of the long-lived component was 591 days (557–632). After primary vaccination 12% (11–13) of the response was estimated to be long-lived, rising to 30% (28–32%) after a booster dose. An anti-circumsporozoite antibody titre of 121 EU/mL (98–153) was estimated to prevent 50% of infections. Waning anti-circumsporozoite antibody titres predict the duration of efficacy against clinical malaria across different age categories and transmission intensities, and efficacy wanes more rapidly at higher transmission intensity. Interpretation Anti-circumsporozoite antibody titres are a surrogate of protection for the magnitude and duration of RTS,S/AS01 efficacy, with or without a booster dose, providing a valuable surrogate of effectiveness for new RTS,S formulations in the age groups considered. Funding UK Medical Research Council.

Insights into long-lasting protection induced by RTS,S/AS02A malaria vaccine: further results from a phase IIb trial in Mozambican children.

Background The pre-erythrocytic malaria vaccine RTS,S/AS02A has shown to confer protection against clinical malaria for at least 21 months in a trial in Mozambican children. Efficacy varied between different endpoints, such as parasitaemia or clinical malaria; however the underlying mechanisms that determine efficacy and its duration remain unknown. We performed a new, exploratory analysis to explore differences in the duration of protection among participants to better understand the protection afforded by RTS,S. Methodology/Principal Findings The study was a Phase IIb double-blind, randomized controlled trial in 2022 children aged 1 to 4 years. The trial was designed with two cohorts to estimate vaccine efficacy against two different endpoints: clinical malaria (cohort 1) and infection (cohort 2). Participants were randomly allocated to receive three doses of RTS,S/AS02A or control vaccines. We did a retrospective, unplanned sub-analysis of cohort 2 data using information collected for safety through the health facility-based passive case detection system. Vaccine efficacy against clinical malaria was estimated over the first six-month surveillance period (double-blind phase) and over the following 12 months (single-blind phase), and analysis was per-protocol. Adjusted vaccine efficacy against first clinical malaria episodes in cohort 2 was of 35.4% (95% CI 4.5–56.3; p = 0.029) over the double-blind phase and of 9.0% (−30.6–36.6; p = 0.609) during the single-blind phase. Conclusions/Significance Contrary to observations in cohort 1, where efficacy against clinical malaria did not wane over time, in cohort 2 the efficacy decreases with time. We hypothesize that this reduced duration of protection is a result of the early diagnosis and treatment of infections in cohort 2 participants, preventing sufficient exposure to asexual-stage antigens. On the other hand, the long-term protection against clinical disease observed in cohort 1 may be a consequence of a prolonged exposure to low-dose blood-stage asexual parasitaemia. Trial Registration ClinicalTrials.gov NCT00197041