Seven-year kinetics of RTS, S/AS01-induced anti-CSP antibodies in young Kenyan children.
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ABSTRACT: Background
RTS,S/AS01, the leading malaria vaccine has been recommended by the WHO for widespread immunization of children at risk. RTS,S/AS01-induced anti-CSP IgG antibodies are associated with the vaccine efficacy. Here, the long-term kinetics of RTS,S/AS01-induced antibodies was investigated.Methods
150 participants were randomly selected from the 447 children who participated in the RTS,S/AS01 phase IIb clinical trial in 2007 from Kilifi-Kenya. Cumulatively, the retrospective follow-up period was 93 months with annual plasma samples collection. The levels of anti-CSP IgM, total IgG, IgG1, IgG2, IgG3, and IgG4 antibodies were then determined using an enzyme-linked immunosorbent assay.Results
RTS,S/AS01 induced high levels of anti-CSP IgG antibodies which exhibited a rapid waning over 6.5 months post-vaccination, followed by a slower decay over the subsequent years. RTS,S/AS01-induced anti-CSP IgG antibodies remained elevated above the control group levels throughout the 7 years follow-up period. The anti-CSP IgG antibodies were mostly IgG1, IgG3, IgG2, and to a lesser extent IgG4. IgG2 predominated in later timepoints. RTS,S/AS01 also induced high levels of anti-CSP IgM antibodies which increased above the control group levels by month 3. The controls exhibited increasing levels of the anti-CSP IgM antibodies which caught up with the RTS,S/AS01 vaccinees levels by month 21. In contrast, there were no measurable anti-CSP IgG antibodies among the controls.Conclusion
RTS,S/AS01-induced anti-CSP IgG antibodies kinetics are consistent with long-lived but waning vaccine efficacy. Natural exposure induces anti-CSP IgM antibodies in children, which increases with age, but does not induce substantial levels of anti-CSP IgG antibodies.
SUBMITTER: Mugo RM
PROVIDER: S-EPMC8641151 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BackgroundThe candidate malaria vaccine RTS,S/AS01 is being evaluated in order to inform a decision regarding its inclusion in routine vaccination schedules.MethodsWe 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.ResultsOver 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]).ConclusionsA 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.).
| S-EPMC4962898 | biostudies-literature
Project description:Background: RTS,S/AS01 E, the most advanced malaria vaccine confers partial immunity. The vaccine-induced pre-erythrocytic immunity reduces exposure to blood-stage parasites, delaying acquisition of antibodies to blood-stage antigens. However, the duration of this effect is unknown. Methods: We measured, by enzyme-linked immunosorbent assay, IgG-antibodies to 4 Plasmodium falciparum blood-stage antigens (AMA1, MSP1 42, EBA175, and MSP3) on 314 children randomized to receive RTS,S/AS01 E or Rabies vaccine at 5 - 17 months of age in a phase 2b trial in Kenya, and thereafter participated in a 7-year study of the duration of vaccine immunity. Results: Antibody levels to MSP1 42, AMA1 and EBA175 were slightly lower among the RTS,S/AS01 E recipients, relative to the Rabies-control vaccinees, during the first 48 months of surveillance. Irrespective of vaccine arm, antibody levels to merozoite antigens were positively associated with the risk for malaria. However, this was only apparent at high levels for EBA175 and AMA1 and was not evident after adjusting for heterogeneity in malaria-exposure. Among children with asymptomatic parasitaemia, antibody levels were associated with reduced clinical malaria. Conclusions: The reduction in levels of antibodies to blood-stage antigens induced by vaccination with RTS,S/AS01 E can last for several years. In absence of asymptomatic infection, anti-merozoite antibody levels were unreliable correlates of clinical immunity.
| S-EPMC6545824 | biostudies-literature
Project description:BackgroundThe nature of protective immune responses elicited by immunization with the candidate malaria vaccine RTS,S is still incompletely understood. Antibody levels correlate with protection against malaria infection, but considerable variation in outcome is unexplained (e.g., children may experience malaria despite high anti-circumsporozoite [CS] titers).Methods and findingsWe measured the avidity index (AI) of the anti-CS antibodies raised in subgroup of 5-17 month old children in Kenya who were vaccinated with three doses of RTS,S/AS01E between March and August 2007. We evaluated the association between the AI and the subsequent risk of clinical malaria. We selected 19 cases (i.e., with clinical malaria) and 42 controls (i.e., without clinical malaria), matching for anti-CS antibody levels and malaria exposure. We assessed their sera collected 1 month after the third dose of the vaccine, in March 2008 (range 4-10 months after the third vaccine), and at 12 months after the third vaccine dose. The mean AI was 45.2 (95% CI: 42.4 to 48.1), 45.3 (95% CI: 41.4 to 49.1) and 46.2 (95% CI; 43.2 to 49.3) at 1 month, in March 2008 (4-10 months), and at 12 months after the third vaccination, respectively (p?=?0.9 by ANOVA test for variation over time). The AI was not associated with protection from clinical malaria (OR?=?0.90; 95% CI: 0.49 to 1.66; p?=?0.74). The AI was higher in children with high malaria exposure, as measured using the weighted local prevalence of malaria, compared to those with low malaria exposure at 1 month post dose 3 (p?=?0.035).ConclusionOur data suggest that in RTS,S/AS01E-vaccinated children residing in malaria endemic countries, the avidity of anti-circumsporozoite antibodies, as measured using an elution ELISA method, was not associated with protection from clinical malaria. Prior natural malaria exposure might have primed the response to RTS,S/AS01E vaccination.
| S-EPMC4266636 | biostudies-literature
Project description:Malaria is a parasitic infection caused by bites from Plasmodium falciparum (P. falciparum)-infected mosquitoes with a present scale of symptoms ranging from moderate fever to neurological disorders. P. falciparum is the most lethal of the five strains of malaria, and is a major case of morbidity and mortality in endemic regions. Recent advancements in malaria diagnostic tools and prevention strategies have improved conjugation antimalarial therapies using fumigation and long-lasting insecticidal sprays, thus lowering malarial infections. Declines in the total number of infected individuals have been correlated with antimalarial drugs. Despite this, malaria remains a major health threat, affecting more than 30 million men, women, and children around the globe, and 20 percent of all children around the globe have malaria parasites in their blood. To overcome this life-threatening condition, novel therapeutic strategies, including immunization, are urgently needed to tackle this infection around the world. In line with this, the development of the RTS, S vaccine was a significant step forward in the fight against malaria. RTS, S is a vaccine for P. falciparum in which R specifies central repeat units, T the T-cell epitopes, and S indicates surface antigen. The RTS, S/AS01 malarial vaccine was synthesized and screened in several clinical trials between 2009 and 2014, involving thousands of young children in seven African countries, showing that children who received the vaccine did not suffer from severe malaria. Mosquirix™ was approved by the World Health Organization in 2021, indicating it to be safe and advocating its integration into routine immunization programs and existing malaria control measures. This paper examines the various stages of the vaccine's development, including the evaluation of its immunogenicity and efficacy on the basis of a total of 2.3 million administered doses through a routine immunization program. The protection and effectiveness provided by the vaccine are strong, and evidence shows that it can be effectively delivered through the routine child immunization platform. The economic cost of the vaccine remains to be considered.
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Project description:Vaccine-induced sterilizing protection from infection by Plasmodium parasites, the pathogens that cause malaria, will be essential in the fight against malaria as it would prevent both malaria-related disease and transmission. Stopping the relatively small number of parasites injected by the mosquito before they can migrate from the skin to the liver is an attractive means to this goal. Antibody-eliciting vaccines have been used to pursue this objective by targeting the major parasite surface protein present during this stage, the circumsporozoite protein (CSP). While CSP-based vaccines have recently had encouraging success in disease reduction, this was only achieved with extremely high antibody titers and appeared less effective for a complete block of infection (i.e., sterile protection). While such disease reduction is important, these and other results indicate that strategies focusing on CSP alone may not achieve the high levels of sterile protection needed for malaria eradication. Here, we show that monoclonal antibodies (mAbs) recognizing another sporozoite protein, TRAP/SSP2, exhibit a range of inhibitory activity and that these mAbs may augment CSP-based protection despite conferring no sterile protection on their own. Therefore, pursuing a multivalent subunit vaccine immunization is a promising strategy for improving infection-blocking malaria vaccines.
| S-EPMC9135708 | biostudies-literature
Project description: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.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.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.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.).
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Project description:BackgroundRTS,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.MethodsWe 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.ResultsVaccine 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.ConclusionsVegetation 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 registrationEfficacy 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.
| S-EPMC7291743 | biostudies-literature
Project description:The RTS,S/AS01 malaria vaccine confers only moderate protection against malaria. Evidence suggests that the effectiveness of the RTS,S/AS01 vaccine depends upon the parasite population genetics, specifically regarding the circumsporozoite protein haplotypes in the population. We investigated Plasmodium falciparum circumsporozoite protein (PfCSP) gene sequences from two endemic sites in 2018 in Senegal. The PfCSP sequences were compared with those retrieved from the Pf3k genome database. In the central repeat region of PfCSP, the distribution of haplotypes differed significantly between the two study sites (Fisher's exact test, P < 0.001). No 3D7 vaccine strain haplotype was observed in this locus. In the C-terminal region, there was no significant difference in haplotypes distribution between Kedougou and Diourbel (Fischer's exact test, P = 0.122). The 3D7 haplotype frequency was 8.4% in early samples (2001-2011), but then it contracted in the subsequent years. The extensive plasticity of the P. falciparum genes coding the RTS,S/AS01 vaccine target antigens may influence the immune responses to circulating alleles. Monitoring the genetic diversity baseline and its dynamics over time and space would be instrumental in rationally improving the malaria RTS,S/AS01 vaccine and/or its implementation schedule.
| S-EPMC8641351 | biostudies-literature
Project description:BackgroundThe candidate malaria vaccine RTS,S/AS01 reduced episodes of both clinical and severe malaria in children 5 to 17 months of age by approximately 50% in an ongoing phase 3 trial. We studied infants 6 to 12 weeks of age recruited for the same trial.MethodsWe administered RTS,S/AS01 or a comparator vaccine to 6537 infants who were 6 to 12 weeks of age at the time of the first vaccination in conjunction with Expanded Program on Immunization (EPI) vaccines in a three-dose monthly schedule. Vaccine efficacy against the first or only episode of clinical malaria during the 12 months after vaccination, a coprimary end point, was analyzed with the use of Cox regression. Vaccine efficacy against all malaria episodes, vaccine efficacy against severe malaria, safety, and immunogenicity were also assessed.ResultsThe incidence of the first or only episode of clinical malaria in the intention-to-treat population during the 14 months after the first dose of vaccine was 0.31 per person-year in the RTS,S/AS01 group and 0.40 per person-year in the control group, for a vaccine efficacy of 30.1% (95% confidence interval [CI], 23.6 to 36.1). Vaccine efficacy in the per-protocol population was 31.3% (97.5% CI, 23.6 to 38.3). Vaccine efficacy against severe malaria was 26.0% (95% CI, -7.4 to 48.6) in the intention-to-treat population and 36.6% (95% CI, 4.6 to 57.7) in the per-protocol population. Serious adverse events occurred with a similar frequency in the two study groups. One month after administration of the third dose of RTS,S/AS01, 99.7% of children were positive for anti-circumsporozoite antibodies, with a geometric mean titer of 209 EU per milliliter (95% CI, 197 to 222).ConclusionsThe RTS,S/AS01 vaccine coadministered with EPI vaccines provided modest protection against both clinical and severe malaria in young infants. (Funded by GlaxoSmithKline Biologicals and the PATH Malaria Vaccine Initiative; RTS,S ClinicalTrials.gov number, NCT00866619.).
| S-EPMC10915853 | biostudies-literature
Project description:The circumsporozoite protein (CS protein) on the malaria parasites in mosquitoes plays an important role in sporogony in mosquitoes. The RTS,S/AS01 malaria vaccine candidate, which has shown significant efficacy against clinical malaria in a large Phase 3 trial, targets the Plasmodium falciparum CS protein, but the ability of serum from vaccinated individuals to inhibit sporogony in mosquitoes has not been evaluated.Previously a double-blind, randomized trial of RTS,S/AS01 vaccine, as compared with rabies vaccine, in five- to 17-month old children in Tanzania was conducted. In this study, polyclonal human antibodies were purified from the pools of sera taken one month after the third vaccination. IgGs were purified from four pools of sera from 25 RTS,S/AS01 vaccinated children each, and two pools of sera from 25 children vaccinated with rabies vaccine each. The ability of antibodies to inhibit P. falciparum oocyst formation and/or sporogony in the mosquito host was evaluated by a standard membrane-feeding assay. The test antibodies were fed on day 0 (at the same time as the gametocyte feed), or on days 3 or 6 (serial-feed experiments). The oocyst and sporozoite counts were performed on days 8 and 16, respectively. In addition, two human anti-CS monoclonal antibodies (mAb) and a control mAb were also evaluated.Polyclonal anti-CS IgG preparations from RTS,S-vaccinated children tested at concentrations of 149-210 ELISA units (EU)/ml did not show significant inhibition in oocyst and sporozoite formation when the antibodies were fed with gametocytes at the same time, or later (serial-feed experiments). Similarly, anti-CS mAbs tested at 6,421 or 7,122 EU/ml did not show reduction in oocyst and sporozoite formation.This study does not support the concept that anti-CS antibodies induced by the RTS,S/AS01 vaccines in humans noticeably reduce malaria transmission by blocking P. falciparum sporozoite development or salivary gland invasion in mosquitoes when taken up during feeding.
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