{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,5]],"date-time":"2026-03-05T20:01:04Z","timestamp":1772740864813,"version":"3.50.1"},"reference-count":74,"publisher":"American Society of Tropical Medicine and Hygiene","issue":"3","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,3,4]]},"abstract":"<jats:title>ABSTRACT.<\/jats:title>\n                  <jats:p>\n                    Two vaccines against\n                    <jats:italic>Plasmodium falciparum<\/jats:italic>\n                    , RTS,S and R21, have been recommended for widespread implementation by the World Health Organization. Both vaccines displayed safety and efficacy in clinical trials, and early RTS,S pilot implementation results suggested reductions in severe disease and death. However, RTS,S efficacy was lower in higher transmission settings during trials. Between- and within-site analyses suggest that reduced efficacy was partially due to greater natural immunity development in control groups in higher transmission settings, resulting in temporary periods of negative efficacy beginning approximately three years after the primary vaccine series. Results from RTS,S pilot implementation and seasonal administration for both vaccines are promising, but study designs have thus far precluded the identification of similar periods of negative efficacy. Because we expect delayed malaria cases of unknown severity in vaccinated individuals during implementation in high-transmission settings, we recommend enhanced surveillance and interventions that supplement malaria vaccination to strengthen prevention.\n                  <\/jats:p>","DOI":"10.4269\/ajtmh.25-0613","type":"journal-article","created":{"date-parts":[[2026,1,15]],"date-time":"2026-01-15T16:49:19Z","timestamp":1768495759000},"page":"410-412","source":"Crossref","is-referenced-by-count":0,"title":["Ensuring the Public Health Impact of Malaria Vaccination in High-Transmission Settings"],"prefix":"10.4269","volume":"114","author":[{"given":"Griffin J.","family":"Bell","sequence":"first","affiliation":[{"name":"Department of Epidemiology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland;"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michael E.","family":"Emch","sequence":"additional","affiliation":[{"name":"Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, North Carolina;"},{"name":"Department of Geography, University of North Carolina, Chapel Hill, North Carolina;"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ann M.","family":"Moormann","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts;"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jeffrey A.","family":"Bailey","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine, Brown University, Providence, Rhode Island"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"2795","reference":[{"key":"b1","article-title":"World Malaria Report 2024.","year":"2024"},{"key":"b2","article-title":"WHO Guidelines for Malaria.","year":"2024"},{"key":"b3","series-title":"Lancet","first-page":"31","article-title":"Efficacy and safety of RTS,S\/AS01 malaria vaccine with or without a booster dose in infants and children in Africa: Final results of a phase 3, individually randomised, controlled trial","volume":"386","year":"2015"},{"key":"b4","series-title":"Lancet","first-page":"533","article-title":"Safety and efficacy of malaria vaccine candidate R21\/Matrix-M in African children: A multicentre, double-blind, randomised, phase 3 trial","volume":"403","author":"Datoo","year":"2024"},{"key":"b5","series-title":"Lancet Infect Dis","first-page":"75","article-title":"Seasonal vaccination with RTS,S\/AS01E vaccine with or without seasonal malaria chemoprevention in children up to the age of 5 years in Burkina Faso and Mali: A double-blind, randomised, controlled, phase 3 trial","volume":"24","author":"Dicko","year":"2024"},{"key":"b6","series-title":"Lancet","first-page":"504","article-title":"Malaria vaccines for children: And now there are two","volume":"403","author":"Moorthy","year":"2024"},{"key":"b7","series-title":"MDM Policy Pract","first-page":"2381468319873324","article-title":"Economic impact of introducing the RTS,S malaria vaccine: Cost-effectiveness and budget impact analysis in 41 countries","volume":"4","author":"Sauboin","year":"2019"},{"key":"b8","series-title":"Lancet Infect Dis","first-page":"465","article-title":"The public health impact and cost-effectiveness of the R21\/Matrix-M malaria vaccine: A mathematical modelling study","volume":"24","author":"Schmit","year":"2024"},{"key":"b9","series-title":"Lancet Infect Dis","first-page":"821","article-title":"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","volume":"19","author":"Tinto","year":"2019"},{"key":"b10","series-title":"N Engl J Med","first-page":"2519","article-title":"Seven-year efficacy of RTS,S\/AS01 malaria vaccine among young African children","volume":"374","author":"Olotu","year":"2016"},{"key":"b11","series-title":"J Infect Dis","first-page":"1646","article-title":"Malaria transmission intensity likely modifies RTS, S\/AS01 efficacy due to a rebound effect in Ghana, Malawi, and Gabon","volume":"226","author":"Bell","year":"2022"},{"key":"b12","series-title":"BMC Infect Dis","first-page":"716","article-title":"Background malaria incidence and parasitemia during the three-dose RTS,S\/AS01 vaccination series do not reduce magnitude of antibody response nor efficacy against the first case of malaria","volume":"23","author":"Bell","year":"2023"},{"key":"b13","series-title":"Lancet Infect Dis","first-page":"335","article-title":"The effect of Plasmodium falciparum exposure and maternal anti-circumsporozoite protein antibodies on responses to RTS,S\/AS01E vaccination in infants and children: An ancillary observational immunological study to a phase 3, randomised clinical trial","volume":"25","author":"Maci\u00e0","year":"2025"},{"key":"b14","series-title":"Lancet Infect Dis","first-page":"1025","article-title":"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","volume":"24","author":"Juraska","year":"2024"},{"key":"b15","series-title":"Malar J","first-page":"77","article-title":"Resurgent and delayed malaria","volume":"21","author":"Greenwood","year":"2022"},{"key":"b16","series-title":"Lancet Infect Dis","first-page":"790","article-title":"Malaria vaccination and rebound malaria","volume":"19","author":"Dicko","year":"2019"},{"key":"b17","series-title":"Lancet Infect Dis","first-page":"e516","article-title":"The effect of disease transmission on time-aggregated treatment efficacy estimates: A critical analysis of factors influencing the RTS,S and R21 malaria vaccine phase 3 trials","volume":"25","author":"Maci\u00e0","year":"2025"},{"key":"b18","series-title":"NPJ Vaccines","first-page":"51","article-title":"Force of infection: A determinant of vaccine efficacy?","volume":"6","author":"Kaslow","year":"2021"},{"key":"b19","series-title":"Curr Epidemiol Rep","first-page":"79","article-title":"Impacts of ecology, parasite antigenic variation, and human genetics on RTS,S\/AS01e malaria vaccine efficacy","volume":"8","author":"Bell","year":"2021"},{"key":"b20","series-title":"BMC Med","first-page":"289","article-title":"Induction, decay, and determinants of functional antibodies following vaccination with the RTS,S malaria vaccine in young children","volume":"20","author":"Feng","year":"2022"},{"key":"b21","series-title":"Malar J","first-page":"437","article-title":"The time-course of protection of the RTS,S vaccine against malaria infections and clinical disease","volume":"14","author":"Penny","year":"2015"},{"key":"b22","series-title":"Lancet","first-page":"367","article-title":"Public health impact and cost-effectiveness of the RTS,S\/AS01 malaria vaccine: A systematic comparison of predictions from four mathematical models","volume":"387","author":"Penny","year":"2016"},{"key":"b23","series-title":"PLoS Med","first-page":"e1003359","article-title":"The impact of delayed treatment of uncomplicated P. falciparum malaria on progression to severe malaria: A systematic review and a pooled multicentre individual-patient meta-analysis","volume":"17","author":"Mousa","year":"2020"},{"key":"b24","series-title":"Lancet","first-page":"1660","article-title":"Feasibility, safety, and impact of the RTS,S\/AS01E malaria vaccine when implemented through national immunisation programmes: Evaluation of cluster-randomised introduction of the vaccine in Ghana, Kenya, and Malawi","volume":"403","author":"Asante","year":"2024"},{"key":"b25","series-title":"Sci Transl Med","first-page":"eaaw9522","article-title":"Immune system development varies according to age, location, and anemia in African children","volume":"12","author":"Hill","year":"2020"},{"key":"b26","series-title":"PLoS One","first-page":"e8988","article-title":"Age-patterns of malaria vary with severity, transmission intensity and seasonality in sub-Saharan Africa: A systematic review and pooled analysis","volume":"5","author":"Carneiro","year":"2010"},{"key":"b27","series-title":"Malar J","first-page":"282","article-title":"The age patterns of severe malaria syndromes in sub-Saharan Africa across a range of transmission intensities and seasonality settings","volume":"9","author":"Roca-Feltrer","year":"2010"},{"key":"b28","series-title":"Science","first-page":"926","article-title":"Malaria infection and severe disease risks in 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trust","volume":"118","author":"Petersen","year":"2021"},{"key":"b37","series-title":"Malar J","first-page":"351","article-title":"Reconsidering rebound malaria: Zanzibari voices on acquired immunity, risk, and history","volume":"24","author":"Graboyes","year":"2025"},{"key":"b1","article-title":"World Malaria Report 2024.","year":"2024"},{"key":"b2","article-title":"WHO Guidelines for Malaria.","year":"2024"},{"key":"b3","series-title":"Lancet","first-page":"31","article-title":"Efficacy and safety of RTS,S\/AS01 malaria vaccine with or without a booster dose in infants and children in Africa: Final results of a phase 3, individually randomised, controlled trial","volume":"386","year":"2015"},{"key":"b4","series-title":"Lancet","first-page":"533","article-title":"Safety and efficacy of malaria vaccine candidate R21\/Matrix-M in African children: A multicentre, double-blind, randomised, phase 3 trial","volume":"403","author":"Datoo","year":"2024"},{"key":"b5","series-title":"Lancet Infect Dis","first-page":"75","article-title":"Seasonal vaccination with RTS,S\/AS01E vaccine with or without seasonal malaria chemoprevention in children up to the age of 5 years in Burkina Faso and Mali: A double-blind, randomised, controlled, phase 3 trial","volume":"24","author":"Dicko","year":"2024"},{"key":"b6","series-title":"Lancet","first-page":"504","article-title":"Malaria vaccines for children: And now there are two","volume":"403","author":"Moorthy","year":"2024"},{"key":"b7","series-title":"MDM Policy Pract","first-page":"2381468319873324","article-title":"Economic impact of introducing the RTS,S malaria vaccine: Cost-effectiveness and budget impact analysis in 41 countries","volume":"4","author":"Sauboin","year":"2019"},{"key":"b8","series-title":"Lancet Infect Dis","first-page":"465","article-title":"The public health impact and cost-effectiveness of the R21\/Matrix-M malaria vaccine: A mathematical modelling study","volume":"24","author":"Schmit","year":"2024"},{"key":"b9","series-title":"Lancet Infect Dis","first-page":"821","article-title":"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","volume":"19","author":"Tinto","year":"2019"},{"key":"b10","series-title":"N Engl J Med","first-page":"2519","article-title":"Seven-year efficacy of RTS,S\/AS01 malaria vaccine among young African children","volume":"374","author":"Olotu","year":"2016"},{"key":"b11","series-title":"J Infect Dis","first-page":"1646","article-title":"Malaria transmission intensity likely modifies RTS, S\/AS01 efficacy due to a rebound effect in Ghana, Malawi, and Gabon","volume":"226","author":"Bell","year":"2022"},{"key":"b12","series-title":"BMC Infect Dis","first-page":"716","article-title":"Background malaria incidence and parasitemia during the three-dose RTS,S\/AS01 vaccination series do not reduce magnitude of antibody response nor efficacy against the first case of malaria","volume":"23","author":"Bell","year":"2023"},{"key":"b13","series-title":"Lancet Infect Dis","first-page":"335","article-title":"The effect of Plasmodium falciparum exposure and maternal anti-circumsporozoite protein antibodies on responses to RTS,S\/AS01E vaccination in infants and children: An ancillary observational immunological study to a phase 3, randomised clinical trial","volume":"25","author":"Maci\u00e0","year":"2025"},{"key":"b14","series-title":"Lancet Infect Dis","first-page":"1025","article-title":"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","volume":"24","author":"Juraska","year":"2024"},{"key":"b15","series-title":"Malar J","first-page":"77","article-title":"Resurgent and delayed malaria","volume":"21","author":"Greenwood","year":"2022"},{"key":"b16","series-title":"Lancet Infect Dis","first-page":"790","article-title":"Malaria vaccination and rebound malaria","volume":"19","author":"Dicko","year":"2019"},{"key":"b17","series-title":"Lancet Infect Dis","first-page":"e516","article-title":"The effect of disease transmission on time-aggregated treatment efficacy estimates: A critical analysis of factors influencing the RTS,S and R21 malaria vaccine phase 3 trials","volume":"25","author":"Maci\u00e0","year":"2025"},{"key":"b18","series-title":"NPJ Vaccines","first-page":"51","article-title":"Force of infection: A determinant of vaccine efficacy?","volume":"6","author":"Kaslow","year":"2021"},{"key":"b19","series-title":"Curr Epidemiol Rep","first-page":"79","article-title":"Impacts of ecology, parasite antigenic variation, and human genetics on RTS,S\/AS01e malaria vaccine efficacy","volume":"8","author":"Bell","year":"2021"},{"key":"b20","series-title":"BMC Med","first-page":"289","article-title":"Induction, decay, and determinants of functional antibodies following vaccination with the RTS,S malaria vaccine in young children","volume":"20","author":"Feng","year":"2022"},{"key":"b21","series-title":"Malar J","first-page":"437","article-title":"The time-course of protection of the RTS,S vaccine against malaria infections and clinical disease","volume":"14","author":"Penny","year":"2015"},{"key":"b22","series-title":"Lancet","first-page":"367","article-title":"Public health impact and cost-effectiveness of the RTS,S\/AS01 malaria vaccine: A systematic comparison of predictions from four mathematical models","volume":"387","author":"Penny","year":"2016"},{"key":"b23","series-title":"PLoS Med","first-page":"e1003359","article-title":"The impact of delayed treatment of uncomplicated P. falciparum malaria on progression to severe malaria: A systematic review and a pooled multicentre individual-patient meta-analysis","volume":"17","author":"Mousa","year":"2020"},{"key":"b24","series-title":"Lancet","first-page":"1660","article-title":"Feasibility, safety, and impact of the RTS,S\/AS01E malaria vaccine when implemented through national immunisation programmes: Evaluation of cluster-randomised introduction of the vaccine in Ghana, Kenya, and Malawi","volume":"403","author":"Asante","year":"2024"},{"key":"b25","series-title":"Sci Transl Med","first-page":"eaaw9522","article-title":"Immune system development varies according to age, location, and anemia in African children","volume":"12","author":"Hill","year":"2020"},{"key":"b26","series-title":"PLoS One","first-page":"e8988","article-title":"Age-patterns of malaria vary with severity, transmission intensity and seasonality in sub-Saharan Africa: A systematic review and pooled analysis","volume":"5","author":"Carneiro","year":"2010"},{"key":"b27","series-title":"Malar J","first-page":"282","article-title":"The age patterns of severe malaria syndromes in sub-Saharan Africa across a range of transmission intensities and seasonality settings","volume":"9","author":"Roca-Feltrer","year":"2010"},{"key":"b28","series-title":"Science","first-page":"926","article-title":"Malaria infection and severe disease risks in Africa","volume":"373","author":"Paton","year":"2021"},{"key":"b29","series-title":"Malar J","first-page":"244","article-title":"Subnational introduction of the RTS,S\/AS01E malaria vaccine into routine immunization: Experience and lessons from the three pilot countries","volume":"24","author":"Jalang\u2019o","year":"2025"},{"key":"b30","series-title":"Sci Rep","first-page":"251","article-title":"Factors associated with vaccine default in Southern Ghana based on data from the RTSS malaria vaccine trial in Cape Coast","volume":"15","author":"Bediako","year":"2025"},{"key":"b31","series-title":"Immun Inflamm Dis","first-page":"e70205","article-title":"Determinants of malaria vaccine acceptance: A systematic review and meta-analysis of awareness, acceptance, hesitancy, and willingness to pay","volume":"13","author":"Bushi","year":"2025"},{"key":"b32","series-title":"PLoS One","first-page":"e0278224","article-title":"A systematic review and meta-analysis of the prevalence of caregiver acceptance of malaria vaccine for under-five children in low-income and middle-income countries (LMICs)","volume":"17","author":"Sulaiman","year":"2022"},{"key":"b33","series-title":"Vaccine X","first-page":"100213","article-title":"Trust is the common denominator for COVID-19 vaccine acceptance: A literature review","volume":"12","author":"Adhikari","year":"2022"},{"key":"b34","series-title":"Nat Med","first-page":"456","article-title":"An epidemic of uncertainty: Rumors, conspiracy theories and vaccine hesitancy","volume":"28","author":"Pertwee","year":"2022"},{"key":"b35","series-title":"Sci 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