Long term efficacy of a pre-erythrocytic malaria vaccine and correlates of protection in children residing in a malaria endemic country
<p>Malaria remains an important cause of morbidity and mortality among children in sub-Saharan Africa despite recent reductions in malaria incidence in some parts of Africa. Current control tools face threats such as the emergence of drug resistant parasites and insecticide resistant mosquitoe...
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| Format: | Thesis |
| Language: | English |
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2013
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| _version_ | 1826316428083462144 |
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| author | Olotu, A |
| author2 | Bejon, P |
| author_facet | Bejon, P Olotu, A |
| author_sort | Olotu, A |
| collection | OXFORD |
| description | <p>Malaria remains an important cause of morbidity and mortality among children in sub-Saharan Africa despite recent reductions in malaria incidence in some parts of Africa. Current control tools face threats such as the emergence of drug resistant parasites and insecticide resistant mosquitoes. A malaria vaccine is needed to complement and/or replace existing tools in order to achieve better malaria control and eventually eliminate the disease.</p> <p>RTS,S/AS01E is the most clinically advanced pre-erythrocytic malaria vaccine candidate and is currently being tested in a phase III trial. The short-term efficacy of RTS,S/AS01E is known but the duration of protection is unknown. Furthermore, although RTS,S is protective, it is unclear which immunological assays predict efficacy: hence there are no known correlates of vaccine-induced protection against clinical malaria.</p> <p>In a randomized controlled trial, I assessed the efficacy of RTS,S/AS01E in children (5-17 months old) residing in Kilifi, Kenya, over 4 years of follow-up and determined the correlates of protection against clinical malaria. In order to examine the effect of variations in malaria exposure on vaccine efficacy, I developed an individual marker of malaria exposure calculated as distance-weighted prevalence of malaria infection within 1 km radius of every child.</p> <p>Over 4 years of follow-up, RTS,S/AS01E had an efficacy of 29.9% (95%CI: 10.3% to 45.3%, p=0.005) and 16.8% (95%CI: -8.6% to 36.3% p=0.18) against first and all malaria episodes, respectively (by intention to treat analysis). Vaccine efficacy waned over time and with increasing malaria exposure. RTS,S/AS01E efficacy was 43.6% (95% CI, 15.5 to 62.3) in the first year but was -0.4% (95% CI, -32.1 to 45.3) in the fourth year. Vaccine efficacy was 45.1% (95%CI 11.3% to 66.0%) among children with lower than average malaria exposure index, but 15.9% (95%CI -11.0 to 36.4%) among children with higher than average malaria exposure index. Despite waning in efficacy, RTS,S/AS01E averted 65 cases of malaria per 100 vaccinated children, with more cases averted among the children in the higher malaria-exposure cohort (78 cases per 100 vaccinated children) than those the low exposure cohort (62 cases per 100 vaccinated children).</p> <p>RTS,S/AS01E induced high titres of anti-CS protein antibodies and CD4+ T cell but not CD8+ T cell responses. Anti-CS antibody titres and the frequency of TNF-α producing CD4+ T cell responses were independently associated with protection from clinical malaria, and the combination of both anti-CS titers and TNF-α producing CD4+ T cell response satisfied the Prentice criteria for surrogate markers of protection.</p> <p>There was no association between avidity of RTS,S-induced anti-CS protein antibodies and protection from clinical malaria.</p> <p><strong>Conclusions:</strong></p> <p>RTS,S/AS01E efficacy against all episodes is 16.8% over the 4 years of follow-up. The vaccine efficacy wanes over time and with increasing malaria exposure. RTS,S/AS01E-induced TNF-α producing CD4 T cell and anti-CS protein antibody responses were independently associated with protection from clinical malaria. Anti-CS avidity did not predict protection from clinical malaria. Long-term follow-ups of malaria vaccine trials are essential in the evaluation of the longevity of vaccine efficacy.</p> |
| first_indexed | 2024-03-06T21:15:59Z |
| format | Thesis |
| id | oxford-uuid:3fcbab1a-689a-41bd-8685-4762941f7b0c |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-12-09T03:44:57Z |
| publishDate | 2013 |
| record_format | dspace |
| spelling | oxford-uuid:3fcbab1a-689a-41bd-8685-4762941f7b0c2024-12-07T16:36:34ZLong term efficacy of a pre-erythrocytic malaria vaccine and correlates of protection in children residing in a malaria endemic countryThesishttp://purl.org/coar/resource_type/c_db06uuid:3fcbab1a-689a-41bd-8685-4762941f7b0cImmunologyVaccinologyMedical sciencesEpidemiologyMalariaInfectious diseasesEnglishOxford University Research Archive - Valet2013Olotu, ABejon, PMarsh, KFegan, G<p>Malaria remains an important cause of morbidity and mortality among children in sub-Saharan Africa despite recent reductions in malaria incidence in some parts of Africa. Current control tools face threats such as the emergence of drug resistant parasites and insecticide resistant mosquitoes. A malaria vaccine is needed to complement and/or replace existing tools in order to achieve better malaria control and eventually eliminate the disease.</p> <p>RTS,S/AS01E is the most clinically advanced pre-erythrocytic malaria vaccine candidate and is currently being tested in a phase III trial. The short-term efficacy of RTS,S/AS01E is known but the duration of protection is unknown. Furthermore, although RTS,S is protective, it is unclear which immunological assays predict efficacy: hence there are no known correlates of vaccine-induced protection against clinical malaria.</p> <p>In a randomized controlled trial, I assessed the efficacy of RTS,S/AS01E in children (5-17 months old) residing in Kilifi, Kenya, over 4 years of follow-up and determined the correlates of protection against clinical malaria. In order to examine the effect of variations in malaria exposure on vaccine efficacy, I developed an individual marker of malaria exposure calculated as distance-weighted prevalence of malaria infection within 1 km radius of every child.</p> <p>Over 4 years of follow-up, RTS,S/AS01E had an efficacy of 29.9% (95%CI: 10.3% to 45.3%, p=0.005) and 16.8% (95%CI: -8.6% to 36.3% p=0.18) against first and all malaria episodes, respectively (by intention to treat analysis). Vaccine efficacy waned over time and with increasing malaria exposure. RTS,S/AS01E efficacy was 43.6% (95% CI, 15.5 to 62.3) in the first year but was -0.4% (95% CI, -32.1 to 45.3) in the fourth year. Vaccine efficacy was 45.1% (95%CI 11.3% to 66.0%) among children with lower than average malaria exposure index, but 15.9% (95%CI -11.0 to 36.4%) among children with higher than average malaria exposure index. Despite waning in efficacy, RTS,S/AS01E averted 65 cases of malaria per 100 vaccinated children, with more cases averted among the children in the higher malaria-exposure cohort (78 cases per 100 vaccinated children) than those the low exposure cohort (62 cases per 100 vaccinated children).</p> <p>RTS,S/AS01E induced high titres of anti-CS protein antibodies and CD4+ T cell but not CD8+ T cell responses. Anti-CS antibody titres and the frequency of TNF-α producing CD4+ T cell responses were independently associated with protection from clinical malaria, and the combination of both anti-CS titers and TNF-α producing CD4+ T cell response satisfied the Prentice criteria for surrogate markers of protection.</p> <p>There was no association between avidity of RTS,S-induced anti-CS protein antibodies and protection from clinical malaria.</p> <p><strong>Conclusions:</strong></p> <p>RTS,S/AS01E efficacy against all episodes is 16.8% over the 4 years of follow-up. The vaccine efficacy wanes over time and with increasing malaria exposure. RTS,S/AS01E-induced TNF-α producing CD4 T cell and anti-CS protein antibody responses were independently associated with protection from clinical malaria. Anti-CS avidity did not predict protection from clinical malaria. Long-term follow-ups of malaria vaccine trials are essential in the evaluation of the longevity of vaccine efficacy.</p> |
| spellingShingle | Immunology Vaccinology Medical sciences Epidemiology Malaria Infectious diseases Olotu, A Long term efficacy of a pre-erythrocytic malaria vaccine and correlates of protection in children residing in a malaria endemic country |
| title | Long term efficacy of a pre-erythrocytic malaria vaccine and correlates of protection in children residing in a malaria endemic country |
| title_full | Long term efficacy of a pre-erythrocytic malaria vaccine and correlates of protection in children residing in a malaria endemic country |
| title_fullStr | Long term efficacy of a pre-erythrocytic malaria vaccine and correlates of protection in children residing in a malaria endemic country |
| title_full_unstemmed | Long term efficacy of a pre-erythrocytic malaria vaccine and correlates of protection in children residing in a malaria endemic country |
| title_short | Long term efficacy of a pre-erythrocytic malaria vaccine and correlates of protection in children residing in a malaria endemic country |
| title_sort | long term efficacy of a pre erythrocytic malaria vaccine and correlates of protection in children residing in a malaria endemic country |
| topic | Immunology Vaccinology Medical sciences Epidemiology Malaria Infectious diseases |
| work_keys_str_mv | AT olotua longtermefficacyofapreerythrocyticmalariavaccineandcorrelatesofprotectioninchildrenresidinginamalariaendemiccountry |