Publicação
Comparative efficacy analysis of whole-sporozoite vaccines against Malaria
| Resumo: | Malaria is a deadly mosquito-borne infectious disease caused by Plasmodium parasites, for which the only licensed vaccine provides modest, rapidly waning protection. Whole-sporozoite (WSp) pre-erythrocytic vaccines constitute a potential solution for inducing long-lasting sterile protection against malaria. WSp vaccines employ live or attenuated Plasmodium sporozoites to induce strong immune responses against the parasite’s pre-erythrocytic stages. Attenuation can be achieved by irradiation to block parasite replication (RAS) or through genetic engineering, leading to the early (EA-GAP) or late (LA-GAP) stage arrest of the parasite’s hepatic development. Live, non-attenuated sporozoites can also be employed, allowing for full hepatic development, with the parasites being killed upon release into the bloodstream by prophylactic treatment with compounds such as chloroquine (CPS). Previous studies suggested that a longer liver-stage development, as observed in CPS and LA-GAP vaccines, induces greater protection than RAS and EA-GAP vaccines, potentially due to the higher parasite biomass and antigenic repertoire presented by the former. We investigated the effect of immunization dosage and regimen on the level and duration of the protective efficacy (PE) conferred by different WSp vaccines. Using rodent parasite surrogates of EAGAP, RAS, LA-GAP and CPS vaccine candidates, and C57BL/6J mice, we assessed overall sterile protection, prepatency, hepatic load, and protection against severe disease achieved with increasing immunization dosages in either a single or a prime-boost-boost vaccination regimens. Our results show that prime-only vaccination by RAS and LA-GAP affords higher levels of short-lived PE than EA-GAP and CPS. Conversely, prime-boost-boost vaccination with either of the WSp vaccines provides similar PE levels, which are differently maintained over time, suggesting a dose-dependent efficacy for RAS and LA-GAP. Collectively, our results indicate that WSp-induced protective immunity is a complex phenomenon in which the extent of parasite liver development may not be the only key feature influencing the efficacy of vaccination. |
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| Autores principais: | Rôla, Catarina Maria Vicente |
| Assunto: | Plasmodium berghei Vacinas de organismo inteiro Desenvolvimento hepático Doses de imunização Teses de mestrado - 2022 |
| Ano: | 2022 |
| País: | Portugal |
| Tipo de documento: | dissertação de mestrado |
| Tipo de acesso: | acesso aberto |
| Instituição associada: | Universidade de Lisboa |
| Idioma: | inglês |
| Origem: | Repositório da Universidade de Lisboa |
| Resumo: | Malaria is a deadly mosquito-borne infectious disease caused by Plasmodium parasites, for which the only licensed vaccine provides modest, rapidly waning protection. Whole-sporozoite (WSp) pre-erythrocytic vaccines constitute a potential solution for inducing long-lasting sterile protection against malaria. WSp vaccines employ live or attenuated Plasmodium sporozoites to induce strong immune responses against the parasite’s pre-erythrocytic stages. Attenuation can be achieved by irradiation to block parasite replication (RAS) or through genetic engineering, leading to the early (EA-GAP) or late (LA-GAP) stage arrest of the parasite’s hepatic development. Live, non-attenuated sporozoites can also be employed, allowing for full hepatic development, with the parasites being killed upon release into the bloodstream by prophylactic treatment with compounds such as chloroquine (CPS). Previous studies suggested that a longer liver-stage development, as observed in CPS and LA-GAP vaccines, induces greater protection than RAS and EA-GAP vaccines, potentially due to the higher parasite biomass and antigenic repertoire presented by the former. We investigated the effect of immunization dosage and regimen on the level and duration of the protective efficacy (PE) conferred by different WSp vaccines. Using rodent parasite surrogates of EAGAP, RAS, LA-GAP and CPS vaccine candidates, and C57BL/6J mice, we assessed overall sterile protection, prepatency, hepatic load, and protection against severe disease achieved with increasing immunization dosages in either a single or a prime-boost-boost vaccination regimens. Our results show that prime-only vaccination by RAS and LA-GAP affords higher levels of short-lived PE than EA-GAP and CPS. Conversely, prime-boost-boost vaccination with either of the WSp vaccines provides similar PE levels, which are differently maintained over time, suggesting a dose-dependent efficacy for RAS and LA-GAP. Collectively, our results indicate that WSp-induced protective immunity is a complex phenomenon in which the extent of parasite liver development may not be the only key feature influencing the efficacy of vaccination. |
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