Person: Tenorio Franca, Camila
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Tenorio Franca
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Camila
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Tenorio Franca, Camila
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Publication Naturally acquired antibody responses to more than 300 Plasmodium vivax proteins in three geographic regions(Public Library of Science (PLoS), 2017-09-11) Longley, Rhea J.; White, Michael T.; Takashima, Eizo; Morita, Masayuki; Kanoi, Bernard N.; Li Wai Suen, Connie S. N.; Betuela, Inoni; Kuehn, Andrea; Sripoorote, Piyarat; Tenorio Franca, Camila; Siba, Peter; Robinson, Leanne J.; Lacerda, Marcus; Sattabongkot, Jetsumon; Tsuboi, Takafumi; Mueller, IvoPlasmodium vivax remains an important cause of malaria in South America and the Asia-Pacific. Naturally acquired antibody responses against multiple P. vivax proteins have been described in numerous countries, however, direct comparison of these responses has been difficult with different methodologies employed. We measured antibody responses against 307 P. vivax proteins at the time of P. vivax infection, and at 2–3 later time-points in three countries. We observed that seropositivity rates at the time of infection were highest in Thailand, followed by Brazil then PNG, reflecting the level of antigenic input. The majority of sero-reactive antigens in all sites induced short-lived antibody responses with estimated half-lives of less than 6 months, although there was a trend towards longer-lived responses in PNG children. Despite these differences, IgG seropositivity rates, magnitude and longevity were highly and significantly rank-correlated between the different regions, suggesting such features are reflective of the individual protein.Publication IgG antibodies to synthetic GPI are biomarkers of immune-status to both Plasmodium falciparum and Plasmodium vivax malaria in young children(Springer Nature, 2017-09-25) Tenorio Franca, Camila; Li Wai Suen, Connie S. N.; Carmagnac, Amandine; Lin, Enmoore; Kiniboro, Benson; Siba, Peter; Schofield, Louis; Mueller, IvoBackground: Further reduction in malaria prevalence and its eventual elimination would be greatly facilitated by the development of biomarkers of exposure and/or acquired immunity to malaria, as well as the deployment of effective vaccines against Plasmodium falciparum and Plasmodium vivax. A better understanding of the acquisition of immunity in naturally-exposed populations is essential for the identification of antigens useful as biomarkers, as well as to inform rational vaccine development. Methods: ELISA was used to measure total IgG to a synthetic form of glycosylphosphatidylinositol from P. falciparum (PfGPI) in a cohort of 1–3 years old Papua New Guinea children with well-characterized individual differences in exposure to P. falciparum and P. vivax blood-stage infections. The relationship between IgG levels to PfGPI and measures of recent and past exposure to P. falciparum and P. vivax infections was investigated, as well as the association between antibody levels and prospective risk of clinical malaria over 16 months of follow-up. Results: Total IgG levels to PfGPI were low in the young children tested. Antibody levels were higher in the presence of P. falciparum or P. vivax infections, but short-lived. High IgG levels were associated with higher risk of P. falciparum malaria (IRR 1.33–1.66, P = 0.008–0.027), suggesting that they are biomarkers of increased exposure to P. falciparum infections. Given the cross-reactive nature of antibodies to PfGPI, high IgG levels were also associated with reduced risk of P. vivax malaria (IRR 0.65–0.67, P = 0.039–0.044), indicating that these antibodies are also markers of acquired immunity to P. vivax. Conclusions: This study highlights that in young children, IgG to PfGPI might be a useful marker of immune-status to both P. falciparum and P. vivax infections, and potentially useful to help malaria control programs to identify populations at-risk. Further functional studies are necessary to confirm the potential of PfGPI as a target for vaccine development.Publication An Antibody Screen of a Plasmodium vivax Antigen Library Identifies Novel Merozoite Proteins Associated with Clinical Protection(Public Library of Science (PLoS), 2016-05-16) Tenorio Franca, Camila; Hostetler, Jessica B.; Sharma, Sumana; White, Michael T.; Lin, Enmoore; Kiniboro, Benson; Waltmann, Andreea; Darcy, Andrew W.; Li Wai Suen, Connie S. N.; Siba, Peter; King, Christopher L.; Rayner, Julian C.; Fairhurst, Rick M.; Mueller, Ivo; Franca, Camila T.Background: Elimination of Plasmodium vivax malaria would be greatly facilitated by the development of an effective vaccine. A comprehensive and systematic characterization of antibodies to P. vivax antigens in exposed populations is useful in guiding rational vaccine design. Methodology/Principal Findings: In this study, we investigated antibodies to a large library of P. vivax entire ectodomain merozoite proteins in 2 Asia-Pacific populations, analysing the relationship of antibody levels with markers of current and cumulative malaria exposure, and socioeconomic and clinical indicators. 29 antigenic targets of natural immunity were identified. Of these, 12 highly-immunogenic proteins were strongly associated with age and thus cumulative lifetime exposure in Solomon Islanders (P<0.001–0.027). A subset of 6 proteins, selected on the basis of immunogenicity and expression levels, were used to examine antibody levels in plasma samples from a population of young Papua New Guinean children with well-characterized individual differences in exposure. This analysis identified a strong association between reduced risk of clinical disease and antibody levels to P12, P41, and a novel hypothetical protein that has not previously been studied, PVX_081550 (IRR 0.46–0.74; P<0.001–0.041). Conclusion/Significance: These data emphasize the benefits of an unbiased screening approach in identifying novel vaccine candidate antigens. Functional studies are now required to establish whether PVX_081550 is a key component of the naturally-acquired protective immune response, a biomarker of immune status, or both.Publication Asymptomatic Plasmodium vivax infections induce robust IgG responses to multiple blood-stage proteins in a low-transmission region of western Thailand(Springer Nature, 2017-04-28) Longley, Rhea J.; Tenorio Franca, Camila; White, Michael T.; Kumpitak, Chalermpon; Sa-angchai, Patiwat; Gruszczyk, Jakub; Hostetler, Jessica B.; Yadava, Anjali; King, Christopher L.; Fairhurst, Rick M.; Rayner, Julian C.; Tham, Wai-Hong; Nguitragool, Wang; Sattabongkot, Jetsumon; Mueller, IvoBackground: Thailand is aiming to eliminate malaria by the year 2024. Plasmodium vivax has now become the dominant species causing malaria within the country, and a high proportion of infections are asymptomatic. A better understanding of antibody dynamics to P. vivax antigens in a low-transmission setting, where acquired immune responses are poorly characterized, will be pivotal for developing new strategies for elimination, such as improved surveillance methods and vaccines. The objective of this study was to characterize total IgG antibody levels to 11 key P. vivax proteins in a village of western Thailand. Methods: Plasma samples from 546 volunteers enrolled in a cross-sectional survey conducted in 2012 in Kanchanaburi Province were utilized. Total IgG levels to 11 diferent proteins known or predicted to be involved in reticulocyte binding or invasion (ARP, GAMA, P41, P12, PVX_081550, and fve members of the PvRBP family), as well as the leading pre-erythrocytic vaccine candidate (CSP) were measured using a multiplexed bead-based assay. Associations between IgG levels and infection status, age, and spatial location were explored. Results: Individuals from a low-transmission region of western Thailand reacted to all 11 P. vivax recombinant proteins. Signifcantly greater IgG levels were observed in the presence of a current P. vivax infection, despite all infected individuals being asymptomatic. IgG levels were also higher in adults (18 years and older) than in children. For most of the proteins, higher IgG levels were observed in individuals living closer to the Myanmar border and further away from local health services. Conclusions: Robust IgG responses were observed to most proteins and IgG levels correlated with surrogates of exposure, suggesting these antigens may serve as potential biomarkers of exposure, immunity, or both.Publication Plasmodium vivax Reticulocyte Binding Proteins Are Key Targets of Naturally Acquired Immunity in Young Papua New Guinean Children(Public Library of Science (PLoS), 2016-09-27) Tenorio Franca, Camila; He, Wen-Qiang; Mueller, Ivo; Tham, Wai-Hong; Siba, Peter M; Kiniboro, Benson; Lin, Enmoore; Lim, Nicholas T. Y.; Gruszczyk, JakubBackground: Major gaps in our understanding of Plasmodium vivax biology and the acquisition of immunity to this parasite hinder vaccine development. P. vivax merozoites exclusively invade reticulocytes, making parasite proteins that mediate reticulocyte binding and/or invasion potential key vaccine or drug targets. While protein interactions that mediate invasion are still poorly understood, the P. vivax Reticulocyte-Binding Protein family (PvRBP) is thought to be involved in P. vivax restricted host-cell selectivity. Methodology/Principal findings: We assessed the binding specificity of five members of the PvRBP family (PvRBP1a, PvRBP1b, PvRBP2a, PvRBP2b, PvRBP2-P2 and a non-binding fragment of PvRBP2c) to normocytes or reticulocytes. PvRBP2b was identified as the only reticulocyte-specific binder (P<0.001), whereas the others preferentially bound to normocytes (PvRBP1a/b P≤0.034), or showed comparable binding to both (PvRBP2a/2-P2, P = 0.38). Furthermore, we measured levels of total and IgG subclasses 1, 2, 3 and 4 to the six PvRBPs in a cohort of young Papua New Guinean children, and assessed their relationship with prospective risk of P. vivax malaria. Children had substantial, highly correlated (rho = 0.49–0.82, P<0.001) antibody levels to all six PvRBPs, with dominant IgG1 and IgG3 subclasses. Both total IgG (Incidence Rate Ratio [IRR] 0.63–0.73, P = 0.008–0.041) and IgG1 (IRR 0.56–0.69, P = 0.001–0.035) to PvRBP2b and PvRBP1a were strongly associated with reduced risk of vivax-malaria, independently of age and exposure. Conclusion/Significance: These results demonstrate a diversity of erythrocyte-binding phenotypes of PvRBPs, indicating binding to both reticulocyte-specific and normocyte-specific ligands. Our findings provide further insights into the naturally acquired immunity to P. vivax and highlight the importance of PvRBP proteins as targets of naturally acquired humoral immunity. In-depth studies of the role of PvRBPs in P. vivax invasion and functional validation of the role of anti-PvRBP antibodies in clinical immunity against P. vivax are now required to confirm the potential of the reticulocyte-binding PvRBP2b and PvRBP1a as vaccine candidate antigens.Publication Identification of highly-protective combinations of Plasmodium vivax recombinant proteins for vaccine development(eLife Sciences Publications, Ltd, 2017-09-26) Tenorio Franca, Camila; White, Michael T; He, Wen-Qiang; Hostetler, Jessica B; Brewster, Jessica; Frato, Gabriel; Malhotra, Indu; Gruszczyk, Jakub; Huon, Christele; Lin, Enmoore; Kiniboro, Benson; Yadava, Anjali; Siba, Peter; Galinski, Mary R; Healer, Julie; Chitnis, Chetan; Cowman, Alan F; Takashima, Eizo; Tsuboi, Takafumi; Tham, Wai-Hong; Fairhurst, Rick M; Rayner, Julian C; King, Christopher L; Mueller, IvoThe study of antigenic targets of naturally-acquired immunity is essential to identify and prioritize antigens for further functional characterization. We measured total IgG antibodies to 38 P. vivax antigens, investigating their relationship with prospective risk of malaria in a cohort of 1–3 years old Papua New Guinean children. Using simulated annealing algorithms, the potential protective efficacy of antibodies to multiple antigen-combinations, and the antibody thresholds associated with protection were investigated for the first time. High antibody levels to multiple known and newly identified proteins were strongly associated with protection (IRR 0.44–0.74, p<0.001–0.041). Among five-antigen combinations with the strongest protective effect (>90%), EBP, DBPII, RBP1a, CyRPA, and PVX_081550 were most frequently identified; several of them requiring very low antibody levels to show a protective association. These data identify individual antigens that should be prioritized for further functional testing and establish a clear path to testing a multicomponent P. vivax vaccine.