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Sporozoite immunization of human volunteers under mefloquine prophylaxis is safe, immunogenic and protective: a double-blind randomized controlled clinical trial.

Bijker EM, Schats R, Obiero JM, Behet MC, van Gemert GJ, van de Vegte-Bolmer M, Graumans W, van Lieshout L, Bastiaens GJ, Teelen K, Hermsen CC, Scholzen A, Visser LG, Sauerwein RW - PLoS ONE (2014)

Bottom Line: Here, we studied whether chloroquine can be replaced by mefloquine, which is the only other licensed anti-malarial chemoprophylactic drug that does not affect pre-erythrocytic stages, exposure to which is considered essential for induction of protection by CPS immunization.CPS-MQ immunization is safe and equally potent compared to CPS-CQ inducing protection in 7/10 (70%) versus 3/5 (60%) volunteers, respectively.We therefore conclude that mefloquine and chloroquine are equally effective in CPS-induced immune responses and protection.

View Article: PubMed Central - PubMed

Affiliation: Radboud university medical center, Department of Medical Microbiology, PO Box 9101, 6500 HB Nijmegen, The Netherlands.

ABSTRACT
Immunization of healthy volunteers with chloroquine ChemoProphylaxis and Sporozoites (CPS-CQ) efficiently and reproducibly induces dose-dependent and long-lasting protection against homologous Plasmodium falciparum challenge. Here, we studied whether chloroquine can be replaced by mefloquine, which is the only other licensed anti-malarial chemoprophylactic drug that does not affect pre-erythrocytic stages, exposure to which is considered essential for induction of protection by CPS immunization. In a double blind randomized controlled clinical trial, volunteers under either chloroquine prophylaxis (CPS-CQ, n = 5) or mefloquine prophylaxis (CPS-MQ, n = 10) received three sub-optimal CPS immunizations by bites from eight P. falciparum infected mosquitoes each, at monthly intervals. Four control volunteers received mefloquine prophylaxis and bites from uninfected mosquitoes. CPS-MQ immunization is safe and equally potent compared to CPS-CQ inducing protection in 7/10 (70%) versus 3/5 (60%) volunteers, respectively. Furthermore, specific antibody levels and cellular immune memory responses were comparable between both groups. We therefore conclude that mefloquine and chloroquine are equally effective in CPS-induced immune responses and protection. Trial registration: ClinicalTrials.gov NCT01422954.

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Antibody responses induced by CPS-CQ and CPS-MQ immunization.Antibodies against CSP (A and B; in AU), LSA-1 (C and D), and MSP-1 (E and F) were analyzed at baseline (B), 28 days after the first (I1) and second (I2) immunization and one day before challenge (C-1; 20 weeks after the last immunization) for all CPS-CQ (A, C and E, n = 5) and CPS-MQ (B, D and F, n = 10) immunized volunteers. Data are shown as individual titers with medians. Open squares indicate protected subjects, filled circles indicate unprotected subjects. Differences between the time points were analyzed by Friedman test with Dunn’s multiple comparison post-hoc test. Significant differences are indicated by asterices with * (p<0.05), ** (p<0.01), *** (p<0.001).
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pone-0112910-g005: Antibody responses induced by CPS-CQ and CPS-MQ immunization.Antibodies against CSP (A and B; in AU), LSA-1 (C and D), and MSP-1 (E and F) were analyzed at baseline (B), 28 days after the first (I1) and second (I2) immunization and one day before challenge (C-1; 20 weeks after the last immunization) for all CPS-CQ (A, C and E, n = 5) and CPS-MQ (B, D and F, n = 10) immunized volunteers. Data are shown as individual titers with medians. Open squares indicate protected subjects, filled circles indicate unprotected subjects. Differences between the time points were analyzed by Friedman test with Dunn’s multiple comparison post-hoc test. Significant differences are indicated by asterices with * (p<0.05), ** (p<0.01), *** (p<0.001).

Mentions: Antibodies against the pre-erythrocytic antigens CSP and LSA-1 and the cross-stage antigen MSP-1 were assessed by ELISA. Antibodies against CSP were induced in both CPS-CQ and CPS-MQ immunized volunteers (p<0.05 and p<0.01 respectively, on C-1; Figure 5A and 5B), but not significantly higher in protected compared to unprotected subjects (p = 0.88 and p = 0.48 respectively). Antibodies against LSA-1 were only significantly induced in CPS-MQ immunized volunteers on I2 (p<0.001; Figure 5C and 5D), although not higher in protected subjects (p = 0.39). Anti-MSP-1 antibodies by CPS immunization were not statistically significant increased in either group (Figure 5E and 5F).


Sporozoite immunization of human volunteers under mefloquine prophylaxis is safe, immunogenic and protective: a double-blind randomized controlled clinical trial.

Bijker EM, Schats R, Obiero JM, Behet MC, van Gemert GJ, van de Vegte-Bolmer M, Graumans W, van Lieshout L, Bastiaens GJ, Teelen K, Hermsen CC, Scholzen A, Visser LG, Sauerwein RW - PLoS ONE (2014)

Antibody responses induced by CPS-CQ and CPS-MQ immunization.Antibodies against CSP (A and B; in AU), LSA-1 (C and D), and MSP-1 (E and F) were analyzed at baseline (B), 28 days after the first (I1) and second (I2) immunization and one day before challenge (C-1; 20 weeks after the last immunization) for all CPS-CQ (A, C and E, n = 5) and CPS-MQ (B, D and F, n = 10) immunized volunteers. Data are shown as individual titers with medians. Open squares indicate protected subjects, filled circles indicate unprotected subjects. Differences between the time points were analyzed by Friedman test with Dunn’s multiple comparison post-hoc test. Significant differences are indicated by asterices with * (p<0.05), ** (p<0.01), *** (p<0.001).
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4232459&req=5

pone-0112910-g005: Antibody responses induced by CPS-CQ and CPS-MQ immunization.Antibodies against CSP (A and B; in AU), LSA-1 (C and D), and MSP-1 (E and F) were analyzed at baseline (B), 28 days after the first (I1) and second (I2) immunization and one day before challenge (C-1; 20 weeks after the last immunization) for all CPS-CQ (A, C and E, n = 5) and CPS-MQ (B, D and F, n = 10) immunized volunteers. Data are shown as individual titers with medians. Open squares indicate protected subjects, filled circles indicate unprotected subjects. Differences between the time points were analyzed by Friedman test with Dunn’s multiple comparison post-hoc test. Significant differences are indicated by asterices with * (p<0.05), ** (p<0.01), *** (p<0.001).
Mentions: Antibodies against the pre-erythrocytic antigens CSP and LSA-1 and the cross-stage antigen MSP-1 were assessed by ELISA. Antibodies against CSP were induced in both CPS-CQ and CPS-MQ immunized volunteers (p<0.05 and p<0.01 respectively, on C-1; Figure 5A and 5B), but not significantly higher in protected compared to unprotected subjects (p = 0.88 and p = 0.48 respectively). Antibodies against LSA-1 were only significantly induced in CPS-MQ immunized volunteers on I2 (p<0.001; Figure 5C and 5D), although not higher in protected subjects (p = 0.39). Anti-MSP-1 antibodies by CPS immunization were not statistically significant increased in either group (Figure 5E and 5F).

Bottom Line: Here, we studied whether chloroquine can be replaced by mefloquine, which is the only other licensed anti-malarial chemoprophylactic drug that does not affect pre-erythrocytic stages, exposure to which is considered essential for induction of protection by CPS immunization.CPS-MQ immunization is safe and equally potent compared to CPS-CQ inducing protection in 7/10 (70%) versus 3/5 (60%) volunteers, respectively.We therefore conclude that mefloquine and chloroquine are equally effective in CPS-induced immune responses and protection.

View Article: PubMed Central - PubMed

Affiliation: Radboud university medical center, Department of Medical Microbiology, PO Box 9101, 6500 HB Nijmegen, The Netherlands.

ABSTRACT
Immunization of healthy volunteers with chloroquine ChemoProphylaxis and Sporozoites (CPS-CQ) efficiently and reproducibly induces dose-dependent and long-lasting protection against homologous Plasmodium falciparum challenge. Here, we studied whether chloroquine can be replaced by mefloquine, which is the only other licensed anti-malarial chemoprophylactic drug that does not affect pre-erythrocytic stages, exposure to which is considered essential for induction of protection by CPS immunization. In a double blind randomized controlled clinical trial, volunteers under either chloroquine prophylaxis (CPS-CQ, n = 5) or mefloquine prophylaxis (CPS-MQ, n = 10) received three sub-optimal CPS immunizations by bites from eight P. falciparum infected mosquitoes each, at monthly intervals. Four control volunteers received mefloquine prophylaxis and bites from uninfected mosquitoes. CPS-MQ immunization is safe and equally potent compared to CPS-CQ inducing protection in 7/10 (70%) versus 3/5 (60%) volunteers, respectively. Furthermore, specific antibody levels and cellular immune memory responses were comparable between both groups. We therefore conclude that mefloquine and chloroquine are equally effective in CPS-induced immune responses and protection. Trial registration: ClinicalTrials.gov NCT01422954.

Show MeSH
Related in: MedlinePlus