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Safety and reactogenicity of an MSP-1 malaria vaccine candidate: a randomized phase Ib dose-escalation trial in Kenyan children.

Withers MR, McKinney D, Ogutu BR, Waitumbi JN, Milman JB, Apollo OJ, Allen OG, Tucker K, Soisson LA, Diggs C, Leach A, Wittes J, Dubovsky F, Stewart VA, Remich SA, Cohen J, Ballou WR, Holland CA, Lyon JA, Angov E, Stoute JA, Martin SK, Heppner DG, MSP-1 Malaria Vaccine Working Gro - PLoS Clin Trials (2006)

Bottom Line: Both vaccines were safe and well tolerated.FMP1/AS02A recipients experienced significantly more pain and injection-site swelling with a dose-effect relationship.The FMP1/AS02A vaccine was safe and immunogenic in malaria-exposed 12- to 47-mo-old children and the magnitude of immune response of the 25 and 50 microg doses was superior to that of the 10 microg dose.

View Article: PubMed Central - PubMed

Affiliation: United States Army Medical Research Unit-Kenya, Nairobi, Kenya. mwithers@us.army.mil

ABSTRACT

Objective: Our aim was to evaluate the safety, reactogenicity, and immunogenicity of an investigational malaria vaccine.

Design: This was an age-stratified phase Ib, double-blind, randomized, controlled, dose-escalation trial. Children were recruited into one of three cohorts (dosage groups) and randomized in 2:1 fashion to receive either the test product or a comparator.

Setting: The study was conducted in a rural population in Kombewa Division, western Kenya.

Participants: Subjects were 135 children, aged 12-47 mo.

Interventions: Subjects received 10, 25, or 50 microg of falciparum malaria protein 1 (FMP1) formulated in 100, 250, and 500 microL, respectively, of AS02A, or they received a comparator (Imovax (rabies vaccine).

Outcome measures: We performed safety and reactogenicity parameters and assessment of adverse events during solicited (7 d) and unsolicited (30 d) periods after each vaccination. Serious adverse events were monitored for 6 mo after the last vaccination.

Results: Both vaccines were safe and well tolerated. FMP1/AS02A recipients experienced significantly more pain and injection-site swelling with a dose-effect relationship. Systemic reactogenicity was low at all dose levels. Hemoglobin levels remained stable and similar across arms. Baseline geometric mean titers were comparable in all groups. Anti-FMP1 antibody titers increased in a dose-dependent manner in subjects receiving FMP1/AS02A; no increase in anti-FMP1 titers occurred in subjects who received the comparator. By study end, subjects who received either 25 or 50 microg of FMP1 had similar antibody levels, which remained significantly higher than that of those who received the comparator or 10 microg of FMP1. A longitudinal mixed effects model showed a statistically significant effect of dosage level on immune response (F(3,1047) = 10.78, or F(3, 995) = 11.22, p < 0.001); however, the comparison of 25 microg and 50 microg recipients indicated no significant difference (F(1,1047) = 0.05; p = 0.82).

Conclusions: The FMP1/AS02A vaccine was safe and immunogenic in malaria-exposed 12- to 47-mo-old children and the magnitude of immune response of the 25 and 50 microg doses was superior to that of the 10 microg dose.

No MeSH data available.


Related in: MedlinePlus

Anti-FMP1 GMTs over Time, by Vaccine GroupArrows indicate vaccination time points.
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pctr-0010032-g002: Anti-FMP1 GMTs over Time, by Vaccine GroupArrows indicate vaccination time points.

Mentions: As expected of a subject population that had been highly exposed to malaria prior to vaccination, no baseline anti-FMP1 titer fell below the limit of detection. Baseline GMTs were comparable across study arms and dosage cohorts, ranging from approximately 1,000 to 3,000 ODUs. The overall baseline GMT in thousands (across all study groups) was 2.3 (95% confidence interval [CI] of 1.7, 3.2). After three vaccinations, no increase in antibody response was observed in subjects who received the comparator; however, antibody response increased with increasing dosage level of FMP1/AS02A (Figure 2). GMT peaked 2 wk after the third immunization (study day 74), at which time the GMTs (in thousands) were 10 (95%CI, 6–17), 43 (95%CI, 29–65), and 58 (95%CI, 38–89) ODU in the 10-μg, 25-μg, and 50-μg groups, respectively. GMT in the comparator group was 1.5 with a 95%CI of 0.8–2.7. The study day 90 GMT (in thousands) for the 10-μg dosage cohort remained constant at 10 (95%CI, 6–18), but the study day 90 GMT for the 25- and 50-μg dosage cohorts dropped to 27 (95%CI, 18–41) and 40 (95%CI, 25–62), respectively. From study day 180, the antibody levels in the 25- and 50-μg dosage groups begin to diminish; however, by study day 364 they still maintained higher antibody levels than the subjects in the 10-μg dosage group and in the comparator group.


Safety and reactogenicity of an MSP-1 malaria vaccine candidate: a randomized phase Ib dose-escalation trial in Kenyan children.

Withers MR, McKinney D, Ogutu BR, Waitumbi JN, Milman JB, Apollo OJ, Allen OG, Tucker K, Soisson LA, Diggs C, Leach A, Wittes J, Dubovsky F, Stewart VA, Remich SA, Cohen J, Ballou WR, Holland CA, Lyon JA, Angov E, Stoute JA, Martin SK, Heppner DG, MSP-1 Malaria Vaccine Working Gro - PLoS Clin Trials (2006)

Anti-FMP1 GMTs over Time, by Vaccine GroupArrows indicate vaccination time points.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC1851726&req=5

pctr-0010032-g002: Anti-FMP1 GMTs over Time, by Vaccine GroupArrows indicate vaccination time points.
Mentions: As expected of a subject population that had been highly exposed to malaria prior to vaccination, no baseline anti-FMP1 titer fell below the limit of detection. Baseline GMTs were comparable across study arms and dosage cohorts, ranging from approximately 1,000 to 3,000 ODUs. The overall baseline GMT in thousands (across all study groups) was 2.3 (95% confidence interval [CI] of 1.7, 3.2). After three vaccinations, no increase in antibody response was observed in subjects who received the comparator; however, antibody response increased with increasing dosage level of FMP1/AS02A (Figure 2). GMT peaked 2 wk after the third immunization (study day 74), at which time the GMTs (in thousands) were 10 (95%CI, 6–17), 43 (95%CI, 29–65), and 58 (95%CI, 38–89) ODU in the 10-μg, 25-μg, and 50-μg groups, respectively. GMT in the comparator group was 1.5 with a 95%CI of 0.8–2.7. The study day 90 GMT (in thousands) for the 10-μg dosage cohort remained constant at 10 (95%CI, 6–18), but the study day 90 GMT for the 25- and 50-μg dosage cohorts dropped to 27 (95%CI, 18–41) and 40 (95%CI, 25–62), respectively. From study day 180, the antibody levels in the 25- and 50-μg dosage groups begin to diminish; however, by study day 364 they still maintained higher antibody levels than the subjects in the 10-μg dosage group and in the comparator group.

Bottom Line: Both vaccines were safe and well tolerated.FMP1/AS02A recipients experienced significantly more pain and injection-site swelling with a dose-effect relationship.The FMP1/AS02A vaccine was safe and immunogenic in malaria-exposed 12- to 47-mo-old children and the magnitude of immune response of the 25 and 50 microg doses was superior to that of the 10 microg dose.

View Article: PubMed Central - PubMed

Affiliation: United States Army Medical Research Unit-Kenya, Nairobi, Kenya. mwithers@us.army.mil

ABSTRACT

Objective: Our aim was to evaluate the safety, reactogenicity, and immunogenicity of an investigational malaria vaccine.

Design: This was an age-stratified phase Ib, double-blind, randomized, controlled, dose-escalation trial. Children were recruited into one of three cohorts (dosage groups) and randomized in 2:1 fashion to receive either the test product or a comparator.

Setting: The study was conducted in a rural population in Kombewa Division, western Kenya.

Participants: Subjects were 135 children, aged 12-47 mo.

Interventions: Subjects received 10, 25, or 50 microg of falciparum malaria protein 1 (FMP1) formulated in 100, 250, and 500 microL, respectively, of AS02A, or they received a comparator (Imovax (rabies vaccine).

Outcome measures: We performed safety and reactogenicity parameters and assessment of adverse events during solicited (7 d) and unsolicited (30 d) periods after each vaccination. Serious adverse events were monitored for 6 mo after the last vaccination.

Results: Both vaccines were safe and well tolerated. FMP1/AS02A recipients experienced significantly more pain and injection-site swelling with a dose-effect relationship. Systemic reactogenicity was low at all dose levels. Hemoglobin levels remained stable and similar across arms. Baseline geometric mean titers were comparable in all groups. Anti-FMP1 antibody titers increased in a dose-dependent manner in subjects receiving FMP1/AS02A; no increase in anti-FMP1 titers occurred in subjects who received the comparator. By study end, subjects who received either 25 or 50 microg of FMP1 had similar antibody levels, which remained significantly higher than that of those who received the comparator or 10 microg of FMP1. A longitudinal mixed effects model showed a statistically significant effect of dosage level on immune response (F(3,1047) = 10.78, or F(3, 995) = 11.22, p < 0.001); however, the comparison of 25 microg and 50 microg recipients indicated no significant difference (F(1,1047) = 0.05; p = 0.82).

Conclusions: The FMP1/AS02A vaccine was safe and immunogenic in malaria-exposed 12- to 47-mo-old children and the magnitude of immune response of the 25 and 50 microg doses was superior to that of the 10 microg dose.

No MeSH data available.


Related in: MedlinePlus