A Phase 3, Double-Blind, Randomized, Active Controlled Study to Evaluate the Safety of MenAfriVac in Healthy Malians

Background. A safe, affordable, and highly immunogenic meningococcal A conjugate vaccine (PsA-TT, MenAfriVac) was developed to control epidemic group A meningitis in Africa. Documentation of the safety specifications of the PsA-TT vaccine was warranted, with sufficient exposure to detect potential rare vaccine-related adverse reactions. Methods. This phase 3, double-blind, randomized, active controlled clinical study was designed to evaluate the safety—primarily vaccine-related serious adverse events (SAEs)—up to 3 months after administration of a single dose of the PsA-TT vaccine to subjects aged 1-29 years in Mali. Safety outcomes were also compared to those following a single dose of a licensed meningococcal ACWY polysaccharide vaccine (PsACWY). Results. No vaccine-related SAEs occurred during the 3 months of follow-up of 4004 subjects vaccinated with a single dose of PsA-TT. When compared to PsACWY (1996 subjects), tenderness at the injection site appeared to be more frequent in the PsA-TT group. However, rates of local induration, systemic reactions, adverse events (AEs), and SAEs were similar in both groups, and unsolicited AEs and SAEs were all unrelated to the study vaccines. Conclusions. The study confirmed on a large scale the excellent safety profile of a single dose of PsA-TT when administered to its entire target population of 1-29 years of age. Clinical Trials Registration. PACTR ATMR20100300019131

Antibody Persistence 1-5 Years Following Vaccination With MenAfriVac in African Children Vaccinated at 12-23 Months of Age.

BACKGROUND: Following mass vaccination campaigns in the African meningitis belt with group A meningococcal conjugate vaccine, MenAfriVac (PsA-TT), disease due to group A meningococci has nearly disappeared. Antibody persistence in healthy African toddlers was investigated. METHODS: African children vaccinated at 12-23 months of age with PsA-TT were followed for evaluation of antibody persistence up to 5 years after primary vaccination. Antibody persistence was evaluated by measuring group A serum bactericidal antibody (SBA) with rabbit complement and by a group A-specific IgG enzyme-linked immunosorbent assay (ELISA). RESULTS: Group A antibodies measured by SBA and ELISA were shown to decline in the year following vaccination and plateaued at levels significantly above baseline for up to 5 years following primary vaccination. CONCLUSIONS: A single dose of PsA-TT induces long-term sustained levels of group A meningococcal antibodies for up to 5 years after vaccination. CLINICAL TRIALS REGISTRATION: ISRTCN78147026

Correction: Phase I Clinical Trial of a Recombinant Blood Stage Vaccine Candidate for Plasmodium falciparum Malaria Based on MSP1 and EBA175.

[This corrects the article DOI: 10.1371/journal.pone.0117820.]

Volunteer Flow Chart (CONSORT diagram).

<p>Volunteer Flow Chart (CONSORT diagram).</p

Phase I Clinical Trial of a Recombinant Blood Stage Vaccine Candidate for <i>Plasmodium falciparum</i> Malaria Based on MSP1 and EBA175

<div><p>Background</p><p>A phase I randomised, controlled, single blind, dose escalation trial was conducted to evaluate safety and immunogenicity of JAIVAC-1, a recombinant blood stage vaccine candidate against <i>Plasmodium falciparum</i> malaria, composed of a physical mixture of two recombinant proteins, PfMSP-1₁₉, the 19 kD conserved, C-terminal region of PfMSP-1 and PfF2 the receptor-binding F2 domain of EBA175.</p><p>Method</p><p>Healthy malaria naïve Indian male subjects aged 18–45 years were recruited from the volunteer database of study site. Fifteen subjects in each cohort, randomised in a ratio of 2:1 and meeting the protocol specific eligibility criteria, were vaccinated either with three doses (10μg, 25μg and 50μg of each antigen) of JAIVAC-1 formulated with adjuvant Montanide ISA 720 or with standard dosage of Hepatitis B vaccine. Each subject received the assigned vaccine in the deltoid muscle of the upper arms on Day 0, Day 28 and Day 180.</p><p>Results</p><p>JAIVAC-1 was well tolerated and no serious adverse event was observed. All JAIVAC-1 subjects sero-converted for PfF2 but elicited poor immune response to PfMSP-1₁₉. Dose-response relationship was observed between vaccine dose of PfF2 and antibody response. The antibodies against PfF2 were predominantly of IgG1 and IgG3 isotype. Sera from JAIVAC-1 subjects reacted with late schizonts in a punctate pattern in immunofluorescence assays. Purified IgG from JAIVAC-1 sera displayed significant growth inhibitory activity against <i>Plasmodium falciparum</i> CAMP strain.</p><p>Conclusion</p><p>Antigen PfF2 should be retained as a component of a recombinant malaria vaccine but PfMSP-1₁₉ construct needs to be optimised to improve its immunogenicity.</p><p>Trial Registration</p><p>Clinical Trial Registry, India <a href="http://ctri.nic.in/Clinicaltrials/pmaindet2.php?trialid=1507&EncHid=&userName=malaria" target="_blank">CTRI/2010/091/000301</a></p></div

Baseline Demographics by Study Groups.

<p>Note</p><p>1)*Age (in years) is calculated from the DOB, as the difference between the date the Pre-screening ICF is signed and the DOB.</p><p>2) Percentages are based on Number of randomised subjects in each study group.</p><p>3) Between group comparison for quantitative variables is performed using ANOVA and qualitative variables is performed using Fisher’s Exact Test</p><p>Baseline Demographics by Study Groups.</p

Geometric Mean Titre (GMT) at 95% Cl PfMSP-1₁₉-specific antibodies elicited after vaccination with 10μg, 25μg and 50μg JAIVAC-1 and Hepatitis B vaccine.

<p>^aLower Limit of Quantitation determined during method validation of ELISA was 10IU (International Unit). Antibody titre ≥10 IU against PfMSP1₁₉ or PfF2 were considered in actual for analysis purpose while values < 10IU were reported as 10 during calculations involving logs.</p><p>Geometric Mean Titre (GMT) at 95% Cl PfMSP-1₁₉-specific antibodies elicited after vaccination with 10μg, 25μg and 50μg JAIVAC-1 and Hepatitis B vaccine.</p

Antibodies to PfF2 and PfMSP-1₁₉ after vaccination with JAIVAC-1.

<p>Anti-PfF2 (A) and PfMSP-1₁₉ (B) antibody levels measured by ELISA. Geometric mean antibody levels (AU) to recombinant PfF2 and PfMSP-1₁₉ measured by ELISA in sera collected from Day 0 to Day 365 in 10μg, 25μg, and 50μg JAIVAC-1/Montanide ISA720 and Hepatitis B vaccine recipients. Study participants were immunized on Days 0, 28 and 180 and sera were collected on Days 0, 28, 56, 180, 208 and 365. Antibody levels measured by ELISA were expressed as Geometric Mean Titres (GMT) for the 10 subjects. Anti-PfF2 specific IgG subclass profiles in the sera of individuals vaccinated with 25μg (C) and 50μg (D) JAIVAC-1 as measured by ELISA are shown.</p