The major challenge facing TBV development is to find a highly safe formulation that induces sustained high antibody responses. LMIV has demonstrated that conjugating Pfs25 and Pfs230 with carrier protein ExoProtein A (EPA) of Pseudomonas aeruginosa greatly enhances the immunogenicity of the recombinant TBVs and has shown to be safe with the adjuvant Alhydrogel, but may need a stronger adjuvant such as AS01 to achieve the antibody responses needed to block transmission. Pfs25H-EPA/Alhydrogel in Healthy US Adults (NIAID protocol 11-I-N237) A phase 1 dose escalation study of Pfs25H-EPA/Alhydrogel was conducted in 30 US malaria-nave adults at the CIR/JHU in 2011 to 2013 to evaluate safety and immunogenicity. Vaccinations were well-tolerated, with minimal local and systemic reactogenicity and AEs. Specific anti-Pfs25 antibodies were detected by ELISA in sera from subjects receiving 2 or 3 doses, and the titers increased further after the booster dose. The immunized antisera displayed various levels of transmission reducing activities, which correlated with antibody titers. Following the 4th dose, a 9/11 of subjects developed functional antibodies with significant transmission reduction activity above 50% and up to 95%. Manuscript summarizing the clinical trial results was published in PLoSONE in 2016. Pfs25H-EPA/Alhydrogel in Healthy Malian Adults (NIAID protocol 13-I-N109) A double-blind dose-escalating randomized controlled phase 1 study in malaria exposed adults of the safety and immunogenicity of Pfs25H-EPA/Alhydrogel was conducted in Bancoumana, Mali. 120 were enrolled and randomized to receive the low dose, the high dose, or the comparator vaccine. Overall, vaccinations were safe and well tolerated in both the Pfs25H and comparator group, with the majority of AEs being Grade 1 or 2. Following each vaccination (0, 2, 4, 16 months), anti-Pfs25 IgG increased with each dose and all but 1 subject responded after receipt of the final dose. Anti-Pfs25 titers correlated with anti-EPA but decayed more rapidly than did anti-EPA after 4th dose. Significant functional activity was not seen after the third dose but was observed after the fourth dose. In general, anti-Pfs25 titers correlated with functional activity, which was assessed to be contained in the IgG fraction directed against Pfs25. The study was completed in Mar 2015 and has been closed with the IRB/EC in Dec 2016; publication is in draft, with planned submission in 2017 to Lancet Inf Dis. Pfs230D1M-EPA/Alhydrogel and Pfs25M-EPA/Alhydrogel in Healthy US and Malian Adults (NIAID protocol 15-I-0044) The phase 1 study of the safety, tolerability, immunogenicity, and functional activity of Pfs230D1M-EPA/Alhydrogel (Pfs230) and Pfs25M-EPA/Alhydrogel (Pfs25M) in adults started in the US (n=35) in Dec 2014 and in Mali (n=225) in Apr 2015. The US portion of the study was to evaluate safety and tolerability with only 2 vaccinations at 0, 1 month of increasing doses of Pfs25M and Pfs230 given alone or in combination prior to moving to Mali for further safety, immunogenicity, and functional activity evaluation during which time those in the functional activity cohort received 4 doses at 0, 1, 6 months and a booster at 18 months during the subsequent malaria season. For the US portion of study, in malaria nave adults, Pfs25M-EPA/Alhydrogel and Pfs230D1M-EPA/Alhydrogel given alone or in combination was safe and tolerable. Detectable responses in all vaccinated subjects to Pfs25, 47g and/or Pfs230, 40g can be seen following receipt of 2 doses at the targeted dose. Appreciable functional activity, though in a limited number of individuals, is achievable following 2 doses of Pfs230D1M or Pfs230D1M and Pfs25M at the highest vaccine dose. The phase 1 study of the safety and immunogenicity of Pfs230D1M and Pfs25M started in Apr 2015 in Mali. Cohort 1, which included the single antigen safety Arms A1 (Pfs25M), B1 (Pfs230D1M), and D1 (Twinrix), and Cohort 2, which included the co-administration safety Arm C1 (Pfs25M + Pfs230D1M) and D2 (Twinrix + saline) have completed enrollment, all follow-up visits, and completed scheduled unblinding in Oct 2015. From the unblinded safety data, overall vaccinations have been well tolerated with all reported AEs being either Grade 1 or 2 and with the majority of AEs reported being unsolicited AEs. The majority of vaccinated subjects developed responses to Pfs25 or Pfs230 following 2 doses of vaccine. Similar to what had been seen before with Pfs25H, antibody responses to Pfs25 decayed rapidly post dose #2. Antibody responses to Pfs230 appeared to persist longer. Cohort 3, which includes an increased sample size for immunogenicity and functional activity assessment, included Arms A2 (Pfs25M), B2 (Pfs230D1M), C2 (Pfs25M + Pfs230D1M) and D3 (Twinrix + saline) have completed enrollment, 4 of the 4 scheduled vaccinations, undergone 6 weeks of intensive DSF assessment, completed follow-up, and scheduled unblinding in Apr 2017. Preliminary safety analysis (final analysis pending database lock) completed thus far for Cohort 3 has not identified any specific safety concerns. Two planned interim analyses (Jun 2016, Feb 2017) of immunogenicity (ELISA) and functional activity (DSF, SMFA) by Arm were completed after dose #3 and #4 in the larger Main Cohort (Cohort 3) during the study to inform about proceeding to a booster 4th dose in 2016 and to inform the study design for protocol 17-I-N006 (TBV with AS01). In conclusion, by ELISA and SMFA, Pfs230 induced superior activity to Pfs25, and Pfs230 in combination with Pfs25, was not superior to Pfs230 alone. The study was completed in Apr 2017, but remains open at this time awaiting a final blood draw from a high Pfs230 antibody responder in Mali and receipt of the last comparator vaccinations offered to TBV vaccinated subjects. Publications of both the US safety study and Mali study are in draft with planned submission in 2017. Pfs230D1M-EPA/AS01 and Pfs25M-EPA/AS01 in Healthy Malian Adults (NIAID protocol 17-I-N006) The phase 1 study of the safety, tolerability, immunogenicity, and functional activity of Pfs25M-EPA/AS01 (Pfs25M) and Pfs230D1M-EPA/AS01 (Pfs230) started recruitment for the Pilot Safety Phase dose-escalation in Sotuba in Dec 2016. All 3 vaccinations (0, 1, and 6 months) for all Arms enrolled in the Safety Pilot Phase of the study have been completed. Recruitment for the randomized double-blind portion of the study (Main Phase) started in Feb 2017, with pre-emptive treatment with AL, en bloc randomization with stratification by village, and 2 of 3 vaccinations being completed in the 0, 1, 6-month vaccination schedule to date. The third and final vaccination is to be completed in Aug/Sept 2017 and beginning in Sep 2017 subjects in the Main Phase will undergo 12 weeks of DSF for a total of 24 mosquito feeds.
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