The major challenge facing Pfs25-based TBV development is to find a highly safe formulation that induces sustained high antibody responses. LMIV has demonstrated that conjugating Pfs25 with carrier protein ExoProtein A (EPA) of Pseudomonas aeruginosa greatly enhances the immunogenicity of the recombinant Pfs25. A Phase 1 trial conducted in US (2011 to 2013) and in Mali (2013 to 2015) using Pfs25H-EPA/Alhydrogel demonstrated that the vaccine was safe, immunogenic, and could induce transmission reducing activity. However, the antibodies induced are short-lived, and hence improvements to the vaccine are required to achieve the activity thought to be needed for malaria elimination campaigns. Pfs25H-EPA/Alhydrogel in Healthy US Adults (NIAID protocol 11-I-N237; Clinicaltrials.gov number NCT01434381) A phase 1 dose escalation study of Pfs25H-EPA/Alhydrogel was conducted in 30 malaria-nave adults at the CIR at the Johns Hopkins School of Public Health in Baltimore, MD, USA in 2011 to 2013 to evaluate safety and immunogenicity. Generally, vaccinations were well-tolerated, with minimal local and systemic reactogenicity and adverse events. 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 fourth dose, a 9 out of 11 of subjects developed functional antibodies with significant transmission reduction activity above 50% and up to 95%. Final manuscript was prepared this year and submitted to PLoSONE for review/publication. An additional publication regarding assessing direct skin feeds as a TBV endpoint as well was submitted to Vaccine for review. Pfs25H-EPA/Alhydrogel in Healthy Malian Adults (NIAID protocol 13-I-N109; Clinicaltrials.gov number NCT01867463) 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. One hundred twenty subjects 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-EPA/Alhydrogel and comparator group, with the majority of AEs being mild or moderate. 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 fourth and 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 March 2015; publication is in draft, with planned submission in 2016 to Clinical Infectious Diseases. We believe testing the combination of Pfs25- and Pfs230-based vaccines may improve overall transmission-blocking efficacy.Pfs230 is expressed early and Pfs25 is expressed late in sexual development of the parasite, which may allow dual actions. Also, the combination may decrease the proportion of poor responders compared to vaccination with a single agent. Increased transmission-blocking activity was observed when antibodies raised separately against recombinant Pfs25M and Pfs230D1M were mixed and fed together with a parasite culture to mosquitoes. In NHPs, antibodies induced by co-administration of Pfs25M-EPA and Pfs230D1M-EPA also displayed stronger transmission-blocking activities than those induced by the individual vaccine candidates. Pfs230D1M-EPA/Alhydrogel and Pfs25M-EPA/Alhydrogel in Healthy Malian Adults (NIAID protocol 15-I-0044; Clinicaltrials.gov number NCT02334462) The phase 1 study of the safety and immunogenicity of Pfs230D1M-EPA/Alhydrogel and Pfs25M-EPA/Alhydrogel in adults in the US (NIH Clinical Center) and Mali (Bancoumana, Mali) started in December 2014 in the US. Study enrollment for the US portion of the study (N=35) was to evaluate safety and tolerability of increasing doses and Pfs25M and Pfs230D1M given alone or in combination prior to moving into Mali, West Africa for further safety, immunogenicity, and functional activity evaluation. For the US portion of study, in malaria nave adults, Pfs25M-EPA/Alhydrogel and Pfs230D1M-EPA/Alhydrogel given alone or in combination is safe and tolerable. Detectable responses in all vaccinated subjects to Pfs25, 47g and/or Pfs230, 40g can be seen following receipt of two vaccinations at the targeted dose. Appreciable functional activity, though in a limited number of individuals, is achievable following two doses of Pfs230D1M-EPA/Alhydrogel or Pfs230D1M-EPA/Alhydrogel and Pfs25M-EPA/Alhydrogel at the highest vaccine dose administered. The phase 1 study of the safety and immunogenicity of Pfs230D1M-EPA/Alhydrogel and Pfs25M-EPA/Alhydrogel started in April 2015 in Mali and has completed enrollment. 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 + normal saline) have completed enrollment and undergone scheduled unblinding in October 2015. From the unblinded safety data, overall vaccinations have been well tolerated with all of the reported being either mild or moderate and with the majority of AEs reported being unsolicited AEs. Cohort 3, which includes increased sample size for immunogenicity and functional activity assessment, included Arms A2 (Pfs25M), B2 (Pfs230D1M), C2 (Pfs25M + Pfs230D1M) and D3 (Twinrix + normal saline) have completed enrollment, 3 of the 4 scheduled vaccinations, and undergone 6 weeks of intensive DSF assessment. Subjects in cohort 3 who are currently active on protocol (171 of 200) are in long term safety follow-up and will receive Vaccination #4 in September 2016, undergo evaluation via DSF following receipt of Vaccination #4, and be unblinded in March/April 2017. Safety analysis completed thus far for the high dose of Pfs25M-EPA/Alhydrogel, 47g of Pfs25M and high dose of Pfs230D1M-EPA/Alhydrogel, 40g of Pfs230D1M, is still blinded. Pfs230D1M-EPA/AS01 and Pfs25M-EPA/AS01 in Healthy Malian Adults (NIAID protocol 16-XX-XXXX; Clinicaltrials.gov number Pending) LMIV is interested in additional vaccine strategies, including alterations in conjugation and by changing the adjuvant from Alhydrogel to a safe, but more potent AS01. Though AS01 adjuvants are not yet in licensed vaccines, one of the immunostimulant components, monophosphoryl lipid (MPL), is a component of a licensed GSK human papillomavirus vaccine, and the AS01 adjuvant system has been a key component of the Mosquirix and RTS,S/AS01B that has been widely tested in children and adults across Africa. Utilizing GSKs adjuvant AS01 with LMIVs leading TBV candidates, this proposed study attempts to explore Pfs25M-EPA/AS01 and Pfs230D1M-EPA/AS01 at full and fractional dosing. The preclinical and toxicology studies were completed in 2015-2016, with the protocol and FDA IND submission prepared and submitted in 2016. The study is planned to start in December 2016 in Mali, West Africa.
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