Mymetics Corp (MYMX)

[Work Harder]

U19AI142636 2022

Description

Abstract Text

The overall objective of administrative Core A is to provide this multi-PI, multi-institutional U19 IPCAVD Project the opportunity to interact synergistically by facilitating the communication among the Project Leaders and all participating scientists. Core A will also serve as liaison between Research Administration at the contact institution, the Texas Biomedical Research Institute (TxBiomed), all the affiliated institutions both in the US and in Europe, and NIAD representatives. The network of partnering scientists includes researchers in Texas, Louisiana, Georgia and several countries in Europe; the major partner is Mymetics in Switzerland. The innovative biotech company has developed gp41-based virosomes into to a novel vaccine platform that is cold-chain independent and can be administered mucosally without needles. The Specific Aims of Core A are to: 1. Provide administrative support and facilitate the collaboration among Projects 1 and 2 and the various subcontract/subaward leaders and partners. This will include the exchange of information, reagents, and material transfer agreements. 2. Set priorities, monitor progress and jointly make go/no-go decisions. This will be achieved with input from the External Scientific Advisory Board (ESAB) and the NIAID IPCAVD Program Officer. 3. Assist in the design of experiments in rhesus macaques (RMs), protocol design and submission, and exchange of samples between the New Iberia Research Center (NIRC), where the primate studies will be conducted, and TxBiomed. 4. Provide statistical support for all IPCAVD scientists through the participation of Dr. Sarah Ratcliffe through a subaward with the University of Virginia (UVA). 5. Provide financial oversight and assure prompt payment of bills as well as the timely achievement of the experimental goals within budget limits. 6. Organize the yearly NIH Site Visit and the External Scientific Advisory Board (ESAB) meeting in the Washington, D.C. area, as well as individual visits between Drs. Ruprecht, Villinger, Santangelo and Fleury. 7. Address intellectual property (IP) issues fairly, timely, and equitably. 8. Facilitate the submission of reports, dissemination of data at meetings, and publication of manuscripts. To meet the goals of this translational, highly interactive U19 Research Program, the Core A Leader/Contact PI depends on the trained professionals with excellent organization skills as well as basic understanding of science and medicine to make this U19 network of scientists successful.

Abstract Text

Project 2 seeks to test virosomal vaccine immunogenicity and efficacy in the rhesus macaque (RM)/SHIV model. Mymetics has improved virosomal vaccines built from empty influenza virus-like particles that display an elongated HIV gp41 peptide on their surface (virosome-P1) or recombinant truncated HIV gp41 (virosome- rgp41). Earlier, Chinese RMs given two intramuscular (IM) primes followed by two intranasal (IN) boosts were 100% protected from persistent systemic infection and did not seroconvert to SIV Gag after low-dose intravaginal SHIV challenges. A follow-up study in Indian RMs showed 78% to 87% protection as long as the SHIV dose was ~7x104 times the median HIV inoculum in human male-to-female HIV transmission, but when the SHIV inoculum was ~105x greater, protection was lost. In these NHP studies, unadjuvanted, liquid formulations of the combination of virosome-P1 + virosome-rgp41 were used. To improve immunogenicity, Mymetics embedded the toll-like receptor (TLR)7/8 adjuvant 3M-052 directly into virosome membranes and developed solid, cold-chain independent vaccine formulations that can be administered needle-free. The powdered virosome forms can be given as IN spray, sublingual (SL) tablets, or packaged into oral capsules (PO). Our overall hypothesis is that the cold-chain independent, needle-free adjuvanted solid virosome forms are significantly more immunogenic than their earlier liquid form in RMs and will induce higher mucosal fluid Ab levels after mucosal priming/mucosal boosting via different routes. Mymetics has performed pilot tests in small animals with the IN and SL forms; vaccine delivery via oral capsules needs to be optimized in RMs. The Specific Aims for Project 2 are to: 1. Optimize vaccine delivery to the ileum via enteric-coated capsules; a) monitor passage of capsules containing 99mTc or 64Cu by scans; b) attach fluorescent labels to the virosomal vaccines for detection in the near-infrared spectrum. Tissues collected at necropsy will be tested by fluorescent microscopy. 2. Test the immunogenicity of different routes of the novel adjuvanted virosomes through a prime/boost approach. We will test their relative immunogenicity via IN, SL and PO routes; boosts will be given via a different mucosal route, a novel approach. Controls will be immunized IM with the soluble virosomal vaccine. 3. Test the efficacy of the cold-chain independent, needle-free, adjuvanted virosomal vaccines against repeated low-dose intrarectal (IR) clade B SHIV (SHIV-B) challenges. The most immunogenic mucosal prime/mucosal boost regimen (see Aim 2) will be used to immunize a group of 12 RMs; control (n=12) will receive empty virosomes. All RMs will undergo ~10 weekly low-dose IR challenges with the tier 2, R5 clade B SHIVSF162P3. 4. Test whether RMs that resisted multiple SHIV-B challenges will be protected against cross-clade challenge with the tier 2 R5 clade C SHIV. Protected RMs will be used to determine correlates of protection. These innovations are highly significant for the developing world, where our novel vaccine will be a major plus to combat the AIDS epidemic.

ABSTRACT – PROJECT 1

The induction of frontline defenses in genital and rectal tissues to prevent sexual HIV transmission is challenging, particularly with standard liquid subunit vaccines generally given intramuscularly. This multi-PI application is a collaboration between Mymetics (Dr. Sylvain Fleury, Project 1 Lead) and the Texas Biomedical Research Institute (Dr. Ruth Ruprecht, Project 2 Lead) that seeks to bring a promising mucosal HIV/AIDS vaccine approach into clinical development. Mymetics had inserted HIV gp41 antigens into the membranes of influenza virosomes, which have an excellent safety record in humans. These earlier, unadjuvanted liquid virosomal HIV gp41 vaccines were >80% efficacious in two independent nonhuman primate (NHP) studies. One of the gp41 vaccines, termed virosome-P1, was also safe and immunogenic in a Phase I trial in healthy women. To improve mucosal immunogenicity in the genital and intestinal tracts, Mymetics has adjuvanted the HIV vaccine formulation with the 3M-052 adjuvant that activates the toll-like receptor (TLR) 7/8; the 3M-052 adjuvant was active in infants, children, teenagers and adults. New, promising “all-in-one” HIV gp41 vaccines were specifically developed for various mucosal administration sites, with the aim to induce more efficient mucosal tissue coverage. A key innovation is the development of needle-free, solid-dosage vaccine formulations that are thermostable: nasal powder spray, sublingual tablets, or oral enteric-coated capsules filled with vaccine powder. All of these new vaccine formulations can withstand high/low temperatures outside the recommended cold-chain conditions without compromising product bioactivity. These novel, solid-form vaccines contain no free-form adjuvant; the HIV gp41-derived antigens as well as the 3M-052 adjuvant are physically bound to surface of the same particle. This prevents systemic adjuvant spread and thus avoids non-specific immune activation. Mymetics and its network of Contract Manufacturing Organizations (CMOs) will manufacture these different vaccines to test the hypothesis that the novel, cold chain-independent, needle-free, adjuvanted solid virosome forms are significantly more immunogenic than the earlier liquid form in NHPs, particularly when administered by mucosal routes. The Specific Aims for Project 1 are to: 1. Select a suitable enteric-coated capsule for vaccine delivery to the small intestine in rhesus macaques 2. Manufacture non-GMP batches of the different solid dosage forms for the NHP studies 3. Optimize the analytical methods and GMP manufacturing processes for the selected vaccine solid forms 4. Perform toxicology studies to show good safety profiles of the solid-form, adjuvanted virosomal vaccines given by mucosal routes – and to generate GMP vaccine for a Phase I trial to be conducted with the HVTN. This Project is significant because thermostable, solid-dosage forms of HIV gp41 virosomal vaccines offering mucosal protection could play a key role in preventing the further spread of HIV in the developing world, where the AIDS epidemic remains a serious problem.

Abstract Text

PROJECT SUMMARY – OVERALL This multi-PI application is a collaboration between Mymetics and the Texas Biomedical Research Institute (TxBiomed), with Drs. Sylvain Fleury (Project 1 Lead; Mymetics) and Ruth Ruprecht (Project 2 Lead; TxBiomed) serving as PIs. We seek to bring a promising HIV/AIDS vaccine approach to the clinic. The vaccine is based upon influenza virosomes, enveloped virus-like particles that display on their surface elongated HIV gp41 peptides (virosome-P1) or recombinant truncated HIV gp41 (virosome-rgp41). Mymetics' Phase I clinical trial with virosome-P1 in healthy women showed safety and immunogenicity. Two independent nonhuman primate (NHP) studies demonstrated the safety and high efficacy of the combination of virosome-P1 + virosome rgp41 against repeated low-dose intravaginal challenges with a tier 2 R5 SHIV in Chinese and Indian-origin rhesus macaques (RMs). In the latter, 78-87% efficacy was noted when the SHIV challenge dose was ~7x104 times the median HIV inoculum in male-to-female HIV transmission. However, when this HIV inoculum was exceeded 105- fold by an even higher SHIV inoculum, protection in Indian RMs was lost, implying a threshold effect whereby vaccine-induced mucosal antibodies were unable to ward off the higher number of invading SHIV particles. The soluble vaccine used in both NHP studies was unadjuvanted. To improve immunogenicity, Mymetics has embedded the toll-like receptor (TLR)7/8 adjuvant 3M-052 into virosomal envelopes. Moreover, Mymetics has developed a powdered form of virosomes that is no longer cold-chain dependent and can be administered as intranasal (IN) spray, sublingual (SL) tablets, or packaged into oral capsules. We hypothesize that these novel solid virosome formulations are significantly more immunogenic, particularly when administered via mucosal routes, than the unadjuvanted liquid form used earlier in NHPs. The Specific Aims of this IPCAVD project are to: 1. Assess the immunogenicity of the new vaccine candidates, the newly 3M-052-adjuvanted HIV virosome-P1 and virosome-rgp41, under solid dosage forms delivered IN, SL, or orally to Indian RMs in order to select the two most immunogenic formulations for subsequent mucosal prime/mucosal boost immunization. 2. Assess the efficacy of the cold-chain independent virosomal vaccine delivered by combined mucosal immunization routes against repeated intrarectal challenges with the heterologous R5 clade B SHIVSF162P3. Protected RMs will be rechallenged with an R5 tier 2 clade C SHIV. 3. Optimize the GMP manufacturing process for the selected virosomal formulations for mucosal delivery, and 4. Perform toxicology studies to show good safety profiles of the adjuvanted, solid-form vaccines given by selected mucosal routes – and generate GMP vaccine for a Phase I trial to be conducted with the HVTN. Our vaccine development plans represent major advances, as the novel needle-free, solid vaccine dosage forms are cold-chain independent and will be mucosally delivered – unique aspects that make the novel virosomal vaccines especially attractive for the developing world, where the AIDS epidemic remains a serious problem

https://reporter.nih.gov/search/K-ztMzgyCk25GZC9F4Nb-A/projects