A novel intravaginal ring (IVR) protects macaques against SHIV-RT infection and reduces HSV-2 shedding after repeated SHIV-RT/HSV-2 co-challenge

Background: MZC gel (MIV-150, zinc acetate [ZA], carrageenan [CG]) significantly reduces vaginal SHIV-RT and HSV-2 infection in macaques when given 8h before challenge. CG gels significantly reduce HPV infection in mice when dosed 24h before challenge. We aim to develop a 90d IVR releasing MZC and levonorgestrel (LNG) to prevent HIV, HSV-2, HPV, and conception. Methods: IVRs contained 3mg MIV-150±0.6mg LNG in the matrix and 30mg ZA/70mg CG in the core (open to fluids via a matrix pore). We measured CG, MIV-150, and LNG in macaque blood and/or vaginal swabs during and after 28d of IVR insertion. For efficacy, we exchanged IVRs every 21d, challenging macaques with 200 TCID_50 SHIV-RT/10^7 pfu HSV-2 on d7, 10, 14 and 17 post IVR insertion (20 challenges total); n = 4 placebo IVR, n = 4 LNG IVR, n=12 MZC IVR, n = 12 MZCL IVR. Results: MIV-150 was detected in swabs and plasma 1h post IVR insertion, peaked at d1 in swabs and d1-3 in plasma, declined from d7-d28, and was undetectable 24h after IVR removal. LNG was detected in serum within 4h, plateaued by d7, and was undetectable 24h after IVR removal. CG was detected in swabs of most animals from d3 until the IVRs were removed. Preliminary data show MZCL IVRs protected (92%) macaques against SHIV-RT (1/12 vs. 4/4 infected in LNG IVR controls; p=0.003); 2/12 MZC and 2/4 placebo IVR animals became SHIV-RT infected (67% protection). MZC and MZCL IVRs significantly protected compared to control IVRs (3/24 vs. 6/8 infected, p = 0.002). Initial data suggest that ∼30% fewer animals became infected with HSV-2 after treatment with MZC and MZCL IVRs (17/24 vs. 8/8 infected controls); the frequency (18/30 vs. 23/95 time points positive; p \u3c 0.0006) and levels (67/180 vs. 31/570 replicates positive; p \u3c 0.0001) of HSV-2 shedding were significantly lower than in the controls. Conclusions: We developed an IVR that releases APIs targeting HIV, HSV-2, HPV, and conception. The IVR significantly reduces SHIV-RT infection and HSV-2 shedding in macaques