Pharmacokinetics and Preliminary Safety of Pod-Intravaginal Rings Delivering the Monoclonal Antibody VRC01-N for HIV Prophylaxis in a Macaque Model

ABSTRACT The broadly neutralizing antibody (bNAb) VRC01, capable of neutralizing 91% of known human immunodeficiency virus type 1 (HIV-1) isolates in vitro, is a promising candidate microbicide for preventing sexual HIV infection when administered topically to the vagina; however, accessibility to antibody-based prophylactic treatment by target populations in sub-Saharan Africa and other underdeveloped regions may be limited by the high cost of conventionally produced antibodies and the limited capacity to manufacture such antibodies. Intravaginal rings of the pod design (pod-IVRs) delivering Nicotiana-manufactured VRC01 (VRC01-N) over a range of release rates have been developed. The pharmacokinetics and preliminary safety of VRC01-N pod-IVRs were evaluated in a rhesus macaque model. The devices sustained VRC01-N release for up to 21 days at controlled rates, with mean steady-state VRC01-N levels in vaginal fluids in the range of 102 to 103 μg g−1 being correlated with in vitro release rates. No adverse safety indications were observed. These findings indicate that pod-IVRs are promising devices for the delivery of the candidate topical microbicide VRC01-N against HIV-1 infection and merit further preclinical evaluation.

Download Full-text

Sulfamethoxazole Susceptibility of Mycobacterium tuberculosis Isolates from HIV-Infected Ugandan Adults with Tuberculosis Taking Trimethoprim-Sulfamethoxazole Prophylaxis

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01101-15 ◽

2015 ◽

Vol 59 (9) ◽

pp. 5844-5846 ◽

Cited By ~ 3

Author(s):

Sam Ogwang ◽

Caryn E. Good ◽

Brenda Okware ◽

Mary Nsereko ◽

Michael R. Jacobs ◽

...

Keyword(s):

Mycobacterium Tuberculosis ◽

Multidrug Resistant ◽

Sub Saharan Africa ◽

Content Type ◽

Pulmonary Tb ◽

Resistant Tuberculosis ◽

Multidrug Resistant Tuberculosis ◽

Sub Saharan

ABSTRACTAdditional drugs are needed for the treatment of multidrug-resistant tuberculosis (TB). Sulfamethoxazole has been shown to havein vitroactivity againstMycobacterium tuberculosis; however, there is concern about resistance given the widespread use of trimethoprim-sulfamethoxazole prophylaxis among HIV-infected patients in sub-Saharan Africa. Thirty-eight of 40Mycobacterium tuberculosisisolates (95%) from pretreatment sputum samples from Ugandan adults with pulmonary TB, including HIV-infected patients taking trimethoprim-sulfamethoxazole prophylaxis, were susceptible with MICs of ≤38.4 μg/ml.

Download Full-text

Physiological Differences in Cryptococcus neoformans Strains In Vitro versus In Vivo and Their Effects on Antifungal Susceptibility

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.02108-16 ◽

2016 ◽

Vol 61 (3) ◽

Cited By ~ 13

Author(s):

Nina T. Grossman ◽

Arturo Casadevall

Keyword(s):

Cryptococcus Neoformans ◽

Cryptococcal Meningitis ◽

Antifungal Susceptibility ◽

Sub Saharan Africa ◽

Content Type ◽

Laboratory Conditions ◽

Physiological Differences ◽

Sub Saharan

ABSTRACT Cryptococcus neoformans is an environmentally ubiquitous fungal pathogen that primarily causes disease in people with compromised immune systems, particularly those with advanced AIDS. There are estimated to be almost 1 million cases per year of cryptococcal meningitis in patients infected with human immunodeficiency virus, leading to over 600,000 annual deaths, with a particular burden in sub-Saharan Africa. Amphotericin B (AMB) and fluconazole (FLC) are key components of cryptococcal meningitis treatment: AMB is used for induction, and FLC is for consolidation, maintenance and, for occasional individuals, prophylaxis. However, the results of standard antifungal susceptibility testing (AFST) for AMB and FLC do not correlate well with therapeutic outcomes and, consequently, no clinical breakpoints have been established. While a number of explanations for this absence of correlation have been proffered, one potential reason that has not been adequately explored is the possibility that the physiological differences between the in vivo infection environment and the in vitro AFST environment lead to disparate drug susceptibilities. These susceptibility-influencing factors include melanization, which does not occur during AFST, the size of the polysaccharide capsule, which is larger in infecting cells than in those grown under normal laboratory conditions, and the presence of large polyploid “titan cells,” which rarely occur under laboratory conditions. Understanding whether and how C. neoformans differentially expresses mechanisms of resistance to AMB and FLC in the AFST environment compared to the in vivo environment could enhance our ability to interpret AFST results and possibly lead to the development of more applicable testing methods.

Download Full-text

Serum Bactericidal Assays To Evaluate Typhoidal and Nontyphoidal Salmonella Vaccines

Clinical and Vaccine Immunology ◽

10.1128/cvi.00115-14 ◽

2014 ◽

Vol 21 (5) ◽

pp. 712-721 ◽

Cited By ~ 32

Author(s):

Mary Adetinuke Boyd ◽

Sharon M. Tennant ◽

Venant A. Saague ◽

Raphael Simon ◽

Khitam Muhsen ◽

...

Keyword(s):

Sub Saharan Africa ◽

Content Type ◽

Vaccine Candidates ◽

Live Attenuated Vaccines ◽

Bactericidal Antibody ◽

Paratyphi B ◽

Sub Saharan ◽

Functional Antibodies ◽

New Vaccines

ABSTRACTInvasiveSalmonellainfections for which improved or new vaccines are being developed include enteric fever caused bySalmonella entericaserovars Typhi, Paratyphi A, and Paratyphi B and sepsis and meningitis in young children in sub-Saharan Africa caused by nontyphoidalSalmonella(NTS) serovars, particularlyS. entericaserovars Typhimurium and Enteritidis. Assays are needed to measure functional antibodies elicited by the new vaccines to assess their immunogenicities and potential protective capacities. We developedin vitroassays to quantify serum bactericidal antibody (SBA) activity induced byS. Typhi,S. Paratyphi A,S. Typhimurium, andS. Enteritidis vaccines in preclinical studies. Complement from various sources was tested in assays designed to measure antibody-dependent complement-mediated killing. Serum from rabbits 3 to 4 weeks of age provided the best complement source compared to serum from pigs, goats, horses, bovine calves, or rabbits 8 to 12 weeks of age. ForS. Enteritidis,S. Typhimurium, andS. Typhi SBA assays to be effective, bacteria had to be harvested at log phase. In contrast,S. Paratyphi A was equally susceptible to killing whether it was grown to the stationary or log phase. The typhoidal serovars were more susceptible to complement-mediated killing than were the nontyphoidal serovars. Lastly, the SBA endpoint titers correlated with serum IgG anti-lipopolysaccharide (LPS) titers in mice immunized with mucosally administeredS. Typhimurium,S. Enteritidis, andS. Paratyphi A but notS. Typhi live attenuated vaccines. The SBA assay described here is a useful tool for measuring functional antibodies elicited bySalmonellavaccine candidates.

Download Full-text

In Vitro, Ex Vivo, and In Vivo Activities of Diamidines against Trypanosoma congolense and Trypanosoma vivax

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.02356-16 ◽

2017 ◽

Vol 61 (5) ◽

Cited By ~ 6

Author(s):

Kirsten Gillingwater ◽

Christina Kunz ◽

Christiane Braghiroli ◽

David W. Boykin ◽

Richard R. Tidwell ◽

...

Keyword(s):

Ex Vivo ◽

Trypanosoma Congolense ◽

Tsetse Fly ◽

Sub Saharan Africa ◽

Content Type ◽

Lead Compounds ◽

Single Bolus Dose ◽

Sub Saharan

ABSTRACT African animal trypanosomosis (AAT) is caused by the tsetse fly-transmitted protozoans Trypanosoma congolense and T. vivax and leads to huge agricultural losses throughout sub-Saharan Africa. Three drugs are available to treat nagana in cattle (diminazene diaceturate, homidium chloride, and isometamidium chloride). With increasing reports of drug-resistant populations, new molecules should be investigated as potential candidates to combat nagana. Dicationic compounds have been demonstrated to have excellent efficacy against different kinetoplastid parasites. This study therefore evaluated the activities of 37 diamidines, using in vitro and ex vivo drug sensitivity assays. The 50% inhibitory concentrations obtained ranged from 0.007 to 0.562 μg/ml for T. congolense and from 0.019 to 0.607 μg/ml for T. vivax. On the basis of these promising results, 33 of these diamidines were further examined using in vivo mouse models of infection. Minimal curative doses of 1.25 mg/kg of body weight for both T. congolense- and T. vivax-infected mice were seen when the diamidines were administered intraperitoneally (i.p.) over 4 consecutive days. From these observations, 15 of these 33 diamidines were then further tested in vivo, using a single bolus dose for administration. The total cure of mice infected with T. congolense and T. vivax was seen with single i.p. doses of 5 and 2.5 mg/kg, respectively. This study identified a selection of diamidines which could be considered lead compounds for the treatment of nagana.

Download Full-text

Safe and Sustained Vaginal Delivery of Pyrimidinedione HIV-1 Inhibitors from Polyurethane Intravaginal Rings

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.05721-11 ◽

2011 ◽

Vol 56 (3) ◽

pp. 1291-1299 ◽

Cited By ~ 39

Author(s):

Todd J. Johnson ◽

Priya Srinivasan ◽

Theodore H. Albright ◽

Karen Watson-Buckheit ◽

Lorna Rabe ◽

...

Keyword(s):

Sexual Transmission ◽

Vaginal Fluid ◽

Vaginal Tissue ◽

Biologically Relevant ◽

Macaque Model ◽

Intravaginal Rings ◽

Native Microflora ◽

Hiv 1

ABSTRACTThe potent antiretroviral pyrimidinediones IQP-0528 (PYD1) and IQP-0532 (PYD2) were formulated in polyurethane intravaginal rings (IVRs) as prophylactic drug delivery systems to prevent the sexual transmission of HIV-1. To aid in the selection of a pyrimidinedione candidate and the optimal loading of the drug in the IVR delivery system, four pyrimidinedione IVR formulations (PYD1 at 0.5 wt% [PYD10.5wt%], PYD11wt%, PYD24wt%, and PYD214wt%) were evaluated in pigtail macaques over 28 days for safety and pyrimidinedione vaginal biodistribution. Kinetic analysis of vaginal proinflammatory cytokines, native microflora, and drug levels suggested that all formulations were safe, but only the high-loaded PYD214wt%IVR demonstrated consistently high pyrimidinedione vaginal fluid and tissue levels over the 28-day study. This formulation delivered drug in excess of 10 μg/ml to vaginal fluid and 1 μg/g to vaginal tissue, a level over 1,000 times thein vitro50% effective concentration. Thein vitrorelease of PYD1 and PYD2 under nonsink conditions correlated well within vivorelease, both in amount and in kinetic profile, and therefore may serve as a more biologically relevant means of evaluating releasein vitrothan typically employed sink conditions. Lastly, the pyrimidinediones in the IVR formulation were chemically stable after 90 days of storage at elevated temperature, and the potent nanomolar-level antiviral activity of both molecules was retained afterin vitrorelease. Altogether, these results point to the successful IVR formulation and vaginal biodistribution of the pyrimidinediones and demonstrate the usefulness of the pigtail macaque model in evaluating and screening antiretroviral IVR formulations prior to preclinical and clinical evaluation.

Download Full-text

Pharmacokinetics and predicted neutralization coverage of VRC01 in HIV-uninfected participants of the Antibody Mediated Prevention (AMP) trials

10.1101/2020.09.02.20182881 ◽

2020 ◽

Author(s):

Yunda Huang ◽

Logashvari Naidoo ◽

Lily Zhang ◽

Lindsay Nicole Carpp ◽

Erika Rudnicki ◽

...

Keyword(s):

Neutralizing Antibody ◽

Volume Of Distribution ◽

Sub Saharan Africa ◽

Study Cohort ◽

Mixed Effects Modeling ◽

Cohort Differences ◽

Transgender Persons ◽

Sub Saharan ◽

Sex With Men ◽

Hiv 1

The phase 2b AMP trials are testing whether the broadly neutralizing antibody VRC01 prevents HIV-1 infection in two cohorts: women in sub-Saharan Africa, and men and transgender persons who have sex with men (MSM/TG) in the Americas and Switzerland. We used nonlinear mixed effects modeling of longitudinal serum VRC01 concentrations to characterize pharmacokinetics and predict HIV-1 neutralization coverage. We found that body weight significantly influenced clearance, and that the mean peripheral volume of distribution, steady state volume of distribution, elimination half-life, and accumulation ratio were significantly higher in MSM/TG than in women. Neutralization coverage was predicted to be higher in the first (versus second) half of a given 8-week infusion interval, and appeared to be higher in MSM/TG than in women overall. Study cohort differences in pharmacokinetics and neutralization coverage provide insights for interpreting the AMP results and for investigating how VRC01 concentration and neutralization correlate with HIV incidence.

Download Full-text