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Clinical Trials at NASA: What Makes A Clinical Trial & What Are the Requirements for International Partners?

ClinicalTrials.gov is a public registry designed to fulfill ethical obligations by providing information about clinical research studies to the general public, patients, medical practitioners and the research community. In the United States, recent revisions to human subject’s regulations have prompted new criteria for what constitutes a clinical trial along with requirements not typically requested for other types of human subject’s research. Identification of investigational clinical trials is the shared responsibility of NASA, the IRB, and the scientific investigators designing and conducting the research. This talk aims to educate attendees on the history of the development of Clinicaltrials.gov, discussion of why these requirements are important to both participants and researchers, and information on how to identify clinical trials research. In addition, we will provide information on the different requirements for clinical trials conducted at NASA or aboard the International Space Station.

Clinicaltrials.gov↗

DOE OSTI2025

Plasma GFAP for populational enrichment of clinical trials in preclinical Alzheimer's disease

Abstract INTRODUCTION Cognitively unimpaired (CU) amyloid beta (Aβ)+ individuals with elevated plasma glial fibrillary acidic protein (GFAP) have an increased risk of Alzheimer's disease (AD)‐related progression. We tested the utility of plasma GFAP for population enrichment CU populations in clinical trials. METHODS We estimated longitudinal progression, effect size, and costs of hypothetical clinical trials designed to test an estimated 25% drug effect on reducing tau positron emission tomography (PET) accumulation in the medial temporal lobe (MTL) and temporal neocortical region (NEO‐T). RESULTS CU GFAP+/Aβ+ individuals present an increased annual rate of change and effect size in tau PET MTL and tau PET NEO‐T compared to the other groups. An enrichment strategy selecting CU GFAP+/Aβ+ individuals would require a smaller sample size (≈ 57% reduction) and fewer Aβ PET scans (≈ 74% reduction) than trials enriched with Aβ PET alone, reducing total clinical trial costs by up to 64%. DISCUSSION Our results suggest that clinical trials focusing on preclinical AD recruiting Aβ+ individuals with elevated GFAP levels would improve cost effectiveness. Highlights Cognitively unimpaired (CU) glial fibrillary acidic protein (GFAP)+/amyloid beta (Aβ)+ shows increased changes in tau positron emission tomography (PET) . CU GFAP+/Aβ+ enriched clinical trials require a reduced sample size compared to Aβ+ only. CU GFAP+/Aβ+ enrichment reduces Aβ PET scans required and costs. CU GFAP+/Aβ+ enrichment allows the selection of individuals at early stages of the Alzheimer's disease continuum.

Neurosciences & Neurology↗

NASA NTRS1995

Reliability Stress-Strength Models for Dependent Observations with Applications in Clinical Trials

We consider the applications of stress-strength models in studies involving clinical trials. When studying the effects and side effects of certain procedures (treatments), it is often the case that observations are correlated due to subject effect, repeated measurements and observing many characteristics simultaneously. We develop maximum likelihood estimator (MLE) and uniform minimum variance unbiased estimator (UMVUE) of the reliability which in clinical trial studies could be considered as the chances of increased side effects due to a particular procedure compared to another. The results developed apply to both univariate and multivariate situations. Also, for the univariate situations we develop simple to use lower confidence bounds for the reliability. Further, we consider the cases when both stress and strength constitute time dependent processes. We define the future reliability and obtain methods of constructing lower confidence bounds for this reliability. Finally, we conduct simulation studies to evaluate all the procedures developed and also to compare the MLE and the UMVUE.

Kushary, Debashis↗

DOE OSTI2025

The Evolution of Randomized Clinical Trial Designs to Assess Therapeutics in Alzheimer Disease

Importance The success of recent randomized clinical trials (RCTs) for Alzheimer disease (AD), particularly those focusing on anti-amyloid therapies, has been discussed at length. However, the evolution of RCT design features for AD that preceded this success remain underexplored. Objective To describe temporal changes in the features of RCT design for interventions in AD. Evidence Review PubMed, Scopus, and Web of Science databases were searched in January 2025 for phase 2 and 3 AD RCTs published between January 1992 and December 2024. RCTs that investigated an intervention for AD, with a placebo or standard-of-care control group, were included. Four assessors independently reviewed full-text articles to capture study characteristics. Main Outcomes and Measures The number of participants and the duration of RCTs as well as the target population, outcomes, and funding were extracted from published reports. These features were analyzed with respect to time using linear regression and χ 2 analyses. Results The study included 203 RCTs with 79 589 participants testing interventions in AD. From 1992 to 2024, the mean sample size increased by 464% for phase 2 RCTs (from 42 to 237), and 50% for phase 3 RCTs (from 632 to 951), while the mean trial duration increased by 188% (from 16 to 46 weeks) for phase 2, and 256% (from 20 to 71 weeks) for phase 3 RCTs. This longer duration of RCTs may be partially attributed by a greater share of disease-modifying rather than symptomatic treatments. Similarly, more recent trials required AD biomarker evidence for enrollment (from 1 of 36 [2.7%] before 2006 to 40 of 76 [52.6%] since 2019). A substantial difference in the type of therapeutics researched was observed, with anti-amyloid and anti-tau RCTs being more likely to be funded by the pharmaceutical industry compared with neurotransmitter or other RCTs (anti-amyloid or anti-tau, 68 of 71 [95.8%]; neurotransmitter, 52 of 69 [77.6%]; other, 33 of 52 [63.5%]). RCT transparency improved, with more frequent data accessibility statements, registered reports, and better reporting on race and ethnicity. Conclusions and Relevance This methodology research of AD RCTs highlights substantial changes in key features of AD clinical trials from 1992 to 2024. AD RCTs have become larger and longer, such that they are powered to detect smaller clinical differences. The increased sample sizes and duration should enable the detection of smaller and more slowly occurring outcomes, which may lead to successful RCTs of therapies with slower and more subtle efficacy.

General & Internal Medicine↗

NASA NTRS2017

It's Only a Phase: Applying the 5 Phases of Clinical Trials to the NSCR Model Improvement Process

NASA limits astronaut radiation exposures to a 3% risk of exposure-induced death from cancer (REID) at the upper 95% confidence level. Since astronauts approach this limit, it is important that the estimate of REID be as accurate as possible. The NASA Space Cancer Risk 2012 (NSCR-2012) model has been the standard for NASA's space radiation protection guidelines since its publication in 2013. The model incorporates elements from U.S. baseline statistics, Japanese atomic bomb survivor research, animal models, cellular studies, and radiation transport to calculate astronaut baseline risk of cancer and REID. The NSCR model is under constant revision to ensure emerging research is incorporated into radiation protection standards. It is important to develop guidelines, however, to determine what new research is appropriate for integration. Certain standards of transparency are necessary in order to assess data quality, statistical quality, and analytical quality. To this effect, all original source code and any raw data used to develop the code are required to confirm there are no errors which significantly change reported outcomes. It is possible to apply a clinical trials approach to select and assess the improvement concepts that will be incorporated into future iterations of NSCR. This poster describes the five phases of clinical trials research, pre-clinical research, and clinical research phases I-IV, explaining how each step can be translated into an appropriate NSCR model selection guideline.

Elgart, S. R.↗

NASA NTRS2011

The First Intervention Study in Elder Self-Neglect: A Randomized Clinical Trial to Improve Vitamin D Levels

Despite high mortality rates, elder self-neglect is characterized by refusal of medical and social interventions. To date there have been no tested clinical interventions in elders who self-neglect. Previous research from the TEAM Institute has shown significantly low vitamin D levels in this population. This study aimed to determine the feasibility of a clinical intervention. Replacement of vitamin D was chosen because of its ease of administration and favorable safety profile. Methods: A randomized clinical trial using directly observed therapy of vitamin D was conducted using 50 elders, >65 years of age, with Adult Protective Services (APS) validated self-neglect. A staggered intervention with waiting controls was used to maximize statistical power. One-third (n=17) of the group was administered 50,000 IU vitamin D2 (ergocalciferol) monthly and the remainder (n=33) were administered 400 IU monthly. Serum 25-OH vitamin D was assessed at baseline and 5-months. Results: 69% agreed to participate in the study and of those n=40 (80%) remained at 5-months. At baseline, 12% (n=7) were deficient in vitamin D (<30nmol/L) and approximately 38% (n=22) had inadequate vitamin D levels (<50nmol/L). The baseline 25-OH vitamin D level was 59 nmol/L +25 (mean SD), and increased significantly to 72nmol/L +21 nmol/L at 5-months. Conclusion: These data are the first to provide evidence that clinical interventions are feasible in elders who self-neglect. The increase in vitamin D levels confirmed that the study personnel were able to successfully intervene community-dwelling elders with self-neglect. This study sets the precedent for future intervention and prevention studies

Burnett, Jason↗

DOE OSTI2025

Emerging Tools to Support DILI Assessment in Clinical Trials with Abnormal Baseline Serum Liver Tests or Pre-existing Liver Diseases

Abstract Based on the late Dr. Hyman Zimmerman’s observation that hepatocellular drug-induced liver injury (DILI) leading to jaundice carries a ≥ 10% fatality risk (coined as Hy’s law by others), evaluation of Drug-Induced Serious Hepatotoxicity (eDISH) continues to play a central role in the assessment of a study drug’s liability for acute hepatocellular DILI. The eDISH identifies drugs in clinical trials with DILI fatality (death or transplant) risk that may be unacceptable in a post-market setting. As a two-dimensional graph that plots peak total bilirubin (TB) versus peak serum aminotransferase levels for each patient during study drug or comparator treatment, eDISH identifies potential cases of acute, modest, and serious hepatocellular DILI for in-depth analysis of liver tests (LT) and clinical course so that the likelihood of causal association with the study drug can be determined. Unfortunately, the generalizable utility of this tool only pertains to trials enrolling patients with normal or near normal (NNN) baseline (BL) serum LTs. The eDISH does not necessarily apply to trials of patients with abnormal baseline (ABN-BL) LTs that often coincide with underlying liver disorders. Because drug development programs being reviewed by the FDA increasingly target liver disorders, we are often challenged to evaluate DILI risk in trials of patients with ABN-BL LTs. Also, the high background prevalence of metabolic dysfunction associated steatotic liver disease (MASLD) means patients with LTs above NNN may need to be enrolled in trials treating non-liver disorders to reflect the target population. Such study populations create challenges for industry and regulators because eDISH may not reliably categorize or identify potential cases of DILI for further analysis, as it so efficiently does in NNN-BL trials. We describe the main functionalities of eDISH in NNN-BL trials to understand what should be emulated by new tools or eDISH modifications. We then discuss non-eDISH–based plots that may be useful in ABN-BL trials.

Amirzadegan, Jasmine↗

DOE OSTI2025

Utility of plasma GFAP as a secondary endpoint for clinical trials in Alzheimer’s disease

Not provided.

Neurosciences & Neurology↗

DOE OSTI2025

Pivotal trial characteristics and types of endpoints used to support Food and Drug Administration rare disease drug approvals between 2013 and 2022

Background/aims Rare disease drug development faces unique challenges, such as genotypic and phenotypic heterogeneity within small patient populations and a lack of established outcome measures for conditions without previously successful drug development programs. These challenges complicate the process of selecting the appropriate trial endpoints and conducting clinical trials in rare diseases. In this descriptive study, we examined novel drug approvals for non-oncologic rare diseases by the U.S. Food and Drug Administration’s Center for Drug Evaluation and Research over the past decade and characterized key regulatory and trial design elements with a focus on the primary efficacy endpoint utilized as the basis of approval. Methods Using the Food and Drug Administration’s Data Analysis Search Host database, we identified novel new drug applications and biologics license applications with orphan drug designation that were approved between 2013 and 2022 for non-oncologic indications. From Food and Drug Administration review documents and other external databases, we examined characteristics of pivotal trials for the included drugs, such as therapeutic area, trial design, and type of primary efficacy endpoints. Differences in trial design elements associated with primary efficacy endpoint type were assessed such as randomization and blinding. Then, we summarized the primary efficacy endpoint types utilized in pivotal trials by therapeutic area, approval pathway, and whether the disease etiology is well defined. Results One hundred and seven drugs that met our inclusion criteria were approved between 2013 and 2022. Assessment of the 107 drug development programs identified 150 pivotal trials that were subsequently analyzed. The pivotal trials were mostly randomized (80%) and blinded (69.3%). Biomarkers (41.1%) and clinical outcomes (42.1%) were commonly utilized as primary efficacy endpoints. Analysis of the use of clinical trial design elements across trials that utilized biomarkers, clinical outcomes, or composite endpoints did not reveal statistically significant differences. The choice of primary efficacy endpoint varied by the drug’s therapeutic area, approval pathway, and whether the indicated disease etiology was well defined. For example, biomarkers were commonly selected as primary efficacy endpoints in hematology drug approvals (70.6%), whereas clinical outcomes were commonly selected in neurology drug approvals (69.6%). Further, if the disease etiology was well defined, biomarkers were more commonly used as primary efficacy endpoints in pivotal trials (44.7%) than if the disease etiology was not well defined (27.3%). Discussion In the past 10 years, numerous novel drugs have been approved to treat non-oncologic rare diseases in various therapeutic areas. To demonstrate their efficacy for regulatory approval, biomarkers and clinical outcomes were commonly utilized as primary efficacy endpoints. Biomarkers were not only frequently used as surrogate efficacy endpoints in accelerated approvals, but also in traditionally approved rare disease drugs. The choice of primary efficacy endpoints varied by therapeutic area, approval pathway, and understanding of disease etiology.

Hong, Kyungwan [Rare Diseases Team, Office of New ↗

NASA NTRS1992

Comparison of computer- and human-derived coronary angiographic end-point measures for controlled therapy trials

The Cholesterol Lowering Atherosclerosis Study, a randomized angiographic clinical trial, demonstrated the beneficial effect of niacin/colestipol plus diet therapy on coronary atherosclerosis. Outcome was determined by panel-based estimates (viewed in both still and cine modes) of percent stenosis severity and change in native artery and bypass graft lesions. Computer-based quantitative coronary angiography (QCA) was also used to measure lesion and bypass graft stenosis severity and change in individual frames closely matched in orientation, opacification, and cardiac phase. Both methods jointly evaluated 350 nonoccluded lesions. The correlation between QCA and panel estimates of lesion size was 0.70 (p less than 0.0001) and for change in lesion size was 0.28 (p = 0.002). Agreement between the two methods in classifying lesion changes (i.e., regression, unchanged, or progression) occurred for 60% (210 of 350) of the lesions kappa +/- SEM = 0.20 +/- 0.05, p less than 0.001). The panel identified 442 nonoccluded lesions for which QCA stenosis measurements could not be obtained. Lesions not measurable by QCA included those with stenosis greater than 85% that could not be reliably edge tracked, segments with diffuse or ecstatic disease that had no reliable reference diameter, and segments for which matched frames could not be located. Seventy-nine lesions, the majority between 21% and 40% stenosis, were identified and measured by QCA but were not identified by the panel. This comparison study demonstrates the need to consider available angiographic measurement methods in relation to the goals of their use.

NASA Center JPL↗

DOE OSTI2024

A Comprehensive Overview of Postbiotics with a Special Focus on Discovery Techniques and Clinical Applications

The increasing interest in postbiotics, a term gaining recognition alongside probiotics and prebiotics, aligns with a growing number of clinical trials demonstrating positive outcomes for specific conditions. Postbiotics present several advantages, including safety, extended shelf life, ease of administration, absence of risk, and patentability, making them more appealing than probiotics alone. This review covers various aspects, starting with an introduction, terminology, classification of postbiotics, and brief mechanisms of action. It emphasizes microbial metabolomics as the initial step in discovering novel postbiotics. Commonly employed techniques such as NMR, GC-MS, and LC-MS are briefly outlined, along with their application principles and limitations in microbial metabolomics. The review also examines existing research where these techniques were used to identify, isolate, and characterize postbiotics derived from different microbial sources. The discovery section concludes by highlighting challenges and future directions to enhance postbiotic discovery. In the second half of the review, we delve deeper into numerous published postbiotic clinical trials to date. We provide brief overviews of system-specific trial applications, their objectives, the postbiotics tested, and their outcomes. The review concludes by highlighting ongoing applications of postbiotics in extended clinical trials, offering a comprehensive overview of the current landscape in this evolving field.

60 APPLIED LIFE SCIENCES↗

NASA NTRS1983

Development and marketing of a prosthetic urinary control valve system

An implantable prosthetic for the control of urinary incontinence was developed and marketed. Three phases are presented: bench development studies, animal trials, and human clinical trials. This work was performed under the direction of a Research Team at Rochester General Hospital (RGH). Bench trials were completed on prototype hardware and provided early verification of the device's ability to withstand repeated cyclic testing. Configurational variants were evaluated and a preferred design concept was established. Silicone rubber (medical grade) was selected as the preferred material for the prosthesis.

Tenney, J. B., Jr.↗

NASA NTRS2011

Pharmacokinetics of Intranasal Scopolamine Gel Formulation During Antiorthostatic Bed Rest, a Microgravity Analog

Statement of Purpose, Innovation or Hypothesis: Space Motion sickness (SMS) is a long-standing problem for astronauts on both short and long duration space flights. Scopolamine (SCOP) is frequently used for the treatment of motion sickness (MS), and is available as transdermal patch and tablet dosage forms. These formulations of SCOP are ineffective for the treatment of SMS. Intranasal dosage forms are noninvasive with rapid absorption and enhanced bioavailability, thus allowing precise and reduced dosing in addition to offering rescue and treatment options. An intranasal gel dosage formulation of scopolamine (INSCOP) was developed and pharmacokinetics (PK) and bioavailability were determined in clinical trials with human subjects under IND guidelines.Description of Methods and Materials: The present clinical trial compares PK and bioavailability of INSCOP in 12 normal, healthy subjects (6 male/ 6 female) during ambulation (AMB) and antiorthostaticbed rest (ABR) used as a ground-based microgravity analog. Subjects received 0.2 mg and 0.4 mg doses of INSCOP during AMB and ABR in a 4-way crossover design.Data and Results: Results indicated no difference between AMB and ABR in PK parameters after 0.2 mg dose, Clearance (Cls) decreased with a concomitant increase in maximum concentration and area under concentration-versus-time curve (AUC) during ABR after the 0.4 mg dose.Interpretation, Conclusion or Significance: The difference in AUC and Cls at the higher (0.4 mg) but not the lower dose (0.2 mg) during ABR suggests that ABR may affect metabolism and/or clearance of INSCOP at higher doses . These results indicate that dosing adjustment may be required for treatment of SMS with INSCOP in space.

Singh, Rajendra P.↗

NASA NTRS1991

Cooperative research and development opportunities with the National Cancer Institute

The Office of Technology Development (OTD) of the National Cancer Institute (NCI) is responsible for negotiating Cooperative Research and Development Agreements (CRADAs), whereby the knowledge resulting from NCI investigators' government-sponsored research is developed in collaboration with universities and/or industry into new products of importance for the diagnosis and treatment of cancer and acquired immunodeficiency syndrome (AIDS). The NCI has recently executed a unique 'clinical trials' CRADA and is developing a model agreement based upon it for the development and commercialization of products for the diagnosis and treatment of cancer and AIDS. NCI drug screening, preclinical testing, clinical trials, and AIDS program capabilities form the basis for this new technology development/technology transfer vehicle. NCI's extensive drug screening program and 'designer foods' program serve as potential sources of investigational new drugs (INDs) and cancer preventatives. Collaborations between NCI and pharmaceutical companies having the facilities, experience, and expertise necessary to develop INDs into approved drugs available to the public are being encouraged where the companies have proprietary rights to INDs, or where NCI has proprietary rights to INDs and invites companies to respond to a collaborator announcement published in the Federal Register. The joint efforts of the NCI and the chosen collaborator are designed to generate the data necessary to obtain pharmaceutic regulatory approval from the Food and Drug Administration (FDA) to market the drugs developed, and thereby make them available to health care providers for the diagnosis and treatment of cancer and AIDS.

Sybert, Kathleen↗

NASA NTRS2014

Pharmacokinetic Modeling of Intranasal Scopolamine in Plasma Saliva and Urine

Wu, L.↗

NASA NTRS2014

Pharmacokinetic Modeling of Intranasal Scopolamine in Plasma Saliva and Urine

An intranasal gel formulation of scopolamine (INSCOP) was developed for the treatment of Space Motion Sickness. The bioavailability and pharmacokinetics (PK) were evaluated under the Food and Drug Administration guidelines for clinical trials for an Investigative New Drug (IND). The aim of this project was to develop a PK model that can predict the relationship between plasma, saliva and urinary scopolamine concentrations using data collected from the IND clinical trial with INSCOP. METHODS: Twelve healthy human subjects were administered three dose levels (0.1, 0.2 and 0.4 mg) of INSCOP. Serial blood, saliva and urine samples were collected between 5 min to 24 h after dosing and scopolamine concentrations measured by using a validated LC-MS-MS assay. Pharmacokinetic Compartmental models, using actual dosing and sampling times, were built using Phoenix (version 1.2). Model discrimination was performed, by minimizing the Akaike Information Criteria (AIC), maximizing the coefficient of determination (r²) and by comparison of the quality of fit plots. RESULTS: The best structural model to describe scopolamine disposition after INSCOP administration (minimal AIC =907.2) consisted of one compartment for plasma, saliva and urine respectively that were inter-connected with different rate constants. The estimated values of PK parameters were compiled in Table 1. The model fitting exercises revealed a nonlinear PK for scopolamine between plasma and saliva compartments for K21, Vmax and Km. CONCLUSION: PK model for INSCOP was developed and for the first time it satisfactorily predicted the PK of scopolamine in plasma, saliva and urine after INSCOP administration. Using non-linear PK yielded the best structural model to describe scopolamine disposition between plasma and saliva compartments, and inclusion of non-linear PK resulted in a significant improved model fitting. The model can be utilized to predict scopolamine plasma concentration using saliva and/or urine data that allows non-invasive assessment of pharmacotherapeutics of scopolamine in space and other remote environments without requiring blood sampling.

Wu, L.↗

NASA NTRS2014

A Population Pharmacokinetic Model for Disposition in Plasma, Saliva and Urine of Scopolamine after Intranasal Administration to Healthy Human Subjects

An intranasal gel formulation of scopolamine (INSCOP) was developed for the treatment of Space Motion Sickness. The bioavailability and pharmacokinetics (PK) were evaluated under the Food and Drug Administration guidelines for clinical trials with an Investigative New Drug (IND) protocol. The aim of this project was to develop a PK model that can predict the relationship between plasma, saliva and urinary scopolamine concentrations using data collected from the IND clinical trials with INSCOP. Methods: Twelve healthy human subjects were administered three dose levels (0.1, 0.2 and 0.4 mg) of INSCOP. Serial blood, saliva and urine samples were collected between 5 min and 24 h after dosing and scopolamine concentrations were measured by using a validated LC‐MS‐MS assay. Pharmacokinetic Compartmental models, using actual dosing and sampling times, were built using Phoenix (version 1.2). Model selection was based on the likelihood ratio test on the difference of criteria (‐2LL) and comparison of the quality of fit plots. Results: The best structural model for INSCOP (minimal ‐2LL= 502.8) was established. It consisted of one compartment each for plasma, saliva and urine, respectively, which were connected with linear transport processes except the nonlinear PK process from plasma to saliva compartment. The best‐fit estimates of PK parameters from individual PK compartmental analysis and Population PK model analysis were shown in Tables 1 and 2, respectively. Conclusion: A population PK model that could predict population and individual PK of scopolamine in plasma, saliva and urine after dosing was developed and validated. Incorporating a non‐linear transfer from plasma to saliva compartments resulted in a significantly improved model fitting. The model could be used to predict scopolamine plasma concentrations from salivary and urinary drug levels, allowing non‐invasive therapeutic monitoring of scopolamine in space and other remote environments.

Wu, L.↗

DOE OSTI2025

A Pentavalent HIV-1 Subtype C Vaccine Containing Computationally Selected gp120 Strains Improves the Breadth of V1V2 Region Responses

Background: HIV-1 envelope (Env) variable loops 1 and 2 (V1V2) directed non-neutralizing antibodies were a correlate of decreased transmission risk in the RV144 vaccine trial. Thus, the elicitation and breadth of antibody responses against the V1V2 of HIV-1 Env are important considerations for HIV-1 vaccine candidates. The V1V2 region’s highly variable nature and the extensive diversity of subtype C HIV-1 Envelopes (Envs) make the V1V2 response breadth a high priority for HIV-1 vaccine regimens aiming for V1V2-mediated protection in Southern Africa. Here, we determined whether the breadth of the anti-V1V2 vaccine response can be broadened by including HIV-1 Env strains computationally designed to enhance the coverage of subtype C V1V2 sequence diversity. Methods: Three subtype C Env strains were selected to maximize antibody binding coverage while complementing subtype C vaccine gp120s that were given in human clinical trials in South Africa, as well as to improve epitope accessibility. Humoral immunogenicity of a novel trivalent gp120 vaccine immunogen, a bivalent gp120 boost already in clinical trials (1086C and TV1), and a pentavalent (all five gp120s combined) were evaluated in a preclinical immunization study in guinea pigs. The pentavalent combination was further evaluated with alum versus glucopyranosyl lipid adjuvants formulated in squalene-in-water emulsion (GLA-SE) adjuvants in non-human primates. The breadth of the anti-V1V2 response was assessed using an array of cross-subtype variable loops 1&2 (V1V2) scaffold proteins and linear V2 peptides. Results: The breadth of the IgG response against V1V2 antigens of the trivalent and pentavalent groups was comparable, and both were greater than the breadth of the bivalent group. Linear epitope mapping showed that two linear epitopes in V2 were targeted by the vaccinated animals: the V2 hotspot focused at 169K that potentially correlated with decreased HIV-1 risk in RV144 and the V2.2 site (179LDV/I181) that is part of the integrin α4β7 binding site. The bivalent vaccine elicited a significantly higher magnitude of binding to the V2 hotspot compared to the trivalent vaccine whereas the trivalent vaccine elicited significantly higher binding to the V2.2 epitope compared to the bivalent vaccine, while the pentavalent recognized both regions. Conclusions: These results demonstrate that the three new computationally selected subtype C Envs successfully complemented 1086C and TV1 for broader V1V2 antibody responses, and, in concert with adjuvants that stimulate V1V2 responses, can be considered as part of a rationale immunogen design to improve V1V2 IgG coverage in future vaccine trials in South Africa.

Immunology↗