The Henry M. Jackson Foundation

Developing an effective HIV vaccine is a momentous challenge. An exceptionally wide range of candidate HIV vaccines have been tested, yet many were poorly immunogenic, and of the select few that advanced into efficacy trials, only one demonstrated any efficacy. Here we report the results of the largest-scale cross-protocol immunogenicity comparison to date: 13 HIV vaccine trials (including 36 vaccine regimens) conducted across nine countries worldwide, strengthened by standardized trial designs, validated assays in centralized laboratories, and harmonized immunogenicity endpoints - providing an objective approach to identify the HIV vaccine candidate(s) with the best immunogenicity. A polyvalent DNA prime + protein boost regimen (HVTN 124) including Env immunogens of four subtypes, matched between prime and boost, achieved the best anti-V1V2 antibody responses by a large margin and also induced high CD4+ T-cell responses - two key immune responses implicated in HIV vaccine protection. Our results provide strong support to test this promising HIV vaccine design in more advanced phase clinical trials and will also guide the future design of additional HIV vaccines.Trial registration: ClinicalTrials.gov identifier: NCT01799954..Trial registration: ClinicalTrials.gov identifier: NCT02109354..Trial registration: ClinicalTrials.gov identifier: NCT02404311..Trial registration: ClinicalTrials.gov identifier: NCT02207920..Trial registration: ClinicalTrials.gov identifier: NCT02296541..Trial registration: ClinicalTrials.gov identifier: NCT03284710..Trial registration: ClinicalTrials.gov identifier: NCT02915016..Trial registration: ClinicalTrials.gov identifier: NCT02997969..Trial registration: ClinicalTrials.gov identifier: NCT03122223..Trial registration: ClinicalTrials.gov identifier: NCT03409276..Trial registration: ClinicalTrials.gov identifier: NCT02968849..Trial registration: ClinicalTrials.gov identifier: NCT03060629..Trial registration: ClinicalTrials.gov identifier: NCT00223080..

Persistent post-concussive symptoms (PPCS) are common and disruptive, particularly in military service members (SM), yet there are no approved therapies targeting underlying physiological processes. This study was designed to compare acoustic neuromodulation using Cereset Research™ Standard Operating Procedures (CR-SOP), with Cereset Research Cranial Electrical Stimulation (CR-CES), on PPCS.

SM, veterans, or dependents with PPCS (Neurobehavioral Symptom Inventory [NSI] Score ≥23) were randomized to receive 10 sessions of engineered tones linked to brainwaves (CR-SOP) or 5 sessions of CR-CES, which adds intermittent low voltage transcranial alternating current stimulation (tACS) to CR-SOP. Designed to assess non-inferiority between varied doses of CR-SOP and CR-CES, the primary outcome was a change in post-concussive symptoms on the NSI, with secondary outcomes of heart rate variability (HRV) and self-report measures of PTSD, sleep, headaches, and depression.

Among study participants (n = 80, 21.3% female, mean age 40.2 [SD 13.2], 4.8 deployments, 3.2 TBIs), mean NSI declined from 45.6 to 29.5 after intervention (p < 0.0001), with gains sustained at 3 months (29.7). No significant between group differences for NSI (CR-SOP: baseline 43.9, post-intervention 26.0, 3-month 27.2, and CR-CES 46.4, 30.7, and 31.1, respectively), and no evidence of inferiority between the groups with respect to NSI. Similar improvements were seen on PCL-5, ISI, HIT-6, and PHQ-9, with no HRV differences between groups.

Both acoustic neuromodulation alone (CR-SOP) and a lower dose of CR-SOP, with tACS added (CR-CES), significantly improved PPCS out to 3 months.

ClinicalTrials.gov - NCT03649958.