Broadly neutralizing antibodies (bnAbs) can protect against HIV infection but have not been induced by human vaccination. A key barrier to bnAb induction is vaccine priming of rare bnAb-precursor B cells. In a randomized, double-blind, placebo-controlled phase 1 clinical trial, the HIV vaccine–priming candidate eOD-GT8 60mer adjuvanted with AS01 B had a favorable safety profile and induced VRC01-class bnAb precursors in 97% of vaccine recipients with median frequencies reaching 0.1% among immunoglobulin G B cells in blood. bnAb precursors shared properties with bnAbs and gained somatic hypermutation and affinity with the boost. The results establish clinical proof of concept for germline-targeting vaccine priming, support development of boosting regimens to induce bnAbs, and encourage application of the germline-targeting strategy to other targets in HIV and other pathogens.
Background A prophylactic HIV-1 vaccine is a global health priority. Objective To assess a novel vaccine platform as a prophylactic HIV-1 vaccine regimen. Design/Setting This randomized, double-blind, placebo-controlled trial assessed two candidate HIV-1 vaccines (Ad26.EnvA and Ad35-Env both at 5×1010 vp) in homologous and heterologous combinations in three geographic regions (US, East and South Africa). Both subjects and study personnel were blinded to treatment allocation. (NCT 01215149). Patients Healthy HIV uninfected adults. Measurements Safety and immunogenicity were assessed and the impact of baseline vector immunity was analyzed. Results 217 subjects received at least 1 vaccination and 210 (>96%) completed follow-up, No vaccine-associated serious adverse events occurred. All regimens were generally well tolerated though more vaccine recipients had transient moderate or severe systemic reactions (36.5%) compared to placebo recipients (20.5%). All regimens elicited humoral and cellular immune responses in nearly all volunteers. There was no impact of pre-existing Ad26 or Ad35 neutralizing antibody titers on vaccine safety and little on immunogenicity. In both homologous and heterologous regimens the second vaccination significantly increased EnvA antibody titers (~20 fold from median ELISA titers of 30–300 to 3000). The heterologous regimen Ad26-Ad35 elicited significantly higher EnvA antibody titers than Ad35-Ad26. T cell responses were modest and lower in East Africa than in South Africa and the United States. Conclusions Both vaccines elicited significant immune responses in all populations. Baseline vector immunity did not have a significant impact on immune responses. Second vaccinations in all regimens significantly boosted EnvA titers though vaccine order in the heterologous regimen had a modest effect on the immune response. Primary Funding IAVI, NIAID/NIH, and the Ragon Institute in collaboration with Crucell Holland BV.
A recombinant modified vaccinia Ankara virus vaccine candidate (TBC-M4) expressing HIV-1 subtype C env, gag, tat-rev, and nef-RT genes was tested in a randomized, double-blind, dose escalation Phase I trial in 32 HIV-uninfected healthy volunteers who received three intramuscular injections of TBC-M4 at 0, 1, and 6 months of 5 x 10(7) plaque-forming units (pfu) (low dosage, LD) (n = 12) or 2.5 x 10(8) pfu (high dosage, HD) (n = 12) or placebo (n = 8). Local and systemic reactogenicity was experienced by approximately 67% and 83% of vaccine recipients, respectively. The reactogenicity events were mostly mild in severity. Severe but transient systemic reactogenicity was seen in one volunteer of the HD group. No vaccine-related serious adverse events or events suggesting perimyocarditis were seen. A higher frequency of local reactogenicity events was observed in the HD group. Cumulative HIV-specific IFN-gamma ELISPOT responses were detected in frozen PBMCs from 9/11 (82%), 12/12 (100%), and 1/8 (13%) volunteers after the third injection of the LD, HD, and placebo groups, respectively. Most of the responses were to gag and env proteins (maximum of 430 SFU/10(6) PBMCs) persisting across multiple time points. HIV-specific ELISA antibody responses were detected in 10/11, 12/12, and 0/8 volunteers post-third vaccination, in the LD, HD, and placebo groups, respectively. No neutralizing activity against HIV-1 subtype C isolates was detected. TBC-M4 appears to be generally safe and well-tolerated. The immune response detected was dose dependent, modest in magnitude, and directed mostly to env and gag proteins, suggesting further evaluation of this vaccine in a prime-boost regimen.
Objectives Children with Down syndrome (DS) have increased difficulty initiating and maintaining sleep (DIMS), excessive daytime sleepiness (EDS), and obstructive sleep apnea (OSA). As part of a quality improvement initiative, parents of children enrolled in the Children's Hospital Boston Down Syndrome Program were surveyed about their child's sleep and breathing patterns while asleep. Methods An anonymous Internet based questionnaire. Results The completion rate was 46.5% (255/548). DIMS and EDS were frequently/almost always present in more than half the children. Amongst parents unconcerned about their child's breathing, 11.8% witnessed apnea and 4.2% gasping/choking more than once monthly. Parents of children status post adenotonsillectomy (AT) reported witnessed apnea (47.5%), gasping/choking (28.9%) more than once monthly. Discussion There is room for improved screening of sleep disturbances, OSA in children with DS. The high frequency of persistence of OSA following AT should prompt for continued screening following AT.
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