Origin and differentiation of human memory CD8 T cells after vaccination.

The differentiation of human memory CD8 T cells is not well understood. Here we address this issue using the live yellow fever virus (YFV) vaccine, which induces long-term immunity in humans. We used in vivo deuterium labelling to mark CD8 T cells that proliferated in response to the virus and then assessed cellular turnover and longevity by quantifying deuterium dilution kinetics in YFV-specific CD8 T cells using mass spectrometry. This longitudinal analysis showed that the memory pool originates from CD8 T cells that divided extensively during the first two weeks after infection and is maintained by quiescent cells that divide less than once every year (doubling time of over 450 days). Although these long-lived YFV-specific memory CD8 T cells did not express effector molecules, their epigenetic landscape resembled that of effector CD8 T cells. This open chromatin profile at effector genes was maintained in memory CD8 T cells isolated even a decade after vaccination, indicating that these cells retain an epigenetic fingerprint of their effector history and remain poised to respond rapidly upon re-exposure to the pathogen.

Safety and immunogenicity of a trivalent virus-like particle vaccine against western, eastern, and Venezuelan equine encephalitis viruses: a phase 1, open-label, dose-escalation, randomised clinical trial.

BACKGROUND: Western (WEEV), eastern (EEEV), and Venezuelan (VEEV) equine encephalitis viruses are mosquito-borne pathogens classified as potential biological warfare agents for which there are currently no approved human vaccines or therapies. We aimed to evaluate the safety, tolerability, and immunogenicity of an investigational trivalent virus-like particle (VLP) vaccine, western, eastern, and Venezuelan equine encephalitis (WEVEE) VLP, composed of WEEV, EEEV, and VEEV VLPs. METHODS: The WEVEE VLP vaccine was evaluated in a phase 1, randomised, open-label, dose-escalation trial at the Hope Clinic of the Emory Vaccine Center at Emory University, Atlanta, GA, USA. Eligible participants were healthy adults aged 18-50 years with no previous vaccination history with an investigational alphavirus vaccine. Participants were assigned to a dose group of 6 µg, 30 µg, or 60 µg vaccine product and were randomly assigned (1:1) to receive the WEVEE VLP vaccine with or without aluminium hydroxide suspension (alum) adjuvant by intramuscular injection at study day 0 and at week 8. The primary outcomes were the safety and tolerability of the vaccine (assessed in all participants who received at least one administration of study product) and the secondary outcome was immune response measured as neutralising titres by plaque reduction neutralisation test (PRNT) 4 weeks after the second vaccination. This trial is registered at ClinicalTrials.gov, NCT03879603. FINDINGS: Between April 2, 2019, and June 13, 2019, 30 trial participants were enrolled (mean age 32 years, range 21-48; 16 [53%] female participants and 14 [47%] male participants). Six groups of five participants each received 6 µg, 30 µg, or 60 µg vaccine doses with or without adjuvant, and all 30 participants completed study follow-up. Vaccinations were safe and well tolerated. The most frequently reported symptoms were mild injection-site pain and tenderness (22 [73%] of 30) and malaise (15 [50%] of 30). Dose-dependent differences in the frequency of pain and tenderness were found between the 6 µg, 30 µg, and 60 µg groups (p=0·0217). No significant differences were observed between dosing groups for any other reactogenicity symptom. Two adverse events (mild elevated blood pressure and moderate asymptomatic neutropenia) were assessed as possibly related to the study product in one trial participant (60 µg dose with alum); both resolved without clinical sequelae. 4 weeks after second vaccine administration, neutralising antibodies were induced in all study groups with the highest response seen against all three vaccine antigens in the 30 µg plus alum group (PRNT80 geometric mean titre for EEEV 60·8, 95% CI 29·9-124·0; for VEEV 111·5, 49·8-249·8; and for WEEV 187·9, 90·0-392·2). Finally, 4 weeks after second vaccine administration, for all doses, the majority of trial participants developed an immune response to all three vaccine components (24 [83%] of 29 for EEEV; 26 [90%] of 29 for VEEV; 27 [93%] of 29 for WEEV; and 22 [76%] of 29 for EEEV, VEEV, and WEEV combined). INTERPRETATION: The favourable safety profile and neutralising antibody responses, along with pressing public health need, support further evaluation of the WEVEE VLP vaccine in advanced-phase clinical trials. FUNDING: The Vaccine Research Center of the National Institute of Allergy and Infectious Diseases, National Institutes of Health funded the clinical trial. The US Department of Defense contributed funding for manufacturing of the study product.

Pregnancy and virologic response to antiretroviral therapy in South Africa.

BACKGROUND: Although women of reproductive age are the largest group of HIV-infected individuals in sub-Saharan Africa, little is known about the impact of pregnancy on response to highly active antiretroviral therapy (HAART) in that setting. We examined the effect of incident pregnancy after HAART initiation on virologic response to HAART. METHODS AND FINDINGS: We evaluated a prospective clinical cohort of adult women who initiated HAART in Johannesburg, South Africa between 1 April 2004 and 30 September 2009, and followed up until an event, death, transfer, drop-out, or administrative end of follow-up on 31 March 2010. Women over age 45 and women who were pregnant at HAART initiation were excluded from the study; final sample size for analysis was 5,494 women. Main exposure was incident pregnancy, experienced by 541 women; main outcome was virologic failure, defined as a failure to suppress virus to ≤ 400 copies/ml by six months or virologic rebound >400 copies/ml thereafter. We calculated adjusted hazard ratios using marginal structural Cox proportional hazards models and weighted lifetable analysis to calculate adjusted five-year risk differences. The weighted hazard ratio for the effect of pregnancy on time to virologic failure was 1.34 (95% confidence limit [CL] 1.02, 1.78). Sensitivity analyses generally confirmed these main results. CONCLUSIONS: Incident pregnancy after HAART initiation was associated with modest increases in both relative and absolute risks of virologic failure, although uncontrolled confounding cannot be ruled out. Nonetheless, these results reinforce that family planning is an essential part of care for HIV-positive women in sub-Saharan Africa. More work is needed to confirm these findings and to explore specific etiologic pathways by which such effects may operate.