Faculty Bibliography

The live yellow fever vaccine (YF-17D) offers a unique opportunity to study memory CD8(+) T cell differentiation in humans following an acute viral infection. We have performed a comprehensive analysis of the virus-specific CD8(+) T cell response using overlapping peptides spanning the entire viral genome. Our results showed that the YF-17D vaccine induces a broad CD8(+) T cell response targeting several epitopes within each viral protein. We identified a dominant HLA-A2-restricted epitope in the NS4B protein and used tetramers specific for this epitope to track the CD8(+) T cell response over a 2 year period. This longitudinal analysis showed the following. 1) Memory CD8(+) T cells appear to pass through an effector phase and then gradually down-regulate expression of activation markers and effector molecules. 2) This effector phase was characterized by down-regulation of CD127, Bcl-2, CCR7, and CD45RA and was followed by a substantial contraction resulting in a pool of memory T cells that re-expressed CD127, Bcl-2, and CD45RA. 3) These memory cells were polyfunctional in terms of degranulation and production of the cytokines IFN-gamma, TNF-alpha, IL-2, and MIP-1beta. 4) The YF-17D-specific memory CD8(+) T cells had a phenotype (CCR7(-)CD45RA(+)) that is typically associated with terminally differentiated cells with limited proliferative capacity (T(EMRA)). However, these cells exhibited robust proliferative potential showing that expression of CD45RA may not always associate with terminal differentiation and, in fact, may be an indicator of highly functional memory CD8(+) T cells generated after acute viral infections.

We report 3 cases of herpes simplex virus encephalitis in patients receiving tumor necrosis factor-alpha (TNF-alpha) inhibitors for rheumatologic disorders. Although TNF-alpha inhibitors have been reported to increase the risk of other infectious diseases, to our knowledge, an association between anti-TNF-alpha drugs and herpes simplex virus encephalitis has not been previously described.

Nearly three decades after the first description in 1981 of the syndrome eventually designated as AIDS, only five efficacy trials testing just three HIV vaccine concepts have been initiated. In 2007, an efficacy analysis was conducted for the first of a newer generation of candidate HIV/AIDS vaccines based entirely on cellular immunity. Data from this study, known as the Step Study, indicated that the vaccine neither protected against infection nor lowered viral loads after infection. Furthermore, certain vaccinees were at higher risk of HIV infection following vaccination. This article explores these disappointing and surprising outcomes, reviews earlier efficacy studies and more recent discovery research, and provides a critical analysis of the field. Other HIV prevention interventions are considered because their successful implementation may dramatically alter the milieu for future HIV vaccine field trials, particularly impacting study designs and increasing sample sizes if incidence falls.

BACKGROUND:The Step Study, a Phase IIb HIV vaccine proof of concept study, enrolled approximately 3000 persons in clade B regions. The Atlanta site sought to enroll a diverse population. This prospective cohort study examined key factors associated with participant enrollment. METHODS:We obtained participant information (eg, sociodemographic, medical) and followed outcomes from 2005 to 2007. Of the 810 potential "Step Study" participants, 340 cases were analyzed. RESULTS:The recruitment strategy generated strong interest among minorities with 37% eligible after prescreening, yet 25% of the minorities enrolled. However, the percentage of whites increased from 62% eligible (prescreened sample) to 75% enrolled. The regression model was significant with educational level being an enrollment predictor (P = 0.0023). Those with at least a bachelor's degree were more likely to enroll compared with those with a K-12 education or some college (odds ratio = 2.424, 95% confidence interval = 1.372 to 4.281, P < 0.01). White race was also a significant factor (odds ratio = 2.330; 95% confidence interval = 1.241 to 4.375, P < 0.01). No difference in enrollment was observed among recruitment approaches, Pearson chi (2) (n = 336) = 5.286, P = 0.07. CONCLUSIONS:The results from this study indicate that women, minorities, and those with lower educational attainment were less likely to enroll in an HIV vaccine efficacy study at our site. The findings highlight an important consideration on the role of health literacy to sustain participation of eligible minorities in HIV vaccine trials.

Vaccines inducing pathogen-specific cell-mediated immunity are being developed using attenuated adenoviral (Ad) vectors. We report the results of two independent Phase I trials of similar replication-deficient Ad5 vaccines containing a near-consensus HIV-1 clade B gag transgene. Healthy HIV-uninfected adults were enrolled in two separate, multicenter, dose-escalating, blinded, placebo-controlled studies to assess the safety and immunogenicity of a three-dose homologous regimen of Ad5 and MRKAd5 HIV-1 gag vaccines given on day 1, week 4, and week 26. Adverse events were collected for 29 days following each intradeltoid injection. The primary immunogenicity endpoint was the proportion of subjects with a positive unfractionated Gag-specific IFN-gamma ELISPOT response measured 4 weeks after the last dose (week 30). Analyses were performed after combining data for each dose group from both protocols, stratifying by baseline Ad5 titers. Overall, 252 subjects were randomized to receive either vaccine or placebo, including 229 subjects (91%) who completed the study through week 30. Tolerability and immunogenicity did not appear to differ between the Ad5 and MRKAd5 vaccines. The frequency of injection-site reactions was dose dependent. Systemic adverse events were also dose dependent and more frequent in subjects with baseline Ad5 titers <200 versus > or =200, especially after the first dose. The percent of ELISPOT responders and the ELISPOT geometric means overall were significantly higher for all four vaccine doses studied compared to placebo, and were generally higher in vaccine recipients with baseline Ad5 titers <200 versus > or = 200. Ad5 titers increased after vaccination in a dose-dependent fashion. Both Ad5-vectored HIV-1 vaccines were generally well tolerated and induced cell-mediated immune responses against HIV Gag-peptides in the majority of healthy adults with baseline Ad5 titers <200. Preexistent and/or vaccine-induced immunity to the Ad5 vector may dampen the CMI response to HIV Gag.

CONTEXT/BACKGROUND:In 1999, the US Congress directed the Centers for Disease Control and Prevention to conduct a pivotal safety and efficacy study of anthrax vaccine adsorbed (AVA). OBJECTIVE:To determine the effects on serological responses and injection site adverse events (AEs) resulting from changing the route of administration of AVA from subcutaneous (s.q.) to intramuscular (i.m.) and omitting the week 2 dose from the licensed schedule. DESIGN, SETTING, AND PARTICIPANTS/METHODS:Assessment of the first 1005 enrollees in a multisite, randomized, double-blind, noninferiority, phase 4 human clinical trial (ongoing from May 2002). INTERVENTION/METHODS:Healthy adults received AVA by the s.q. (reference group) or i.m. route at 0, 2, and 4 weeks and 6 months (4-SQ or 4-IM; n = 165-170 per group) or at a reduced 3-dose schedule (3-IM; n = 501). A control group (n = 169) received saline injections at the same time intervals. MAIN OUTCOME MEASURES/METHODS:Noninferiority at week 8 and month 7 of anti-protective antigen IgG geometric mean concentration (GMC), geometric mean titer (GMT), and proportion of responders with a 4-fold rise in titer (%4 x R). Reactogenicity outcomes were proportions of injection site and systemic AEs. RESULTS:At week 8, the 4-IM group (GMC, 90.8 microg/mL; GMT, 1114.8; %4 x R, 97.7) was noninferior to the 4-SQ group (GMC, 105.1 microg/mL; GMT, 1315.4; %4 x R, 98.8) for all 3 primary end points. The 3-IM group was noninferior for only the %4 x R (GMC, 52.2 microg/mL; GMT, 650.6; %4 x R, 94.4). At month 7, all groups were noninferior to the licensed regimen for all end points. Solicited injection site AEs assessed during examinations occurred at lower proportions in the 4-IM group compared with 4-SQ. The odds ratio for ordinal end point pain reported immediately after injection was reduced by 50% for the 4-IM vs 4-SQ groups (P < .001). Route of administration did not significantly influence the occurrence of systemic AEs. CONCLUSIONS:The 4-IM and 3-IM regimens of AVA provided noninferior immunological priming by month 7 when compared with the 4-SQ licensed regimen. Intramuscular administration significantly reduced the occurrence of injection site AEs. Trial Registration clinicaltrials.gov Identifier: NCT00119067.

The purpose of this exploratory study was to examine personal characteristics, socio-environmental conditions, and motivational factors that potentially influence HIV vaccine research community engagement. Specifically, the study identified predictive aspects that may aid in future community program development on HIV vaccine issues. A cross-sectional survey consisting of evaluative measures, demographics, social interaction, and health information-seeking behaviors was conducted. Participants were a diverse group of 452 adults (>or=18 years) at HIV vaccine awareness-building and community education gatherings in Atlanta. The sample included large numbers of women (n=251) and minorities (n=224). In multivariate analysis, the overall logistic regression model was significant, with a resulting coefficient of determination (Nagelkerke R(2)) of .505. Highly significant factors included an excellent activity/event rating (log odds beta = 4.521, P< .001), White race (beta= -.835, P= .005), greater educational attainment (beta= .725, P= .011), travel distance (beta = 1.186, P= .002), and excellent perception of the study site (beta=2.131, P< .001). Subgroup analyses by gender and race revealed similar findings. These data demonstrate the importance of building a favorable study site image and gaining familiarity in the community to aid in the promotion of HIV vaccine research on an ongoing basis.

To explore the human T cell response to acute viral infection, we performed a longitudinal analysis of CD8(+) T cells responding to the live yellow fever virus and smallpox vaccines--two highly successful human vaccines. Our results show that both vaccines generated a brisk primary effector CD8(+) T cell response of substantial magnitude that could be readily quantitated with a simple set of four phenotypic markers. Secondly, the vaccine-induced T cell response was highly specific with minimal bystander effects. Thirdly, virus-specific CD8(+) T cells passed through an obligate effector phase, contracted more than 90% and gradually differentiated into long-lived memory cells. Finally, these memory cells were highly functional and underwent a memory differentiation program distinct from that described for human CD8(+) T cells specific for persistent viruses. These results provide a benchmark for CD8(+) T cell responses induced by two of the most effective vaccines ever developed.