Faculty Bibliography

From September 2014 to April 2015, 6 persons who had occupational exposures to Zaire ebolavirus in West Africa received investigational agent rVSV-ZEBOV or TKM-100802 for postexposure prophylaxis and were monitored in the United States. All patients experienced self-limited symptoms after postexposure prophylaxis; none developed Ebola virus disease.

Zika virus (ZIKV) is an emerging mosquito-borne flavivirus of significant public health concern. ZIKV shares a high degree of sequence and structural homology compared with other flaviviruses, including dengue virus (DENV), resulting in immunological cross-reactivity. Improving our current understanding of the extent and characteristics of this immunological cross-reactivity is important, as ZIKV is presently circulating in areas that are highly endemic for dengue. To assess the magnitude and functional quality of cross-reactive immune responses between these closely related viruses, we tested acute and convalescent sera from nine Thai patients with PCR-confirmed DENV infection against ZIKV. All of the sera tested were cross-reactive with ZIKV, both in binding and in neutralization. To deconstruct the observed serum cross-reactivity in depth, we also characterized a panel of DENV-specific plasmablast-derived monoclonal antibodies (mAbs) for activity against ZIKV. Nearly half of the 47 DENV-reactive mAbs studied bound to both whole ZIKV virion and ZIKV lysate, of which a subset also neutralized ZIKV. In addition, both sera and mAbs from the dengue-infected patients enhanced ZIKV infection of Fc gamma receptor (FcγR)-bearing cells in vitro. Taken together, these findings suggest that preexisting immunity to DENV may impact protective immune responses against ZIKV. In addition, the extensive cross-reactivity may have implications for ZIKV virulence and disease severity in DENV-experienced populations.

HIV incidence rates are higher among black men who have sex with men (BMSM) as compared with MSM of other race/ethnicities in the USA. We found that blood memory CD4 cells from BMSM express higher levels of α4β7, the gut-homing integrin, compared with white MSM. Higher expression of α4β7 on blood CD4 cells correlated with higher percentage of proliferating CD4α4β7 cells in rectal tissue suggesting increased trafficking of potential HIV target cells to rectal mucosa could increase HIV susceptibility among BMSM.

BACKGROUND:Increasing the breadth of human immunodeficiency virus type 1 (HIV-1) vaccine-elicited immune responses or targeting conserved regions may improve coverage of circulating strains. HIV Vaccine Trials Network 083 tested whether cellular immune responses with these features are induced by prime-boost strategies, using heterologous vectors, heterologous inserts, or a combination of both. METHODS:A total of 180 participants were randomly assigned to receive combinations of adenovirus vectors (Ad5 or Ad35) and HIV-1 envelope (Env) gene inserts (clade A or B) in a prime-boost regimen. RESULTS:T-cell responses to heterologous and homologous insert regimens targeted a similar number of epitopes (ratio of means, 1.0; 95% confidence interval [CI], .6-1.6; P = .91), but heterologous insert regimens induced significantly more epitopes that were shared between EnvA and EnvB than homologous insert regimens (ratio of means, 2.7; 95% CI, 1.2-5.7; P = .01). Participants in the heterologous versus homologous insert groups had T-cell responses that targeted epitopes with greater evolutionary conservation (mean entropy [±SD], 0.32 ± 0.1 bits; P = .003), and epitopes recognized by responders provided higher coverage (49%; P = .035). Heterologous vector regimens had higher numbers of total, EnvA, and EnvB epitopes than homologous vector regimens (P = .02, .044, and .045, respectively). CONCLUSIONS:These data demonstrate that vaccination with heterologous insert prime boosting increased T-cell responses to shared epitopes, while heterologous vector prime boosting increased the number of T-cell epitopes recognized. CLINICAL TRIALS REGISTRATION/BACKGROUND:NCT01095224.

Systems approaches have been used to describe molecular signatures driving immunity to influenza vaccination in humans. Whether such signatures are similar across multiple seasons and in diverse populations is unknown. We applied systems approaches to study immune responses in young, elderly, and diabetic subjects vaccinated with the seasonal influenza vaccine across five consecutive seasons. Signatures of innate immunity and plasmablasts correlated with and predicted influenza antibody titers at 1 month after vaccination with >80% accuracy across multiple seasons but were not associated with the longevity of the response. Baseline signatures of lymphocyte and monocyte inflammation were positively and negatively correlated, respectively, with antibody responses at 1 month. Finally, integrative analysis of microRNAs and transcriptomic profiling revealed potential regulators of vaccine immunity. These results identify shared vaccine-induced signatures across multiple seasons and in diverse populations and might help guide the development of next-generation vaccines that provide persistent immunity against influenza.

BACKGROUND:The current West Africa Ebola virus disease (EVD) outbreak has resulted in multiple individuals being medically evacuated to other countries for clinical management. METHODS:We report two patients who were transported from West Africa to the United States for treatment of EVD. Both patients received aggressive supportive care measures, as well as an investigational therapeutic (TKM-100802) and convalescent plasma. RESULTS:While one patient experienced critical illness with multi-organ failure requiring mechanical ventilation and renal replacement therapy, both patients recovered without serious long-term sequelae to date. CONCLUSIONS:It is unclear what role the experimental drug and convalescent plasma had in the recovery of these patients. Prospective clinical trials are needed to delineate the role of investigational therapies in the care of patients with EVD.

BACKGROUND:Variant influenza A(H3N2) viruses (H3N2v) have transmitted recently from pigs to humans in the United States. Vaccines strategies are needed. METHODS:Healthy adults received 2 doses of subvirion H3N2v vaccine (15 µg of hemagglutinin/dose) 21 days apart in this open-label trial. Serum hemagglutination inhibition (HAI) and neutralizing (Neut) antibody (Ab) titers were measured before and 8 and 21 days after each dose. Memory B-cell (MBC) responses were assessed. RESULTS:Vaccine was well tolerated. A total of 40% of subjects had an HAI Ab titer of ≥40 before vaccination. Eight-seven percent (95% confidence interval [CI], 79%-93%) and 73% (95% CI, 63%-81%) of subjects 18-64 years old (98 subjects) and ≥65 years old (90 subjects), respectively, had an HAI titer of ≥40 21 days after dose 1 (P = .01); 51% (95% CI, 41%-61%) and 52% (95% CI, 41%-62%) of younger and older subjects, respectively, developed ≥4-fold rises in titer (P = not significant). Neut Ab response patterns were similar. Geometric mean titers were higher in younger subjects. Dose 2 provided no significant enhancement in responses. Cross-reactive MBCs were detected before vaccination and expanded after vaccination. Preexisting H3N2v-specific MBCs positively correlated with early increases in vaccine-induced Ab. CONCLUSIONS:In most healthy adults, one 15-µg dose of vaccine elicited levels of HAI Abs associated with protection. Studies in children and elderly individuals are indicated to define the immunization needs of these groups. CLINICAL TRIALS REGISTRATION/BACKGROUND:NCT01746082.

PURPOSE/OBJECTIVE:To describe factors associated with racial disparities in HIV (human immunodeficiency virus) incidence among men who have sex with men (MSM) in the United States. METHODS:In a longitudinal cohort of black and white HIV-negative MSM in Atlanta, HIV incidence rates were compared by race. Incidence hazard ratios (HRs) between black and white MSM were estimated with an age-scaled Cox proportional hazards model. A change-in-estimate approach was used to understand mediating time-independent and -dependent factors that accounted for the elevated HR. RESULTS:Thirty-two incident HIV infections occurred among 260 black and 302 white MSM during 843 person-years (PY) of follow-up. HIV incidence was higher among black MSM (6.5/100 PY; 95% confidence interval [CI]: 4.2-9.7) than white MSM (1.7/100 PY; CI: 0.7-3.3) and highest among young (18-24 years) black MSM (10.9/100 PY; CI: 6.2-17.6). The unadjusted hazard of HIV infection for black MSM was 2.9 (CI: 1.3-6.4) times that of white MSM; adjustment for health insurance status and partner race explained effectively all of the racial disparity. CONCLUSIONS:Relative to white MSM in Atlanta, black MSM, particularly young black MSM, experienced higher HIV incidence that was not attributable to individual risk behaviors. In a setting where partner pool risk is a driver of disparities, it is also important to maximize care and treatment for HIV-positive MSM.