[Show abstract][Hide abstract] ABSTRACT: An HIV-1 DNA prime vaccine, with a recombinant adenovirus type 5 (rAd5) boost, failed to protect from HIV-1 acquisition. We studied the nature of the vaccine-induced antibody (Ab) response to HIV-1 envelope (Env). HIV-1-reactive plasma Ab titers were higher to Env gp41 than to gp120, and repertoire analysis demonstrated that 93% of HIV-1-reactive Abs from memory B cells responded to Env gp41. Vaccine-induced gp41-reactive monoclonal antibodies were non-neutralizing and frequently polyreactive with host and environmental antigens, including intestinal microbiota (IM). Next-generation sequencing of an immunoglobulin heavy chain variable region repertoire before vaccination revealed an Env-IM cross-reactive Ab that was clonally related to a subsequent vaccine-induced gp41-reactive Ab. Thus, HIV-1 Env DNA-rAd5 vaccine induced a dominant IM-polyreactive, non-neutralizing gp41-reactive Ab repertoire response that was associated with no vaccine efficacy.
[Show abstract][Hide abstract] ABSTRACT: It has been a year since the first case associated with the current Ebola virus outbreak in West Africa was identified and just over 8 months since we first started reporting on the outbreaks that stemmed from that patient in Guinea.(1) Today's posts at NEJM.org include an anniversary update on the fight against Ebola virus disease (EVD).(2) It is painfully clear that the world's initial handling of this dangerous outbreak was far from optimal, but we now appear to be making progress in the battle. This headway is evidenced by the observations that the rate of appearance of new cases . . .
New England Journal of Medicine 12/2014; 372(6). DOI:10.1056/NEJMe1415398 · 55.87 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Although the Ebola virus was recognized in 1976,(1) until now Ebola virus disease (EVD) had been confined to remote areas in Africa, occurring in discrete outbreaks. Even with the thousands of cases in the current outbreak, most cases occur in areas where tragically few resources are available to care for affected patients - in Guinea, Liberia, and Sierra Leone. However, a small number of patients have been transferred to hospitals with modern technology. In addition, in-country transmission has led to new cases of Ebola in Nigeria, Spain, and the United States. This is a troubling development, but it affords us . . .
New England Journal of Medicine 11/2014; 371(25). DOI:10.1056/NEJMe1412744 · 55.87 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background: Biological or behavioral factors may impact vaccine immunogenicity and efficacy. We investigated the relationship between trial volunteer baseline demographic and behavioral factors and vaccine-specific immune responses in 3 phase I HIV vaccine clinical trials.
Methods: Volunteers at low-risk for HIV infection received 2-4 injections of candidate HIV vaccines over 3 to 6 months in 3 phase I HIV vaccine clinical trials in Kenya, Uganda, Rwanda, Zambia, South Africa and the US from 2010–2013. Vaccine recipients in trial arms with robust IFN-g ELISPOT responses at 4 weeks after the last vaccination were included in the analysis. Multivariate logistic regression model with backward selection was used to assess the relationship between parameters at baseline (gender, age, body mass index (BMI), alcohol use, drug use) and the odds of a positive IFN-g ELISPOT, defined as>38 spot forming cells/ml and>4 fold mean background.
Results: 284 volunteers receiving at least one vaccine dose were included in the analysis. Of these, 44% were female, 54%≤age 26, mean BMI 23.1 (range 14–48). 13% reported weekly or daily alcohol use. Self-reported drug use was rare. Overweight BMI (≥30) correlated with 78% decreased odds of a positive ELISPOT response, p<0.005 When analyzed as a continuous variable, one unit increase in BMI correlated to a 8% decrease in the odds of a positive ELISPOT response, p<0.001. Daily or weekly alcohol use, compared to no alcohol use correlated with 3-fold increase in the odds of positive ELISPOT responses (p<0.05). Age, gender, and any drug use were not associated with ELISPOT responses.
Conclusions: Overweight BMI appears to be associated with decreased immune response to certain HIV vaccine candidates when measured by IFN-g ELISPOT in healthy, HIV low-risk populations. This effect may impact interpretation of phase I trials which typically have small group sizes. The positive association with alcohol use deserves further analysis.
AIDS Research and Human Retroviruses 10/2014; DOI:10.1089/aid.2014.5399.abstract. · 2.33 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The governors of a number of states, including New York and New Jersey, recently imposed 21-day quarantines on health care workers returning to the United States from regions of the world where they may have cared for patients with Ebola virus disease. We understand their motivation for this policy - to protect the citizens of their states from contracting this often-fatal illness. This approach, however, is not scientifically based, is unfair and unwise, and will impede essential efforts to stop these awful outbreaks of Ebola disease at their source, which is the only satisfactory goal. The governors' action is like . . .
New England Journal of Medicine 10/2014; 371(21). DOI:10.1056/NEJMe1413139 · 55.87 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background:
Invasive aspergillosis (IA) remains a leading cause of mortality in immunocompromised patients, in part due to the difficulty of diagnosing this infection.
Using thermal desorption-gas chromatography/mass spectrometry, we characterized the in vitro volatile metabolite profile of Aspergillus fumigatus, the most common cause of IA, and other pathogenic aspergilli. We prospectively collected breath samples from patients with suspected invasive fungal pneumonia from 2011 to 2013, and assessed whether we could discriminate patients with proven or probable IA from patients without aspergillosis, as determined by European Organization for Research and Treatment of Cancer/Mycoses Study Group consensus definitions, by direct detection of fungal volatile metabolites in these breath samples.
The monoterpenes camphene, α- and β-pinene, and limonene, and the sesquiterpene compounds α- and β-trans-bergamotene were distinctive volatile metabolites of A. fumigatus in vitro, distinguishing it from other pathogenic aspergilli. Of 64 patients with suspected invasive fungal pneumonia based on host risk factors, clinical symptoms, and radiologic findings, 34 were diagnosed with IA, whereas 30 were ultimately diagnosed with other causes of pneumonia, including other invasive mycoses. Detection of α-trans-bergamotene, β-trans-bergamotene, a β-vatirenene-like sesquiterpene, or trans-geranylacetone identified IA patients with 94% sensitivity (95% confidence interval [CI], 81%-98%) and 93% specificity (95% CI, 79%-98%).
In patients with suspected fungal pneumonia, an Aspergillus secondary metabolite signature in breath can identify individuals with IA. These results provide proof-of-concept that direct detection of exogenous fungal metabolites in breath can be used as a novel, noninvasive, pathogen-specific approach to identifying the precise microbial cause of pneumonia.
[Show abstract][Hide abstract] ABSTRACT: Finding an effective human immunodeficiency virus type 1 (HIV-1) vaccine remains a major global health priority. In a phase I/II, placebo-controlled trial, healthy, HIV-1-negative adults were randomized to receive one of 5 vaccine regimens: LIPO-5 (combination of 5 lipopeptides) alone (250 mu g), ALVAC-HIV (vCP1452) alone, or 3 groups of ALVAC-HIV (vCP1452) followed by ALVAC-HIV (vCP1452) plus LIPO-5 (250, 750, and 2,500 mu g). Only 73/174 participants (42%) received all four vaccinations due to a study halt related to myelitis. There were no significant differences in systemic reactions between groups or in local reactogenicity between groups receiving ALVAC-HIV (vCP1452). Significant differences in local reactogenicity occurred between groups receiving LIPO-5 (P <= 0.05). Gag and Env antibodies were undetectable by ELISA 2 weeks after the fourth vaccination for all but one recipient. Antibodies to Gag and Env were present in 32% and 24% of recipients of ALVAC-HIV (vCP1452) alone and in 47% and 35% of ALVAC-HIV (vCP1452) + LIPO recipients, respectively. Coadministration of LIPO-5 did not significantly increase the response rate compared to ALVAC-HIV (vCP1452) alone, nor was there a significant relationship between dose and antibody responses among ALVAC-HIV (vCP1452) + LIPO groups. Over 90% of study participants had no positive gamma interferon (IFN-gamma) enzyme-linked immunosorbent spot assay (ELISpot) responses to any peptide pool at any time point. The study was halted due to a case of myelitis possibly related to the LIPO-5 vaccine; this case of myelitis remains an isolated event. In general, there was no appreciable cell-mediated immunity detected in response to the vaccines used in this study, and antibody responses were limited.
[Show abstract][Hide abstract] ABSTRACT: In March 2014, an outbreak of a febrile illness associated with a high case fatality rate was identified in the Guéckédou region of Guinea-Conakry, a remote part of West Africa. An international field investigation was initiated. On April 16, the Journal published a preliminary report identifying the outbreak as due to Ebola virus.(1) The initial sequence data showed that the outbreak strain was Zaire ebolavirus, but a strain distinct from those identified in prior outbreaks, such as those in the Democratic Republic of Congo (DRC) and Gabon. In Guinea there appeared to be ongoing human-to-human transmission. Over the next 4 . . .
New England Journal of Medicine 09/2014; 371(15). DOI:10.1056/NEJMe1411378 · 55.87 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background Defining mucosal immune responses and inflammation to candidate human immunodeficiency virus type 1 (HIV-1) vaccines represents a current research priority for the HIV-1 vaccine field. In particular, it is unclear whether intramuscular immunization can elicit immune responses at mucosal surfaces in humans. Methods In this double-blind, randomized, placebo-controlled clinical trial, we evaluated systemic and mucosal immune responses to a candidate adenovirus serotype 26 (Ad26) vectored HIV-1 envelop (Env) vaccine in baseline Ad26-seronegative and Ad26-seropositive healthy volunteers. Systematic mucosal sampling with rectal Weck-Cel sponges and rectal biopsies were performed. Results Intramuscular immunization elicited both systemic and mucosal Env-specific humoral and cellular immune responses in the majority of subjects. Individuals with preexisting Ad26-specific neutralizing antibodies had vaccine-elicited immune responses comparable to those of subjects who were Ad26 seronegative. We also observed no increase in activated total or vector-specific mucosal CD4+ T lymphocytes following vaccination by either histopathology or flow cytometry. Conclusions These data demonstrate that a single intramuscular administration of this Ad26-vectored HIV-1 Env vaccine elicited both systemic and mucosal immune responses in humans. Induction of antigen-specific humoral and cellular mucosal immunity was not accompanied by a detectable increase in mucosal inflammation. Clinical Trials Registration NCT01103687.
The Journal of Infectious Diseases 08/2014; 211(4). DOI:10.1093/infdis/jiu485 · 6.00 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background:
Comprehensive data that address current HIV nonoccupational postexposure prophylaxis (nPEP) practices in the emergency care of sexual assault patients are limited. The U.S. Centers for Disease Control and Prevention released HIV nPEP guidelines in 2005 and updated guidelines for Sexually Transmitted Disease Treatment in 2006 and 2010, each of which support providing nPEP to sexual assault patients. This study examined the offer, acceptance, and adherence rates of nPEP among sexual assault patients treated at an emergency department (ED).
We conducted a retrospective review between January 1, 2008, and December 31, 2011, of women, aged 16 years and older, treated for sexual assault in an academic ED that participates in the sexual assault nurse examiner program.
One hundred seventy-one female patients were treated in the ED for 179 sexual assault events. nPEP was not indicated in 19 cases and was offered to all 138 of patients for whom nPEP was appropriate. Five patient cases that exceeded the 72-hour exposure window were offered nPEP. Of the 143 patient cases offered nPEP, 124 (86.7%) initiated nPEP. Of the 124 who accepted PEP, 34 (27.4%) had documented completion of the 28-day course.
nPEP was offered in all 138 cases where patients were eligible for treatment. Of patients who accepted nPEP, a minority are documented to have completed a course of treatment. Systems to improve postassault follow-up care should be considered.
Women s Health Issues 07/2014; 24(4):e407-12. DOI:10.1016/j.whi.2014.04.003 · 1.61 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Optimal hepatitis B (HBV) vaccination strategies for lung transplantation (LT) candidates are not well established.
LT candidates with negative anti-HBs and anti-HBc antibody titers at baseline who received standard-dose HBV vaccination (Recombivax-HB 10 mcg/mL or Engerix-B 20 mcg/mL) administered at months 0, 1, and 6 or an accelerated vaccination schedule on days 0, 7 to 14, and 21 to 28 between June 1988 and October 2012 were studied. Patients who were more likely to undergo LT within 6 months of evaluation received the accelerated vaccination schedule starting in August 2009.
Ninety-six HBV-seronegative patients who completed the vaccination series and had postvaccination anti-HBs titers available were identified. Median age was 60 years; 55.2% were female, and 92.7% were white. Underlying lung diseases included COPD (44.8%), idiopathic pulmonary fibrosis (22.9%), interstitial lung disease (15.6%), and cystic fibrosis (8.3%). The overall anti-HBs response rate was 54.2%. There was no significant difference in vaccine responses between accelerated and standard vaccination schedules (54.2% vs. 54.1%; P=1.0). Patients who received steroids or other immunosuppressants before transplantation had lower response rates compared with those who did not (38.9% vs. 63.3%; P=0.03).
Better vaccination strategies to improve response rate are needed in this population. The accelerated HBV vaccination schedule elicited similar anti-HBs responses as the standard schedule and could be advantageous in this population, given current organ allocation practices, and it could allow repeat vaccination series for initial nonresponders before transplantation.
[Show abstract][Hide abstract] ABSTRACT: Research to develop and validate novel methods for diagnosis of aspergillosis based on detection of galactomannan requires
the use of clinical specimens that have been stored frozen. Data indicating that galactomannan remains stable when frozen
are scant. The objective of this study was to determine the stability of galactomannan in clinical specimens stored at −20°C
that were positive in the Platelia Aspergillus enzyme immunoassay when initially tested. Prospective real-time testing of serum and bronchoalveolar lavage (BAL) fluid pools
from positive and negative patient specimens showed no decline in galactomannan index (GMI) over 11 months at −20°C and no
development of positive reactions in the negative-control pool. Retrospective testing of positive specimens that had been
stored at −20°C for 5 years showed that 28 of 30 serum (n = 15) or BAL (n = 15) specimens remained positive. These findings support the use of frozen serum or BAL specimens stored for at least 5
years in evaluation of diagnostic tests based on detection of galactomannan.
[Show abstract][Hide abstract] ABSTRACT: Background:
We report the first-in-human safety and immunogenicity assessment of a prototype hexon chimeric adenovirus (Ad) serotype 5 (Ad5) vector containing the hexon hypervariable regions of Ad serotype 48 (Ad48) and expressing human immunodeficiency virus (HIV) type 1 EnvA.
Forty-eight Ad5 and Ad48 seronegative, HIV-uninfected subjects were enrolled in a randomized, double-blind, placebo-controlled, dose escalation phase 1 study. Four groups of 12 subjects received 10(9) to 10(11) viral particles (vp) of the Ad5HVR48.EnvA.01 vaccine (n = 10 per group) or placebo (n = 2 per group) at week 0 or weeks 0, 4, and 24. Safety and immunogenicity were assessed.
Self-limited reactogenicity was observed after the initial immunization in the highest (10(11) vp) dose group. Responses in vaccinees included Ad48 neutralizing antibody (nAb) titers higher than Ad5 nAb titers, EnvA-specific enzyme-linked immunosorbent assay titers, and EnvA-specific enzyme-linked immunospot assay responses, and these responses generally persisted at week 52. At week 28 in the 10(9), 10(10), and 10(11) vp 3-dose groups, geometric mean EnvA enzyme-linked immunosorbent assay titers were 5721, 10 929, and 3420, respectively, and Ad48 nAb titers were a median of 1.7-fold higher than for Ad5.
Ad5HVR48.ENVA.01 was safe, well tolerated, and immunogenic at all doses tested. Vector-elicited nAb responses were greater for Ad48 than Ad5, confirming that Ad-specific nAbs in humans are primarily, but not exclusively, directed against the hexon hypervariable regions. Clinical Trials Registration. NCT00695877.
The Journal of Infectious Diseases 04/2014; 210(7). DOI:10.1093/infdis/jiu217 · 6.00 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Novel treatment modalities for previously fatal diseases, including newer chemotherapeutic and biologic agents and the expansion of the indications for solid organ and stem cell transplantation, have resulted in prolonged patient survival and a significant increase in the population of immunocompromised hosts (ICHs).
This review discusses the increasing spectrum of opportunistic infections in the ICH, the general approach for early diagnosis and treatment of pulmonary infections in this population, and the current and novel diagnostic modalities available to establish a rapid and specific microbiologic diagnosis, focusing on recent controversies and advances.
Early diagnosis and prompt initiation of effective therapy for infection help reduce morbidity in ICHs. Advances in diagnostic assays using nonculture-based methods, such as nucleic acid amplification, may allow for earlier targeted therapy. Invasive procedures including bronchoscopy and biopsy remain essential and should be vigorously pursued in ICHs given the broad differential diagnosis of possible pulmonary pathogens in this population, and the need to establish a specific diagnosis to allow accurate targeted therapy.
Current opinion in pulmonary medicine 03/2014; 20(3). DOI:10.1097/MCP.0000000000000051 · 2.76 Impact Factor