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The potential use of Bacillus anthracis as a bioterrorism weapon requires a safe and effective vaccine that can be immediately distributed for mass vaccination. Protective antigen (PA), a principal component of virulence factors edema toxin and lethal toxin of B. anthracis, has been the topic of extensive research. Previously, full-length PA (PA83) was manufactured using a transient plant-based expression system. Immunization with this PA83 antigen formulated with Alhydrogel® adjuvant elicited strong neutralizing immune responses in mice and rabbits and protected 100% of rabbits from a lethal aerosolized B. anthracis challenge. This Phase 1 study evaluates this vaccine's safety and immunogenicity in healthy human volunteers.This first-in-human, single-blind, Phase 1 study was performed at a single center to investigate the safety, reactogenicity, and immunogenicity of the plant-derived PA83-FhCMB vaccine at four escalating dose levels (12.5, 25, 50 or 100 µg) with Alhydrogel® in healthy adults 18-49 years of age (inclusive). Recipients received three doses of vaccine intramuscularly at 28-day intervals. Safety was evaluated on days 3, 7, and 14 following vaccination. Immunogenicity was assessed using an enzyme-linked immunosorbent assay (ELISA) and a toxin neutralizing antibody (TNA) assay on days 0, 14, 28, 56, 84, and 180.All four-dose ranges were safe and immunogenic, with no related serious adverse events observed. Peak ELISA Geometric Mean Concentration (GMC) and TNA EDThis is the first study demonstrating a plant-derived subunit anthrax vaccine's safety and immunogenicity in healthy adults. The results support further clinical investigation of the PA83-FhCMB vaccine. ClinicalTrials.gov identifier. NCT02239172.

The preferred antibiotic salvage regimen for persistent methicillin-resistant Staphylococcus aureus bacteremia (MRSAB) is unclear. We sought to evaluate the effectiveness and safety of vancomycin plus ceftaroline for persistent MRSAB. The primary outcome was time to MRSAB clearance post-ceftaroline initiation. Secondary outcomes included microbiological cure, hospital length of stay, 90-day readmission for MRSAB, 90-day all-cause mortality, MRSAB-related mortality, and incidence of antibiotic-associated adverse effects.Single-center, retrospective cohort study between January 1, 2016, and December 31, 2021.State University of New York Upstate University Hospital, a 748-bed tertiary care, academic medical center in Syracuse, NY.Adult patients were included if they had blood cultures positive for MRSA ≥72 h, received vancomycin monotherapy initially, and received vancomycin plus ceftaroline for ≥24 h. Patients were excluded if they received other anti-MRSA antibiotics, were pregnant, or were incarcerated. Of the 178 patients identified, 30 unique patients were evaluated.Patients were medically complex with a median Pitt bacteremia score of 3, 63.3% (19/30) were admitted to the intensive care unit, and 66.7% (20/30) had infective endocarditis. Vancomycin-associated acute kidney injury was observed in 10% (3/30) of patients, which resulted in dose adjustments. No patients experienced ceftaroline-associated neutropenia or Clostridioides difficile infection, but 6.7% (2/30) developed a rash attributed to ceftaroline. Median time to MRSAB clearance post-ceftaroline initiation was 2.6 days. Microbiologic cure occurred in nearly all patients 96.7% (29/30). Median hospital length of stay was 19.5 days, and 6.7% (2/30) of patients had 90-day readmission for MRSAB. 90-day all-cause mortality and MRSAB-related mortality occurred in 26.7% (8/30) and 13.3% (4/30) of patients, respectively.Vancomycin plus ceftaroline may represent an effective and well-tolerated salvage regimen option for persistent MRSAB.

Background Dengue is a global health problem and the development of a tetravalent dengue vaccine with durable protection is a high priority. A heterologous prime-boost strategy has the advantage of eliciting immune responses through different mechanisms and therefore may be superior to homologous prime-boost strategies for generating durable tetravalent immunity. Methods In this phase 1 first-in-human heterologous prime-boost study, 80 volunteers were assigned to 4 groups and received a tetravalent dengue virus (DENV-1–4) purified inactivated vaccine (TDENV-PIV) with alum adjuvant and a tetravalent dengue virus (DENV-1–4) live attenuated vaccine (TDENV-LAV) in different orders and dosing schedules (28 or 180 days apart). Results All vaccination regimens had acceptable safety profiles and there were no vaccine-related serious adverse events. TDEN-PIV followed by TDEN-LAV induced higher neutralizing antibody titers and a higher rate of tetravalent seroconversions compared to TDEN-LAV followed by TDEN-PIV. Both TDEN-PIV followed by TDEN-LAV groups demonstrated 100% tetravalent seroconversion 28 days following the booster dose, which was maintained for most of these subjects through the day 180 measurement. Conclusions A heterologous prime-boost vaccination strategy for dengue merits additional evaluation for safety, immunogenicity, and potential for clinical benefit. Clinical Trials Registration NCT02239614.

Background Dengue human infection models (DHIM) have been used as a safe means to test the viability of prophylaxis and therapeutics. Methods A phase 1 study of 12 healthy adult volunteers using a challenge virus, DENV-1-LVHC strain 45AZ5, was performed. A dose escalating design was used to determine the safety and performance profile of the challenge virus. Subjects were evaluated extensively until 28 days and then out to 6 months. Results Twelve subjects received the challenge virus: 6 with 0.5 mL of 6.5 × 103 plaque-forming units (PFU)/mL (low-dose group) and 6 with 0.5 mL of 6.5 × 104 PFU/mL (mid-dose group). All except 1 in the low-dose group developed detectable viremia. For all subjects the mean incubation period was 5.9 days (range 5–9 days) and mean time of viremia was 6.8 days (range 3–9 days). Mean peak for all subjects was 1.6 × 107 genome equivalents (GE)/mL (range 4.6 × 103 to 5 × 107 GE/mL). There were no serious adverse events or long-term safety signals noted. Conclusions We conclude that DENV-1-LVHC was well-tolerated, resulted in an uncomplicated dengue illness, and may be a suitable DHIM for therapeutic and prophylactic product testing. Clinical Trials Registration NCT02372175.

BackgroundPlasmodium vivax malaria requires a 2-week course of primaquine (PQ) for radical cure. Evidence suggests that the hepatic isoenzyme cytochrome P450 2D6 (CYP2D6) is the key enzyme required to convert PQ into its active metabolite.MethodsCYP2D6 genotypes and phenotypes of 550 service personnel were determined, and the pharmacokinetics (PK) of a 30-mg oral dose of PQ was measured in 45 volunteers. Blood and urine samples were collected, with PQ and metabolites were measured using ultraperformance liquid chromatography with mass spectrometry.ResultsSeventy-six CYP2D6 genotypes were characterized for 530 service personnel. Of the 515 personnel for whom a single phenotype was predicted, 58% had a normal metabolizer (NM) phenotype, 35% had an intermediate metabolizer (IM) phenotype, 5% had a poor metabolizer (PM) phenotype, and 2% had an ultrametabolizer phenotype. The median PQ area under the concentration time curve from 0 to ∞ was lower for the NM phenotype as compared to the IM or PM phenotypes. The novel 5,6-ortho-quinone was detected in urine but not plasma from all personnel with the NM phenotype.ConclusionThe plasma PK profile suggests PQ metabolism is decreased in personnel with the IM or PM phenotypes as compared to those with the NM phenotype. The finding of 5,6-ortho-quinone, the stable surrogate for the unstable 5-hydroxyprimaquine metabolite, almost exclusively in personnel with the NM phenotype, compared with sporadic or no production in those with the IM or PM phenotypes, provides further evidence for the role of CYP2D6 in radical cure.Clinical Trials RegistrationNCT02960568.

Antibody effector functions such as antibody dependent cellular cytotoxicity (ADCC) and antibody dependent cellular phagocytosis (ADCP) are considered important immunologic parameters following results from the RV144 clinical trial where a reduced risk of infection was associated with non-neutralizing antibody against the V1/V2 region of HIV envelope. The rapid and fluorometric ADCC (RFADCC) assay has been widely used to measure ADCC, however, the mechanism behind the activity measured remains unclear. Here, we demonstrate that monocytes acquire the PKH26 dye used in the RFADCC assay and that the commonly used RFADCC readout correlates with phagocytosis. The RFADCC assay was combined with an amine reactive dye staining to confirm target cell killing. Interestingly, the majority of RFADCC and amine indices were mutually exclusive. In fact, the amine reactive assay results correlated with results from another assays that directly measure NK cell antibody effector functions not associated with phagocytosis. Together, this combined assay offers the opportunity to discriminate monocytes and NK cell antibody effector functions simultaneously.

This is the accepted manuscript version of the work published in its final form asBershteyn, A., Schwartz, M. D., Thorpe, L. E., Paasche-orlow, M. K., Kissinger, P., Karita, H. C. S., Laufer, M. K., Hoffman, R. M., Landovitz, R. J., Paolino, K., & Ruanne V. Barnabas. (2021). Taking a stand against the politicization of medical research: How 'swinging the pendulum' poses a hazard to clinical trials, study participants, and the progress of science.Expert Review of Clinical Immunology,17(1), 101-103. https://doi.org/10.1080/1744666x.2020.1860758 Deposited byshareyourpaper.organdopenaccessbutton.org. We've taken reasonable steps to ensure this content doesn't violate copyright. However, if you think it does you can request a takedown by emailinghelp@openaccessbutton.org. &nbsp

Background: Treatment options for outpatients with COVID-19 could reduce morbidity and prevent SARS-CoV-2 transmission. Methods: In this randomized, double-blind, three-arm (1:1:1) placebo-equivalent control trial conducted remotely throughout the United States, adult outpatients with laboratory-confirmed SARS-CoV-2 infection were recruited. Participants were randomly assigned to receive HCQ (400mg BID x1day, followed by 200mg BID x9days) or placebo-equivalent (ascorbic acid) and AZ (500mg, then 250mg daily x4days) or placebo-equivalent (folic acid), stratified by risk for progression to severe COVID-19 (high-risk vs. low-risk). Self-collected mid-turbinate nasal swabs for SARS-CoV-2 PCR, FLUPro symptom surveys, EKGs and vital signs collected daily. Primary endpoints were: (a) 14-day progression to lower respiratory tract infection (LRTI), 28-day COVID-19 related hospitalization, or death; (b) 14-day time to viral clearance; secondary endpoints included time to symptom resolution (ClinicalTrials.gov: NCT04354428). Due to the low rate of clinical outcomes, the study was terminated for operational futility. Findings: Between 15th April and 27th July 2020, 231 participants were enrolled and 219 initiated medication a median of 5.9 days after symptom onset. Incident LRTI occurred in six participants (two control, four HCQ/AZ) and COVID-19 related hospitalization in nine (four control, two HCQ, three HCQ/AZ). There were no deaths. Median time to clearance was 5 days (95% CI=4-6) in HCQ, 6 days (95% CI=4-8) in HCQ/AZ, and 8 days (95% CI=6-10) in control. HCQ but not HCQ/AZ had faster time to viral clearance (HR=1.62, 95% CI=1.01-2.60, p=0.047 & HR=1.25, 95% CI=0.75-2.07, p=0.39) compared to control. Among 197 participants who met the COVID-19 definition at enrollment, time to symptom resolution did not differ by group. Interpretation: Neither HCQ nor HCQ/AZ shortened the clinical course of outpatients with COVID-19, and HCQ, but not HCQ/AZ, had only a modest effect on SARS-CoV-2 viral shedding. HCQ and HCQ/AZ are not effective therapies for outpatient treatment of SARV-CoV-2 infection. Trial Registration Number: ClinicalTrials.gov: NCT04354428 Funding: The COVID-19 Early Treatment Study was funded by the Bill & Melinda Gates Foundation (INV-017062) through the COVID-19 Therapeutics Accelerator. University of Washington Institute of Translational Health Science (ITHS) grant support (UL1 TR002319), KL2 TR002317, and TL1 TR002318 from NCATS/NIH funded REDCap. The content is solely the responsibility of the authors and does not necessarily represent the views, decisions, or policies of the institutions with which they are affiliated. PAN and MJA were supported by the Mayo Clinic Windland Smith Rice Comprehensive Sudden Cardiac Death Program. Conflict of Interest: Declaration of interests: CJ reports grants from BMGF for conduct of the study, and grants from CDC and NIH outside of the submitted work. HSK reports funding from NIH. PAN and MJA have a potential financial relationship with AliveCor related to QT assessment using the device, however the investigators would receive no financial benefit for use of the technology for patients at Mayo Clinic or for its use in the current study. AB reports consulting for Gates Ventures and grants from BMGF and NIH outside of the submitted work. HYC reports consulting for BMGF, Pfizer, Ellume, and Merck, and grants from Gates Ventures, NIH, CDC, BMGF, DARPA, Apple Inc., Sanofi-Pasteur, and Roche-Genentech, outside of the submitted work. Ethical Approval: Study visits were conducted via Health Insurance Portability and Accountability Act (HIPAA)-compliant telemedicine. The Western Institutional Review Board (WIRB) approved this study with reliance agreements with collaborating institutions.

To evaluate a pharmacist-facilitated evidence-based bundle (EBB) initiative with infectious disease consultation (IDC) for Staphylococcus aureus bacteremia (SAB).This was a before-and-after quasi-experimental study of adult patients with SAB before and after the pharmacist-facilitated EBB initiative, which included IDC, timely definitive antibiotics, source control, echocardiography, and repeat blood cultures.Ninety and 111 patients were included in pre- and post-intervention cohorts, respectively. We observed significant increases in adherence to all 5 (4.4% vs 68.5%, P0.001) and 4 (10.0% vs 76.6%, P0.001) EBB elements. Time to definitive antibiotics (48 vs 16 hours, P0.001), time to IDC (43.5 vs 32 hours, P0.001), SAB duration (95 vs 66 hours, P = 0.009), persistent SAB (18.9% vs 9.0%, P = 0.041), and length of stay (14 vs 13 days, P = 0.027) also improved. No statistically significant differences for SAB-related readmission or all-cause mortality were observed.Our pharmacist-facilitated SAB initiative was associated with improved EBB adherence and clinical outcomes.

The safety and immunogenicity of four formulations of an investigational tetravalent dengue purified inactivated vaccine (DPIV), formulated at 1 or 4 μg with aluminum hydroxide (alum) or at 1 μg with an adjuvant system (AS01E or AS03B), were evaluated in a first-time-in-human, placebo-controlled, randomized, observer-blind, phase 1 trial in the continental United States. Two doses of vaccine or placebo were administered intramuscularly 4 weeks apart to 100 healthy adults 18-39 years of age, randomized 1:1:1:1:1 to receive one of four DPIV formulations or saline placebo. The response to a third dose was evaluated in a subset of nine participants remote from primary vaccination. Humoral immunogenicity was assessed using a 50% microneutralization assay. All DPIV formulations were well tolerated. No vaccine-related serious adverse events were observed through 12 months after the second vaccine dose. In all DPIV groups, geometric mean antibody titers peaked at Day 56, waned through 6 months after the second vaccine dose, and then stabilized. In the nine subjects where boosting was evaluated, a strong anamnestic response was observed. These results support continuation of the clinical development of this dengue vaccine candidate (clinicaltrials.gov: NCT01666652).

The worst Ebola virus disease (EVD) outbreak in history has resulted in more than 28,000 cases and 11,000 deaths. We present the final results of two phase 1 trials of an attenuated, replication-competent, recombinant vesicular stomatitis virus (rVSV)-based vaccine candidate designed to prevent EVD.We conducted two phase 1, placebo-controlled, double-blind, dose-escalation trials of an rVSV-based vaccine candidate expressing the glycoprotein of a Zaire strain of Ebola virus (ZEBOV). A total of 39 adults at each site (78 participants in all) were consecutively enrolled into groups of 13. At each site, volunteers received one of three doses of the rVSV-ZEBOV vaccine (3 million plaque-forming units [PFU], 20 million PFU, or 100 million PFU) or placebo. Volunteers at one of the sites received a second dose at day 28. Safety and immunogenicity were assessed.The most common adverse events were injection-site pain, fatigue, myalgia, and headache. Transient rVSV viremia was noted in all the vaccine recipients after dose 1. The rates of adverse events and viremia were lower after the second dose than after the first dose. By day 28, all the vaccine recipients had seroconversion as assessed by an enzyme-linked immunosorbent assay (ELISA) against the glycoprotein of the ZEBOV-Kikwit strain. At day 28, geometric mean titers of antibodies against ZEBOV glycoprotein were higher in the groups that received 20 million PFU or 100 million PFU than in the group that received 3 million PFU, as assessed by ELISA and by pseudovirion neutralization assay. A second dose at 28 days after dose 1 significantly increased antibody titers at day 56, but the effect was diminished at 6 months.This Ebola vaccine candidate elicited anti-Ebola antibody responses. After vaccination, rVSV viremia occurred frequently but was transient. These results support further evaluation of the vaccine dose of 20 million PFU for preexposure prophylaxis and suggest that a second dose may boost antibody responses. (Funded by the National Institutes of Health and others; rVSV∆G-ZEBOV-GP ClinicalTrials.gov numbers, NCT02269423 and NCT02280408 .).

Background Infectious diseases (ID) consultation has been associated with improved outcomes for Staphylococcus aureus bacteremia (SAB) largely by providing guidance to follow widely accepted standards. However, ID consultation may be delayed due to numerous factors. ID pharmacists may be able to facilitate timely and optimal management of SAB in collaboration with ID providers and microbiology. The primary outcome of this study was to evaluate the impact of a pharmacist-driven collaborative initiative for SAB. Methods This was a single-center, quasi-experimental study of patients with SAB before (8/1/16–7/31/17) and after (8/1/18-7/31/19) implementation of pharmacist-driven collaborative initiative for SAB management. After direct notification of SAB and penicillin-binding protein assay results from microbiology personnel, the ID pharmacist promptly contacted the primary team to facilitate ID consultation and identified opportunities to optimize treatment or diagnosis prior to consult. Recommendations were also collaboratively discussed with the ID consult service. Included patients were ≥18 years old with SAB. Excluded patients were < 18 years old, under palliative care or expired prior to S. aureus speciation, refused care against medical advice, pregnant, incarcerated, or had polymicrobial bacteremia. Results Ninety and 111 patients were included in the pre- and post-intervention cohort, respectively. Demographic data were similar between cohorts. Most SAB cases were community-acquired (72% vs 81%, p=0.137), complicated (83% vs 71%, p=0.059), and methicillin-susceptible (57% vs 65%, p=0.236). The most common sources were catheter (23%) and skin and soft tissue (30%) in pre- and post-intervention cohorts, respectively. Table 1 displays compliance with evidence-based SAB measures and clinical outcomes. Compliance with the SAB bundle was significantly higher in the post-intervention cohort (91% vs 50%, p< 0.001). Table 1. Compliance with Evidence-Based Staphylococcus aureus Bacteremia Management Bundle Elements and Clinical Outcomes Conclusion Increased compliance with evidence-based SAB recommendations decreased SAB duration, time to targeted antibiotics, and infection-related hospital length of stay after implementation of a pharmacist-driven collaborative initiative for SAB. Disclosures Wesley D. Kufel, PharmD, Melinta (Research Grant or Support)Merck (Research Grant or Support)Theratechnologies, Inc. (Advisor or Review Panel member) Jeffrey Steele, PharMD, Paratek Pharmaceuticals (Advisor or Review Panel member)

BACKGROUND Three full doses of RTS,S/AS01 malaria vaccine provides partial protection against controlled human malaria parasite infection (CHMI) and natural exposure. Immunization regimens, including a delayed fractional third dose, were assessed for potential increased protection against malaria and immunologic responses. METHODS In a phase 2a, controlled, open-label, study of healthy malaria-naive adults, 16 subjects vaccinated with a 0-, 1-, and 2-month full-dose regimen (012M) and 30 subjects who received a 0-, 1-, and 7-month regimen, including a fractional third dose (Fx017M), underwent CHMI 3 weeks after the last dose. Plasmablast heavy and light chain immunoglobulin messenger RNA sequencing and antibody avidity were evaluated. Protection against repeat CHMI was evaluated after 8 months. RESULTS A total of 26 of 30 subjects in the Fx017M group (vaccine efficacy [VE], 86.7% [95% confidence interval [CI], 66.8%-94.6%]; P < .0001) and 10 of 16 in the 012M group (VE, 62.5% [95% CI, 29.4%-80.1%]; P = .0009) were protected against infection, and protection differed between schedules (P = .040, by the log rank test). The fractional dose boosting increased antibody somatic hypermutation and avidity and sustained high protection upon rechallenge. DISCUSSIONS A delayed third fractional vaccine dose improved immunogenicity and protection against infection. Optimization of the RTS,S/AS01 immunization regimen may lead to improved approaches against malaria. CLINICAL TRIALS REGISTRATION NCT01857869.

BACKGROUND: A radiation-attenuated Plasmodium falciparum (Pf) sporozoite (SPZ) malaria vaccine, PfSPZ Vaccine, protected 6 of 6 subjects (100%) against homologous Pf (same strain as in the vaccine) controlled human malaria infection (CHMI) 3 weeks after 5 doses administered intravenously. The next step was to assess protective efficacy against heterologous Pf (different from Pf in the vaccine), after fewer doses, and at 24 weeks. METHODS: The trial assessed tolerability, safety, immunogenicity, and protective efficacy of direct venous inoculation (DVI) of 3 or 5 doses of PfSPZ Vaccine in non-immune subjects. RESULTS: Three weeks after final immunization, 5 doses of 2.7 × 105 PfSPZ protected 12 of 13 recipients (92.3% [95% CI: 48.0, 99.8]) against homologous CHMI and 4 of 5 (80.0% [10.4, 99.5]) against heterologous CHMI; 3 doses of 4.5 × 105 PfSPZ protected 13 of 15 (86.7% [35.9, 98.3]) against homologous CHMI. Twenty-four weeks after final immunization, the 5-dose regimen protected 7 of 10 (70.0% [17.3, 93.3]) against homologous and 1 of 10 (10.0% [-35.8, 45.6]) against heterologous CHMI; the 3-dose regimen protected 8 of 14 (57.1% [21.5, 76.6]) against homologous CHMI. All 22 controls developed Pf parasitemia. PfSPZ Vaccine was well tolerated, safe, and easy to administer. No antibody or T cell responses correlated with protection. CONCLUSIONS: We have demonstrated for the first time to our knowledge that PfSPZ Vaccine can protect against a 3-week heterologous CHMI in a limited group of malaria-naive adult subjects. A 3-dose regimen protected against both 3-week and 24-week homologous CHMI (87% and 57%, respectively) in this population. These results provide a foundation for developing an optimized immunization regimen for preventing malaria. TRIAL REGISTRATION: ClinicalTrials.gov NCT02215707. FUNDING: Support was provided through the US Army Medical Research and Development Command, Military Infectious Diseases Research Program, and the Naval Medical Research Center's Advanced Medical Development Program.

Several candidate vaccines against Shigella spp. are in development, but the lack of a clear correlate of protection from challenge with the induction of adequate immune responses among the youngest age groups in the developing world has hampered Shigella vaccine development over the past several decades. Bioconjugation technology, exploited here for an Shigella flexneri 2a candidate vaccine, offers a novel and potentially cost-effective way to develop and produce vaccines against a major pathogen of global health importance. Flexyn2a, a novel S. flexneri 2a bioconjugate vaccine made of the polysaccharide component of the S. flexneri 2a O-antigen, conjugated to the exotoxin protein A of Pseudomonas aeruginosa (EPA), was evaluated for safety and immunogenicity among healthy adults in a single-blind, phase I study with a staggered randomization approach. Thirty subjects (12 receiving 10 μg Flexyn2a, 12 receiving Flexyn2a with aluminum adjuvant, and 6 receiving placebo) were administered two injections 4 weeks apart and were followed for 168 days. Flexyn2a was well-tolerated, independently of the adjuvant and number of injections. The Flexyn2a vaccine elicited statistically significant S. flexneri 2a lipopolysaccharide (LPS)-specific humoral responses at all time points postimmunization in all groups that received the vaccine. Elicited serum antibodies were functional, as evidenced by bactericidal activity against S. flexneri 2a. The bioconjugate candidate vaccine Flexyn2a has a satisfactory safety profile and elicited a robust humoral response to S. flexneri 2a LPS with or without inclusion of an adjuvant. Moreover, the bioconjugate also induced functional antibodies, showing the technology's features in producing a promising candidate vaccine. (This study has been registered at ClinicalTrials.gov under registration no. NCT02388009.)

The most recent Zaire Ebolavirus (ZEBOV) outbreak was the largest and most widespread in recorded history, emphasizing the need for an effective vaccine. Here, we analyzed human cellular immune responses induced by a single dose of the rVSV-ZEBOV vaccine candidate, which showed significant protective efficacy in endemic populations in Guinea. This is the first in-depth characterization of ZEBOV-GP specific, circulating follicular T cells (cTfh). Since antibody titers correlated with protection in preclinical models of ZEBOV infection, Tfh were predicted to correlate with protection. Indeed, the ZEBOV-specific cTfh data correlated with antibody titers in human vaccines and unexpectedly with the Tfh17 subset. The combination of two cutting edge technologies allowed the immuno-profiling of rare cell populations and may help elucidate correlates of protection for a variety of vaccines.

Invasive mold infections are a rare complication of traumatic wounds. We examined the incidence and outcomes of these infections in combat wounds. A retrospective chart review from March 2002 through July 2008 of U.S. soldiers returning from Iraq and Afghanistan with traumatic wounds was performed. A confirmed fungal wound infection was defined as growth of a known pathogenic mold and visualization of fungal elements on histopathology. Six cases were identified for an incidence of 0.4 cases/1,000 admissions. The incidence of invasive mold infections increased over time (p = 0.008) with a peak of 5.2 cases/1,000 admissions in 2007. Isolated molds included Aspergillus (n = 4), Bipolaris (n = 2), and 1 each Mucor and Absidia. All patients were male with a mean age of 22. Blast (n = 5) and gunshot wound (n = 1) were the sources of injury. All patients had fever (mean 39.4 degrees C) and leukocytosis (mean white blood cell count 25 x 10(3)/microL). The average acute physiology and chronic health evaluation II score was 22. All patients received antifungal agents, surgical debridement, and 3 required amputation revision. Average length of stay was 97 days. There were no deaths. Invasive mold infections are a rare complication of combat wounds but are associated with significant morbidity and may be increasing in frequency.

Early recognition and implementation of appropriate infection control measures were effective in preventing further transmission., In 2009, a lethal case of Crimean–Congo hemorrhagic fever (CCHF), acquired by a US soldier in Afghanistan, was treated at a medical center in Germany and resulted in nosocomial transmission to 2 health care providers (HCPs). After his arrival at the medical center (day 6 of illness) by aeromedical evacuation, the patient required repetitive bronchoscopies to control severe pulmonary hemorrhage and renal and hepatic dialysis for hepatorenal failure. After showing clinical improvement, the patient died suddenly on day 11 of illness from cerebellar tonsil herniation caused by cerebral/cerebellar edema. The 2 infected HCPs were among 16 HCPs who received ribavirin postexposure prophylaxis. The infected HCPs had mild or no CCHF symptoms. Transmission may have occurred during bag-valve-mask ventilation, breaches in personal protective equipment during resuscitations, or bronchoscopies generating infectious aerosols. This case highlights the critical care and infection control challenges presented by severe CCHF cases, including the need for experience with ribavirin treatment and postexposure prophylaxis.

Background A vaccine to prevent infection and disease caused by Plasmodium vivax is needed both to reduce the morbidity caused by this parasite and as a key component in efforts to eradicate malaria worldwide. Vivax malaria protein 1 (VMP001), a novel chimeric protein that incorporates the amino- and carboxy- terminal regions of the circumsporozoite protein (CSP) and a truncated repeat region that contains repeat sequences from both the VK210 (type 1) and the VK247 (type 2) parasites, was developed as a vaccine candidate for global use. Methods We conducted a first-in-human Phase 1 dose escalation vaccine study with controlled human malaria infection (CHMI) of VMP001 formulated in the GSK Adjuvant System AS01B. A total of 30 volunteers divided into 3 groups (10 per group) were given 3 intramuscular injections of 15μg, 30μg, or 60μg respectively of VMP001, all formulated in 500μL of AS01B at each immunization. All vaccinated volunteers participated in a P. vivax CHMI 14 days following the third immunization. Six non-vaccinated subjects served as infectivity controls. Results The vaccine was shown to be well tolerated and immunogenic. All volunteers generated robust humoral and cellular immune responses to the vaccine antigen. Vaccination did not induce sterile protection; however, a small but significant delay in time to parasitemia was seen in 59% of vaccinated subjects compared to the control group. An association was identified between levels of anti-type 1 repeat antibodies and prepatent period. Significance This trial was the first to assess the efficacy of a P. vivax CSP vaccine candidate by CHMI. The association of type 1 repeat-specific antibody responses with delay in the prepatency period suggests that augmenting the immune responses to this domain may improve strain-specific vaccine efficacy. The availability of a P. vivax CHMI model will accelerate the process of P. vivax vaccine development, allowing better selection of candidate vaccines for advancement to field trials., Author Summary Plasmodium vivax malaria has several unique features. Two of the main features are the inability to culture this parasite in vitro and its propensity to form dormant stages within the liver, which can only be treated with a single class of drugs that are contraindicated for a proportion of the population. Therefore, vaccines will play an important role in preventing this geographically widespread malaria species. In this clinical trial, we tested increasing amounts of the vaccine candidate VMP001/AS01B for safety and immunogenicity. In order to test if the vaccine can afford protection, we challenged the volunteers via the bite of infected mosquitoes, the first time such a human infection model has been used to evaluate vaccine efficacy for P. vivax malaria. While the vaccine did not protect any of the vaccinated subjects, this study resulted in some important findings, including the observation that a significant proportion of the subjects displayed a trend towards a delay in infection in individuals that correlated with antibodies to the repeat region of the vaccine antigen.

Methods In an observer blind, phase 2 trial, 55 adults were randomized to receive one dose of Ad35.CS.01 vaccine followed by two doses of RTS,S/AS01 (ARR-group) or three doses of RTS,S/AS01 (RRR-group) at months 0, 1, 2 followed by controlled human malaria infection. Results ARR and RRR vaccine regimens were well tolerated. Efficacy of ARR and RRR groups after controlled human malaria infection was 44% (95% confidence interval 21%-60%) and 52% (25%-70%), respectively. The RRR-group had greater anti-CS specific IgG titers than did the ARR-group. There were higher numbers of CS-specific CD4 T-cells expressing > 2 cytokine/activation markers and more ex vivo IFN-γ enzyme-linked immunospots in the ARR-group than the RRR-group. Protected subjects had higher CS-specific IgG titers than non-protected subjects (geometric mean titer, 120.8 vs 51.8 EU/ml, respectively; P = .001). Conclusions An increase in vaccine efficacy of ARR-group over RRR-group was not achieved. Future strategies to improve upon RTS,S-induced protection may need to utilize alternative highly immunogenic prime-boost regimens and/or additional target antigens. Trial Registration ClinicalTrials.gov NCT01366534