A potent malaria vaccine based on adenovirus with dual modifications at Hexon and pVII

Publication date: Available online 28 October 2017
Source:Vaccine
Author(s): Takayuki Shiratsuchi, Urvashi Rai, Izumi Kaneko, Min Zhang, Shiroh Iwanaga, Masao Yuda, Moriya Tsuji
Adenovirus (Ad) is thought to be one of the most promising platforms for a malaria vaccine targeted against its liver stages, because of its ability to induce a strong T-cell response against a transgene. However, a further improvement of this platform is needed in order to elicit another arm of the immunity, i.e. humoral response, against malaria.In order to augment immunogenicity and protective efficacy of Ad-based malaria vaccine, we inserted B-cell, as well as CD4+ T-cell, epitopes of Plasmodium falciparum circumsporozoite protein (PfCSP) into the capsid protein, Hexon, and the core protein, VII (pVII), of Ad, respectively, in addition to the PfCSP transgene. Insertion of PfCSP-derived B cell epitope to Hexon significantly enhanced the epitope-specific antibody response compared to AdPfCSP, an Ad vaccine expressing only PfCSP transgene. PfCSP-derived CD4+ T-cell epitope insertion into pVII augmented not only PfCSP-specific CD4+ T-cell response but also anti-PfCSP antibody response. Finally, mice immunized with AdPfCSP having both Hexon and pVII modifications were more protected than AdPfCSP or Hexon-modified AdPfCSP against challenge with transgenic rodent malaria parasites expressing the PfCSP.Overall, this study has demonstrated that Hexon and pVII-modified AdPfCSP vaccine is a promising malaria vaccine which induces strong PfCSP-specific humoral, CD4+ T-cell, and CD8+ T-cell responses and protects against infection with transgenic malaria parasites expressing the PfCSP.



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A multi-site feasibility study to assess fever and wheezing in children after influenza vaccines using text messaging

Publication date: Available online 28 October 2017
Source:Vaccine
Author(s): Melissa S. Stockwell, Colin D. Marchant, A. Patrica Wodi, Elizabeth D. Barnett, Karen R. Broder, Kathleen Jakob, Paige Lewis, Meyer Kattan, Anne Marie Rezendes, Angela Barrett, Devindra Sharma, Nadira Fernandez, Philip LaRussa
BackgroundUsing text messaging for vaccine safety monitoring, particularly for non-medically attended events, would be valuable for pandemic influenza and emergency vaccination program preparedness. We assessed the feasibility and acceptability of text messaging to evaluate fever and wheezing post-influenza vaccination in a prospective, observational, multi-site pediatric study.MethodsChildren aged 2–11 years old, with an emphasis on children with asthma, were recruited during the 2014–2015 influenza season from three community-based clinics in New York City, and during the 2014–2015 and 2015–2016 seasons from a private practice in Fall River, Massachusetts. Parents of enrolled children receiving quadrivalent live attenuated (LAIV4) or inactivated influenza vaccine (IIV4) replied to text messages assessing respiratory symptoms (day 3 and 7, then weekly through day 42), and temperature on the night of vaccination and the next seven nights (day 0–7). Missing data were collected via diary (day 0–7 only) and phone. Phone confirmation was obtained for both presence and absence of respiratory symptoms. Reporting rates, fever (T≥100.4 °F) frequency, proportion of wheezing and/or chest tightness reports captured via text message versus all sources (text, phone, diary, electronic health record) and parental satisfaction were assessed.ResultsAcross both seasons, 266 children were analyzed; 49.2% with asthma. Parental text message response rates were high (>70%) across sites. Overall, fever frequency was low (day 0–2: 4.1% [95% confidence interval (CI) 2.3–7.4%]; d3–7: 6.7% [95% CI 4.1–10.8%]). A third (39.2%) of parents reported a respiratory problem in their child, primarily cough. Most (88.2%) of the 52 wheezing and/or chest tightness reports were by text message. Most (88.1%) participants preferred text messaging over paper reporting.ConclusionsText messaging can provide information about pediatric post-vaccination fever and wheezing and was viewed positively by parents. It could be a helpful tool for rapid vaccine safety monitoring during a pandemic or other emergency vaccination program.Trial registration: clinicaltrials.gov Identifier: NCT02295007.



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Use of surveillance data to calculate the sample size and the statistical power of randomized clinical trials testing Staphylococcus aureus vaccine efficacy in orthopedic surgery

Publication date: Available online 28 October 2017
Source:Vaccine
Author(s): Marie-Paule Gustin, Robin Ohannessian, Marine Giard, Emmanuelle Caillat-Vallet, Anne Savey, Philippe Vanhems
BackgroundPatients undergoing primary total hip arthroplasty (THA) would be a worthy population for anti-staphylococcal vaccines. The objective is to assess sample size for significant vaccine efficacy (VE) in a randomized clinical trial (RCT).MethodsData from a surveillance network of surgical site infection in France between 2008 and 2011 were used. The outcome was S. aureus SSI (SASSI) within 30 days after surgery. Statistical power was estimated by simulations repeated for theoretical VE ranging from 20% to 100% and for sample sizes from 250 to 8000 individuals per arm.Results18,688 patients undergoing THA were included; 66 (0.35%) SASSI occurred. For a 1% SASSI rate, the sample size would be at least 1316 patients per arm to detect significant VE of 80% with 80% power.ConclusionSimulations with real-life data from surveillance of hospital acquired infections allow estimation of power for RCT and sample size to reach the required power.



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Superior immunogenicity of HCV envelope glycoproteins when adjuvanted with cyclic-di-AMP, a STING activator or archaeosomes

Publication date: Available online 28 October 2017
Source:Vaccine
Author(s): A. Landi, J. Law, D. Hockman, M. Logan, K. Crawford, C. Chen, J. Kundu, T. Ebensen, C.A. Guzman, L. Deschatelets, L. Krishnan, D.L.J. Tyrrell, M. Houghton
Three decades after the discovery, hepatitis C virus (HCV) is still the leading cause of liver transplantation and poses a major threat to global health. In spite of recent advances in the development of direct acting antivirals, there is still a need for a prophylactic vaccine to limit the virus spread and protect at-risk populations, especially in developing countries, where the cost of the new treatments may severely limit access. The use of recombinant HCV glycoproteins E1E2 (rE1E2) in combination with the MF59, an oil-in-water emulsion-based adjuvant, has previously been shown to reduce the rate of chronicity in chimpanzees and to induce production of cross-neutralizing antibodies and cellular immune responses in human volunteers. To further improve neutralizing antibody responses in recipients along with robust T cell responses, we have explored the immunogenicity of different adjuvants when formulated with the HCV rE1E2 vaccine in mice.Our data show that cyclic di-adenosine monophosphate (c-di-AMP) and archaeosomes elicit strong neutralizing antibodies similar to those elicited using aluminum hydroxide/monophosphoryl lipid A (Alum/monophos. /MPLA) and MF59. However, both c-di-AMP and archaeosomes induced a more robust cellular immune response, which was confirmed by the detection of vaccine-specific poly-functional CD4⁺ T cells. We conclude that these adjuvants may substantially boost the immunogenicity of our E1E2 vaccine. In addition, our data also indicates that use of a partial or exclusive intranasal immunization regimen may also be feasible using c-di-AMP as adjuvant.



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Driving immunization through the Medicare Annual Wellness Visit: A growing opportunity

Publication date: Available online 28 October 2017
Source:Vaccine
Author(s): Angela K. Shen, Rob Warnock, Jeffrey A. Kelman
IntroductionThe Annual Wellness Visit (AWV) is a Medicare benefit designed to help prevent disease and disability based on individualized health and risk factors.MethodsThis study analyzes Medicare Part B fee-for-service claims from 2011 to 2016 to assess AWV and seasonal influenza and pneumococcal conjugate vaccinations utilization over time.ResultsUtilization of the AWV has increased from 8% of Medicare beneficiaries in 2011 to 19% in 2015. In each year, influenza and PCV13 vaccination rates are higher among those who utilize the benefit. More than one-third (33%) of patients who had an AWV in 2015 received a PCV13 vaccination in that same year, compared to 14% of those who did not. Similarly, the seasonal influenza vaccination rate was 64% among those with an AWV and 44% among those without.ConclusionThe AWV demonstrates promise for improving immunization rates among Medicare beneficiaries particularly at the point of care.



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Is the coronary artery calcium score associated with acute coronary events in breast cancer patients treated with radiotherapy?

Publication date: Available online 28 October 2017
Source:Radiotherapy and Oncology
Author(s): Catharina T.G. Roos, Veerle A.B. van den Bogaard, Marcel J.W. Greuter, Rozemarijn Vliegenthart, Ewoud Schuit, Johannes A. Langendijk, Arjen van der Schaaf, Anne P.G. Crijns, John H. Maduro
Background and purposeThe main objective of this study was to test whether pre-treatment coronary artery calcium (CAC) was associated with the cumulative incidence of acute coronary events (ACE) among breast cancer (BC) patients treated with postoperative radiotherapy (RT).Material and methodsThe study population consisted of 939 consecutive female BC patients treated with RT. The association between CAC and ACE was tested using Cox-proportional hazard models. Known risk factors for ACE and the mean heart dose (MHD), collected from three-dimensional computed tomography planning data, were tested for confounding.ResultsCAC scores varied from 0 to 2,859 (mean 27.3). The 9-year cumulative incidence of ACE was 3.2%, this was significantly associated with the pre-treatment CAC score. After correction for confounders, age, history of ischemic heart disease, diabetes, Body Mass Index ≥30, MHD, hypercholesterolemia and hypertension, the hazard ratio for ACE for the low and the combined intermediate and high CAC score category were 1.42 (95%CI: 0.49–4.17; p = 0.519) and 4.95 (95%CI: 1.69–14.53; p = 0.004) respectively, compared to the CAC zero category.ConclusionsHigh pre-treatment CAC is associated with ACE in BC patients treated with postoperative RT, even after correction for confounding factors such as MHD.



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ABC-transporter blockage mediated by xanthotoxin and bergapten is the major pathway for chemosensitization of multidrug-resistant cancer cells.

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ABC-transporter blockage mediated by xanthotoxin and bergapten is the major pathway for chemosensitization of multidrug-resistant cancer cells.

Toxicol Appl Pharmacol. 2017 Oct 24;:

Authors: Mirzaei SA, Dehkordi NG, Ghamghami M, Amiri AH, Abdolahinia ED, Elahian F

Abstract
Furanocoumarins derived from herbal and citrus extracts can act as antibacterial, antioxidant, immunomodulator, apoptotic, and selective anticancer agents, prompting a biological investigation to determine and predict their clinical therapeutic significance. Here, the cell cytotoxic effects of bergapten and xanthotoxin were analyzed alone and in combination with standard chemotherapeutics on three multidrug resistant cells and their nonresistant parental counterparts. The furanocoumarins modulatory effects on MDR1, BCRP, and MRP pump expression and function were investigated. Although quantitative real time PCR demonstrated that the MDR transcript level changes in a time dependent manner, flow cytometric analyses using fluorescent-labeled antibodies have indicated that bergapten and xanthotoxin had no significant effect on the protein levels. FACS analyses indicated that these prominent anticancer agents significantly blocked MDR1, BCRP, and MRP transporter function. Maximum furanocoumarin-mediated pump activity blockage in the MDR-resistant cells was quantified as 87% of normal and consequently, chemotherapeutic accumulation increased up to 2.7-fold and cytotoxicity tension increased 104-fold. MDR1 efflux kinetics also revealed that the maximum velocity and the pump affinity to daunorubicin were uncompetitively decreased. We conclude that bergapten and xanthotoxin are cytotoxic agents capable of preventing daunorubicin, mitoxantrone, and cisplatin binding to ABC-transporters and subsequently inhibiting their efflux out of cells and they may be a potential combination therapy for malignant cancers.

PMID: 29079042 [PubMed - as supplied by publisher]

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