BACKGROUND. Both seasonal and novel avian influenza viruses can result in severe infections requiring hospitalization. Anti-influenza antibodies (Abs) with Fc-mediated effector functions, such as Ab-dependent cellular cytotoxicity (ADCC), are of growing interest in control of influenza but have not previously been studied during severe human infections. As such, the objective of this study was to examine Fc-mediated Ab functions in humans hospitalized with influenza infection. METHODS. Serum Ab response was studied in subjects hospitalized with either pandemic H7N9 avian influenza virus in China (n = 18) or circulating seasonal influenza viruses in Melbourne, Australia (n = 16). Recombinant soluble Fc receptor dimer ELISAs, natural killer (NK) cell activation assays, and Ab-dependent killing assays with influenza-infected target cells were used to assess the Fc functionality of anti-influenza hemagglutinin (HA) Abs during severe human influenza infection. RESULTS. We found that the peak generation of Fc functional HA Abs preceded that of neutralizing Abs for both severe H7N9 and seasonal influenza infections. Subjects who succumbed to complications of H7N9 infection demonstrated reduced HA-specific Fc receptor–binding Abs (in magnitude and breadth) immediately prior to death compared with those who survived. Subjects who recovered from H7N9 and severe seasonal influenza infections demonstrated increased Fc receptor–binding Abs not only against the homologous infecting strain but against HAs from different influenza A subtypes. CONCLUSION. Collectively, survivors of severe influenza infection rapidly generate a functional Ab response capable of mediating ADCC against divergent influenza viruses. Broadly binding HA Abs with Fc-mediated functions may be a useful component of protective immunity to severe influenza infection. FUNDING. The National Health and Medical Research Council ([NHMRC] grants 1023294, 1041832, and 1071916), the Australian Department of Health, and the joint University of Melbourne/Fudan University International Research and Research Training Fund provided funding for this study.
Hillary A. Vanderven, Lu Liu, Fernanda Ana-Sosa-Batiz, Thi H.O. Nguyen, Yanmin Wan, Bruce Wines, P. Mark Hogarth, Danielle Tilmanis, Arnold Reynaldi, Matthew S. Parsons, Aeron C. Hurt, Miles P. Davenport, Tom Kotsimbos, Allen C. Cheng, Katherine Kedzierska, Xiaoyan Zhang, Jianqing Xu, Stephen J. Kent
BACKGROUND. Plasmodium vivax is the most widespread human malaria geographically; however, no effective vaccine exists. Red blood cell invasion by the P. vivax merozoite depends on an interaction between the Duffy antigen receptor for chemokines (DARC) and region II of the parasite’s Duffy-binding protein (PvDBP_RII). Naturally acquired binding-inhibitory antibodies against this interaction associate with clinical immunity, but it is unknown whether these responses can be induced by human vaccination. METHODS. Safety and immunogenicity of replication-deficient chimpanzee adenovirus serotype 63 (ChAd63) and modified vaccinia virus Ankara (MVA) viral vectored vaccines targeting PvDBP_RII (Salvador I strain) were assessed in an open-label dose-escalation phase Ia study in 24 healthy UK adults. Vaccines were delivered by the intramuscular route in a ChAd63-MVA heterologous prime-boost regimen using an 8-week interval. RESULTS. Both vaccines were well tolerated and demonstrated a favorable safety profile in malaria-naive adults. PvDBP_RII–specific ex-vivo IFN-γ T cell, antibody-secreting cell, memory B cell, and serum IgG responses were observed after the MVA boost immunization. Vaccine-induced antibodies inhibited the binding of vaccine homologous and heterologous variants of recombinant PvDBP_RII to the DARC receptor, with median 50% binding-inhibition titers greater than 1:100. CONCLUSION. We have demonstrated for the first time to our knowledge that strain-transcending antibodies can be induced against the PvDBP_RII antigen by vaccination in humans. These vaccine candidates warrant further clinical evaluation of efficacy against the blood-stage P. vivax parasite. TRIAL REGISTRATION. Clinicaltrials.gov NCT01816113. FUNDING. Support was provided by the UK Medical Research Council, UK National Institute of Health Research Oxford Biomedical Research Centre, and the Wellcome Trust.
Ruth O. Payne, Sarah E. Silk, Sean C. Elias, Kathryn H. Milne, Thomas A. Rawlinson, David Llewellyn, A. Rushdi Shakri, Jing Jin, Geneviève M. Labbé, Nick J. Edwards, Ian D. Poulton, Rachel Roberts, Ryan Farid, Thomas Jørgensen, Daniel G.W. Alanine, Simone C. de Cassan, Matthew K. Higgins, Thomas D. Otto, James S. McCarthy, Willem A. de Jongh, Alfredo Nicosia, Sarah Moyle, Adrian V.S. Hill, Eleanor Berrie, Chetan E. Chitnis, Alison M. Lawrie, Simon J. Draper
BACKGROUND. Cannabidiol (CBD) is a nonpsychoactive phytocannabinoid used in multiple sclerosis and intractable epilepsies. Preclinical studies show CBD has numerous cardiovascular benefits, including a reduced blood pressure (BP) response to stress. The aim of this study was to investigate if CBD reduces BP in humans. METHODS. Nine healthy male volunteers were given 600 mg of CBD or placebo in a randomized, placebo-controlled, double-blind, crossover study. Cardiovascular parameters were monitored using a finometer and laser Doppler. RESULTS. CBD reduced resting systolic BP (–6 mmHg; P < 0.05) and stroke volume (–8 ml; P < 0.05), with increased heart rate (HR) and maintained cardiac output. Subjects who had taken CBD had lower BP (–5 mmHg; P < 0.05, especially before and after stress), increased HR (+10 bpm; P < 0.01), decreased stroke volume (–13 ml; P < 0.01), and a blunted forearm skin blood flow response to isometric exercise. In response to cold stress, subjects who had taken CBD had blunted BP (–6 mmHg; P < 0.01) and increased HR (+7 bpm; P < 0.05), with lower total peripheral resistance. CONCLUSIONS. This data shows that acute administration of CBD reduces resting BP and the BP increase to stress in humans, associated with increased HR. These hemodynamic changes should be considered for people taking CBD. Further research is required to establish whether CBD has a role in the treatment of cardiovascular disorders.
Khalid A. Jadoon, Garry D. Tan, Saoirse E. O’Sullivan
Brateil Badal, Alexander Solovyov, Serena Di Cecilia, Joseph Minhow Chan, Li-Wei Chang, Ramiz Iqbal, Iraz T. Aydin, Geena S. Rajan, Chen Chen, Franco Abbate, Kshitij S. Arora, Antoine Tanne, Stephen B. Gruber, Timothy M. Johnson, Douglas R. Fullen, Leon Raskin, Robert Phelps, Nina Bhardwaj, Emily Bernstein, David T. Ting, Georg Brunner, Eric E. Schadt, Benjamin D. Greenbaum, Julide Tok Celebi
Vivek Subbiah, Muhammad Rizwan Khawaja, David S. Hong, Behrang Amini, Jiang Yungfang, Hui Liu, Adrienne Johnson, Alexa B. Schrock, Siraj M. Ali, James X. Sun, David Fabrizio, Sarina Piha-Paul, Siqing Fu, Apostolia M. Tsimberidou, Aung Naing, Filip Janku, Daniel D. Karp, Michael Overman, Cathy Eng, Scott Kopetz, Funda Meric-Bernstam, Gerald S. Falchook
Background. Reports on long-term (≥10 years) effects of cancer vaccines are missing. Therefore, in 2002, we initiated a phase I/II trial in cutaneous melanoma patients to further explore the immunogenicity of our DC vaccine and to establish its long-term toxicity and clinical benefit after a planned 10-year followup.
Methods. Monocyte-derived DCs matured by TNFα, IL-1β, IL-6, and PGE2 and then loaded with 4 HLA class I and 6 class II–restricted tumor peptides were injected intradermally in high doses over 2 years. We performed serial immunomonitoring in all 53 evaluable patients.
Results. Vaccine-specific immune responses including high-affinity, IFNγ-producing CD4+ and lytic polyfunctional CD8+ T cells were de novo induced or boosted in most patients. Exposure of mature DCs to trimeric soluble CD40 ligand, unexpectedly, did not further enhance such immune responses, while keyhole limpet hemocyanin (KLH) pulsing to provide unspecific CD4+ help promoted CD8+ T cell responses — notably, their longevity. An unexpected 19% of nonresectable metastatic melanoma patients are still alive after 11 years, a survival rate similar to that observed in ipilimumab-treated patients and achieved without any major (>grade 2) toxicity. Survival correlated significantly with the development of intense vaccine injection site reactions, and with blood eosinophilia after the first series of vaccinations, suggesting that prolonged survival was a consequence of DC vaccination.
Conclusions. Long-term survival in advanced melanoma patients undergoing DC vaccination is similar to ipilimumab-treated patients and occurs upon induction of tumor-specific T cells, blood eosinophilia, and strong vaccine injection site reactions occurring after the initial vaccinations.
TRIAL REGISTRATION. ClinicalTrials.gov NCT00053391.
FUNDING. European Community, Sixth Framework Programme (Cancerimmunotherapy LSHC-CT-2006-518234; DC-THERA LSHB-CT-2004-512074), and German Research Foundation (CRC 643, C1, Z2).
Stefanie Gross, Michael Erdmann, Ina Haendle, Steve Voland, Thomas Berger, Erwin Schultz, Erwin Strasser, Peter Dankerl, Rolf Janka, Stefan Schliep, Lucie Heinzerling, Karl Sotlar, Pierre Coulie, Gerold Schuler, Beatrice Schuler-Thurner
Wiebke Arlt, Katharina Lang, Alice J. Sitch, Anna S. Dietz, Yara Rhayem, Irina Bancos, Annette Feuchtinger, Vasileios Chortis, Lorna C. Gilligan, Philippe Ludwig, Anna Riester, Evelyn Asbach, Beverly A. Hughes, Donna M. O’Neil, Martin Bidlingmaier, Jeremy W. Tomlinson, Zaki K. Hassan-Smith, D. Aled Rees, Christian Adolf, Stefanie Hahner, Marcus Quinkler, Tanja Dekkers, Jaap Deinum, Michael Biehl, Brian G. Keevil, Cedric H.L. Shackleton, Jonathan J. Deeks, Axel K. Walch, Felix Beuschlein, Martin Reincke
Shadab A. Rahman, Melissa A. St. Hilaire, Anne-Marie Chang, Nayantara Santhi, Jeanne F. Duffy, Richard E. Kronauer, Charles A. Czeisler, Steven W. Lockley, Elizabeth B. Klerman
Martin Niethammer, Chris C. Tang, Peter A. LeWitt, Ali R. Rezai, Maureen A. Leehey, Steven G. Ojemann, Alice W. Flaherty, Emad N. Eskandar, Sandra K. Kostyk, Atom Sarkar, Mustafa S. Siddiqui, Stephen B. Tatter, Jason M. Schwalb, Kathleen L. Poston, Jaimie M. Henderson, Roger M. Kurlan, Irene H. Richard, Christine V. Sapan, David Eidelberg, Matthew J. During, Michael G. Kaplitt, Andrew Feigin
Melanie A. Gasper, Anneke C. Hesseling, Isaac Mohar, Landon Myer, Tali Azenkot, Jo-Ann S. Passmore, Willem Hanekom, Mark F. Cotton, I. Nicholas Crispe, Donald L. Sodora, Heather B. Jaspan
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