Featured
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| Open AccessIron-dependent histone 3 lysine 9 demethylation controls B cell proliferation and humoral immune responses
The authors show an important role for iron in B cell proliferation via histone 3 lysine 9 (H3K9) demethylation at the cyclin E1 promoter. Using a measles vaccination murine model, they show that iron-deficient individuals have a significantly reduced antibody response to the vaccine when compared to iron-normal controls.
- Yuhang Jiang
- , Cuifeng Li
- & Xiaoren Zhang
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Article
| Open AccessDifficult-to-neutralize global HIV-1 isolates are neutralized by antibodies targeting open envelope conformations
Here, the authors report that specific monoclonal antibodies isolated from vaccinated rhesus macaques can neutralize a subset of Tier 2 difficult-to-neutralize HIV-1 that express Env in an open conformation, suggesting that V3 loop-specific targeting can bias the estimation of vaccine-induced bnAbs.
- Qifeng Han
- , Julia A. Jones
- & Kevin O. Saunders
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| Open AccessStructure and immunogenicity of a stabilized HIV-1 envelope trimer based on a group-M consensus sequence
Stabilized, native-like trimers of the HIV envelope protein, such as SOSIP trimers, are potential antigens for an HIV vaccine. Here, the authors generate a SOSIP trimer based on the consensus sequence of group M isolates, determine its structure and exposure of common epitopes, and show immunogenicity in rabbits and non-human primates.
- Kwinten Sliepen
- , Byung Woo Han
- & Rogier W. Sanders
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| Open AccessConcentration and avidity of antibodies to different circumsporozoite epitopes correlate with RTS,S/AS01E malaria vaccine efficacy
RTS,S/AS01E has been tested in a phase 3 malaria vaccine trial and has shown partial efficacy in children and infants. Here, the authors analyze IgG concentration and avidity to CSP in ~1000 participants and show that IgG avidity to the C-terminus of CSP is significantly associated with vaccine-mediated protection.
- Carlota Dobaño
- , Hèctor Sanz
- & Claudia Daubenberger
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| Open AccessIdentifying immunologically-vulnerable regions of the HCV E2 glycoprotein and broadly neutralizing antibodies that target them
A good vaccine should direct the immune response to virus regions that are most difficult to escape. Here, Quadeer et al. develop a predictive in-silico evolutionary model for HCV E2 which identifies one such antigenic region and identifies multiple broadly neutralizing human antibodies that appear difficult to escape from.
- Ahmed A. Quadeer
- , Raymond H. Y. Louie
- & Matthew R. McKay
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Article
| Open AccessA defined mechanistic correlate of protection against Plasmodium falciparum malaria in non-human primates
Proof of protection against blood-stage P. falciparum malaria by a single immunological mechanism has been elusive. Here, using engineered anti-PfRH5 chimeric monoclonal antibodies in non-human primates, the authors show that high levels of merozoite-neutralizing antibodies can achieve protection.
- Alexander D. Douglas
- , G. Christian Baldeviano
- & Simon J. Draper
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| Open AccessMapping vaccination coverage to explore the effects of delivery mechanisms and inform vaccination strategies
The success of vaccination programs depends largely on the mechanisms used in vaccine delivery. Here, the authors evaluate the relative effectiveness of two major vaccine delivery strategies, namely routine immunization and supplementary immunization activities in five study countries.
- C. Edson Utazi
- , Julia Thorley
- & Andrew J. Tatem
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| Open AccessSystematic comparison of respiratory syncytial virus-induced memory B cell responses in two anatomical compartments
Here, the authors isolate over 800 RSV F-specific antibodies from paired nasopharyngeal tonsil and peripheral blood samples from four young children undergoing adenoidectomy and find that adenoid derived antibodies have overall higher binding affinities and neutralization potencies.
- Laila Shehata
- , Wendy F. Wieland-Alter
- & Laura M. Walker
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Article
| Open AccessVaccination to prevent T cell subversion can protect against persistent hepacivirus infection
Development of a HCV vaccine is hampered by a lack of appropriate small animal models. Here, Hartlage et al. describe a rat model of hepacivirus persistence and show that persistence can be prevented by vaccination with viral non-structural proteins.
- Alex S. Hartlage
- , Satyapramod Murthy
- & Amit Kapoor
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Article
| Open AccessRationally designed carbohydrate-occluded epitopes elicit HIV-1 Env-specific antibodies
Areas of HIV envelope (Env) that aren’t covered by glycans are potential targets for antibodies. Here, the authors computationally design small protein mimics of four such epitopes and show that they can induce Env binding antibodies in rabbits.
- Cheng Zhu
- , Elena Dukhovlinova
- & Nikolay V. Dokholyan
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Article
| Open AccessA platform for glycoengineering a polyvalent pneumococcal bioconjugate vaccine using E. coli as a host
Bioconjugation is a promising process to manufacture conjugate vaccines, but currently employed enzymes cannot generate the full spectrum of bacterial glycoproteins. Here, the authors use an O-linking oligosaccharyltransferase to generate a polyvalent pneumococcal bioconjugate vaccine with polysaccharides containing glucose at their reducing end.
- Christian M. Harding
- , Mohamed A. Nasr
- & Mario F. Feldman
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Article
| Open AccessIntegrated systems approach defines the antiviral pathways conferring protection by the RV144 HIV vaccine
The RV144 vaccine trial showed reduced risk of HIV-1 acquisition, but mechanisms underlying protection are poorly understood. Here, Fourati et al. assess the transcriptomic profile of blood collected from 223 vaccinees and 40 placebo recipients and identify IRF7 as a mediator of protection.
- Slim Fourati
- , Susan Pereira Ribeiro
- & Rafick-Pierre Sékaly
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Article
| Open AccessOutcomes of controlled human malaria infection after BCG vaccination
Immune activation induces long-term alterations of setpoints, impacting responses to subsequent unrelated stimuli. Here the authors show that volunteers vaccinated with BCG respond to controlled human malaria infection with increased clinical symptoms and an inverse correlation between immune activation markers and parasitemia.
- Jona Walk
- , L. Charlotte J. de Bree
- & Robert W. Sauerwein
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| Open AccessHIV-1 vaccination by needle-free oral injection induces strong mucosal immunity and protects against SHIV challenge
Oral vaccination is a potential option to elicit systemic and mucosal immunity against HIV. Here, Jones et al. show that oral vaccination with a modified needle-free injector induces protective immunity against SHIV in non-human primates and is superior to topical application of vaccines to oral tissues.
- Andrew T. Jones
- , Xiaoying Shen
- & Rama Rao Amara
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Article
| Open AccessDiversity within the adenovirus fiber knob hypervariable loops influences primary receptor interactions
Adenovirus based (AdV) vectors are promising platforms for therapeutics and vaccines, but receptor usage of serotypes in clinical development remains unclear. Here, based on crystal structures and modeling, Baker et al. show that HAdV-D26/48 fiber knob protein interacts weakly with CAR but not with CD46 or DSG2.
- Alexander T. Baker
- , Alexander Greenshields-Watson
- & Alan L. Parker
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Article
| Open AccessTargets of complement-fixing antibodies in protective immunity against malaria in children
Antibodies against Plasmodium falciparum merozoites that fix complement can inhibit blood-stage replication. Here, Reiling et al. show that complement-fixing antibodies strongly correlate with protective immunity in children, identify the merozoite targets, and predict antigen combinations that should result in strong protection.
- Linda Reiling
- , Michelle J. Boyle
- & James G. Beeson
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| Open AccessEfficient oral vaccination by bioengineering virus-like particles with protozoan surface proteins
Giardia lamblia express a dense coat of variant-specific surface proteins (VSPs) on trophozoites that protects the parasite inside the host´s intestine. Here the authors show that stability and immunomodulatory properties of VSPs can be exploited to both protect and adjuvant vaccine antigens for oral administration.
- Marianela C. Serradell
- , Lucía L. Rupil
- & Hugo D. Luján
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Article
| Open AccessCross-lineage protection by human antibodies binding the influenza B hemagglutinin
Immune recognition of Influenza B virus (IBV) is poorly understood. Here, Liu et al. use flow cytometry to characterize IBV-specific memory B cell responses following seasonal vaccination and show that elicited cross-reactive antibodies can protect against infection, providing a platform for vaccine design.
- Yi Liu
- , Hyon-Xhi Tan
- & Adam K. Wheatley
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| Open AccessIndirect protection from vaccinating children against influenza in households
Relevance of indirect protection of household members of vaccinees is unclear. Here, Tsang et al. quantify the direct and indirect protection of vaccination in a randomized controlled trial and show that benefits of individual vaccination remain important even when other household members are vaccinated.
- Tim K. Tsang
- , Vicky J. Fang
- & Simon Cauchemez
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| Open AccessRational design of a triple-type human papillomavirus vaccine by compromising viral-type specificity
More than 18 human papillomaviruses (HPV) are associated with cervical cancer, and ideally vaccines should protect from all of them. Here, the authors engineer a triple-type, chimeric HPV vaccine, using loop swapping, that elicits robust neutralizing antibody titers in mice and non-human primates.
- Zhihai Li
- , Shuo Song
- & Ningshao Xia
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Article
| Open AccessRoutes of Zika virus dissemination in the testis and epididymis of immunodeficient mice
The mechanisms of ZIKV persistence in the male reproductive tract (MRT) are poorly understood. Here, Tsetsarkin et al. applied microRNA-targeting approach to trace routes of ZIKV dissemination in the testis and epididymis and to generate immunogenic live-attenuated ZIKV vaccine candidate, restricted for MRT infection.
- Konstantin A. Tsetsarkin
- , Olga A. Maximova
- & Alexander G. Pletnev
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Article
| Open AccessHuman preprocalcitonin self-antigen generates TAP-dependent and -independent epitopes triggering optimised T-cell responses toward immune-escaped tumours
Tumours can escape CD8 T-cell immunity by down-regulating antigen presentation machinery components, such as TAP. Here the authors describe tumour antigenic peptides processed by TAP-independent and -dependent pathways and show in mouse models that these peptides can be exploited to induce antitumor T-cell activity when TAP expression is downregulated.
- Aurélie Durgeau
- , Yasemin Virk
- & Fathia Mami-Chouaib
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Article
| Open AccessSelective expansion of myeloid and NK cells in humanized mice yields human-like vaccine responses
Humanized mice are an enabling technology to explore human immunity and disease. Here, Douam et al. provide an in-depth comparison of immune responses to yellow fever vaccine in human vaccinees, conventional and second-generation humanized mice and define a workflow to evaluate and refine these models.
- Florian Douam
- , Carly G. K. Ziegler
- & Alexander Ploss
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Article
| Open AccessHuman milk oligosaccharides, milk microbiome and infant gut microbiome modulate neonatal rotavirus infection
Neonatal rotavirus infections are associated with gastrointestinal symptoms in some settings, but the role of host factors in clinical presentation is unclear. Here, Ramani et al. show that human milk oligosaccharides and microbiome are associated with symptomatic infection with neonatal strain G10P[11].
- Sasirekha Ramani
- , Christopher J. Stewart
- & Mary K. Estes
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Article
| Open AccessCommon helical V1V2 conformations of HIV-1 Envelope expose the α4β7 binding site on intact virions
Antibodies blocking the V1V2 domain of HIV Envelope from binding integrin are associated with positive disease outcomes. Here, Wibmer et al. determine the structure of full length V1V2 bound to these antibodies, revealing an alternative fold of V1V2 with exposed integrin-binding sites that functions on non-native Envelope.
- Constantinos Kurt Wibmer
- , Simone I. Richardson
- & Lynn Morris
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Article
| Open AccessNon-neutralizing antibodies elicited by recombinant Lassa–Rabies vaccine are critical for protection against Lassa fever
There is currently no approved vaccine for Lassa fever virus (LASV). Here, Abreu-Mota et al. develop an inactivated, adjuvanted vaccine candidate expressing LASV glycoprotein (GPC) in a rabies virus vector, and show that non-neutralizing LASV GPC-specific antibodies are a major mechanism of protection.
- Tiago Abreu-Mota
- , Katie R. Hagen
- & Matthias J. Schnell
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Article
| Open AccessEngineered mRNA-expressed antibodies prevent respiratory syncytial virus infection
Engineered neutralizing antibodies are potential therapeutics for numerous viruses, such as respiratory syncytial virus (RSV). Here, the authors develop an mRNA-based approach to express membrane-anchored neutralizing antibodies in the lung and demonstrate that it inhibits RSV infections in mice.
- Pooja Munnilal Tiwari
- , Daryll Vanover
- & Philip J. Santangelo
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Article
| Open AccessA naturally protective epitope of limited variability as an influenza vaccine target
Current influenza vaccine approaches largely focus on highly variable epitopes with high immunogenicity or epitopes of low variability that often have low immunogenicity. Here, Thompson et al. identify a highly immunogenic epitope of limited variability in the head domain of the H1 haemagglutinin and show protection from diverse H1N1 strains in mice.
- Craig P. Thompson
- , José Lourenço
- & Sunetra Gupta
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| Open AccessStructural basis for recognition of the malaria vaccine candidate Pfs48/45 by a transmission blocking antibody
Pfs48/45 is a promising component for a transmission-blocking malaria vaccine. Here, the authors develop a system to produce full-length Pfs48/45 for immunisation, characterise a panel of monoclonal antibodies and determine the structure of a potent transmission-blocking epitope.
- Frank Lennartz
- , Florian Brod
- & Matthew K. Higgins
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Article
| Open AccessAugmentation of vaccine-induced humoral and cellular immunity by a physical radiofrequency adjuvant
Vaccine adjuvants ensure sufficient engagement of the immune system in vaccination, however safety issues can be associated with novel chemical adjuvants. Here, Cao et al. report a physical radiofrequency adjuvant to simultaneously augment vaccine-induced humoral and cellular immune responses without potentially harmful adverse reactions.
- Yan Cao
- , Xiaoyue Zhu
- & Xinyuan Chen
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Article
| Open AccessDifferential processing of HIV envelope glycans on the virus and soluble recombinant trimer
HIV envelope (Env) is a potential vaccine antigen and its N-glycans are part of the epitope of broadly neutralizing antibodies. Here, the authors show that glycosylation of Env from infectious virus closely matches Env from recombinant membrane-bound trimers, while it differs significantly from recombinant soluble, cleaved Env trimers.
- Liwei Cao
- , Matthias Pauthner
- & James C. Paulson
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| Open AccessRefined efficacy estimates of the Sanofi Pasteur dengue vaccine CYD-TDV using machine learning
Clinical trials for the CYD-TDV dengue vaccine showed that vaccine efficacy varies with prior dengue exposure, but baseline serostatus is only known for 12% of subjects. Here, Dorigatti et al. use machine learning to impute baseline serostatus and determine vaccine efficacy by baseline serostatus, age and dengue serotype.
- I. Dorigatti
- , C. A. Donnelly
- & N. M. Ferguson
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| Open AccessNucleoside-modified mRNA immunization elicits influenza virus hemagglutinin stalk-specific antibodies
The highly conserved influenza virus hemagglutinin (HA) stalk represents a potential target for a broadly protective vaccine. Here, the authors show that immunization with nucleoside-modified mRNA encoding full-length HA formulated in lipid nanoparticles elicits HA stalk-specific antibodies and protects from heterosubtypic virus infection.
- Norbert Pardi
- , Kaela Parkhouse
- & Drew Weissman
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| Open AccessA Zika virus vaccine expressing premembrane-envelope-NS1 polyprotein
Current Zika virus (ZIKV) subunit vaccine development largely focuses on prM and E proteins, and the role of NS1 for immune response and protection is unclear. Here, Li et al. develop an attenuated VSV-based vaccine expressing a ZIKV prM-E-NS1 polyprotein and characterize immune response and protection in mice.
- Anzhong Li
- , Jingyou Yu
- & Jianrong Li
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| Open AccessNeutralization of the Plasmodium-encoded MIF ortholog confers protective immunity against malaria infection
Plasmodium species produce an ortholog of the cytokine macrophage migration inhibitory factor, PMIF, which modulates the host inflammatory response to malaria. Here, the authors show that inhibition of PMIF may have translational benefits for managing malaria infections.
- Alvaro Baeza Garcia
- , Edwin Siu
- & Richard Bucala
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Article
| Open AccessRational Zika vaccine design via the modulation of antigen membrane anchors in chimpanzee adenoviral vectors
Zika virus (ZIKV) is an emerging global health issue, but currently no licensed vaccine achieves lasting protective immunity. Here the authors show that a ZIKV vaccine containing the envelop protein without the transmembrane domain and the precursor membrane protein can provide effective protection in mouse models.
- César López-Camacho
- , Peter Abbink
- & Arturo Reyes-Sandoval
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Article
| Open AccessA CD4-mimetic compound enhances vaccine efficacy against stringent immunodeficiency virus challenge
The HIV Env trimer exhibits a closed confirmation and restricts access to known antibody binding sites. Here the authors show that a small-molecule CD4-mimetic compound binds the HIV Env trimer and enhances antibody-mediated protection in a non-human primate model of infection.
- Navid Madani
- , Amy M. Princiotto
- & Joseph Sodroski
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Article
| Open AccessStructure of a cleavage-independent HIV Env recapitulates the glycoprotein architecture of the native cleaved trimer
Native-like soluble HIV envelope (Env) trimers are potential vaccine immunogens, and elimination of furin-dependence could provide a DNA-based alternative. Here, Sarkar et al. show that a cleavage-independent Env construct recapitulates the architecture and glycosylation of the native cleaved trimer.
- Anita Sarkar
- , Shridhar Bale
- & Ian A. Wilson
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Article
| Open AccessEfficacy of a respiratory syncytial virus vaccine candidate in a maternal immunization model
RSV infection is a major cause of bronchiolitis in infants and maternal vaccination is a potential preventive option. Here, Blanco et al. show efficacy of a Newcastle disease virus-based virus-like particle vaccine candidate in naive and pre-exposed cotton rat dams and their offspring.
- Jorge C. G. Blanco
- , Lioubov M. Pletneva
- & Trudy G. Morrison
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Article
| Open AccessVaccine-elicited receptor-binding site antibodies neutralize two New World hemorrhagic fever arenaviruses
The five known New World hemorrhagic fever arenaviruses use the same entry receptor, but their viral glycoproteins are markedly different. Here, the authors isolate monoclonal antibodies from a Junin virus vaccinated person that cross-neutralize Machupo virus and identify a conserved epitope in the receptor-binding domain.
- Lars E. Clark
- , Selma Mahmutovic
- & Jonathan Abraham
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Article
| Open AccessA comprehensive model for assessment of liver stage therapies targeting Plasmodium vivax and Plasmodium falciparum
Currently available platforms to study liver stage of Plasmodium species have limitations. Here, the authors show that primary human hepatocyte cultures in 384-well format support hypnozoite and other liver stage development and are suitable for drug and antibody screens.
- Alison Roth
- , Steven P. Maher
- & John H. Adams
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Article
| Open AccessHost-mediated selection impacts the diversity of Plasmodium falciparum antigens within infections
Host immune responses exert selective pressure on Plasmodium falciparum. Here, the authors show that allele-specific immunity impacts the antigenic diversity of individual malaria infections. This process partially explains the extreme amino acid diversity of many parasite antigens and suggests that vaccines should account for allele-specific immunity.
- Angela M. Early
- , Marc Lievens
- & Daniel E. Neafsey
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Article
| Open AccessA vaccinia-based single vector construct multi-pathogen vaccine protects against both Zika and chikungunya viruses
Zika and chikungunya virus are co-circulating in many regions and currently there is no approved vaccine for either virus. Here, the authors engineer one vaccinia virus based vaccine for both, Zika and chikungunya, and show protection from infection and pathogenesis in mice.
- Natalie A. Prow
- , Liang Liu
- & Andreas Suhrbier
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Article
| Open AccessHIV envelope V3 region mimic embodies key features of a broadly neutralizing antibody lineage epitope
The V3 region of HIV Env elicits broadly neutralizing antibodies (bnAbs) in patients and represents a potential vaccine antigen. Here, Fera et al. show that the structure of a synthetic V3-glycopeptide closely resembles the conformation in intact HIV Env and identify amino acids in bnAbs that are important for neutralization breadth.
- Daniela Fera
- , Matthew S. Lee
- & Stephen C. Harrison
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Article
| Open AccessStructure-based design of chimeric antigens for multivalent protein vaccines
Factor H binding protein (fHbp) and PorA are components of experimental serogroup B N. meningitidis vaccines. Here the authors graft the VR2 loop of PorA onto an fHBp-based scaffold to demonstrate proof-of-principle of a chimeric antigen strategy and vaccination against meningococcal disease.
- S. Hollingshead
- , I. Jongerius
- & C. M. Tang
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Article
| Open AccessA systematic approach to the development of a safe live attenuated Zika vaccine
A Zika virus (ZIKV) vaccine should provide long-lasting immunity, which may be achieved with a live-attenuated vaccine. Here, Kwek et al. select an interferon-restricted, attenuated ZIKV variant and evaluate replication and immunogenicity in mouse and mosquito models.
- Swee Sen Kwek
- , Satoru Watanabe
- & Eng Eong Ooi
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| Open AccessDevelopment of a chimeric Zika vaccine using a licensed live-attenuated flavivirus vaccine as backbone
Given the recent Zika virus (ZIKV) epidemic, development of an effective vaccine is of high importance. Here, the authors use a licensed live-attenuated flavivirus vaccine backbone to develop a ZIKV vaccine and determine immunogenicity, safety and protection profiles in different animal models.
- Xiao-Feng Li
- , Hao-Long Dong
- & Cheng-Feng Qin
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| Open AccessCrystal structure reveals vaccine elicited bactericidal human antibody targeting a conserved epitope on meningococcal fHbp
Factor H binding protein (fHbp) is a meningococcal virulence factor and a component of vaccines against serogroup B Neisseria meningitidis. Here, the authors characterize the vaccine-elicited human antibody Fab 1A12 and present both the free and the fHbp-bound Fab 1A12 crystal structures.
- Jacinto López-Sagaseta
- , Peter T. Beernink
- & Matthew J. Bottomley
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Article
| Open AccessDouble-layered protein nanoparticles induce broad protection against divergent influenza A viruses
Relatively well conserved domains of influenza A virus (IAV) proteins are potential candidates for the development of a universal IAV vaccine. Here, Deng et al. combine two such conserved antigens (M2e and HA stalk) in a double-layered protein nanoparticle and show that it protects against divergent IAVs in mice.
- Lei Deng
- , Teena Mohan
- & Bao-Zhong Wang