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| Open AccessBacterially derived synthetic mimetics of mammalian oligomannose prime antibody responses that neutralize HIV infectivity
Neutralizing antibodies to oligomannose glycans on HIV Env are difficult to elicit, possibly due to B cell tolerance. Here, Pantophlet et al. synthesize mimetics based on a bacterial oligosaccharide and show that they evoke HIV-neutralizing antibody responses in animals with a human Ig repertoire.
- Ralph Pantophlet
- , Nino Trattnig
- & Paul Kosma
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Article
| Open AccessMolecular definition of multiple sites of antibody inhibition of malaria transmission-blocking vaccine antigen Pfs25
Plasmodium falciparum protein Pfs25 is a promising malaria transmission blocking vaccine antigen. Here, Scally et al. determine the crystal structure of Pfs25 and identify antigenic sites that are recognized by transmission-blocking antibodies elicited in human immunoglobulin loci transgenic mice.
- Stephen W. Scally
- , Brandon McLeod
- & Jean-Philippe Julien
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| Open AccessStructure and immunogenicity of pre-fusion-stabilized human metapneumovirus F glycoprotein
An efficient vaccine for human metapneumovirus (hMPV) will likely rely on neutralizing antibodies against the fusion protein (F). Here, the authors determine the crystal structure of pre-fusion-stabilized hMPV F and identify a dense glycan shield that affects generation of neutralizing antibodies.
- Michael B. Battles
- , Vicente Más
- & Jason S. McLellan
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| Open AccessPre-fusion RSV F strongly boosts pre-fusion specific neutralizing responses in cattle pre-exposed to bovine RSV
Boosting of maternal antibodies against RSV is a potential approach to protect infants from severe infection, but data from animal models is missing. Here Steff et al. test two different boosts in seropositive cattle pre-exposed to bovine RSV and show that pre-fusion F strongly boosts neutralizing responses.
- Ann-Muriel Steff
- , James Monroe
- & Andrea Carfi
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| Open AccessA single-dose live-attenuated vaccine prevents Zika virus pregnancy transmission and testis damage
Zika virus infection can result in congenital disorders and cause disease in adults, and there is currently no approved vaccine. Here Shan et al. show that a single dose of a live-attenuated Zika vaccine prevents infection, testis damage and transmission to the fetus during pregnancy in different animal models.
- Chao Shan
- , Antonio E. Muruato
- & Pei-Yong Shi
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| Open AccessPlant-made polio type 3 stabilized VLPs—a candidate synthetic polio vaccine
Despite the success of current vaccination against poliomyelitis, safe, cheap and effective vaccines remain sought for continuing eradication effort. Here the authors use plants to express stabilized virus-like particles of type 3 poliovirus that can induce a protective immune response in mice transgenic for the human poliovirus receptor.
- Johanna Marsian
- , Helen Fox
- & George P. Lomonossoff
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| Open AccessDeciphering minimal antigenic epitopes associated with Burkholderia pseudomallei and Burkholderia mallei lipopolysaccharide O-antigens
Melioidosis and glanders are multifaceted infections caused by gram-negative bacteria. Here, the authors synthesize a series of oligosaccharides that mimic the lipopolysaccharides present on the pathogens’ surface and use them to develop novel glycoconjugates for vaccine development.
- Marielle Tamigney Kenfack
- , Marcelina Mazur
- & Charles Gauthier
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| Open AccessReactogenicity to major tuberculosis antigens absent in BCG is linked to improved protection against Mycobacterium tuberculosis
MTBVAC, a live attenuatedMycobacterium tuberculosisvaccine under clinical evaluation, contains the major tuberculosis antigens ESAT6 and CFP10, which are absent from the current vaccine, BCG. Here, the authors show that these antigens contribute to enhanced vaccine efficacy in mouse models.
- Nacho Aguilo
- , Jesus Gonzalo-Asensio
- & Carlos Martin
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Article
| Open AccessPentavalent HIV-1 vaccine protects against simian-human immunodeficiency virus challenge
A previous human HIV-1 vaccine clinical trial, boosting with HIV envelope protein from two strains, demonstrated moderate vaccine efficacy. Here, Bradleyet al. show that a pentavalent HIV envelope protein boost improves protection from viral challenge in non-human primates and they identify immune correlates of protection.
- Todd Bradley
- , Justin Pollara
- & Barton F. Haynes
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| Open AccessDNA vaccination protects mice against Zika virus-induced damage to the testes
Zika virus (ZIKV) can persist in human semen and sperm, which can result in sexual transmission. Here, Griffinet al. show that a DNA vaccine, expressing ZIKV pre-membrane and envelope proteins, protects mice from infection-associated damage to testes and sperm, and prevents viral persistence in testes.
- Bryan D. Griffin
- , Kar Muthumani
- & Gary P. Kobinger
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| Open AccessAdenovirus prime, Env protein boost vaccine protects against neutralization-resistant SIVsmE660 variants in rhesus monkeys
Protection from neutralization-resistant SIV variants is particularly difficult to achieve by vaccination. Here, Keeleet al. use sieve analysis and show that TRIM5a restrictive rhesus monkeys are protected from neutralization-resistant SIVsmE660 variants by an adenovirus prime, env protein boost vaccine.
- Brandon F. Keele
- , Wenjun Li
- & Dan H. Barouch
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Article
| Open AccessReplicating viral vector platform exploits alarmin signals for potent CD8+ T cell-mediated tumour immunotherapy
Viruses trigger potent cytotoxic T cell responses, whereas anti-tumour immunity has been difficult to establish. Here the authors engineer a replicating viral delivery system for tumour-associated antigens, which induces alarmin release, innate activation and protective anti-tumour immunity in mice.
- Sandra M. Kallert
- , Stephanie Darbre
- & Daniel D. Pinschewer
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| Open AccessDesign of live attenuated bacterial vaccines based on D-glutamate auxotrophy
D-glutamate is an essential component of the bacterial cell wall. Here, the authors use mouse models of infection withAcinetobacter baumannii, Pseudomonas aeruginosa and Staphylococcus aureusto show that bacterial mutants unable to synthesize D-glutamate can potentially be used as live attenuated vaccines.
- Maria P. Cabral
- , Patricia García
- & Germán Bou
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| Open AccessThe geography of measles vaccination in the African Great Lakes region
The WHO targets measles elimination by 2020, a goal that relies on high vaccination coverage. Here, Takahashiet al. identify ‘coldspots’ in the African Great Lakes region where measles vaccine coverage is below 80%, suggesting that these regions should be targeted in future vaccination campaigns.
- Saki Takahashi
- , C. Jessica E. Metcalf
- & Justin Lessler
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| Open AccessInduction of resident memory T cells enhances the efficacy of cancer vaccine
Resident memory T cells (Trm) are memory T cells that remain in tissue. Here, the authors show that induction of Trm cells is required for control of tumour growth following mucosal vaccination in mice bearing head and neck cancer and that Trm cells in human lung cancer correlates with a better survival.
- Mevyn Nizard
- , Hélène Roussel
- & Eric Tartour
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Article
| Open AccessCovalently linked dengue virus envelope glycoprotein dimers reduce exposure of the immunodominant fusion loop epitope
The immunodominant epitope of dengue virus envelope protein (E) induces poorly neutralizing antibodies, which poses a problem for vaccine development. Here, the authors engineer covalently locked E dimers exposing an epitope that has been shown to induce potent and broadly neutralizing antibodies.
- Alexander Rouvinski
- , Wanwisa Dejnirattisai
- & Gavin R. Screaton
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| Open AccessNotch-mediated conversion of activated T cells into stem cell memory-like T cells for adoptive immunotherapy
Tumour-specific T cells can be expandedin vitroand adoptively transferred for therapy, but this strategy is limited by induction of short-lived T cell populations. Here the authors activate Notch signalling in cultured mouse or human T cells, resulting in the production of a long-lived stem cell memory T cell population that can fight tumours in mice.
- Taisuke Kondo
- , Rimpei Morita
- & Akihiko Yoshimura
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Article
| Open AccessP113 is a merozoite surface protein that binds the N terminus of Plasmodium falciparum RH5
The secretedPlasmodium falciparum protein RH5 is essential for invasion of erythrocytes and is a promising vaccine candidate. Here, Galaway et al. show that the N-terminal region of RH5 binds the GPI-anchored merozoite surface protein P113 and can elicit invasion-blocking antibodies.
- Francis Galaway
- , Laura G. Drought
- & Gavin J. Wright
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| Open AccessA defined syphilis vaccine candidate inhibits dissemination of Treponema pallidum subspecies pallidum
There are no vaccines for the prevention of syphilis, a disease caused by the bacteriumTreponema pallidum subsp. pallidum. Here, the authors use an animal model of infection to show that immunization with the Tp0751 bacterial protein inhibits the pathogen’s spread within the body.
- Karen V. Lithgow
- , Rebecca Hof
- & Caroline E. Cameron
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| Open AccessTargeting dendritic cells to accelerate T-cell activation overcomes a bottleneck in tuberculosis vaccine efficacy
A delay in T cell responses is postulated as a possible explanation for the limited efficacy of vaccines against tuberculosis. Here the authors demonstrate this T-cell block and remove it by activating endogenous dendritic cells or delivering activated dendritic cells to the lungs, enhancing immunity of mice toMycobacterium tuberculosis.
- Kristin L. Griffiths
- , Mushtaq Ahmed
- & Shabaana A. Khader
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| Open AccessA live RSV vaccine with engineered thermostability is immunogenic in cotton rats despite high attenuation
Development of a safe and efficacious vaccine for respiratory syncytial virus (RSV) has been challenging. Here the authors generate a live-attenuated RSV vaccine that shows increased thermostability and immunogenicity, and protects cotton rats from RSV challenge.
- Christopher C. Stobart
- , Christina A. Rostad
- & Martin L. Moore
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| Open AccessAdditives for vaccine storage to improve thermal stability of adenoviruses from hours to months
Keeping viral vaccines cold from the manufacturers to patients is problematic and costly. Here, Krol and others show additives that can significantly improve at very low concentrations the storage of adenovirus type 5 at ambient and elevated temperature.
- Maria Pelliccia
- , Patrizia Andreozzi
- & Silke Krol
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| Open AccessIntroduction of neutralizing immunogenicity index to the rational design of MERS coronavirus subunit vaccines
Viral subunit vaccines contain epitopes that elicit non-neutralizing immune responses. Here, Duet al. mask an immunodominant non-neutralizing epitope on a MERS coronavirus subunit vaccine with a glycan probe, leading to significantly improved efficacy of the vaccine.
- Lanying Du
- , Wanbo Tai
- & Fang Li
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| Open AccessSaponin-based adjuvants induce cross-presentation in dendritic cells by intracellular lipid body formation
Saponin-based adjuvants are being explored as vaccine components as they induce high levels of antigen cross-presentation, but it is unknown how. Here the authors show that these adjuvants enhance cross-presentation by driving production of lipid bodies inside CD11b dendritic cells.
- Martijn H. den Brok
- , Christian Büll
- & Gosse J. Adema
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| Open AccessA polyvalent inactivated rhinovirus vaccine is broadly immunogenic in rhesus macaques
Existence of 150–170 serologically distinct human rhinoviruses (HRV) has hampered vaccine development for this human pathogen. Here, the authors show that a prime-boost regimen with an inactivated 50-valent HRV vaccine induces neutralizing antibody responses to diverse HRV serotypes in rhesus macaques.
- Sujin Lee
- , Minh Trang Nguyen
- & Martin L. Moore
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| Open AccessEnvelope-specific B-cell populations in African green monkeys chronically infected with simian immunodeficiency virus
Infection of African green monkeys with simian immunodeficiency virus is a potential model for HIV vaccine development. Here, Zhang et al. catalogue the immunoglobulin loci present in the genome of these animals, and experimentally study their B-cell response to the viral envelope protein.
- Ruijun Zhang
- , David R. Martinez
- & Sallie R. Permar
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| Open AccessPresenting native-like trimeric HIV-1 antigens with self-assembling nanoparticles
The development of native-like envelope trimers has been a major focus in the efforts to produce HIV vaccines. Here the authors demonstrate the production and characterization of virus-like nanoparticles displaying trimeric HIV-1 antigens with the potential to elicit broadly neutralizing antibodies.
- Linling He
- , Natalia de Val
- & Jiang Zhu
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| Open AccessUncleaved prefusion-optimized gp140 trimers derived from analysis of HIV-1 envelope metastability
A major goal of HIV-1 vaccine development is to produce antigens that can induce broadly neutralizing antibodies. Here the authors examine the underlying causes of HIV-1 envelope metastability and design uncleaved, prefusion-optimized gp140 trimers with potential for use as HIV-1 vaccine antigens.
- Leopold Kong
- , Linling He
- & Jiang Zhu
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| Open AccessMost neutralizing human monoclonal antibodies target novel epitopes requiring both Lassa virus glycoprotein subunits
Lassa virus can cause haemorrhagic fever for which no specific treatment currently exists. Here the authors have cloned 113 monoclonal antibodies from the survivors of Lassa infection and show that the majority of neutralizing antibodies target a complex of GP1 and GP2 viral proteins.
- James E. Robinson
- , Kathryn M. Hastie
- & Robert F. Garry
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| Open AccessThe TatD-like DNase of Plasmodium is a virulence factor and a potential malaria vaccine candidate
Neutrophil extracellular traps (NETs), composed of DNA and proteases, contribute to the innate immune response by capturing pathogens. Here, Chang et al. identify a NET-degrading DNase in Plasmodiumparasites and show that immunization with this protein provides protective immunity in a malaria mouse model.
- Zhiguang Chang
- , Ning Jiang
- & Qijun Chen
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| Open AccessMultivalent display of minimal Clostridium difficile glycan epitopes mimics antigenic properties of larger glycans
Immunologically-active glycans are promising vaccine candidates but can be difficult to synthesize. Here, the authors show that pentavalent display of a minimal disaccharde epitope on a chemical scaffold can mimic a native C. difficileglycan antigen, representing a simple approach to synthetic vaccine production.
- Felix Broecker
- , Jonas Hanske
- & Peter H. Seeberger
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| Open AccessT-cell activation is an immune correlate of risk in BCG vaccinated infants
BCG vaccine confers only partial protection against tuberculosis. Here the authors show that the risk of tuberculosis infection and progression to disease in BCG-immunized children positively correlates with the frequency of activated HLA-DR+CD4+T cells.
- Helen A. Fletcher
- , Margaret A. Snowden
- & Helen McShane
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| Open AccessType 1 diabetes vaccine candidates promote human Foxp3+Treg induction in humanized mice
Type 1 diabetes is associated with the loss of self-tolerance to the insulin-producing β-cells in the pancreas. Here the authors show that vaccination with insulin mimetopes can induce human insulin-specific regulatory T cells to mediate tolerance in a humanized mouse model.
- Isabelle Serr
- , Rainer W. Fürst
- & Carolin Daniel
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| Open AccessFollicular regulatory T cells can be specific for the immunizing antigen and derive from naive T cells
T follicular regulatory cells control the magnitude of the germinal centre response. Here the authors show that these cells display specificity to self as well as foreign antigens, and can arise from Foxp3-negative precursors at early stages of immunization in a PD-L1 dependent manner.
- Meryem Aloulou
- , Edward J. Carr
- & Michelle A. Linterman
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| Open AccessPre-vaccination inflammation and B-cell signalling predict age-related hyporesponse to hepatitis B vaccination
Ageing is associated with poor responses to vaccines but the underlying mechanism remains unclear. Here the authors use a systems-based approach to define molecular signatures present before vaccination that correlate with non-responsiveness to hepatitis B vaccination in healthy, elderly adults.
- Slim Fourati
- , Razvan Cristescu
- & Rafick-Pierre Sékaly
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| Open AccessMucosal vaccination with attenuated Mycobacterium tuberculosis induces strong central memory responses and protects against tuberculosis
BCG, the only vaccine currently used against tuberculosis, confers only limited protection. Here the authors show that mucosal immunization of macaques with an attenuated strain of Mycobacterium tuberculosisconfers a high level of protection from a lethal challenge with the bacterium.
- Deepak Kaushal
- , Taylor W. Foreman
- & Smriti Mehra
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Article
| Open AccessLigand-dependent genomic function of glucocorticoid receptor in triple-negative breast cancer
Glucocorticoids are widely used as coadjuvants in the treatment of solid tumours. Here, Chen et al. show that genes regulated by dexamethasone- but not Compound A-liganded glucocorticoid receptor are associated with therapy resistance and unfavourable clinical outcomes in triple-negative breast cancer.
- Zhong Chen
- , Xun Lan
- & Qianben Wang
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Article
| Open AccessA highly stable prefusion RSV F vaccine derived from structural analysis of the fusion mechanism
Respiratory syncytial virus (RSV) is a highly contagious childhood pathogen of the respiratory tract for which no vaccine is currently available. Here the authors present a strategy to stabilize the RSV F protein in a prefusion conformation that can elicit a strong protective immune response in animal models.
- Anders Krarup
- , Daphné Truan
- & Johannes P. M. Langedijk
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Article
| Open AccessDevelopment of high-yield influenza A virus vaccine viruses
The availability of high-yield virus strains remains an important bottleneck in the rapid production of influenza vaccines. Here, the authors report the development of influenza A vaccine backbone that improves the virus yield of various seasonal and pandemic influenza vaccine strains in cell culture.
- Jihui Ping
- , Tiago J.S. Lopes
- & Yoshihiro Kawaoka
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Article
| Open AccessEvaluation of candidate vaccine approaches for MERS-CoV
Unmet need exists for a vaccine against Middle East respiratory syndrome coronavirus (MERS-CoV). Here the authors report the establishment and evaluation, in mice and primates, of a series of MERS-CoV immunogens and show that they can serve as promising leads for vaccine development.
- Lingshu Wang
- , Wei Shi
- & Barney S. Graham
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Article
| Open AccessA potent broad-spectrum protective human monoclonal antibody crosslinking two haemagglutinin monomers of influenza A virus
Monoclonal antibodies with broadly neutralizing activity are being developed as potential treatment of influenza infections. Here, the authors describe a broadly neutralizing antibody with an unusual mode of binding to viral haemagglutinin, which has been isolated from patients convalescent from pandemic H1N1 influenza infection.
- Ying Wu
- , MyungSam Cho
- & Ruben O. Donis
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Article
| Open AccessAnalysis of immunoglobulin transcripts and hypermutation following SHIVAD8 infection and protein-plus-adjuvant immunization
HIV vaccine development will be facilitated by having animal models that are predictive for translation to humans. Here, the authors use two nonhuman primate models to compare the effects of natural infection and different adjuvants on antigen persistence, diversity and humoral immunity.
- Joseph R. Francica
- , Zizhang Sheng
- & Robert A. Seder
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Generation of cellular immune memory and B-cell immunity is impaired by natural killer cells
The need to develop vaccines against pathogens such as HIV requires the development of strategies to overcome inhibitory immunoregulatory mechanisms. Here, the authors report that murine natural killer cells inhibit CD4- and follicular helper T cells, leading to a weaker germinal center response and diminished virus-specific immune memory.
- Carolyn Rydyznski
- , Keith A. Daniels
- & Stephen N. Waggoner
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Defined TLR3-specific adjuvant that induces NK and CTL activation without significant cytokine production in vivo
Activation of TLRs by microbial ligands induces complex innate immune responses to activate host defence. Here the authors show that a synthetic TLR3 ligand can boost protective immunity without robust inflammatory cytokine production, minimizing toxic effects of immunization.
- Misako Matsumoto
- , Megumi Tatematsu
- & Tsukasa Seya
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| Open AccessClearance of persistent HPV infection and cervical lesion by therapeutic DNA vaccine in CIN3 patients
While several human papilloma virus (HPV) vaccines exist, a highly effective vaccine that mediates regression of HPV-induced tumours is lacking. Here the authors show that a therapeutic DNA vaccine-induced HPV-specific polyfunctional CD8 T cell in 7 out of 9 patients who all exhibited complete regression of lesions and viral clearance.
- Tae Jin Kim
- , Hyun-Tak Jin
- & Young Chul Sung
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| Open AccessTranscriptional specialization of human dendritic cell subsets in response to microbial vaccines
The effects of vaccines on human dendritic cells (DCs) are incompletely understood. Here the authors build a transcriptional modular network based on in vitroinfection of human DCs and apply it for the characterization of the DC response to 13 different vaccines.
- Romain Banchereau
- , Nicole Baldwin
- & Virginia Pascual
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A micro-sterile inflammation array as an adjuvant for influenza vaccines
There is a need of improved adjuvants for influenza vaccines. Here, the authors describe an adjuvant strategy using micro-fractional laser treatment combined with a topical cream containing a TLR 7 ligand that can enhance the immune response to intradermal vaccination with transient, constrained local inflammation.
- Ji Wang
- , Dilip Shah
- & Mei X. Wu
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Antigen capture and archiving by lymphatic endothelial cells following vaccination or viral infection
Viral antigens can persist within the secondary lymphoid tissues of the host for many weeks after resolution of the infection. Tamburini et al.demonstrate that antigens remaining following viral infection or vaccination can be captured and maintained for extended periods of time by lymphatic endothelial cells.
- Beth A. Tamburini
- , Matthew A. Burchill
- & Ross M. Kedl
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Receptor mimicry by antibody F045–092 facilitates universal binding to the H3 subtype of influenza virus
Influenza A H3 viruses circulate in humans and bind host cells using the haemagglutinin (HA) glycoprotein. Here, Lee et al.perform a structural analysis of antibody F045–092 with broadly neutralizing activity against the H3 subtype and reveal its interaction with the HA receptor binding site.
- Peter S. Lee
- , Nobuko Ohshima
- & Ian A. Wilson