Checkpoint inhibitors successful on multiple fronts
The anti-PD-L1 MAb Tecentriq (MPDL3280A, Roche) was granted priority review by the U.S. Food and Drug Administration for treatment of patients with locally advanced or metastatic urothelial carcinoma who failed prior chemotherapy. Urothelial carcinoma accounts for ∼90% of bladder cancers with almost 80,000 diagnoses annually in U.S. alone. The decision is based on the Phase 2 IMvigor 210 study, in which atezolizumab was associated with long-term clinical benefits.
The anti-PD1 MAb nivolumab (Opdivo, BMS) was successful in treating squamous cell carcinoma and advanced melanoma in the CheckMate study series. In a Phase 3 trial involving >360 patients with squamous cell carcinoma, the one-year survival rate was 36% in nivolumab-treated patients compared to 16% in a control group.
Nivolumab was also tested in combination with ipilimumab (Yervoy, BMS), a checkpoint-inhibitor MAb targeting CTLA-4. The Phase 2 study reported 55% progression-free survival rate at one year in patients who received the cocktail, compared to 16% in an ipilimumab-only cohort.
Finally, another PD-L1-specific MAb durvalumab (AstraZeneca) is entering a Phase 2 trial in combination with the cancer vaccine TPIV 200 (TapImmune), a multi-epitope peptide derived from Folate Receptor Alpha, which is upregulated in multiple cancer types. The study will assess efficacy in treating platinum-resistant ovarian cancer.
Therapeutic vaccine against genital herpes had promising results in a Phase 2 trial
Therapeutic genital herpes vaccine GEN-003 (Genocea) reduced viral shedding by >60% and genital lesions by /50% at one year. These results were comparable to the standard-of-care oral antivirals. The vaccine, which contains two viral proteins and an adjuvant, elicits both T- and B-cell responses. The two best-performing doses are being tested in a Phase 2b study.
Genital herpes is a global disease affecting >400 million people around the world. While antiviral pills need to be taken daily, GEN-003 is administered in three doses three weeks apart.
Early-trial successes for adoptive T-cell transfer therapies
27 of 29 patients with refractory acute lymphoblastic leukemia (ALL) went into remission in an early-stage clinical trial of CAR-T immunotherapy.1 Their T cells were harvested and genetically engineered to recognize CD19 marker on the tumor cells. An even mixture of helper and killer T cells was infused back into the subjects. Currently, patients with refractory ALL face very limited options for treatment.
A different approach was taken in a trial involving 14 patients with MAGE-A3-positive metastatic cancers. Helper T cells were isolated from their peripheral blood following MAGE-A3 peptide vaccination. The cells were multiplied in vitro and infused back in doses ranging from 106 to 1011 cells. The treatment was safe and elicited clinical response in 3 subjects, and it has been taken to a Phase 2 trial.
Turtle CJ, Hanafi LA, Berger C, Gooley TA, Cherian S, Hudecek M, Sommermeyer D, Melville K, Pender B, Budiarto TM, Robinson E, Steevens NN, Chaney C, Soma L, Chen X, Yeung C, Wood B, Li D, Cao J, Heimfeld S, Jensen MC, Riddell SR, Maloney DG. CD19 CAR-T cells of defined CD4+:CD8+ composition in adult B cell ALL patients. J Clin Invest 2016; doi: 10.1172/JCI85309
<!--${if: isGetFTREnabled}--><!--${/if:}--> <!--${ifNot: isGetFTREnabled}--><!--${/ifNot:}--><!--${if: isGetFTREnabled}--><!--${/if:}--><!--${googleScholarLinkReplacer: 10.1172%2FJCI85309 journal CD19+CAR-T+cells+of+defined+CD4%2B%3ACD8%2B+composition+in+adult+B+cell+ALL+patients author%3DCJ+Turtle%26author%3DLA+Hanafi%26author%3DC+Berger%26author%3DTA+Gooley%26author%3DS+Cherian%26author%3DM+Hudecek%26author%3DD+Sommermeyer%26author%3DK+Melville%26author%3DB+Pender%26author%3DTM+Budiarto%26author%3DE+Robinson%26author%3DNN+Steevens%26author%3DC+Chaney%26author%3DL+Soma%26author%3DX+Chen%26author%3DC+Yeung%26author%3DB+Wood%26author%3DD+Li%26author%3DJ+Cao%26author%3DS+Heimfeld%26author%3DMC+Jensen%26author%3DSR+Riddell%26author%3DDG+Maloney 2016 Turtle+CJ%2C+Hanafi+LA%2C+Berger+C%2C+Gooley+TA%2C+Cherian+S%2C+Hudecek+M%2C+Sommermeyer+D%2C+Melville+K%2C+Pender+B%2C+Budiarto+TM%2C+Robinson+E%2C+Steevens+NN%2C+Chaney+C%2C+Soma+L%2C+Chen+X%2C+Yeung+C%2C+Wood+B%2C+Li+D%2C+Cao+J%2C+Heimfeld+S%2C+Jensen+MC%2C+Riddell+SR%2C+Maloney+DG.+CD19+CAR-T+cells+of+defined+CD4%2B%3ACD8%2B+composition+in+adult+B+cell+ALL+patients.+J+Clin+Invest+2016%3B+doi%3A+ %00empty%00 J+Clin+Invest %00empty%00 %00null%00 10.1172%2FJCI85309 %00empty%00 %00null%00 getFTREnabled FULL_TEXT %00empty%00}--><!--${sfxLinkReplacer: e_1_2_3_3_4_1_1_1 %00empty%00 url_ver%3DZ39.88-2004%26rft.genre%3Darticle%26rfr_id%3Dinfo%3Asid%2Fliteratum%253Atandf%26rft.aulast%3DTurtle%26rft.aufirst%3DCJ%26rft.atitle%3DCD19%2520CAR-T%2520cells%2520of%2520defined%2520CD4%252B%253ACD8%252B%2520composition%2520in%2520adult%2520B%2520cell%2520ALL%2520patients%26rft.jtitle%3DJ%2520Clin%2520Invest%26rft.date%3D2016 %00empty%00}-->
Influenza vaccination might be more effective when administered in the morning
Immune responses to influenza vaccine depend on the time of the day when administered, as a study published in the journal Vaccine suggests.1 276 adults aged >65 received trivalent seasonal influenza vaccine in the morning (9-11 am) or afternoon (3-5 pm). One month later, the former group had higher titers of antibodies to two of the three virus strains. The third strain was not connected with any difference.
“We know that there are fluctuations in immune responses throughout the day and wanted to examine whether this would extend to the antibody response to vaccination. Being able to see that morning vaccinations yield a more efficient response will not only help in strategies for flu vaccination, but might provide clues to improve vaccination strategies more generally,” senior author Anna Phillips of University of Birmingham said in a press release.
Long JE, Drayson MT, Taylor AE, Toellner KM, Lord JM, Phillips AC. Morning vaccination enhances antibody response over afternoon vaccination: A cluster-randomised trial. Vaccine 2016; doi: 10.1016/j.vaccine.2016.04.032
<!--${if: isGetFTREnabled}--><!--${/if:}--> <!--${ifNot: isGetFTREnabled}--><!--${/ifNot:}--><!--${if: isGetFTREnabled}--><!--${/if:}--><!--${googleScholarLinkReplacer: 10.1016%2Fj.vaccine.2016.04.032 journal Morning+vaccination+enhances+antibody+response+over+afternoon+vaccination%3A+A+cluster-randomised+trial author%3DJE+Long%26author%3DMT+Drayson%26author%3DAE+Taylor%26author%3DKM+Toellner%26author%3DJM+Lord%26author%3DAC+Phillips 2016 Long+JE%2C+Drayson+MT%2C+Taylor+AE%2C+Toellner+KM%2C+Lord+JM%2C+Phillips+AC.+Morning+vaccination+enhances+antibody+response+over+afternoon+vaccination%3A+A+cluster-randomised+trial.+Vaccine+2016%3B+doi%3A+ %00empty%00 Vaccine %00empty%00 %00null%00 10.1016%2Fj.vaccine.2016.04.032 %00empty%00 %00null%00 getFTREnabled FULL_TEXT %00empty%00}--><!--${sfxLinkReplacer: e_1_2_4_3_1_1_1_1 %00empty%00 url_ver%3DZ39.88-2004%26rft.genre%3Darticle%26rfr_id%3Dinfo%3Asid%2Fliteratum%253Atandf%26rft.aulast%3DLong%26rft.aufirst%3DJE%26rft.atitle%3DMorning%2520vaccination%2520enhances%2520antibody%2520response%2520over%2520afternoon%2520vaccination%253A%2520A%2520cluster-randomised%2520trial%26rft.jtitle%3DVaccine%26rft.date%3D2016 %00empty%00}-->
Progress in allergy immunotherapy
The Japanese cedar pollen sublingual immunotherapy tablet STAGR120 (Stallergenes) ameliorated allergic rhinitis symptoms and met primary endpoints in a Phase 2 placebo-controlled, dose-ranging trial. 330 patients aged 12–.49 years were treated for 4 months, and improvements were noted in all dose-groups.
Another placebo-controlled, dose-ranging study assessed the efficacy of a house dust mite (HDM) sublingual allergen immunotherapy in preventing asthma.1 Among almost 700 subjects that received daily treatment, the experimental group reported decrease in moderate to severe HDM-related asthma, and no severe allergic reactions were observed.
Virchow JC, Backer V, Kuna P, Prieto L, Nolte H, Villesen HH, Ljørring C, Riis B, de Blay F. Efficacy of a House Dust Mite Sublingual Allergen Immunotherapy Tablet in Adults With Allergic Asthma: A Randomized Clinical Trial. JAMA 2016; 315(16):1715-25.
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New hepatitis B vaccine candidate outperformed the standard-of-care in a late-stage trial
Hepatitis B vaccine candidate HeplisavB (Dynavax) induced higher seroprotection rates than EngerixB (GSK), which has been in use in the U.S. since 1989. In a Phase 3 HBV-23 trial, subjects aged 18-39 had seroprotection rates of 99% after vaccination with HeplisavB and 93% when immunized with Engerix-B. The figures were 95% and 79%, respectively, in individuals aged 40-70.
While EngerixB is administered in three doses over 6 months, HeplisavB requires only two doses one month apart. The safety profile for both vaccines was similar. HeplisavB is an adult vaccine containing HBV surface antigen and a TLR9 agonist as an adjuvant.
Mesothelioma vaccine promising in early-stage trial
The cancer vaccine CRS-207 was safe and elicited tumor-specific immunity in 34 patients with malignant pleural mesothelioma (MPM) when administered in combination with chemotherapy. Tumor shrinkage was noted in 85% of the subjects. CRS-207 is a live attenuated Listeria monocytogenes expressing the tumor-associated antigen mesothelin, which is induced in some mesothelioma cases.
MPM is an aggressive cancer with poor prognosis, and in most cases it cannot be removed surgically. “CRS-207 is an exciting agent for patients with mesothelioma. Our preliminary results are encouraging, suggesting superior clinical activity when added to standard chemotherapy. This supports assessing the impact of CRS-207 in a randomized trial, which is currently in the planning stages,” lead author Thierry Jahan of UCSF said in a statement.
WHO endorsed the use of Dengvaxia in dengue-endemic countries
The World Health Organization has recommended the dengue vaccine Dengvaxia (Sanofi) in countries where the seroprevalence of the disease is ≥ 70%. It is not recommended for countries with < 50% seroprevalence. Dengue affects almost 400 million people annually, especially in Latin America and Asia.
In a recent Phase 3 trial, Dengvaxia has been shown to prevent 66% of dengue cases and 93% of severe dengue. It is the first dengue vaccine on the market, approved in the Philippines, Brazil, El Salvador and Mexico. Thus far, Philippines has included Dengvaxia in a national immunization program.
Ebola vaccine combination stimulated long-term immunogenicity in all subjects
A prime-boost regimen of vaccination against Ebola elicited specific antibodies that persisted for 8 months in 100% of volunteers. According to the results of a Phase 1 clinical trial published in JAMA,1 the most effective combination was AdVac (J&J) as the primer and MVA-BN (Bavarian Nordic) as the booster dose. At least 80% of the subjects developed Ebola-specific T-cell immunity.
The study was the first of a series of 10 clinical trials in U.S., Europe and Africa to assess the prime-boost combination. While the Ebola epidemic in West Africa is over, vaccine development remains a priority due to future potential outbreaks.
Milligan ID, Gibani MM, Sewell R, Clutterbuck EA, Campbell D, Plested E, Nuthall E, Voysey M, Silva-Reyes L, McElrath MJ, De Rosa SC, Frahm N, Cohen KW, Shukarev G, Orzabal N, van Duijnhoven W, Truyers C, Bachmayer N, Splinter D, Samy N, Pau MG, Schuitemaker H, Luhn K, Callendret B, Van Hoof J, Douoguih M, Ewer K, Angus B, Pollard AJ, Snape MD. Safety and Immunogenicity of Novel Adenovirus Type 26- and Modified Vaccinia Ankara-Vectored Ebola Vaccines: A Randomized Clinical Trial. JAMA 2016; 315(15):1610-23.
<!--${if: isGetFTREnabled}--><!--${/if:}--> <!--${ifNot: isGetFTREnabled}--><!--${/ifNot:}--><!--${if: isGetFTREnabled}--><!--${/if:}--><!--${googleScholarLinkReplacer: %00empty%00 journal Safety+and+Immunogenicity+of+Novel+Adenovirus+Type+26-+and+Modified+Vaccinia+Ankara-Vectored+Ebola+Vaccines%3A+A+Randomized+Clinical+Trial author%3DID+Milligan%26author%3DMM+Gibani%26author%3DR+Sewell%26author%3DEA+Clutterbuck%26author%3DD+Campbell%26author%3DE+Plested%26author%3DE+Nuthall%26author%3DM+Voysey%26author%3DL+Silva-Reyes%26author%3DMJ+McElrath%26author%3DSC+De+Rosa%26author%3DN+Frahm%26author%3DKW+Cohen%26author%3DG+Shukarev%26author%3DN+Orzabal%26author%3DW+van+Duijnhoven%26author%3DC+Truyers%26author%3DN+Bachmayer%26author%3DD+Splinter%26author%3DN+Samy%26author%3DMG+Pau%26author%3DH+Schuitemaker%26author%3DK+Luhn%26author%3DB+Callendret%26author%3DJ+Van+Hoof%26author%3DM+Douoguih%26author%3DK+Ewer%26author%3DB+Angus%26author%3DAJ+Pollard%26author%3DMD+Snape 2016 Milligan+ID%2C+Gibani+MM%2C+Sewell+R%2C+Clutterbuck+EA%2C+Campbell+D%2C+Plested+E%2C+Nuthall+E%2C+Voysey+M%2C+Silva-Reyes+L%2C+McElrath+MJ%2C+De+Rosa+SC%2C+Frahm+N%2C+Cohen+KW%2C+Shukarev+G%2C+Orzabal+N%2C+van+Duijnhoven+W%2C+Truyers+C%2C+Bachmayer+N%2C+Splinter+D%2C+Samy+N%2C+Pau+MG%2C+Schuitemaker+H%2C+Luhn+K%2C+Callendret+B%2C+Van+Hoof+J%2C+Douoguih+M%2C+Ewer+K%2C+Angus+B%2C+Pollard+AJ%2C+Snape+MD.+Safety+and+Immunogenicity+of+Novel+Adenovirus+Type+26-+and+Modified+Vaccinia+Ankara-Vectored+Ebola+Vaccines%3A+A+Randomized+Clinical+Trial.+JAMA+2016%3B+315%2815%29%3A1610-23. 1610-23 JAMA 315 15 %00empty%00 %00empty%00 %00null%00 getFTREnabled FULL_TEXT %00empty%00}--><!--${sfxLinkReplacer: e_1_2_9_3_1_1_1_1 %00empty%00 url_ver%3DZ39.88-2004%26rft.genre%3Darticle%26rfr_id%3Dinfo%3Asid%2Fliteratum%253Atandf%26rft.aulast%3DMilligan%26rft.aufirst%3DID%26rft.atitle%3DSafety%2520and%2520Immunogenicity%2520of%2520Novel%2520Adenovirus%2520Type%252026-%2520and%2520Modified%2520Vaccinia%2520Ankara-Vectored%2520Ebola%2520Vaccines%253A%2520A%2520Randomized%2520Clinical%2520Trial%26rft.jtitle%3DJAMA%26rft.date%3D2016%26rft.volume%3D315%26rft.issue%3D15%26rft.spage%3D1610%26rft.epage%3D23 %00empty%00}-->
Broad immune response elicited in mice with a novel influenza vaccine design technology
The computationally optimized broadly reactive antigen (COBRA) technology was successful in designing potent influenza vaccine with broad specificity, according to results of a preclinical study.1 Researchers sequenced hemagglutinin (HA) genes of multiple influenza strains, and computationally optimized a synthetic HA vaccine.
Of 9 tested candidates, 4 elicited HA-inhibition activity against 17 H1N1 strains. In addition, the approach successfully designed vaccine against multiple seasonal strains.
Carter DM, Darby CA, Lefoley BC, Crevar CJ, Alefantis T, Oomen R, Anderson SF, Strugnell T, Cortés-Garcia G, Vogel TU, Parrington M, Kleanthous H, Ross TM. Design and Characterization of a Computationally Optimized Broadly Reactive Hemagglutinin Vaccine for H1N1 Influenza Viruses. J Virol 2016; 90(9):4720-34.
<!--${if: isGetFTREnabled}--><!--${/if:}--> <!--${ifNot: isGetFTREnabled}--><!--${/ifNot:}--><!--${if: isGetFTREnabled}--><!--${/if:}--><!--${googleScholarLinkReplacer: %00empty%00 journal Design+and+Characterization+of+a+Computationally+Optimized+Broadly+Reactive+Hemagglutinin+Vaccine+for+H1N1+Influenza+Viruses author%3DDM+Carter%26author%3DCA+Darby%26author%3DBC+Lefoley%26author%3DCJ+Crevar%26author%3DT+Alefantis%26author%3DR+Oomen%26author%3DSF+Anderson%26author%3DT+Strugnell%26author%3DG+Cort%C3%A9s-Garcia%26author%3DTU+Vogel%26author%3DM+Parrington%26author%3DH+Kleanthous%26author%3DTM+Ross 2016 Carter+DM%2C+Darby+CA%2C+Lefoley+BC%2C+Crevar+CJ%2C+Alefantis+T%2C+Oomen+R%2C+Anderson+SF%2C+Strugnell+T%2C+Cort%C3%A9s-Garcia+G%2C+Vogel+TU%2C+Parrington+M%2C+Kleanthous+H%2C+Ross+TM.+Design+and+Characterization+of+a+Computationally+Optimized+Broadly+Reactive+Hemagglutinin+Vaccine+for+H1N1+Influenza+Viruses.+J+Virol+2016%3B+90%289%29%3A4720-34. 4720-34. J+Virol 90 9 %00empty%00 %00empty%00 %00null%00 getFTREnabled FULL_TEXT %00empty%00}--><!--${sfxLinkReplacer: e_1_2_10_3_1_1_1_1 %00empty%00 url_ver%3DZ39.88-2004%26rft.genre%3Darticle%26rfr_id%3Dinfo%3Asid%2Fliteratum%253Atandf%26rft.aulast%3DCarter%26rft.aufirst%3DDM%26rft.atitle%3DDesign%2520and%2520Characterization%2520of%2520a%2520Computationally%2520Optimized%2520Broadly%2520Reactive%2520Hemagglutinin%2520Vaccine%2520for%2520H1N1%2520Influenza%2520Viruses%26rft.jtitle%3DJ%2520Virol%26rft.date%3D2016%26rft.volume%3D90%26rft.issue%3D9%26rft.spage%3D4720%26rft.epage%3D34 %00empty%00}-->
‘Superglue’ successfully used for antigen display on VLPs
A novel technique of tethering antigens to the surface of virus-like particles produced potent vaccines against various diseases. According to an article published in Journal of Nanobiotechnology,1 eleven antigens were covalently attached to the Acinetobacter phage AP205 capsid protein via SpyTag / SpyCatcher peptide conjugation system. Vaccines presenting the malaria proteins Pfs25 or VAR2CSA increased antibody titer, affinity, longevity and functional efficacy in mice compared to vaccines consisting of monomeric proteins.
In addition, the method was successfully used to break self-tolerance and induced potent and durable responses upon vaccination with cancer- or allergy-associated self-antigens. “The method is generic, which means that we can glue, for example, different parts of pathogenic organisms onto the surface of the virus-like platform,” lead author Susan Thrane of University of Copenhagen said in a press release.
Thrane S, Janitzek CM, Matondo S, Resende M, Gustavsson T, de Jongh WA, Clemmensen S, Roeffen W, van de Vegte-Bolmer M, van Gemert GJ, Sauerwein R, Schiller JT, Nielsen MA, Theander TG, Salanti A, Sander AF. Bacterial superglue enables easy development of efficient virus-like particle based vaccines. J Nanobiotechnology 2016; 14:30.
<!--${if: isGetFTREnabled}--><!--${/if:}--> <!--${ifNot: isGetFTREnabled}--><!--${/ifNot:}--><!--${if: isGetFTREnabled}--><!--${/if:}--><!--${googleScholarLinkReplacer: %00empty%00 journal Bacterial+superglue+enables+easy+development+of+efficient+virus-like+particle+based+vaccines author%3DS+Thrane%26author%3DCM+Janitzek%26author%3DS+Matondo%26author%3DM+Resende%26author%3DT+Gustavsson%26author%3DWA+de+Jongh%26author%3DS+Clemmensen%26author%3DW+Roeffen%26author%3DM+van+de+Vegte-Bolmer%26author%3DGJ+van+Gemert%26author%3DR+Sauerwein%26author%3DJT+Schiller%26author%3DMA+Nielsen%26author%3DTG+Theander%26author%3DA+Salanti%26author%3DAF+Sander 2016 Thrane+S%2C+Janitzek+CM%2C+Matondo+S%2C+Resende+M%2C+Gustavsson+T%2C+de+Jongh+WA%2C+Clemmensen+S%2C+Roeffen+W%2C+van+de+Vegte-Bolmer+M%2C+van+Gemert+GJ%2C+Sauerwein+R%2C+Schiller+JT%2C+Nielsen+MA%2C+Theander+TG%2C+Salanti+A%2C+Sander+AF.+Bacterial+superglue+enables+easy+development+of+efficient+virus-like+particle+based+vaccines.+J+Nanobiotechnology+2016%3B+14%3A30. 30 J+Nanobiotechnology 14 %00null%00 %00empty%00 %00empty%00 %00null%00 getFTREnabled FULL_TEXT %00empty%00}--><!--${sfxLinkReplacer: e_1_2_11_3_1_1_1_1 %00empty%00 url_ver%3DZ39.88-2004%26rft.genre%3Darticle%26rfr_id%3Dinfo%3Asid%2Fliteratum%253Atandf%26rft.aulast%3DThrane%26rft.aufirst%3DS%26rft.atitle%3DBacterial%2520superglue%2520enables%2520easy%2520development%2520of%2520efficient%2520virus-like%2520particle%2520based%2520vaccines%26rft.jtitle%3DJ%2520Nanobiotechnology%26rft.date%3D2016%26rft.volume%3D14%26rft.spage%3D30 %00empty%00}-->