Nanoparticle delivery of a tetravalent E protein subunit vaccine induces balanced, type-specific neutralizing antibodies to each dengue virus serotype

Metz, Stefan; Thomas, Ashlie; Brackbill, Alex; Yi, Xin; Stone, Michele; Horvath, Katie; Miley, Michael J.; Luft, Chris J.; DeSimone, Joseph M.; Tian, Shaomin; Silva, Aravinda M. de

doi:10.1371/journal.pntd.0006793

Cited by 23 publications

(17 citation statements)

References 41 publications

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“…ZIKV specific IgG responses were measured as previously described 28 . Briefly, ZIKV was captured on 1M7-coated ELISA plates and incubated with 1:50 or serially diluted mouse sera 3, 4, 10 and 16 weeks post immunization.…”

Section: Methodsmentioning

confidence: 99%

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Oligomeric state of the ZIKV E protein defines protective immune responses

Metz

Thomas

Brackbill

et al. 2019

Preprint

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8The current leading Zika vaccine candidates in clinical testing are based on live or killed virus 9 platforms, which have safety issues, especially in pregnant women. Zika subunit vaccines, 10 however, have shown poor performance in preclinical studies. We hypothesized that Zika 11Envelope (E) protein subunit vaccines have performed poorly because the antigens tested have 12been recombinant E monomers that do not display critical quaternary structure epitopes present 13on Zika E protein homodimers that cover the surface of the virus. To test this hypothesis, we 14 engineered and produced stable recombinant E protein homodimers. Unlike the E monomer, the 15 dimer was recognized by strongly neutralizing monoclonal antibodies isolated from Zika-immune 16 individuals. In a mouse model of vaccination, the dimeric antigen stimulated strongly neutralizing 17 antibodies that targeted epitopes that were similar to epitopes recognized by human antibodies 18 following natural Zika virus infection. In contrast, the monomer antigen stimulated lower levels of 19 neutralizing antibodies directed to simple epitopes on domain III of E protein. In a mouse model 20 of ZIKV challenge, only E dimer antigen stimulated protective antibodies, not the 21 monomer. These results highlight the importance of mimicking the highly structured flavivirus 22 surface when designing subunit vaccines. The flavivirus field has a long history of using E 23 monomers as vaccine antigens with limited success. These results are applicable to developing 24 second generation subunit vaccines against Zika as well as other medically important flaviviruses 25 such as dengue and yellow fever viruses. 26 130 Figure 3: ZIKV rE D stimulates antibodies that target complex epitopes on the virion. A) Method for 131 depleting EDIII binding antibodies from mouse immune sera. Recombinant ZIKV EDIII (His-tagged) was 132 coupled to nickel beads i then incubated with immune sera ii . Magnetic pull down removes nickel beads and 133 EDIII binding antibodies iii , leaving leavind sera depleted from EDIII binding antibodies iv . B) The level of 134 EDIII-binding antibodies in the serum of mice immunized with the indicated antigens is shown as a 135 percentage of the total level of ZIKV specific IgG, as measured by ELISA of EDIII-depleted and control-136 depleted serum. C) The neutralizing activity of EDIII-depleted and undepleted sera was determined and 137 expressed as the dilution at which 50% of the virus was neutralized (Neut50). D) A blockade of binding 138 (BOB) assay was used to evaluate if mice immunized with rE M or rE D developed antibodies that blocked 139 the binding of A9E, G9E and EDE C10 human mAbs. Data points represent individual mice. Statistical140differences were determined by one-way ANOVA followed by a Tukey's test (p<0.05).

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Section: Methodsmentioning

confidence: 99%

“…Neutralizing antibody titers were determined as previously described 28 . In short, Vero-81 cells were seeded (25000 cells/well) and incubated at 37°C overnight.…”

Section: Methodsmentioning

confidence: 99%

Oligomeric state of the ZIKV E protein defines protective immune responses

Metz

Thomas

Brackbill

et al. 2019

Preprint

Self Cite

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“…Several types of materials were used to develop vaccine-based nanoparticles. For dengue vaccines, it seemed that several types of organic (bovine serum albumin, lipid) and inorganic materials (calcium chloride, carbon, and calcium phosphate) were used [33,[53][54][55][56][57][58][59][60][61]. For ZIKV vaccines, only lipid and poly(amidoamine) nanoparticles were used [62][63][64][65][66][67], and for JEV vaccines, protein-VLPs, chitosan, and poly(gamma-glutamic acid) nanoparticles were tested [68][69][70][71][72][73][74][75].…”

Section: Nanovaccines Against Arbovirusesmentioning

confidence: 99%

Nanoparticles as Vaccines to Prevent Arbovirus Infection: A Long Road Ahead

et al. 2021

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Arthropod-borne viruses (arboviruses) are a significant public health problem worldwide. Vaccination is considered one of the most effective ways to control arbovirus diseases in the human population. Nanoparticles have been widely explored as new vaccine platforms. Although nanoparticles’ potential to act as new vaccines against infectious diseases has been identified, nanotechnology’s impact on developing new vaccines to prevent arboviruses is unclear. Thus, we used a comprehensive bibliographic survey to integrate data concerning the use of diverse nanoparticles as vaccines against medically important arboviruses. Our analysis showed that considerable research had been conducted to develop and evaluate nanovaccines against Chikungunya virus, Dengue virus, Zika virus, Japanese encephalitis virus, and West Nile virus. The main findings indicate that nanoparticles have great potential for use as a new vaccine system against arboviruses. Most of the studies showed an increase in neutralizing antibody production after mouse immunization. Nevertheless, even with significant advances in this field, further efforts are necessary to address the nanoparticles’ potential to act as a vaccine against these arboviruses. To promote advances in the field, we proposed a roadmap to help researchers better characterize and evaluate nanovaccines against medically important arboviruses.

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“…A tetravalent DENV protein subunit vaccine, based on recombinant envelope protein (rE) adsorbed to the surface of PLGA NPs, was designed. Particulate rE induced higher neutralizing antibody titers compared to the soluble rE antigen alone and stimulated a more balanced serotype-specific antibody response to each DENV serotype compared to soluble antigens, suggesting that such vaccines might overcome unbalanced immunity observed for leading live attenuated vaccine candidates (Metz et al 2018). AgNPs showed in vitro antiviral activity against dengue serotype DEN-2 infecting Vero cells and the activity of AgNPs against the dengue vector Aedes aegypti expressed by IC 50 values ranged from 10.24 ppm (I instar larvae) to 21.17 ppm (pupae) (Sujitha et al 2015).…”

Section: Dengue Virus and Zika Virusmentioning

confidence: 99%

Nanoformulations: A Valuable Tool in the Therapy of Viral Diseases Attacking Humans and Animals

Jampílek

Kráľová

2019

Nanotheranostics

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Various viruses can be considered as one of the most frequent causes of human diseases, from mild illnesses to really serious sicknesses that end fatally. Numerous viruses are also pathogenic to animals and plants, and many of them, mutating, become pathogenic also to humans. Several cases of affecting humans by originally animal viruses have been confirmed. Viral infections cause significant morbidity and mortality in humans, the increase of which is caused by general immunosuppression of the world population, changes in climate, and overall globalization. In spite of the fact that the pharmaceutical industry pays great attention to human viral infections, many of clinically used antivirals demonstrate also increased toxicity against human cells, limited bioavailability, and thus, not entirely suitable therapeutic profile. In addition, due to resistance, a combination of antivirals is needed for life-threatening infections. Thus, the development of new antiviral agents is of great importance for the control of virus spread. On the other hand, the discovery and development of structurally new antivirals represent risks. Therefore, another strategy is being developed, namely the reformulation of existing antivirals into nanoformulations and investigation of various metal and metalloid nanoparticles with respect to their diagnostic, prophylactic, and therapeutic antiviral applications. This chapter is focused on nanoscale materials/formulations with the potential to be used for the treatment or inhibition of the spread of viral diseases caused by human immunodeficiency virus, influenza A viruses (subtypes H3N2 and H1N1), avian influenza and swine influenza viruses, respiratory syncytial virus, herpes simplex virus, hepatitis B and C viruses, Ebola and Marburg viruses, Newcastle disease virus, dengue and Zika viruses, and pseudorabies virus. Effective antiviral long-lasting and target-selective nanoformulations developed for oral, intravenous, intramuscular, intranasal, intrarectal, intravaginal, and intradermal applications are discussed.

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Nanoparticle delivery of a tetravalent E protein subunit vaccine induces balanced, type-specific neutralizing antibodies to each dengue virus serotype

Cited by 23 publications

References 41 publications

Oligomeric state of the ZIKV E protein defines protective immune responses

Oligomeric state of the ZIKV E protein defines protective immune responses

Nanoparticles as Vaccines to Prevent Arbovirus Infection: A Long Road Ahead

Nanoformulations: A Valuable Tool in the Therapy of Viral Diseases Attacking Humans and Animals

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