Publications by authors named "Theodore C Pierson"

125 Publications

Implications of a highly divergent dengue virus strain for cross-neutralization, protection, and vaccine immunity.

Cell Host Microbe 2021 Sep 29. Epub 2021 Sep 29.

Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110-1010, USA; Department of Pathology & Immunology, Washington University School of Medicine, St. Louis, MO 63110-1010, USA; Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, MO 63110-1010, USA; The Andrew M. Jane M. Bursky Center for Human Immunology & Immunotherapy Programs, Washington University School of Medicine, St. Louis, MO 63110-1010, USA; Center for Vaccines and Immunity to Microbial Pathogens, Washington University School of Medicine, Saint Louis, MO 63110-1010, USA. Electronic address:

Although divergent dengue viruses (DENVs) have been isolated in insects, nonhuman primates, and humans, their relationships to the four canonical serotypes (DENV 1-4) are poorly understood. One virus isolated from a dengue patient, DKE-121, falls between genotype and serotype levels of sequence divergence to DENV-4. To examine its antigenic relationship to DENV-4, we assessed serum neutralizing and protective activity. Whereas DENV-4-immune mouse sera neutralize DKE-121 infection, DKE-121-immune sera inhibit DENV-4 less efficiently. Passive transfer of DENV-4 or DKE-121-immune sera protects mice against homologous, but not heterologous, DENV-4 or DKE-121 challenge. Antigenic cartography suggests that DENV-4 and DKE-121 are related but antigenically distinct. However, DENV-4 vaccination confers protection against DKE-121 in nonhuman primates, and serum from humans immunized with a tetravalent vaccine neutralize DENV-4 and DKE-121 infection equivalently. As divergent DENV strains, such as DKE-121, may meet criteria for serotype distinction, monitoring their capacity to impact dengue disease and vaccine efficacy appears warranted.
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http://dx.doi.org/10.1016/j.chom.2021.09.006DOI Listing
September 2021

Dengue virus serotype 1 conformational dynamics confers virus strain-dependent patterns of neutralization by polyclonal sera.

J Virol 2021 Sep 22:JVI0095621. Epub 2021 Sep 22.

Viral Pathogenesis Section, Laboratory of Viral Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.

Dengue virus co-circulates globally as four serotypes (DENV1-4) that vary up to 40% at the amino acid level. Viral strains within a serotype further cluster into multiple genotypes. Eliciting a protective tetravalent neutralizing antibody response is a major goal of vaccine design, and efforts to characterize epitopes targeted by polyclonal mixtures of antibodies are ongoing. Previously, we identified two E protein residues (126/157) that defined the serotype-specific antibody response to DENV1 genotype 4 strain West Pac-74. DENV1 and DENV2 human vaccine sera neutralized DENV1 viruses incorporating these substitutions equivalently. In this study, we explored the contribution of these residues in the neutralization of DENV1 strains representing distinct genotypes. While neutralization of the genotype 1 strain TVP2130 was similarly impacted by mutation at E residues 126/157, mutation of these residues in the genotype 2 strain 16007 did not markedly change neutralization sensitivity, indicating the existence of additional DENV1 type-specific antibody targets. The accessibility of antibody epitopes can be strongly influenced by the conformational dynamics of virions and modified allosterically by amino acid variation. We found that changes at E domain II residue 204, shown previously to impact access to a poorly accessible E domain III epitope, impacted sensitivity of DENV1 16007 to neutralization by vaccine immune sera. Our data identify a role for minor sequence variation in changes to the antigenic structure that impacts antibody recognition by polyclonal immune sera. Understanding how the many structures sampled by flaviviruses influences antibody recognition will inform the design and evaluation of DENV immunogens. Dengue virus (DENV) is an important human pathogen that co-circulates globally as four serotypes. Because sequential infection by different DENV serotypes is associated with more severe disease, eliciting a protective neutralizing antibody response against all four serotypes is a major goal of vaccine efforts. Here, we report that neutralization of DENV serotype 1 by polyclonal antibody is impacted by minor sequence variation among virus strains. Our data suggests mechanisms that control neutralization sensitivity extend beyond variation within antibody epitopes, but also include the influence of single amino acids on the ensemble of structural states sampled by structurally dynamic virions. A more detailed understanding of the antibody targets of DENV-specific polyclonal sera and factors that govern their access to antibody has important implications for flavivirus antigen design and evaluation.
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http://dx.doi.org/10.1128/JVI.00956-21DOI Listing
September 2021

Levels of Circulating NS1 Impact West Nile Virus Spread to the Brain.

J Virol 2021 09 4;95(20):e0084421. Epub 2021 Aug 4.

Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri, USA.

Dengue virus (DENV) and West Nile virus (WNV) are arthropod-transmitted flaviviruses that cause systemic vascular leakage and encephalitis syndromes, respectively, in humans. However, the viral factors contributing to these specific clinical disorders are not completely understood. Flavivirus nonstructural protein 1 (NS1) is required for replication, expressed on the cell surface, and secreted as a soluble glycoprotein, reaching high levels in the blood of infected individuals. Extracellular DENV NS1 and WNV NS1 interact with host proteins and cells, have immune evasion functions, and promote endothelial dysfunction in a tissue-specific manner. To characterize how differences in DENV NS1 and WNV NS1 might function in pathogenesis, we generated WNV NS1 variants with substitutions corresponding to residues found in DENV NS1. We discovered that the substitution NS1-P101K led to reduced WNV infectivity in the brain and attenuated lethality in infected mice, although the virus replicated efficiently in cell culture and peripheral organs and bound at wild-type levels to brain endothelial cells and complement components. The P101K substitution resulted in reduced NS1 antigenemia in mice, and this was associated with reduced WNV spread to the brain. Because exogenous administration of NS1 protein rescued WNV brain infectivity in mice, we conclude that circulating WNV NS1 facilitates viral dissemination into the central nervous system and impacts disease outcomes. Flavivirus NS1 serves as an essential scaffolding molecule during virus replication but also is expressed on the cell surface and is secreted as a soluble glycoprotein that circulates in the blood of infected individuals. Although extracellular forms of NS1 are implicated in immune modulation and in promoting endothelial dysfunction at blood-tissue barriers, it has been challenging to study specific effects of NS1 on pathogenesis without disrupting its key role in virus replication. Here, we assessed WNV NS1 variants that do not affect virus replication and evaluated their effects on pathogenesis in mice. Our characterization of WNV NS1-P101K suggests that the levels of NS1 in the circulation facilitate WNV dissemination to the brain and affect disease outcomes. Our findings facilitate understanding of the role of NS1 during flavivirus infection and support antiviral strategies for targeting circulating forms of NS1.
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http://dx.doi.org/10.1128/JVI.00844-21DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8475509PMC
September 2021

Fe-S cofactors in the SARS-CoV-2 RNA-dependent RNA polymerase are potential antiviral targets.

Science 2021 07 3;373(6551):236-241. Epub 2021 Jun 3.

Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, USA.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causal agent of COVID-19, uses an RNA-dependent RNA polymerase (RdRp) for the replication of its genome and the transcription of its genes. We found that the catalytic subunit of the RdRp, nsp12, ligates two iron-sulfur metal cofactors in sites that were modeled as zinc centers in the available cryo-electron microscopy structures of the RdRp complex. These metal binding sites are essential for replication and for interaction with the viral helicase. Oxidation of the clusters by the stable nitroxide TEMPOL caused their disassembly, potently inhibited the RdRp, and blocked SARS-CoV-2 replication in cell culture. These iron-sulfur clusters thus serve as cofactors for the SARS-CoV-2 RdRp and are targets for therapy of COVID-19.
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http://dx.doi.org/10.1126/science.abi5224DOI Listing
July 2021

Non-structural protein 1-specific antibodies directed against Zika virus in humans mediate antibody-dependent cellular cytotoxicity.

Immunology 2021 10 14;164(2):386-397. Epub 2021 Jun 14.

Department of Cell and Molecular Biology, Institute for Immunology and Informatics, University of Rhode Island, Providence, RI, USA.

There is growing interest in understanding antibody (Ab) function beyond neutralization. The non-structural protein 1 (NS1) of Zika virus (ZIKV) is an attractive candidate for an effective vaccine as Abs against NS1, unlike the envelope or premembrane, do not carry the risk of mediating antibody-dependent enhancement. Our aim was to evaluate whether ZIKV NS1 Abs elicited following natural infection in humans can mediate antibody-dependent cellular cytotoxicity (ADCC). We evaluated the isotype specificity of ZIKV-specific Abs in immune sera and supernatants from stimulated immune PBMC and found that Abs against ZIKV NS1 and virus-like particles were predominantly of the IgG1 isotype. Using a recently developed FluoroSpot assay, we found robust frequencies of NS1-specific Ab-secreting cells in PBMC of individuals who were naturally infected with ZIKV. We developed assays to measure both natural killer cell activation by flow cytometry and target cell lysis of ZIKV NS1-expressing cells using an image cytometry assay in the presence of ZIKV NS1 Abs. Our data indicate efficient opsonization of ZIKV NS1-expressing CEM-NK cell lines using ZIKV-immune but not ZIKV-naïve sera, a prerequisite of ADCC. Furthermore, sera from immune donors were able to induce both NK cell degranulation and lysis of ZIKV NS1 CEM-NK cells in vitro. Our data suggest that ADCC is a possible mechanism for ZIKV NS1 Abs to eliminate virally infected target cells.
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http://dx.doi.org/10.1111/imm.13380DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8442231PMC
October 2021

Limited flavivirus cross-reactive antibody responses elicited by a ZIKV DNA vaccine candidate in humans.

J Infect Dis 2021 May 7. Epub 2021 May 7.

Laboratory of Viral Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.

ZIKV DNA vaccine VRC5283 encoding viral structural genes, has been shown to be immunogenic in humans. Recognizing that antigenically-related flaviviruses co-circulate in regions with ZIKV activity, we explored the degree of antibody cross-reactivity elicited by this vaccine candidate using genetically-diverse flaviviruses. The antibody response of vaccinated individuals with no evidence of prior flavivirus infection or vaccine experience had a limited capacity to bind heterologous viruses. In contrast, vaccine-elicited antibodies from individuals with prior flavivirus experience had a greater capacity to bind, but not neutralize, distantly-related flaviviruses. These findings suggest that prior flavivirus exposure shapes the humoral immune response to vaccination.
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http://dx.doi.org/10.1093/infdis/jiab185DOI Listing
May 2021

Lipid nanoparticle encapsulated nucleoside-modified mRNA vaccines elicit polyfunctional HIV-1 antibodies comparable to proteins in nonhuman primates.

NPJ Vaccines 2021 Apr 9;6(1):50. Epub 2021 Apr 9.

Duke Human Vaccine Institute, Duke School of Medicine, Durham, NC, USA.

The development of an effective AIDS vaccine remains a challenge. Nucleoside-modified mRNAs formulated in lipid nanoparticles (mRNA-LNP) have proved to be a potent mode of immunization against infectious diseases in preclinical studies, and are being tested for SARS-CoV-2 in humans. A critical question is how mRNA-LNP vaccine immunogenicity compares to that of traditional adjuvanted protein vaccines in primates. Here, we show that mRNA-LNP immunization compared to protein immunization elicits either the same or superior magnitude and breadth of HIV-1 Env-specific polyfunctional antibodies. Immunization with mRNA-LNP encoding Zika premembrane and envelope or HIV-1 Env gp160 induces durable neutralizing antibodies for at least 41 weeks. Doses of mRNA-LNP as low as 5 μg are immunogenic in macaques. Thus, mRNA-LNP can be used to rapidly generate single or multi-component vaccines, such as sequential vaccines needed to protect against HIV-1 infection. Such vaccines would be as or more immunogenic than adjuvanted recombinant protein vaccines in primates.
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http://dx.doi.org/10.1038/s41541-021-00307-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8035178PMC
April 2021

Broadly neutralizing monoclonal antibodies protect against multiple tick-borne flaviviruses.

J Exp Med 2021 05;218(5)

Department of Medicine, Washington University School of Medicine, St. Louis, MO.

Although Powassan virus (POWV) is an emerging tick-transmitted flavivirus that causes severe or fatal neuroinvasive disease in humans, medical countermeasures have not yet been developed. Here, we developed a panel of neutralizing anti-POWV mAbs recognizing six distinct antigenic sites. The most potent of these mAbs bind sites within domain II or III of the envelope (E) protein and inhibit postattachment viral entry steps. A subset of these mAbs cross-react with other flaviviruses. Both POWV type-specific and cross-reactive neutralizing mAbs confer protection in mice against POWV infection when given as prophylaxis or postexposure therapy. Several cross-reactive mAbs mapping to either domain II or III also protect in vivo against heterologous tick-transmitted flaviviruses including Langat and tick-borne encephalitis virus. Our experiments define structural and functional correlates of antibody protection against POWV infection and identify epitopes targeted by broadly neutralizing antibodies with therapeutic potential against multiple tick-borne flaviviruses.
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http://dx.doi.org/10.1084/jem.20210174DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8040518PMC
May 2021

Functional Profiling of Antibody Immune Repertoires in Convalescent Zika Virus Disease Patients.

Front Immunol 2021 24;12:615102. Epub 2021 Feb 24.

Department of Pharmaceutical Chemistry, The University of Kansas, Lawrence, KS, United States.

The re-emergence of Zika virus (ZIKV) caused widespread infections that were linked to Guillain-Barré syndrome in adults and congenital malformation in fetuses, and epidemiological data suggest that ZIKV infection can induce protective antibody responses. A more detailed understanding of anti-ZIKV antibody responses may lead to enhanced antibody discovery and improved vaccine designs against ZIKV and related flaviviruses. Here, we applied recently-invented library-scale antibody screening technologies to determine comprehensive functional molecular and genetic profiles of naturally elicited human anti-ZIKV antibodies in three convalescent individuals. We leveraged natively paired antibody yeast display and NGS to predict antibody cross-reactivities and coarse-grain antibody affinities, to perform in-depth immune profiling of IgM, IgG, and IgA antibody repertoires in peripheral blood, and to reveal virus maturation state-dependent antibody interactions. Repertoire-scale comparison of ZIKV VLP-specific and non-specific antibodies in the same individuals also showed that mean antibody somatic hypermutation levels were substantially influenced by donor-intrinsic characteristics. These data provide insights into antiviral antibody responses to ZIKV disease and outline systems-level strategies to track human antibody immune responses to emergent viral infections.
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http://dx.doi.org/10.3389/fimmu.2021.615102DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7959826PMC
July 2021

Lipid nanoparticle encapsulated nucleoside-modified mRNA vaccines elicit polyfunctional HIV-1 antibodies comparable to proteins in nonhuman primates.

bioRxiv 2020 Dec 31. Epub 2020 Dec 31.

Development of an effective AIDS vaccine remains a challenge. Nucleoside-modified mRNAs formulated in lipid nanoparticles (mRNA-LNP) have proved to be a potent mode of immunization against infectious diseases in preclinical studies, and are being tested for SARS-CoV-2 in humans. A critical question is how mRNA-LNP vaccine immunogenicity compares to that of traditional adjuvanted protein vaccines in primates. Here, we found that mRNA-LNP immunization compared to protein immunization elicited either the same or superior magnitude and breadth of HIV-1 Env-specific polyfunctional antibodies. Immunization with mRNA-LNP encoding Zika premembrane and envelope (prM-E) or HIV-1 Env gp160 induced durable neutralizing antibodies for at least 41 weeks. Doses of mRNA-LNP as low as 5 μg were immunogenic in macaques. Thus, mRNA-LNP can be used to rapidly generate single or multi-component vaccines, such as sequential vaccines needed to protect against HIV-1 infection. Such vaccines would be as or more immunogenic than adjuvanted recombinant protein vaccines in primates.
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http://dx.doi.org/10.1101/2020.12.30.424745DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7781333PMC
December 2020

Nonhuman primates exposed to Zika virus in utero are not protected against reinfection at 1 year postpartum.

Sci Transl Med 2020 10;12(567)

Emerging Pathogens Section, Critical Care Medicine Department, Clinical Center, National Institutes of Health, Bethesda, MD 20892, USA.

There is limited information about the impact of Zika virus (ZIKV) exposure in utero on the anti-ZIKV immune responses of offspring. We infected six rhesus macaque dams with ZIKV early or late in pregnancy and studied four of their offspring over the course of a year postpartum. Despite evidence of ZIKV exposure in utero, we observed no structural brain abnormalities in the offspring. We detected infant-derived ZIKV-specific immunoglobulin A antibody responses and T cell memory responses during the first year postpartum in the two offspring born to dams infected with ZIKV early in pregnancy. Critically, although the infants had acquired some immunological memory of ZIKV, it was not sufficient to protect them against reinfection with ZIKV at 1 year postpartum. The four offspring reexposed to ZIKV at 1 year postpartum all survived but exhibited acute viremia and viral tropism to lymphoid tissues; three of four reexposed offspring exhibited spinal cord pathology. These data suggest that macaque infants born to dams infected with ZIKV during pregnancy remain susceptible to postnatal infection and consequent neuropathology.
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http://dx.doi.org/10.1126/scitranslmed.aaz4997DOI Listing
October 2020

Development of a potent Zika virus vaccine using self-amplifying messenger RNA.

Sci Adv 2020 Aug 7;6(32):eaba5068. Epub 2020 Aug 7.

Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.

Zika virus (ZIKV) is the cause of a pandemic associated with microcephaly in newborns and Guillain-Barre syndrome in adults. Currently, there are no available treatments or vaccines for ZIKV, and the development of a safe and effective vaccine is a high priority for many global health organizations. We describe the development of ZIKV vaccine candidates using the self-amplifying messenger RNA (SAM) platform technology delivered by cationic nanoemulsion (CNE) that allows bedside mixing and is particularly useful for rapid responses to pandemic outbreaks. Two immunizations of either of the two lead SAM (CNE) vaccine candidates elicited potent neutralizing antibody responses to ZIKV in mice and nonhuman primates. Both SAM (CNE) vaccines protected these animals from ZIKV challenge, with one candidate providing complete protection against ZIKV infection in nonhuman primates. The data provide a preclinical proof of concept that a SAM (CNE) vaccine candidate can rapidly elicit protective immunity against ZIKV.
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http://dx.doi.org/10.1126/sciadv.aba5068DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7413734PMC
August 2020

Distinct neutralizing antibody correlates of protection among related Zika virus vaccines identify a role for antibody quality.

Sci Transl Med 2020 06;12(547)

Laboratory of Viral Diseases, NIAID, NIH, Bethesda, MD 20892, USA.

The emergence of Zika virus (ZIKV) in the Americas stimulated the development of multiple ZIKV vaccine candidates. We previously developed two related DNA vaccine candidates encoding ZIKV structural proteins that were immunogenic in animal models and humans. We sought to identify neutralizing antibody (NAb) properties induced by each vaccine that correlated with protection in nonhuman primates (NHPs). Despite eliciting equivalent NAb titers in NHPs, these vaccines were not equally protective. The transfer of equivalent titers of vaccine-elicited NAb into AG129 mice also revealed nonequivalent protection, indicating qualitative differences among antibodies (Abs) elicited by these vaccines. Both vaccines elicited Abs with similar binding titers against envelope protein monomers and those incorporated into virus-like particles, as well as a comparable capacity to orchestrate phagocytosis. Functional analysis of vaccine-elicited NAbs from NHPs and humans revealed a capacity to neutralize the structurally mature form of the ZIKV virion that varied in magnitude among vaccine candidates. Conversely, sensitivity to the virion maturation state was not a characteristic of NAbs induced by natural or experimental infection. Passive transfer experiments in mice revealed that neutralization of mature ZIKV virions more accurately predicts protection from ZIKV infection. These findings demonstrate that NAb correlates of protection may differ among vaccine antigens when assayed using standard neutralization platforms and suggest that measurements of Ab quality, including the capacity to neutralize mature virions, will be critical for defining correlates of ZIKV vaccine-induced immunity.
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http://dx.doi.org/10.1126/scitranslmed.aaw9066DOI Listing
June 2020

The Challenges of Vaccine Development against a New Virus during a Pandemic.

Cell Host Microbe 2020 05;27(5):699-703

Laboratory of Viral Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA. Electronic address:

The rapid emergence of a highly pathogenic, readily transmissible coronavirus has resulted in a global pandemic, affecting millions and destabilizing economies. This catastrophe triggered a clarion call for the immediate deployment of a protective vaccine. We describe the unique challenges of developing a vaccine against SARS-CoV-2 in a pandemic setting.
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http://dx.doi.org/10.1016/j.chom.2020.04.021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7219397PMC
May 2020

The continued threat of emerging flaviviruses.

Nat Microbiol 2020 06 4;5(6):796-812. Epub 2020 May 4.

Departments of Medicine, Molecular Microbiology, Pathology & Immunology, Andrew M. and Jane M. Bursky Center for Human Immunology and Immunotherapy Programs, Washington University School of Medicine, St. Louis, MO, USA.

Flaviviruses are vector-borne RNA viruses that can emerge unexpectedly in human populations and cause a spectrum of potentially severe diseases including hepatitis, vascular shock syndrome, encephalitis, acute flaccid paralysis, congenital abnormalities and fetal death. This epidemiological pattern has occurred numerous times during the last 70 years, including epidemics of dengue virus and West Nile virus, and the most recent explosive epidemic of Zika virus in the Americas. Flaviviruses are now globally distributed and infect up to 400 million people annually. Of significant concern, outbreaks of other less well-characterized flaviviruses have been reported in humans and animals in different regions of the world. The potential for these viruses to sustain epidemic transmission among humans is poorly understood. In this Review, we discuss the basic biology of flaviviruses, their infectious cycles, the diseases they cause and underlying host immune responses to infection. We describe flaviviruses that represent an established ongoing threat to global health and those that have recently emerged in new populations to cause significant disease. We also provide examples of lesser-known flaviviruses that circulate in restricted areas of the world but have the potential to emerge more broadly in human populations. Finally, we discuss how an understanding of the epidemiology, biology, structure and immunity of flaviviruses can inform the rapid development of countermeasures to treat or prevent human infections as they emerge.
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http://dx.doi.org/10.1038/s41564-020-0714-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7696730PMC
June 2020

Effect of a Chikungunya Virus-Like Particle Vaccine on Safety and Tolerability Outcomes: A Randomized Clinical Trial.

JAMA 2020 04;323(14):1369-1377

Instituto Dermatologico y Cirugia de Piel (IDCP), Dominican Republic.

Importance: Chikungunya virus (CHIKV) is a mosquito-borne Alphavirus prevalent worldwide. There are currently no licensed vaccines or therapies.

Objective: To evaluate the safety and tolerability of an investigational CHIKV virus-like particle (VLP) vaccine in endemic regions.

Design, Setting, And Participants: This was a randomized, placebo-controlled, double-blind, phase 2 clinical trial to assess the vaccine VRC-CHKVLP059-00-VP (CHIKV VLP). The trial was conducted at 6 outpatient clinical research sites located in Haiti, Dominican Republic, Martinique, Guadeloupe, and Puerto Rico. A total of 400 healthy adults aged 18 through 60 years were enrolled after meeting eligibility criteria. The first study enrollment occurred on November 18, 2015; the final study visit, March 6, 2018.

Interventions: Participants were randomized 1:1 to receive 2 intramuscular injections 28 days apart (20 µg, n = 201) or placebo (n = 199) and were followed up for 72 weeks.

Main Outcomes And Measures: The primary outcome was the safety (laboratory parameters, adverse events, and CHIKV infection) and tolerability (local and systemic reactogenicity) of the vaccine, and the secondary outcome was immune response by neutralization assay 4 weeks after second vaccination.

Results: Of the 400 randomized participants (mean age, 35 years; 199 [50%] women), 393 (98%) completed the primary safety analysis. All injections were well tolerated. Of the 16 serious adverse events unrelated to the study drugs, 4 (25%) occurred among 4 patients in the vaccine group and 12 (75%) occurred among 11 patients in the placebo group. Of the 16 mild to moderate unsolicited adverse events that were potentially related to the drug, 12 (75%) occurred among 8 patients in the vaccine group and 4 (25%) occurred among 3 patients in the placebo group. All potentially related adverse events resolved without clinical sequelae. At baseline, there was no significant difference between the effective concentration (EC50)-which is the dilution of sera that inhibits 50% infection in viral neutralization assay-geometric mean titers (GMTs) of neutralizing antibodies of the vaccine group (46; 95% CI, 34-63) and the placebo group (43; 95% CI, 32-57). Eight weeks following the first administration, the EC50 GMT in the vaccine group was 2005 (95% CI, 1680-2392) vs 43 (95% CI, 32-58; P < .001) in the placebo group. Durability of the immune response was demonstrated through 72 weeks after vaccination.

Conclusions And Relevance: Among healthy adults in a chikungunya endemic population, a virus-like particle vaccine compared with placebo demonstrated safety and tolerability. Phase 3 trials are needed to assess clinical efficacy.

Trial Registration: ClinicalTrials.gov Identifier: NCT02562482.
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http://dx.doi.org/10.1001/jama.2020.2477DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7156994PMC
April 2020

Characterization of a Species E Adenovirus Vector as a Zika virus vaccine.

Sci Rep 2020 02 27;10(1):3613. Epub 2020 Feb 27.

School of Biological Sciences, Nebraska Center for Virology, University of Nebraska, Lincoln, USA.

The development of a safe and efficacious Zika virus (ZIKV) vaccine remains a global health priority. In our previous work, we developed an Adenovirus vectored ZIKV vaccine using a low-seroprevalent human Adenovirus type 4 (Ad4-prM-E) and compared it to an Ad5 vector (Ad5-prM-E). We found that vaccination with Ad4-prM-E leads to the development of a strong anti-ZIKV T-cell response without eliciting significant anti-ZIKV antibodies, while vaccination with Ad5-prM-E leads to the development of both anti-ZIKV antibody and T-cell responses in C57BL/6 mice. However, both vectors conferred protection against ZIKV infection in a lethal challenge model. Here we continued to characterize the T-cell biased immune response observed in Ad4 immunized mice. Vaccination of BALB/c mice resulted in immune correlates similar to C57BL/6 mice, confirming that this response is not mouse strain-specific. Vaccination with an Ad4 expressing an influenza hemagglutinin (HA) protein resulted in anti-HA T-cell responses without the development of significant anti-HA antibodies, indicating this unique response is specific to the Ad4 serotype rather than the transgene expressed. Co-administration of a UV inactivated Ad4 vector with the Ad5-prM-E vaccine led to a significant reduction in anti-ZIKV antibody development suggesting that this serotype-specific immune profile is capsid-dependent. These results highlight the serotype-specific immune profiles elicited by different Adenovirus vector types and emphasize the importance of continued characterization of these alternative Ad serotypes.
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http://dx.doi.org/10.1038/s41598-020-60238-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7046724PMC
February 2020

DNA vaccination before conception protects Zika virus-exposed pregnant macaques against prolonged viremia and improves fetal outcomes.

Sci Transl Med 2019 12;11(523)

Vaccine Research Center, NIAID, NIH, Bethesda, MD 20892, USA.

Zika virus (ZIKV) infection of pregnant women is associated with congenital Zika syndrome (CZS) and no vaccine is available, although several are being tested in clinical trials. We tested the efficacy of ZIKV DNA vaccine VRC5283 in a rhesus macaque model of congenital ZIKV infection. Most animal vaccine experiments have a set pathogen exposure several weeks or months after vaccination. In the real world, people encounter pathogens years or decades after vaccination, or may be repeatedly exposed if the virus is endemic. To more accurately mimic how this vaccine would be used, we immunized macaques before conception and then exposed them repeatedly to ZIKV during early and mid-gestation. In comparison to unimmunized animals, vaccinated animals had a significant reduction in peak magnitude and duration of maternal viremia, early fetal loss, fetal infection, and placental and fetal brain pathology. Vaccine-induced neutralizing antibody titers on the day of first ZIKV exposure were negatively associated with the magnitude of maternal viremia, and the absence of prolonged viremia was associated with better fetal outcomes. These data support further clinical development of ZIKV vaccine strategies to protect against negative fetal outcomes.
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http://dx.doi.org/10.1126/scitranslmed.aay2736DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7093037PMC
December 2019

Simian Immunodeficiency Virus Infection of Rhesus Macaques Results in Delayed Zika Virus Clearance.

mBio 2019 12 3;10(6). Epub 2019 Dec 3.

Barrier Immunity Section, Laboratory of Viral Diseases, NIAID/NIH, Bethesda, Maryland, USA

Flaviviruses are controlled by adaptive immune responses but are exquisitely sensitive to interferon-stimulated genes (ISGs). How coinfections, particularly simian immunodeficiency viruses (SIVs), that induce robust ISG signatures influence flavivirus clearance and pathogenesis is unclear. Here, we studied how Zika virus (ZIKV) infection is modulated in SIV-infected nonhuman primates. We measured ZIKV replication, cellular ZIKV RNA levels, and immune responses in non-SIV-infected and SIV-infected rhesus macaques (RMs), which we infected with ZIKV. Coinfected animals had a 1- to 2-day delay in peak ZIKV viremia, which was 30% of that in non-SIV-infected animals. However, ZIKV viremia was significantly prolonged in SIV-positive (SIV) RMs. ISG levels at the time of ZIKV infection were predictive for lower ZIKV viremia in the SIV RMs, while prolonged ZIKV viremia was associated with muted and delayed adaptive responses in SIV RMs. Immunocompromised individuals often become symptomatic with infections which are normally fairly asymptomatic in healthy individuals. The particular mechanisms that underlie susceptibility to coinfections in human immunodeficiency virus (HIV)-infected individuals are multifaceted. ZIKV and other flaviviruses are sensitive to neutralizing antibodies, whose production can be limited in HIV-infected individuals but are also sensitive to type I interferons, which are expressed at high levels in HIV-infected individuals. Data in this study highlight how individual components of the innate and adaptive immune responses which become perturbed in HIV-infected individuals influence ZIKV infection.
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http://dx.doi.org/10.1128/mBio.02790-19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6890994PMC
December 2019

Mechanism of differential Zika and dengue virus neutralization by a public antibody lineage targeting the DIII lateral ridge.

J Exp Med 2020 02;217(2)

Department of Pathology & Immunology, Washington University School of Medicine, Saint Louis, MO.

We previously generated a panel of human monoclonal antibodies (mAbs) against Zika virus (ZIKV) and identified one, ZIKV-116, that shares germline usage with mAbs identified in multiple donors. Here we show that ZIKV-116 interferes with ZIKV infection at a post-cellular attachment step by blocking viral fusion with host membranes. ZIKV-116 recognizes the lateral ridge of envelope protein domain III, with one critical residue varying between the Asian and African strains responsible for differential binding affinity and neutralization potency (E393D). ZIKV-116 also binds to and cross-neutralizes some dengue virus serotype 1 (DENV1) strains, with genotype-dependent inhibition explained by variation in a domain II residue (R204K) that potentially modulates exposure of the distally located, partially cryptic epitope. The V-J reverted germline configuration of ZIKV-116 preferentially binds to and neutralizes an Asian ZIKV strain, suggesting that this epitope may optimally induce related B cell clonotypes. Overall, these studies provide a structural and molecular mechanism for a cross-reactive mAb that uniquely neutralizes ZIKV and DENV1.
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http://dx.doi.org/10.1084/jem.20191792DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7041715PMC
February 2020

Protective Efficacy of Nucleic Acid Vaccines Against Transmission of Zika Virus During Pregnancy in Mice.

J Infect Dis 2019 10;220(10):1577-1588

Department of Medicine, Washington University School of Medicine, St. Louis, Missouri.

Zika virus (ZIKV) caused an epidemic of congenital malformations in 2015-2016. Although many vaccine candidates have been generated, few have demonstrated efficacy against congenital ZIKV infection. Here, we evaluated lipid-encapsulated messenger RNA (mRNA) vaccines and a DNA plasmid vaccine encoding the prM-E genes of ZIKV in mouse models of congenital infection. Although the DNA vaccine provided comparable efficacy against vertical transmission of ZIKV, the mRNA vaccines, including one that minimizes antibody-dependent enhancement of infection, elicited higher levels of antigen-specific long-lived plasma cells and memory B cells. Despite the induction of robust neutralizing antibody titers by all vaccines, breakthrough seeding of the placenta and fetal head was observed in a small subset of type I interferon signaling-deficient immunocompromised dams. In comparison, evaluation of one of the mRNA vaccines in a human STAT2-knockin transgenic immunocompetent mouse showed complete protection against congenital ZIKV transmission. These data will inform ongoing human ZIKV vaccine development efforts and enhance our understanding of the correlates of vaccine-induced protection.
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http://dx.doi.org/10.1093/infdis/jiz338DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6782106PMC
October 2019

Dengue and Zika Virus Cross-Reactive Human Monoclonal Antibodies Protect against Spondweni Virus Infection and Pathogenesis in Mice.

Cell Rep 2019 02;26(6):1585-1597.e4

Department of Medicine, Washington University School of Medicine, Saint Louis, MO 63110, USA; Department of Pathology & Immunology, Washington University School of Medicine, Saint Louis, MO 63110, USA; Department of Molecular Microbiology, Washington University School of Medicine, Saint Louis, MO 63110, USA; The Andrew M. and Jane M. Bursky Center for Human Immunology and Immunotherapy Programs, Washington University School of Medicine, Saint Louis, MO 63110, USA. Electronic address:

Spondweni virus (SPOV) is the flavivirus that is most closely related to Zika virus (ZIKV). Although SPOV causes sporadic human infections in Africa, recently it was found in Culex mosquitoes in Haiti. To investigate the pathogenic spectrum of SPOV, we developed infection models in mice. Although two SPOV strains failed to cause disease in immunocompetent mice, each accumulated in the brain, spleen, eye, testis, and kidney when type I interferon signaling was blocked and unexpectedly caused infection, immune cell infiltration, and swelling in the ankle. In pregnant mice, SPOV replicated in the placenta and fetus but did not cause placental insufficiency or microcephaly. We identified human antibodies from ZIKV or DENV immune subjects that neutralized SPOV infection and protected against lethal challenge. Our experiments describe similarities and differences in clinical syndromes between SPOV and ZIKV and suggest that their serological relatedness has implications for antibody therapeutics and flavivirus vaccine development.
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http://dx.doi.org/10.1016/j.celrep.2019.01.052DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6420780PMC
February 2019

An mRNA Vaccine Protects Mice against Multiple Tick-Transmitted Flavivirus Infections.

Cell Rep 2018 12;25(12):3382-3392.e3

Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA; Department of Pathology & Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA; Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, MO 63110, USA; The Andrew M. and Jane M. Bursky Center for Human Immunology and Immunotherapy Programs, Washington University School of Medicine, St. Louis, MO 63110, USA. Electronic address:

Powassan virus (POWV) is an emerging tick-transmitted flavivirus that circulates in North America and Russia. Up to 5% of deer ticks now test positive for POWV in certain regions of the northern United States. Although POWV infections cause life-threatening encephalitis, there is no vaccine or countermeasure available for prevention or treatment. Here, we developed a lipid nanoparticle (LNP)-encapsulated modified mRNA vaccine encoding the POWV prM and E genes and demonstrated its immunogenicity and efficacy in mice following immunization with one or two doses. The POWV mRNA vaccine induced high titers of neutralizing antibody and sterilizing immunity against lethal challenge with different POWV strains. The mRNA vaccine also induced cross-neutralizing antibodies against multiple other tick-borne flaviviruses and protected mice against the distantly related Langat virus. These data demonstrate the utility of the LNP-mRNA vaccine platform for the development of vaccines with protective activity against multiple flaviviruses.
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http://dx.doi.org/10.1016/j.celrep.2018.11.082DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6353567PMC
December 2018

A protective human monoclonal antibody targeting the West Nile virus E protein preferentially recognizes mature virions.

Nat Microbiol 2019 01 19;4(1):71-77. Epub 2018 Nov 19.

Viral Pathogenesis Section, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.

West Nile virus (WNV), a member of the Flavivirus genus, is a leading cause of viral encephalitis in the United States. The development of neutralizing antibodies against the flavivirus envelope (E) protein is critical for immunity and vaccine protection. Previously identified candidate therapeutic mouse and human neutralizing monoclonal antibodies (mAbs) target epitopes within the E domain III lateral ridge and the domain I-II hinge region, respectively. To explore the neutralizing antibody repertoire elicited by WNV infection for potential therapeutic application, we isolated ten mAbs from WNV-infected individuals. mAb WNV-86 neutralized WNV with a 50% inhibitory concentration of 2 ng ml, one of the most potently neutralizing flavivirus-specific antibodies ever isolated. WNV-86 targets an epitope in E domain II, and preferentially recognizes mature virions lacking an uncleaved form of the chaperone protein prM, unlike most flavivirus-specific antibodies. In vitro selection experiments revealed a neutralization escape mechanism involving a glycan addition to E domain II. Finally, a single dose of WNV-86 administered two days post-infection protected mice from lethal WNV challenge. This study identifies a highly potent human neutralizing mAb with therapeutic potential that targets an epitope preferentially displayed on mature virions.
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http://dx.doi.org/10.1038/s41564-018-0283-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6435290PMC
January 2019

Cross-Reactive Flavivirus Antibody: Friend and Foe?

Cell Host Microbe 2018 11;24(5):622-624

Laboratory of Viral Diseases, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD, USA. Electronic address:

The introduction of Zika virus (ZIKV) into the Americas sparked interest in the influence of heterologous antibodies on sequential ZIKV and dengue virus (DENV) infections. In this issue of Cell Host & Microbe, Fowler et al. (2018) demonstrate in mice that maternally acquired anti-ZIKV antibodies exacerbate disease following DENV challenge.
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http://dx.doi.org/10.1016/j.chom.2018.10.016DOI Listing
November 2018

Zika Virus Vaccine Development: Progress in the Face of New Challenges.

Annu Rev Med 2019 01 2;70:121-135. Epub 2018 Nov 2.

Laboratory of Viral Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA; email:

Zika virus (ZIKV) emerged at a global level when it spread to the Americas and began causing congenital malformations and microcephaly in 2015. A rapid response by academia, government, public health infrastructure, and industry has enabled the expedited development and testing of a suite of vaccine platforms aiming to control and eliminate ZIKV-induced disease. Analysis of key immunization and pathogenesis studies in multiple animal models, including during pregnancy, has begun to define immune correlates of protection. Nonetheless, the deployment of ZIKV vaccines, along with the confirmation of their safety and efficacy, still has major challenges, one of which is related to the waning of the epidemic. In this review, we discuss the measures that enabled rapid progress and highlight the path forward for successful deployment of ZIKV vaccines.
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http://dx.doi.org/10.1146/annurev-med-040717-051127DOI Listing
January 2019

The Many Faces of a Dynamic Virion: Implications of Viral Breathing on Flavivirus Biology and Immunogenicity.

Annu Rev Virol 2018 09;5(1):185-207

Viral Pathogenesis Section, Laboratory of Viral Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA; email: ,

Flaviviruses are arthropod-borne RNA viruses that are a significant threat to global health due to their widespread distribution, ability to cause severe disease in humans, and capacity for explosive spread following introduction into new regions. Members of this genus include dengue, tick-borne encephalitis, yellow fever, and Zika viruses. Vaccination has been a highly successful means to control flaviviruses, and neutralizing antibodies are an important component of a protective immune response. High-resolution structures of flavivirus structural proteins and virions, alone and in complex with antibodies, provide a detailed understanding of viral fusion mechanisms and virus-antibody interactions. However, mounting evidence suggests these structures provide only a snapshot of an otherwise structurally dynamic virus particle. The contribution of the structural ensemble arising from viral breathing to the biology, antigenicity, and immunity of flaviviruses is discussed, including implications for the development and evaluation of flavivirus vaccines.
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http://dx.doi.org/10.1146/annurev-virology-092917-043300DOI Listing
September 2018

The emergence of Zika virus and its new clinical syndromes.

Nature 2018 08 29;560(7720):573-581. Epub 2018 Aug 29.

Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA.

Zika virus (ZIKV) is a mosquito-transmitted flavivirus that has emerged as a global health threat because of its potential to generate explosive epidemics and ability to cause congenital disease in the context of infection during pregnancy. Whereas much is known about the biology of related flaviviruses, the unique features of ZIKV pathogenesis, including infection of the fetus, persistence in immune-privileged sites and sexual transmission, have presented new challenges. The rapid development of cell culture and animal models has facilitated a new appreciation of ZIKV biology. This knowledge has created opportunities for the development of countermeasures, including multiple ZIKV vaccine candidates, which are advancing through clinical trials. Here we describe the recent advances that have led to a new understanding of the causes and consequences of the ZIKV epidemic.
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http://dx.doi.org/10.1038/s41586-018-0446-yDOI Listing
August 2018

A VSV-based Zika virus vaccine protects mice from lethal challenge.

Sci Rep 2018 07 23;8(1):11043. Epub 2018 Jul 23.

Laboratory of Virology, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, MT, USA.

Infection with Zika virus (ZIKV) is commonly mild in humans but has been associated with alarming negative health outcomes including Guillain-Barré syndrome in adults and microcephaly in fetuses. As such, developing a vaccine for ZIKV is a global public health priority. Recombinant vesicular stomatitis virus (VSV) expressing the Ebola virus (EBOV) glycoprotein (GP) has been successfully used as a vaccine platform in the past. In this study, two novel VSV-ZIKV vaccines were generated utilizing the favorable immune targeting of the existing VSV-EBOV vector. In addition to the EBOV GP, these new vaccines express the full-length pre-membrane and envelope proteins or pre-membrane and truncated soluble envelope proteins as antigens. Efficacy testing of both of the VSV vectors against ZIKV was conducted in IFNAR mice and resulted in uniform protection when a single dose was administered 28 days prior to lethal challenge. Furthermore, this vaccine is fast-acting and can uniformly protect mice from lethal disease when administered as late as 3 days prior to ZIKV challenge. Thus, VSV-ZIKV vectors are promising vaccine candidates and should move forward along the licensure pathway.
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http://dx.doi.org/10.1038/s41598-018-29401-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6056530PMC
July 2018
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