scholarly journals Single dose of chimeric dengue-2/Zika vaccine candidate protects mice and non-human primates against Zika virus

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Whitney R. Baldwin ◽  
Holli A. Giebler ◽  
Janae L. Stovall ◽  
Ginger Young ◽  
Kelly J. Bohning ◽  
...  
Keyword(s):  
Zika Virus ◽  
Vaccine Development ◽  
Rhesus Macaques ◽  
Vero Cells ◽  
Vaccine Virus ◽  
Live Attenuated Vaccine ◽  
Vaccine Candidates ◽  
Virus Serotype ◽  
Flavivirus Vaccine ◽  
Deficient Mice

AbstractThe development of a safe and effective Zika virus (ZIKV) vaccine has become a global health priority since the widespread epidemic in 2015-2016. Based on previous experience in using the well-characterized and clinically proven dengue virus serotype-2 (DENV-2) PDK-53 vaccine backbone for live-attenuated chimeric flavivirus vaccine development, we developed chimeric DENV-2/ZIKV vaccine candidates optimized for growth and genetic stability in Vero cells. These vaccine candidates retain all previously characterized attenuation phenotypes of the PDK-53 vaccine virus, including attenuation of neurovirulence for 1-day-old CD-1 mice, absence of virulence in interferon receptor-deficient mice, and lack of transmissibility in the main mosquito vectors. A single DENV-2/ZIKV dose provides protection against ZIKV challenge in mice and rhesus macaques. Overall, these data indicate that the ZIKV live-attenuated vaccine candidates are safe, immunogenic and effective at preventing ZIKV infection in multiple animal models, warranting continued development.

scholarly journals The role of IL-5, IL-6 and IL-10 in primary and vaccine-primed immune responses to infection with Friend retrovirus (Murine leukaemia virus)

2001 ◽  
Vol 82 (6) ◽  
pp. 1349-1354 ◽  
Author(s):  
Beatrice D. Strestik ◽  
Anke R. M. Olbrich ◽  
Kim J. Hasenkrug ◽  
Ulf Dittmer
Keyword(s):  
Immune Responses ◽  
Viral Infections ◽  
Vaccine Virus ◽  
Live Attenuated Vaccine ◽  
Leukaemia Virus ◽  
Murine Leukaemia Virus ◽  
Friend Retrovirus ◽  
Suppressive Cytokine ◽  
Deficient Mice

The defence of a host against viral infections is strongly influenced by cytokines. We investigated the role of the B-cell stimulating cytokines IL-5 and IL-6, and the immuno-suppressive cytokine IL-10, during primary and secondary immune responses in mice against infection with Friend retrovirus (FV) (Murine leukaemia virus). IL-5−/− mice were comparable to C57BL/6 wild-type mice in their ability to control acute FV infection. In contrast, IL-6−/− and IL-10−/− mice showed significantly enhanced virus loads in spleen cells. However, this impaired control of acute FV replication did not alter the long-term control over persistent FV in IL-6−/− and IL-10−/− mice. Immunization with a live attenuated vaccine virus prior to challenge protected all three types of cytokine-deficient mice from high levels of spleen virus, despite the finding that the vaccinated IL-5- and IL-6-deficient mice had significantly reduced titres of virus-neutralizing IgG class antibodies. The results indicate that IL-6 and IL-10 contribute to primary immune responses against FV, but are dispensable during persistent infection and vaccine-primed secondary responses.

scholarly journals Replication-Defective West Nile Virus with NS1 Deletion as a New Vaccine Platform for Flavivirus

2019 ◽  
Vol 93 (17) ◽  
Author(s):  
Na Li ◽  
Ya-Nan Zhang ◽  
Cheng-Lin Deng ◽  
Pei-Yong Shi ◽  
Zhi-Ming Yuan ◽  
...  
Keyword(s):  
Single Dose ◽  
West Nile Virus ◽  
Cell Line ◽  
Vaccine Development ◽  
Vero Cells ◽  
High Dose ◽  
Ns1 Protein ◽  
Vaccine Platform ◽  
West Nile ◽  
Flavivirus Vaccine

ABSTRACTWe previously produced a replication-defective West Nile virus (WNV) lacking NS1 (WNV-ΔNS1) that could propagate at low levels (105infectious units [IU]/ml) in a 293T cell line expressing wild-type (WT) NS1. This finding indicates the potential of developing WNV-ΔNS1 as a noninfectious vaccine. To explore this idea, we developed an NS1-expressing Vero cell line (VeroNS1) that significantly improved the yield of WNV-ΔNS1 (108 IU/ml). We evaluated the safety and efficacy of WNV-ΔNS1 in mice. WNV-ΔNS1 appeared to be safe, as no replicative virus was found in naive Vero cells after continuous culturing of WNV-ΔNS1 in VeroNS1cells for 15 rounds. WNV-ΔNS1 was noninfectious in mice, even when IFNAR−/−mice were administered a high dose of WNV-ΔNS1. Vaccination with a single dose of WNV-ΔNS1 protected mice from a highly lethal challenge with WT WNV. The antibody response against WNV correlated well with the protection of vaccinated mice. Our study demonstrates the potential of the NS1transcomplementation system as a new platform for flavivirus vaccine development.IMPORTANCEMany flaviviruses are significant human pathogens that frequently cause outbreaks and epidemics around the world. Development of novel vaccine platforms against these pathogens is a public health priority. Using WNV as a model, we developed a new vaccine platform for flaviviruses. WNV containing a NS1 deletion (WNV-ΔNS1) could be efficientlytranscomplemented in Vero cells that constitutively expressed WT NS1 protein. A single-dose immunization with WNV-ΔNS1 elicited robust immune responses in mice. The immunized animals were fully protected against pathogenic WNV infection. No adverse effects related to the WNV-ΔNS1 vaccination were observed. The results have demonstrated the potential of the NS1 complementation system as an alternative platform for flavivirus vaccine development, especially for highly pathogenic flaviviruses.

scholarly journals Long-term protection of rhesus macaques from Zika virus reinfection

2019 ◽  
Author(s):  
Gage K. Moreno ◽  
Christina M. Newman ◽  
Michelle R. Koenig ◽  
Mariel S. Mohns ◽  
Andrea M. Weiler ◽  
...  
Keyword(s):  
Zika Virus ◽  
Neutralizing Antibodies ◽  
Protective Immunity ◽  
Vaccine Development ◽  
Rhesus Macaques ◽  
Herd Immunity ◽  
Minimal Length ◽  
Plasma Viremia ◽  
Zikv Infection ◽  
Congenital Zika Syndrome

AbstractBy the end of the 2016 Zika virus (ZIKV) outbreak, it is estimated that there were up to 100 million infections in the Americas. In approximately one in seven infants born to mothers infected during pregnancy, ZIKV has been linked to microcephaly, developmental delays, or other congenital disorders collectively known as congenital Zika syndrome (CZS). Guillain-Barré syndrome (GBS) in ZIKV infected adults. It is a global health priority to develop a vaccine against ZIKV that elicits long-lasting immunity, however, the durability of immunity to ZIKV is unknown. Previous studies in mice and nonhuman primates have been crucial in vaccine development but have not defined the duration of immunity generated by ZIKV infection. In this study, we rechallenged five rhesus macaques with ZIKV two years after a primary ZIKV infection. We show that primary ZIKV infection generates high titers of neutralizing antibodies (nAbs) that protect from detectable plasma viremia following rechallenge and persist for at least 27 months. While additional longitudinal studies are necessary with longer time frames, this study establishes a new experimentally defined minimal length of protective ZIKV immunity.Author SummaryZIKV emerged as a vector-borne pathogen capable of causing illness in infected adults and congenital birth defects in infants born to mothers infected during pregnancy. Despite the drop in ZIKV cases since the 2015-16 epidemic, questions concerning the prevalence and longevity of protective immunity have left vulnerable communities fearful that they may become the center of next ZIKV outbreak. While pre-existing herd immunity in regions of past outbreaks may dampen the potential for future outbreaks to occur, we currently do not know the longevity of protective immunity to ZIKV after a person becomes infected. Here, we establish a new experimentally defined minimal length of protective ZIKV immunity. We show that five rhesus macaques initially infected with ZIKV two years prior to rechallenge elicit a durable immune response that protected from detectable plasma viremia. While this work establishes a new minimal length of protective immunity, additional studies are necessary to define the maximum length of protective immunity following ZIKV infection.

scholarly journals Recent Advances in Zika Virus Vaccines

Viruses ◽  
2018 ◽  
Vol 10 (11) ◽  
pp. 631 ◽  
Author(s):  
Himanshu Garg ◽  
Tugba Mehmetoglu-Gurbuz ◽  
Anjali Joshi
Keyword(s):  
Zika Virus ◽  
Viral Vectors ◽  
Vaccine Development ◽  
Treatment Strategies ◽  
Target Population ◽  
Primary Objective ◽  
Vaccine Candidates ◽  
Diagnostic Assays ◽  
Recent Advances ◽  
Short Period

The recent outbreaks of Zika virus (ZIKV) infections and associated microcephaly in newborns has resulted in an unprecedented effort by researchers to target this virus. Significant advances have been made in developing vaccine candidates, treatment strategies and diagnostic assays in a relatively short period of time. Being a preventable disease, the first line of defense against ZIKV would be to vaccinate the highly susceptible target population, especially pregnant women. Along those lines, several vaccine candidates including purified inactivated virus (PIV), live attenuated virus (LAV), virus like particles (VLP), DNA, modified RNA, viral vectors and subunit vaccines have been in the pipeline with several advancing to clinical trials. As the primary objective of Zika vaccination is the prevention of vertical transmission of the virus to the unborn fetus, the safety and efficacy requirements for this vaccine remain unique when compared to other diseases. This review will discuss these recent advances in the field of Zika vaccine development.

scholarly journals Arenavirus reverse genetics for vaccine development

2013 ◽  
Vol 94 (6) ◽  
pp. 1175-1188 ◽  
Author(s):  
Emilio Ortiz-Riaño ◽  
Benson Yee Hin Cheng ◽  
Juan Carlos de la Torre ◽  
Luis Martínez-Sobrido
Keyword(s):  
Reverse Genetics ◽  
Vaccine Development ◽  
Vero Cells ◽  
Lymphocytic Choriomeningitis ◽  
Human Pathogens ◽  
Live Attenuated Vaccine ◽  
Prophylactic Efficacy ◽  
Virus Rescue ◽  
Negative Sense ◽  
Human Vaccine

Arenaviruses are important human pathogens with no Food and Drug Administration (FDA)-licensed vaccines available and current antiviral therapy being limited to an off-label use of the nucleoside analogue ribavirin of limited prophylactic efficacy. The development of reverse genetics systems represented a major breakthrough in arenavirus research. However, rescue of recombinant arenaviruses using current reverse genetics systems has been restricted to rodent cells. In this study, we describe the rescue of recombinant arenaviruses from human 293T cells and Vero cells, an FDA-approved line for vaccine development. We also describe the generation of novel vectors that mediate synthesis of both negative-sense genome RNA and positive-sense mRNA species of lymphocytic choriomeningitis virus (LCMV) directed by the human RNA polymerases I and II, respectively, within the same plasmid. This approach reduces by half the number of vectors required for arenavirus rescue, which could facilitate virus rescue in cell lines approved for human vaccine production but that cannot be transfected at high efficiencies. We have shown the feasibility of this approach by rescuing both the Old World prototypic arenavirus LCMV and the live-attenuated vaccine Candid#1 strain of the New World arenavirus Junín. Moreover, we show the feasibility of using these novel strategies for efficient rescue of recombinant tri-segmented both LCMV and Candid#1.

scholarly journals Passage of Dengue Virus Type 4 Vaccine Candidates in Fetal Rhesus Lung Cells Selects Heparin-Sensitive Variants That Result in Loss of Infectivity and Immunogenicity in Rhesus Macaques

2009 ◽  
Vol 83 (20) ◽  
pp. 10384-10394 ◽  
Author(s):  
Germán Añez ◽  
Ruhe Men ◽  
Kenneth H. Eckels ◽  
Ching-Juh Lai
Keyword(s):  
Dengue Virus ◽  
Virus Type ◽  
Rhesus Macaques ◽  
Consensus Sequence ◽  
Neutralizing Antibody ◽  
Vero Cells ◽  
Heparin Binding ◽  
African Green Monkey Kidney ◽  
Vaccine Candidates ◽  
Domain Iii

ABSTRACT Three dengue virus type 4 (DENV-4) vaccine candidates containing deletions in the 3′ noncoding region were prepared by passage in DBS-FRhL-2 (FRhL) cells. Unexpectedly, these vaccine candidates and parental DENV-4 similarly passaged in the same cells failed to elicit either viremia or a virus-neutralizing antibody response. Consensus sequence analysis revealed that each of the three viruses, as well as the parental DENV-4 when passaged in FRhL cells, rapidly acquired a single Glu327-Gly substitution in domain III (DIII) of the envelope protein (E). These variants appear to have accumulated in response to growth adaptation to FRhL cells as shown by growth analysis, and the mutation was not detected in the virus following passage in C6/36 cells, primary African green monkey kidney cells, or Vero cells. The Glu327-Gly substitution was predicted by molecular modeling to increase the net positive charge on the surface of E. The Glu327-Gly variant of the full-length DENV-4 selected after three passages in FRhL cells showed increased affinity for heparan sulfate compared to the unpassaged DENV-4, as measured by heparin binding and infectivity inhibition assays. Evidence indicates that the Glu327-Gly mutation in DIII of the DENV-4 E protein was responsible for reduced infectivity and immunogenicity in rhesus monkeys. Our results point out the importance of cell substrates for vaccine preparation since the virus may change during passages in certain cells through adaptive selection, and such mutations may affect cell tropism, virulence, and vaccine efficacy.

scholarly journals Long-Term Protection of Rhesus Macaques from Zika Virus Reinfection

2019 ◽  
Vol 94 (5) ◽  
Author(s):  
Gage K. Moreno ◽  
Christina M. Newman ◽  
Michelle R. Koenig ◽  
Mariel S. Mohns ◽  
Andrea M. Weiler ◽  
...  
Keyword(s):  
Zika Virus ◽  
Neutralizing Antibodies ◽  
Protective Immunity ◽  
Vaccine Development ◽  
Rhesus Macaques ◽  
Herd Immunity ◽  
Minimal Length ◽  
Plasma Viremia ◽  
Zikv Infection ◽  
Congenital Zika Syndrome

ABSTRACT By the end of the 2016 Zika virus (ZIKV) outbreak, it is estimated that there were up to 100 million infections in the Americas. In approximately one in seven infants born to mothers infected during pregnancy, ZIKV has been linked to microcephaly, developmental delays, or other congenital disorders collectively known as congenital Zika syndrome, as well as Guillain-Barré syndrome, in ZIKV-infected adults. It is a global health priority to develop a vaccine against ZIKV that elicits long-lasting immunity; however, the durability of immunity to ZIKV is unknown. Previous studies in mice and nonhuman primates have been crucial in vaccine development but have not defined the duration of immunity generated by ZIKV infection. In this study, we rechallenged five rhesus macaques with ZIKV 22 to 28 months after a primary ZIKV infection. We show that primary ZIKV infection generates high titers of neutralizing antibodies that protect from detectable plasma viremia following rechallenge and persist for at least 22 to 28 months. While additional longitudinal studies are necessary with longer time frames, this study establishes a new experimentally defined minimal length of protective ZIKV immunity. IMPORTANCE ZIKV emerged as a vector-borne pathogen capable of causing illness in infected adults and congenital birth defects in infants born to mothers infected during pregnancy. Despite the decrease in ZIKV cases since the 2015-2016 epidemic, questions concerning the prevalence and longevity of protective immunity have left vulnerable communities fearful that they may become the center of next ZIKV outbreak. Although preexisting herd immunity in regions of past outbreaks may dampen the potential for future outbreaks to occur, we currently do not know the longevity of protective immunity to ZIKV after a person becomes infected. Here, we establish a new experimentally defined minimal length of protective ZIKV immunity. We show that five rhesus macaques initially infected with ZIKV 22 to 28 months prior to rechallenge elicit a durable immune response that protected from detectable plasma viremia. This study establishes a new minimal length of protective immunity.

scholarly journals Dengue 2 PDK-53 Virus as a Chimeric Carrier for Tetravalent Dengue Vaccine Development

2003 ◽  
Vol 77 (21) ◽  
pp. 11436-11447 ◽  
Author(s):  
Claire Y.-H. Huang ◽  
Siritorn Butrapet ◽  
Kiyotaka R. Tsuchiya ◽  
Natth Bhamarapravati ◽  
Duane J. Gubler ◽  
...  
Keyword(s):  
Vaccine Development ◽  
Neutralizing Antibody ◽  
Vero Cells ◽  
Vaccine Virus ◽  
Wild Type ◽  
Dengue Vaccine ◽  
Virus Challenge ◽  
Viral Interference ◽  
Antibody Titers ◽  
Virus Expression

ABSTRACT Attenuation markers of the candidate dengue 2 (D2) PDK-53 vaccine virus are encoded by mutations that reside outside of the structural gene region of the genome. We engineered nine dengue virus chimeras containing the premembrane (prM) and envelope (E) genes of wild-type D1 16007, D3 16562, or D4 1036 virus within the genetic backgrounds of wild-type D2 16681 virus and the two genetic variants (PDK53-E and PDK53-V) of the D2 PDK-53 vaccine virus. Expression of the heterologous prM-E genes in the genetic backgrounds of the two D2 PDK-53 variants, but not that of wild-type D2 16681 virus, resulted in chimeric viruses that retained PDK-53 characteristic phenotypic markers of attenuation, including small plaque size and temperature sensitivity in LLC-MK2 cells, limited replication in C6/36 cells, and lack of neurovirulence in newborn ICR mice. Chimeric D2/1, D2/3, and D2/4 viruses replicated efficiently in Vero cells and were immunogenic in AG129 mice. Chimeric D2/1 viruses protected adult AG129 mice against lethal D1 virus challenge. Two tetravalent virus formulations, comprised of either PDK53-E- or PDK53-V-vectored viruses, elicited neutralizing antibody titers in mice against all four dengue serotypes. These antibody titers were similar to the titers elicited by monovalent immunizations, suggesting that viral interference did not occur in recipients of the tetravalent formulations. The results of this study demonstrate that the unique attenuation loci of D2 PDK-53 virus make it an attractive vector for the development of live attenuated flavivirus vaccines.

scholarly journals Enhanced dengue vaccine virus replication and neutralizing antibody responses in immune primed rhesus macaques

npj Vaccines ◽  
2021 ◽  
Vol 6 (1) ◽  
Author(s):  
Michael K. McCracken ◽  
Caitlin H. Kuklis ◽  
Chandrika B. Kannadka ◽  
David A. Barvir ◽  
Mark A. Sanborn ◽  
...  
Keyword(s):  
Neutralizing Antibodies ◽  
Rhesus Macaques ◽  
Neutralizing Antibody ◽  
Denv Infection ◽  
Vaccine Virus ◽  
Dengue Vaccine ◽  
Live Attenuated Vaccine ◽  
Vaccination Strategies ◽  
Inactivated Vaccines

AbstractAntibody-dependent enhancement (ADE) is suspected to influence dengue virus (DENV) infection, but the role ADE plays in vaccination strategies incorporating live attenuated virus components is less clear. Using a heterologous prime-boost strategy in rhesus macaques, we examine the effect of priming with DENV purified inactivated vaccines (PIVs) on a tetravalent live attenuated vaccine (LAV). Sera exhibited low-level neutralizing antibodies (NAb) post PIV priming, yet moderate to high in vitro ADE activity. Following LAV administration, the PIV primed groups exhibited DENV-2 LAV peak viremias up to 1,176-fold higher than the mock primed group, and peak viremia correlated with in vitro ADE. Furthermore, PIV primed groups had more balanced and higher DENV-1–4 NAb seroconversion and titers than the mock primed group following LAV administration. These results have implications for the development of effective DENV vaccine prime-boost strategies and for our understanding of the role played by ADE in modulating DENV replication.

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