scholarly journals A chimeric Japanese encephalitis vaccine protects against lethal yellow fever virus infection without inducing neutralizing antibodies

2019 ◽  
Author(s):  
Niraj Mishra ◽  
Robbert Boudewijns ◽  
Michael A. Schmid ◽  
Rafael Elias Marques ◽  
Sapna Sharma ◽  
...  
Keyword(s):  
Yellow Fever ◽  
Japanese Encephalitis ◽  
Neutralizing Antibodies ◽  
Yellow Fever Virus ◽  
Neutralizing Antibody ◽  
Fever Virus ◽  
Off Label Use ◽  
Off Label ◽  
Japanese Encephalitis Vaccine ◽  
Label Use

ABSTRACTRecent massive outbreaks of yellow fever virus (YFV) in West Africa and Brazil resulted in rapid depletion of global vaccine emergency stockpiles and raised concerns about being not prepared against future YFV epidemics. Here we report that a live-attenuated virus similar to the Japanese encephalitis virus (JEV) vaccine JE-CVax/Imojev® that consists of YFV-17D vaccine from which the structural (prM/E) genes have been replaced with those of the JEV SA14-14-2 vaccine strain confers full protection in mice against lethal YFV challenge. In contrast to the YFV-17D mediated protection against YFV, this protection is not mediated by neutralizing antibodies but correlates with YFV-specific non-neutralizing antibodies and T cell responses against cell-associated YFV NS1 and other YFV non-structural (NS) proteins. Our findings reveal the importance of YFV NS proteins to mediate protection and demonstrate that chimeric flavivirus vaccines, such as Imojev® can confer protection against two flaviviruses. This dual protection has implications for the possible off-label use of JE-CVax in case of emergency and vaccine shortage during YFV outbreaks. In addition, populations in Asia that have been vaccinated with Imojev® may already be protected against YFV should outbreaks ever occur on that continent as feared by WHO.IMPORTANCEEfficient and safe vaccines exist against yellow fever (e.g. YFV-17D) that provide long-lasting protection by rapidly inducing neutralizing antibody responses. However, vaccine supply cannot cope with an increasing demand posed by massive urban outbreaks in recent years. Here we report that JE-CVax/Imojev®, a YFV-17D-based chimeric Japanese encephalitis vaccine also efficiently protects against YFV infection in mice. In case of shortage of the YFV vaccine during yellow fever outbreaks, (off-label) use of JE-CVax/Imojev® may be considered. Moreover, wider use of JE-CVax/Imojev® in Asia may lower the risk of the much-feared YFV spill over to the continent. More in general chimeric vaccines that combine surface antigens and replication machineries of two distinct flaviviruses can be considered dual vaccines, for the latter pathogen without induction of surface-specific antibodies. Following this rationale, novel flavivirus vaccines that do not hold a risk for antibody-dependent enhancement (ADE) of infection [inherent to current dengue vaccines and dengue vaccine candidates] could be designed.

scholarly journals A Chimeric Japanese Encephalitis Vaccine Protects against Lethal Yellow Fever Virus Infection without Inducing Neutralizing Antibodies

mBio ◽  
2020 ◽  
Vol 11 (2) ◽  
Author(s):  
Niraj Mishra ◽  
Robbert Boudewijns ◽  
Michael Alexander Schmid ◽  
Rafael Elias Marques ◽  
Sapna Sharma ◽  
...  
Keyword(s):  
Yellow Fever ◽  
Japanese Encephalitis ◽  
Neutralizing Antibodies ◽  
Yellow Fever Virus ◽  
Fever Virus ◽  
Asia Pacific ◽  
Off Label Use ◽  
Off Label ◽  
Japanese Encephalitis Vaccine ◽  
Label Use

ABSTRACT Recent outbreaks of yellow fever virus (YFV) in West Africa and Brazil resulted in rapid depletion of global vaccine emergency stockpiles and raised concerns about being unprepared against future YFV epidemics. Here we report that a live attenuated virus similar to the Japanese encephalitis virus (JEV) vaccine JE-CVax/Imojev that consists of YFV-17D vaccine from which the structural (prM/E) genes have been replaced with those of the JEV SA14-14-2 vaccine strain confers full protection in mice against lethal YFV challenge. In contrast to the YFV-17D-mediated protection against YFV, this protection is not mediated by neutralizing antibodies but correlates with YFV-specific nonneutralizing antibodies and T cell responses against cell-associated YFV NS1 and other YFV nonstructural (NS) proteins. Our findings reveal the potential of YFV NS proteins to mediate protection and demonstrate that chimeric flavivirus vaccines, such as Imojev, could confer protection against two flaviviruses. This dual protection may have implications for the possible off-label use of JE-CVax in case of emergency and vaccine shortage during YFV outbreaks. In addition, populations in Asia that have been vaccinated with Imojev may already be protected against YFV should outbreaks ever occur on that continent, as several countries/regions in the Asia-Pacific are vulnerable to international spread of the YFV. IMPORTANCE Efficient and safe vaccines against yellow fever (e.g., YFV-17D) that provide long-lasting protection by rapidly inducing neutralizing antibody responses exist. However, the vaccine supply cannot cope with an increasing demand posed by urban outbreaks in recent years. Here we report that JE-CVax/Imojev, a YFV-17D-based chimeric Japanese encephalitis vaccine, also efficiently protects against YFV infection in mice. In case of shortage of the YFV vaccine during yellow fever outbreaks, (off-label) use of JE-CVax/Imojev may be considered. Moreover, wider use of JE-CVax/Imojev in Asia may lower the risk of the much-feared YFV spillover to the continent. More generally, chimeric vaccines that combine surface antigens and replication machineries of two distinct flaviviruses may be considered dual vaccines for the latter pathogen without induction of surface-specific antibodies. Following this rationale, novel flavivirus vaccines that do not hold a risk for antibody-dependent enhancement (ADE) of infection (inherent to current dengue vaccines and dengue vaccine candidates) could be designed.

scholarly journals Persistence of Neutralizing Antibody Responses Among Yellow Fever Virus 17D Vaccinees Living in a Nonendemic Setting

2019 ◽  
Vol 221 (12) ◽  
pp. 2018-2025 ◽  
Author(s):  
Bettie W Kareko ◽  
Brian L Booty ◽  
Chad D Nix ◽  
Zoe L Lyski ◽  
Mark K Slifka ◽  
...  
Keyword(s):  
Logistic Regression ◽  
Yellow Fever ◽  
Neutralizing Antibodies ◽  
Yellow Fever Virus ◽  
Booster Vaccination ◽  
Neutralizing Antibody ◽  
Fever Virus ◽  
Cross Sectional ◽  
Vaccination History ◽  
Sectional Analysis

Abstract Background The once-in-a-lifetime recommendation for vaccination against yellow fever virus (YFV) has been controversial, leading to increased scrutiny of the durability of immunity after 17D vaccination. Methods This is a cross-sectional analysis of 17D vaccinees living in nonendemic Portland, Oregon. Neutralization assays were used to determine YFV immunity. The relationships between 17D immunity and vaccination history, demographics, and travel were evaluated using nominal logistic regression. Results Seventy-one of 92 (77.2%) subjects were YFV seropositive (90 percent plaque reduction neutralization test ≥1:10) at all timepoints, and 24 of 38 (63.8%) were YFV seropositive at ≥10 years after single-dose vaccination. No relationship was found between YFV immunity and time in endemic countries, other flavivirus immunity, or demographics. Subjects were most likely to become seronegative between 3 and 12 years postvaccination (logistic regression, odds ratio [OR] = 1.75; 95% confidence interval [CI], 1.12–2.73). A comparison of our results and 4 previous studies of YFV nonendemic vaccinees found that overall, 79% (95% CI, 70%–86%) of vaccinees are likely to be seropositive ≥10 years postvaccination. Conclusions These results suggest that 1 in 5 17D vaccinees will lack neutralizing antibodies at ~10 years postvaccination, and a booster vaccination should be considered for nonendemic vaccinees before travel to regions where there is a high risk of YFV transmission.

scholarly journals Prevalence and titers of yellow fever virus neutralizing antibodies in previously vaccinated adults

2017 ◽  
Vol 59 (0) ◽  
Author(s):  
Karina Takesaki Miyaji ◽  
Vivian Iida Avelino-Silva ◽  
Marisol Simões ◽  
Marcos da Silva Freire ◽  
Carlos Roberto de Medeiros ◽  
...  
Keyword(s):  
Yellow Fever ◽  
Neutralizing Antibodies ◽  
Yellow Fever Virus ◽  
Fever Virus

scholarly journals A Yellow Fever Virus 17D Infection and Disease Mouse Model Used to Evaluate a Chimeric Binjari-Yellow Fever Virus Vaccine

Vaccines ◽  
2020 ◽  
Vol 8 (3) ◽  
pp. 368 ◽  
Author(s):  
Kexin Yan ◽  
Laura J. Vet ◽  
Bing Tang ◽  
Jody Hobson-Peters ◽  
Daniel J. Rawle ◽  
...  
Keyword(s):  
Weight Loss ◽  
Mouse Model ◽  
Yellow Fever ◽  
Virus Vaccine ◽  
Neutralizing Antibodies ◽  
Yellow Fever Virus ◽  
Fever Virus ◽  
Liver Pathology ◽  
Vaccine Production ◽  
Mosquito Cells

Despite the availability of an effective, live attenuated yellow fever virus (YFV) vaccine (YFV 17D), this flavivirus still causes up to ≈60,000 deaths annually. A number of new approaches are seeking to address vaccine supply issues and improve safety for the immunocompromised vaccine recipients. Herein we describe an adult female IFNAR-/- mouse model of YFV 17D infection and disease that recapitulates many features of infection and disease in humans. We used this model to evaluate a new YFV vaccine that is based on a recently described chimeric Binjari virus (BinJV) vaccine technology. BinJV is an insect-specific flavivirus and the chimeric YFV vaccine (BinJ/YFV-prME) was generated by replacing the prME genes of BinJV with the prME genes of YFV 17D. Such BinJV chimeras retain their ability to replicate to high titers in C6/36 mosquito cells (allowing vaccine production), but are unable to replicate in vertebrate cells. Vaccination with adjuvanted BinJ/YFV-prME induced neutralizing antibodies and protected mice against infection, weight loss and liver pathology after YFV 17D challenge.

Heparin removal by ecteola-cellulose pre-treatment enables the use of plasma samples for accurate measurement of anti-Yellow fever virus neutralizing antibodies

2017 ◽  
Vol 448 ◽  
pp. 9-20 ◽  
Author(s):  
Ana Carolina Campi-Azevedo ◽  
Vanessa Peruhype-Magalhães ◽  
Jordana Grazziela Coelho-dos-Reis ◽  
Christiane Costa-Pereira ◽  
Anna Yoshida Yamamura ◽  
...  
Keyword(s):  
Yellow Fever ◽  
Neutralizing Antibodies ◽  
Yellow Fever Virus ◽  
Fever Virus ◽  
Plasma Samples ◽  
Pre Treatment

scholarly journals Yellow Fever Virus Vaccine Reduces T Cell Receptor Signaling and the Levels of Phosphatase PTPRE In Vivo

Proceedings ◽  
2020 ◽  
Vol 50 (1) ◽  
pp. 97
Author(s):  
Jinhua Xiang ◽  
James H. McLinden ◽  
Qing Chang ◽  
Thomas M Kaufman ◽  
Judy A. Streit ◽  
...  
Keyword(s):  
T Cell ◽  
Yellow Fever ◽  
Neutralizing Antibodies ◽  
Noncoding Rna ◽  
Cell Function ◽  
Yellow Fever Virus ◽  
Fever Virus ◽  
Tcr Signaling ◽  
T Cell Function ◽  
A Genome

Background: A Src kinase-activating phosphatase (PTPRE) is targeted by a genome-derived yellow fever virus (YFV) short noncoding RNA (vsRNA) in vitro. The vsRNA reduces PTPRE translation, which leads to reduced TCR signaling. vsRNA point mutations restore PTPRE expression and T cell function. We examined TCR signaling and PTPRE levels in individuals before and after YFV vaccination (YFVax). Methods: Fourteen individuals receiving YFVax (104.7–5.6) IM for travel prophylaxis provided written informed consent for these studies. Blood was obtained once before vaccination and four times after vaccination (days 3 to 28). Serum and PBMCs were purified and YFV was quantified by RNA and infectivity. PBMCs were assessed for activation following anti-CD3 stimulation by measuring phospho-tyrosine-394-Lck and IL-2 release. PBMC PTPRE levels were determined by immunoblot analyses (normalized to actin). A YFV-neutralizing antibody was determined by PRNT. Results: YFVax was administered alone (six out of 14 subjects) or in combination with other vaccines (eight out of 14). All subjects demonstrated reduced resting PBMC PTPRE levels and post-TCR stimulation had reduced IL-2 release between days 4 and 21 compared to pre- and day 28 samples. Phospho-Lck was reduced in all but two subjects on the same days, and both of these subjects also received an influenza vaccine. Low-level viremia was detected in 10/14 subjects, with infectious titers of 100/mL. Viremia was not detected in four out of 14 subjects. All recipients developed neutralizing antibodies by day 21. Conclusion: YFV vaccination regulates PBMC PTPRE levels 4–21 days after infection, despite the low to absent infectious YFV detected in serum, suggesting that enough YFV vsRNA is produced and released from cells to have a functional (and measurable) effect on T cell function. Studies are underway to determine if this is mediated by exosomes or defective particles containing the vsRNA that targets PTPRE. Furthermore, the association between PTPRE and TCR signaling confirms a role for PTPRE in TCR function.

scholarly journals Chimeric Yellow Fever Virus 17D-Japanese Encephalitis Virus Vaccine: Dose-Response Effectiveness and Extended Safety Testing in Rhesus Monkeys

2000 ◽  
Vol 74 (4) ◽  
pp. 1742-1751 ◽  
Author(s):  
T. P. Monath ◽  
I. Levenbook ◽  
K. Soike ◽  
Z.-X. Zhang ◽  
M. Ratterree ◽  
...  
Keyword(s):  
Japanese Encephalitis Virus ◽  
Yellow Fever ◽  
Japanese Encephalitis ◽  
Rhesus Monkeys ◽  
Neutralizing Antibodies ◽  
Standardized Test ◽  
Neutralizing Antibody ◽  
Encephalitis Virus ◽  
Envelope Gene ◽  
Wild Type

ABSTRACT ChimeriVax-JE is a live, attenuated recombinant virus prepared by replacing the genes encoding two structural proteins (prM and E) of yellow fever 17D virus with the corresponding genes of an attenuated strain of Japanese encephalitis virus (JE), SA14-14-2 (T. J. Chambers et al., J. Virol. 73:3095–3101, 1999). Since the prM and E proteins contain antigens conferring protective humoral and cellular immunity, the immune response to vaccination is directed principally at JE. The prM-E genome sequence of the ChimeriVax-JE in diploid fetal rhesus lung cells (FRhL, a substrate acceptable for human vaccines) was identical to that of JE SA14-14-2 vaccine and differed from sequences of virulent wild-type strains (SA14 and Nakayama) at six amino acid residues in the envelope gene (E107, E138, E176, E279, E315, and E439). ChimeriVax-JE was fully attenuated for weaned mice inoculated by the intracerebral (i.c.) route, whereas commercial yellow fever 17D vaccine (YF-Vax) caused lethal encephalitis with a 50% lethal dose of 1.67 log10 PFU. Groups of four rhesus monkeys were inoculated by the subcutaneous route with 2.0, 3.0, 4.0, and 5.0 log10PFU of ChimeriVax-JE. All 16 monkeys developed low viremias (mean peak viremia, 1.7 to 2.1 log10 PFU/ml; mean duration, 1.8 to 2.3 days). Neutralizing antibodies appeared between days 6 and 10; by day 30, neutralizing antibody responses were similar across dose groups. Neutralizing antibody titers to the homologous (vaccine) strain were higher than to the heterologous wild-type JE strains. All immunized monkeys and sham-immunized controls were challenged i.c. on day 54 with 5.2 log10 PFU of wild-type JE. None of the immunized monkeys developed viremia or illness and had mild residual brain lesions, whereas controls developed viremia, clinical encephalitis, and severe histopathologic lesions. Immunized monkeys developed significant (≥4-fold) increases in serum and cerebrospinal fluid neutralizing antibodies after i.c. challenge. In a standardized test for neurovirulence, ChimeriVax-JE and YF-Vax were compared in groups of 10 monkeys inoculated i.c. and analyzed histopathologically on day 30. Lesion scores in brains and spinal cord were significantly higher for monkeys inoculated with YF-Vax. ChimeriVax-JE meets preclinical safety and efficacy requirements for a human vaccine; it appears safer than yellow fever 17D vaccine but has a similar profile of immunogenicity and protective efficacy.

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