This site needs JavaScript to work properly. Please enable it to take advantage of the complete set of features!
Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

NIH NLM Logo
Log in
Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2011 Aug 11;29(35):6008-16.
doi: 10.1016/j.vaccine.2011年06月03日4. Epub 2011 Jun 28.

Immune correlates of protection against yellow fever determined by passive immunization and challenge in the hamster model

Affiliations

Immune correlates of protection against yellow fever determined by passive immunization and challenge in the hamster model

Justin G Julander et al. Vaccine. .

Abstract

Live, attenuated yellow fever (YF) 17D vaccine is highly efficacious but causes rare, serious adverse events resulting from active replication in the host and direct viral injury to vital organs. We recently reported development of a potentially safer β-propiolactone-inactivated whole virion YF vaccine (XRX-001), which was highly immunogenic in mice, hamsters, monkeys, and humans [10,11]. To characterize the protective efficacy of neutralizing antibodies stimulated by the inactivated vaccine, graded doses of serum from hamsters immunized with inactivated XRX-001 or live 17D vaccine were transferred to hamsters by the intraperitoneal (IP) route 24h prior to virulent, viscerotropic YF virus challenge. Neutralizing antibody (PRNT(50)) titers were determined in the sera of treated animals 4h before challenge and 4 and 21 days after challenge. Neutralizing antibodies were shown to mediate protection. Animals having 50% plaque reduction neutralization test (PRNT(50)) titers of ≥40 4h before challenge were completely protected from disease as evidenced by viremia, liver enzyme elevation, and protection against illness (weight change) and death. Passive titers of 10-20 were partially protective. Immunization with the XRX-001 vaccine stimulated YF neutralizing antibodies that were equally effective (based on dose response) as antibodies stimulated by live 17D vaccine. The results will be useful in defining the level of seroprotection in clinical studies of new yellow fever vaccines.

PubMed Disclaimer

Figures

Figure 1
Figure 1
A. Experiment 1 Survival and B time-course weight change between day 3 and 6 of hamsters passively immunized with various dilutions of serum from hamsters immunized with XRX-001 or YFVAX®. C and D. Corresponding data for Experiment 2 (***P<0.001, **P<0.01, *P<0.05, †P=0.08, as compared with placebo controls).
Figure 2
Figure 2
A. Experiment 1: viremia on day 4 post challenge for individual hamsters passively immunized with various dilutions of immune serum generated after immunization with XRX-001 or YF-VAX®. B. Experiment 1: serum ALT 6 days post challenge for individual hamsters passively immunized with various dilutions of immune serum generated after immunization with XRX-001 or YF-VAX®. C. Experiment 2. Viremia on day 4 post-challenge. D. Experiment 2: serum ALT on day 6 post challenge. Differences between groups were performed by one-way ANOVA with a Bonferroni multiple comparison post-test analysis comparing the antibody treated groups to the aluminum hydroxide-saline control group [***P<0.001, **P<0.01, as compared with saline+alum (Experiment 1) or normal hamster serum (Experiment 2) controls].
Figure 3
Figure 3
A. Experiment 1. Relationship between passive neutralizing antibody 4 hours before challenge and ALT elevations determined on day 6. Individual sera were tested in the XRX-001 1:10 treatment group, whereas serum pools representing hamsters that developed no ALT elevation or had ALT elevations were tested. The passive titers are shown. B. Experiment 2. Correlation between neutralizing antibody 4 hours before challenge and viremia (day 4 after challenge), alanine aminotransferase (ALT) concentrations (Day 6 after challenge), and death/survival, by individual animal. Hamsters were treated with a hamster serum pool from animals previously immunized with XRX-001. Different color symbols are used to distinguish treatment (dose) groups (see Table 1B). LOD= limit of detection. ULN= upper limit of normal. C. Experiment 2. Same display of data as in Fig 3B. Hamsters were treated with a hamster serum pool from animals previously immunized with YF-VAX®. Different color symbols are used to distinguish treatment (dose) groups (see Table 1B). LOD= limit of detection. ULN= upper limit of normal.
Figure 3
Figure 3
A. Experiment 1. Relationship between passive neutralizing antibody 4 hours before challenge and ALT elevations determined on day 6. Individual sera were tested in the XRX-001 1:10 treatment group, whereas serum pools representing hamsters that developed no ALT elevation or had ALT elevations were tested. The passive titers are shown. B. Experiment 2. Correlation between neutralizing antibody 4 hours before challenge and viremia (day 4 after challenge), alanine aminotransferase (ALT) concentrations (Day 6 after challenge), and death/survival, by individual animal. Hamsters were treated with a hamster serum pool from animals previously immunized with XRX-001. Different color symbols are used to distinguish treatment (dose) groups (see Table 1B). LOD= limit of detection. ULN= upper limit of normal. C. Experiment 2. Same display of data as in Fig 3B. Hamsters were treated with a hamster serum pool from animals previously immunized with YF-VAX®. Different color symbols are used to distinguish treatment (dose) groups (see Table 1B). LOD= limit of detection. ULN= upper limit of normal.
Figure 3
Figure 3
A. Experiment 1. Relationship between passive neutralizing antibody 4 hours before challenge and ALT elevations determined on day 6. Individual sera were tested in the XRX-001 1:10 treatment group, whereas serum pools representing hamsters that developed no ALT elevation or had ALT elevations were tested. The passive titers are shown. B. Experiment 2. Correlation between neutralizing antibody 4 hours before challenge and viremia (day 4 after challenge), alanine aminotransferase (ALT) concentrations (Day 6 after challenge), and death/survival, by individual animal. Hamsters were treated with a hamster serum pool from animals previously immunized with XRX-001. Different color symbols are used to distinguish treatment (dose) groups (see Table 1B). LOD= limit of detection. ULN= upper limit of normal. C. Experiment 2. Same display of data as in Fig 3B. Hamsters were treated with a hamster serum pool from animals previously immunized with YF-VAX®. Different color symbols are used to distinguish treatment (dose) groups (see Table 1B). LOD= limit of detection. ULN= upper limit of normal.
Figure 4
Figure 4
Logistic regression, showing correlations between passive antibody titers 4 hours before challenge and A. Weight gain; B. Viremia; and C. ALT elevation. For the viremia display, logarithmic units were used for both dependent and independent variables.

References

    1. Monath TP, Cetron MS, Teuwen DE. In: Yellow fever vaccine In Vaccines. 5th Edition. Plotkin SA, Orenstein WA, Offit PA, editors. New York: Elsevier; 2008. pp. 959–1055.
    1. Staples JE, Monath TP. Yellow fever: 100 years of discovery. JAMA. 2008;300:960–962. - PubMed
    1. Hayes EB. Acute viscerotropic disease following vaccination against yellow fever. Trans R Soc Trop Med Hyg. 2007;101:967–971. - PubMed
    1. Lindsey NP, Schroeder BA, Miller ER, Braun MM, Hinckley AF, Marano N, Slade BA, Barnett ED, Brunette GW, Horan K, Staples JE, Kozarsky PE, Hayes EB. Adverse event reports following yellow fever vaccination. Vaccine. 2008;26:6077–6082. - PubMed
    1. Whittembury A, Ramirez G, Hernandez H, Ropero AM, Waterman S, Ticona M, Brinton M, Uchuya J, Gershman M, Toledo W, Staples E, Campos C, Martinez M, Chang GJ, Cabezas C, Lanciotti R, Zaki S, Montgomery JM, Monath T, Hayes E. Viscerotropic disease following yellow fever vaccination in Peru. Vaccine. 2009;27:5974–5981. - PubMed

Publication types

MeSH terms

Full text links
Elsevier Science full text link Elsevier Science Free PMC article
Cite

AltStyle によって変換されたページ (->オリジナル) /