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Influence of Fc?RIIa-Expressing Cells on the Assessment of Neutralizing and Enhancing Serum Antibodies Elicited by a Live-Attenuated Tetravalent Dengue Vaccine.

ABSTRACT: Background. ?Recent trials of recombinant, live-attenuated chimeric yellow fever-dengue tetravalent dengue vaccine (CYD-TDV) demonstrated efficacy against symptomatic, virologically confirmed dengue disease with higher point estimates of efficacy toward dengue virus (DENV)3 and DENV4 and moderate levels toward DENV1 and DENV2. It is interesting to note that serotype-specific efficacy did not correlate with absolute neutralizing antibody (nAb) geometric mean titer (GMT) values measured in a Vero-based plaque reduction neutralization test assay. The absence of Fc? receptors on Vero cells may explain this observation. Methods. ?We performed parallel seroneutralization assays in Vero cells and CV-1 cells that express Fc?RIIa (CV-1-Fc) to determine the neutralizing and enhancing capacity of serotype-specific DENV Abs present in CYD-TDV clinical trial sera. Results. ?Enhancement of DENV infection was observed in CV-1-Fc cells in naturally exposed nonvaccine sera, mostly for DENV3 and DENV4, at high dilutions. The CYD-TDV-vaccinated sera showed similar enhancement patterns. The CV-1-Fc nAb GMT values were 2- to 9-fold lower than Vero for all serotypes in both naturally infected individuals and CYD-TDV-vaccinated subjects with and without previous dengue immunity. The relative (CV-1-Fc/Vero) GMT decrease for anti-DENV1 and anti-DENV2 responses was not greater than for the other serotypes. Conclusions. ?In vitro neutralization assays utilizing Fc?RIIa-expressing cells provide evidence that serotype-specific Ab enhancement may not be a primary factor in the serotype-specific efficacy differences exhibited in the CYD-TDV trials.

SUBMITTER: Byers AM

PROVIDER: S-EPMC4689971 | biostudies-literature | 2015 Dec

REPOSITORIES: biostudies-literature

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Influence of FcγRIIa-Expressing Cells on the Assessment of Neutralizing and Enhancing Serum Antibodies Elicited by a Live-Attenuated Tetravalent Dengue Vaccine.

Byers Anthony M AM Broder Ryan R Haupfear Kelly K Timiryasova Tatyana M TM Hu Branda T BT Boaz Mark M Warren William L WL Jackson Nicholas N Moser Janice M JM Guy Bruno B

Open forum infectious diseases 20151112 4

Background. Recent trials of recombinant, live-attenuated chimeric yellow fever-dengue tetravalent dengue vaccine (CYD-TDV) demonstrated efficacy against symptomatic, virologically confirmed dengue disease with higher point estimates of efficacy toward dengue virus (DENV)3 and DENV4 and moderate levels toward DENV1 and DENV2. It is interesting to note that serotype-specific efficacy did not correlate with absolute neutralizing antibody (nAb) geometric mean titer (GMT) values measured in a Vero- ...[more]

PMID: 26719844

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Project description:BACKGROUND: Progress in dengue vaccine development has been hampered by limited understanding of protective immunity against dengue virus infection. Conventional neutralizing antibody titration assays that use Fc?R-negative cells do not consider possible infection-enhancement activity. We reasoned that as Fc?R-expressing cells are the major target cells of dengue virus, neutralizing antibody titration assays using Fc?R-expressing cells that determine the sum of neutralizing and infection-enhancing activity, may better reflect the biological properties of antibodies in vivo. METHODS AND FINDINGS: We evaluated serum samples from 80 residents of a dengue endemic country, Malaysia, for neutralizing activity, and infection-enhancing activity at 1?10 serum dilution by using Fc?R-negative BHK cells and Fc?R-expressing BHK cells. The serum samples consisted of a panel of patients with acute DENV infection (31%, 25/80) and a panel of donors without acute DENV infection (69%, 55/80). A high proportion of the tested serum samples (75%, 60/80) demonstrated DENV neutralizing activity (PRNT(50)?10) and infection-enhancing activity. Eleven of 18 serum samples from patients with acute secondary DENV infection demonstrated neutralizing activity to the infecting serotype determined by using Fc?R-negative BHK cells (PRNT(50)?10), but not when determined by using Fc?R-expressing cells. CONCLUSION: Human serum samples with low neutralizing activity determined by using Fc?R-negative cells showed DENV infection-enhancing activity using Fc?R-expressing cells, whereas those with high neutralizing activity determined by using Fc?R-negative cells demonstrate low or no infection-enhancing activity using Fc?R-expressing cells. The results suggest an inverse relationship between neutralizing antibody titer and infection-enhancing activity, and that neutralizing activity determined by using Fc?R-expressing cells, and not the activity determined by using Fc?R-negative cells, may better reflect protection to DENV infection in vivo.

Dataset Information

Influence of Fc?RIIa-Expressing Cells on the Assessment of Neutralizing and Enhancing Serum Antibodies Elicited by a Live-Attenuated Tetravalent Dengue Vaccine.

Publications

Influence of FcγRIIa-Expressing Cells on the Assessment of Neutralizing and Enhancing Serum Antibodies Elicited by a Live-Attenuated Tetravalent Dengue Vaccine.

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