The Specificity of the Persistent IgM Neutralizing Antibody Response in Zika Virus Infections among Individuals with Prior Dengue Virus Exposure - PubMed (original) (raw)

The Specificity of the Persistent IgM Neutralizing Antibody Response in Zika Virus Infections among Individuals with Prior Dengue Virus Exposure

Amanda E Calvert et al. J Clin Microbiol. 2021.

Abstract

Dengue viruses (DENV) and Zika virus (ZIKV) are related mosquito-borne flaviviruses with similar disease manifestations, vector ecologies, and geographic ranges. The ability to differentiate these viruses serologically is vital due to the teratogenic nature of ZIKV and the potential confounding of preexisting cross-reactive anti-DENV antibodies. Here, we illustrate the kinetics of the IgM neutralizing antibody (NAb) response using longitudinal samples ranging from acute ZIKV infection to late convalescence from individuals with evidence of prior DENV infection. By serially depleting antibody isotypes prior to the neutralization assay, we determined that IgM contributes predominantly to ZIKV neutralization and is less cross-reactive than the IgG NAb. The IgM NAb peaked around 14 days (95% confidence interval [95% CI], 13 to 15) and had a median duration of 257 days (95% CI, 133 to 427). These results demonstrate the persistence of IgM NAb after ZIKV infection and imply its potential role in diagnosis, vaccine evaluation, serosurveillance, and research on flavivirus-host interactions.

Keywords: IgM neutralization; Zika virus; dengue virus; serology diagnostics.

PubMed Disclaimer

Figures

FIG 1

FIG 1

Individuals with highly ZIKV-specific neutralizing IgM. (A) NAbs of longitudinal plasma samples from 6 individuals in group 1. Lower limits of detection (LLOD) of IgG-depleted NAb (1.3 log10) and total NAb (1.6 log10) of the assay are represented by dashed lines. Upper limits of detection (ULOD) of IgG-depleted NAb (4.01 log10) and total NAb (4.31 log10) are represented by dotted lines. Bold black line represents estimated average NAb kinetic curves from the spline model with 95% confidence bounds (shaded regions). Colored lines represent longitudinal NAb titers of each individual. (B) Neutralization curves for 6 individual plasma samples at the time point with peak ZIKV NAb. Dotted line represents 90% neutralization (EC90). (C) Samples from the assay whose results are shown in panel B were further depleted of IgM (IgG/M dep) before R-mFRNT for comparison of the geometric mean NAb titers among total, IgG-depleted, and IgG/M-depleted outcomes. LLOD (1.3 log10) and ULOD (4.31 log10) are represented by dotted lines. Significance was measured by two-tailed paired t test (*, P < 0.05; **, P < 0.0001).

FIG 2

FIG 2

Individuals with cross-reactive neutralizing IgM to DENV1 and DENV2. NAbs of longitudinal plasma samples from 11 individuals in group 2. Lower limits of detection (LLOD) of IgM NAb (1.3 log10) and total NAb (1.6 log10) are represented by dashed lines. Upper limits of detection (ULOD) of IgM NAb (4.01 log10) and total NAb (4.31 log10) are represented by dotted lines. Bold black lines represent average NAb kinetic curves from the spline model with 95% confidence bounds (shaded regions). Colored lines represent longitudinal NAb titers of each individual.

FIG 3

FIG 3

A subject with extremely high anamnestic DENV1 NAbs attributed mainly to IgA. (A) Neutralization curves with and without IgG depletion for plasma samples from individual 19 with higher NAb to DENV1 than to ZIKV at each time point. Dotted lines represent 90% neutralization. (B) Comparison of PRNT90 titers using DENV1 16007 and West Pac74 for 4 samples from the subject. No significant difference in NAb titers was measured by a two-tailed paired t test, indicating that the higher DENV1 titer was not attributable to the use of the DENV1 16007 strain in R-WN/DENV1. (C) NAb was tested in the R-mFRNT with DENV1 and ZIKV after IgG depletion, IgG/M depletion, and IgG/A depletion of plasma samples from the same individual. Asterisks indicate significant differences by ANOVA with Tukey’s multiple-comparison test (*, P < 0.05; **, P < 0.001; ***, P < 0.0001).

FIG 4

FIG 4

Persistence of anti-ZIKV neutralizing IgM. The seroreversion curve with 95% CI was calculated by parametric lognormal survival model fitted with data of all 17 individuals in the study. The day of initial NAT detectability was imputed for each individual using viral RNA loads at index and a previously determined ZIKV RNA doubling time in plasma (32). The median line indicates loss of detectable neutralizing IgM among 50% of individuals.

References

    1. Bhatt S, Gething PW, Brady OJ, Messina JP, Farlow AW, Moyes CL, Drake JM, Brownstein JS, Hoen AG, Sankoh O, Myers MF, George DB, Jaenisch T, Wint GR, Simmons CP, Scott TW, Farrar JJ, Hay SI. 2013. The global distribution and burden of dengue. Nature 496:504–507. 10.1038/nature12060. -DOI -PMC -PubMed
    1. Fauci AS, Morens DM. 2016. Zika virus in the Americas—yet another arbovirus threat. N Engl J Med 374:601–604. 10.1056/NEJMp1600297. -DOI -PubMed
    1. Heymann DL, Hodgson A, Sall AA, Freedman DO, Staples JE, Althabe F, Baruah K, Mahmud G, Kandun N, Vasconcelos PF, Bino S, Menon KU. 2016. Zika virus and microcephaly: why is this situation a PHEIC? Lancet 387:719–721. 10.1016/S0140-6736(16)00320-2. -DOI -PMC -PubMed
    1. Lazear HM, Diamond MS. 2016. Zika virus: new clinical syndromes and its emergence in the Western Hemisphere. J Virol 90:4864–4875. 10.1128/JVI.00252-16. -DOI -PMC -PubMed
    1. Musso D, Gubler DJ. 2016. Zika virus. Clin Microbiol Rev 29:487–524. 10.1128/CMR.00072-15. -DOI -PMC -PubMed

MeSH terms

Substances

LinkOut - more resources