Prediction of Protection against Asian Enterovirus 71 Outbreak Strains by Cross-neutralizing Capacity of Serum from Dutch Donors, The Netherlands

Abstract

Outbreaks of human enterovirus 71 (EV-71) in Asia are related to high illness and death rates among children. To gain insight into the potential threat for the population of Europe, we determined the neutralizing activity in intravenous immunoglobulin (IVIg) batches and individual serum samples from donors in the Netherlands against EV-71 strains isolated in Europe and in Asia. All IVIg batches and 41%, 79%, and 65% of serum samples from children ≤5 years of age, women of childbearing age, and HIV-positive men, respectively, showed high neutralizing activity against a Dutch C1 strain, confirming widespread circulation of EV-71 in the Netherlands. Asian B3-4 and C4 strains were efficiently cross-neutralized, predicting possible protection against extensive circulation and associated outbreaks of those types in Europe. However, C2 and C5 strains that had few mutations in the capsid region consistently escaped neutralization, emphasizing the importance of monitoring antigenic diversity among circulating EV-71 strains.

Keywords: Asian enterovirus 71; Dutch; Europe; Picornaviruses; cross protection; cross-neutralization; enterovirus; human enterovirus 71; intravenous immunoglobulins; seroprevalence; the Netherlands; viruses.

Figure 1

EV-71 nAb titers in IVIg batches composed of plasma from Dutch (6 batches), Japanese (2 batches), and Vietnamese (1 batch) donors and in a polyclonal rabbit serum against EV-71 C1 91–480. nAb titers are presented as log₂ values. EV-71, enterovirus 71; IVIg, intravenous immunoglobulin; nAb, neutralizing antibody; NL, the Netherlands.

Figure 2

Enterovirus 71 nAb titers in serum collected from Dutch children ≤5 years of age, women of childbearing age, and HIV-positive men during 2010–2014. nAb titers are presented as log₂ values. Median titers (wide horizontal lines) with interquartile ranges (error bars) are indicated for each category. nAb, neutralizing antibody.

Figure 3

Enterovirus 71 nAb titers in serum collected from Dutch children (<0.5 years, 0.5–2 years and >2–5 years of age) during 2010–2014. nAb titers are presented as log₂ values. Median titers (wide horizontal lines) with interquartile ranges (error bars) are indicated for each category. nAb, neutralizing antibody.

Figure 4

Amino acid sequence comparison of the capsid regions of EV-71 strains used for serologic analysis of strains isolated in Asia and Europe in study of immunity to these strains after exposure to IVIg from viruses from the Netherlands. Residues 164, 240, and 241 of VP1 (differing among genogroup B and C viruses and located in known antigenic sites) and residues that differ among neutralizable and nonneutralizable strains are marked by boxes. Known epitopes and antigenic determinants for EV-71 are marked in gray (22–25). EV-71, enterovirus 71; IVIg, intravenous immunoglobulin; VN, Vietnam; VP, viral protein.