The cross-neutralizing activity of enterovirus 71 subgenotype c4 vaccines in healthy chinese infants and children

Qunying Mao, Tong Cheng, Fengcai Zhu, Jingxin Li, Yiping Wang, Yanping Li, Fan Gao, Lisheng Yang, Xin Yao, Jie Shao, Ningshao Xia, Zhenglun Liang, Junzhi Wang, Qunying Mao, Tong Cheng, Fengcai Zhu, Jingxin Li, Yiping Wang, Yanping Li, Fan Gao, Lisheng Yang, Xin Yao, Jie Shao, Ningshao Xia, Zhenglun Liang, Junzhi Wang

Abstract

Background: EV71 is one of major etiologic causes of hand-foot-mouth disease (HFMD) and leads to severe neurological complications in young children and infants. Recently inactivated EV71 vaccines have been developed by five manufactures and clinically show good safety and immunogenicity. However, the cross-neutralizing activity of these vaccines remains unclear, and is of particular interest because RNA recombination is seen more frequently in EV71 epidemics.

Methodology/principal findings: In this post-hoc study, sera from a subset of 119 infants and children in two clinical trials of EV71 subgenotype C4 vaccines (ClinicalTrials.gov Identifier: NCT01313715 and NCT01273246), were detected for neutralizing antibody (NTAb) titres with sera from infected patients as controls. Cytopathogenic effect method was employed to test NTAb against EV71 subgenotype B4, B5, C2, C4 and C5, which were prominent epidemic strains worldwide over the past decade. To validate the accuracy of the results, ELISpot assay was employed in parallel to detect NTAb in all the post-vaccine sera. After two-dose vaccination, 49 out of 53 participants in initially seronegative group and 52 out of 53 participants in initially seropositive group showed less than 4-fold differences in NTAb titers against five EV71 strains, whereas corresponding values among sera from pediatric patients recovering from EV71-induced HFMD and subclinically infected participants were 8/8 and 41/43, respectively. The geometric mean titers of participants against five subgenotypes EV71 all grew significantly after vaccinations, irrespective of the baseline NTAb titer. The relative fold increase in antibody titers (NTAb-FI) against B4, B5, C2, and C5 displayed a positive correlation to the NTAb-FI against C4.

Conclusions/significance: The results demonstrated broad cross-neutralizing activity induced by two C4 EV71 vaccines in healthy Chinese infants and children. However, the degree of induced cross-protective immunity, and the potential escape evolution for EV71 still need to be monitored and researched in future for these new vaccines.

Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Figure 1. Correlation analyses of NTAb-FI against…
Figure 1. Correlation analyses of NTAb-FI against different EV71 genotypes in infants and children after vaccination.
A) Correlation of NTAb-FI against different genotypes in response to Vaccine A in initially seronegative infants and children. B) Correlation of NTAb-FI against different genotypes in response to Vaccine B in initially seronegative infants and children. C) Correlation of NTAb-FI against different genotypes in response to Vaccine B in initially seropositive infants and children.
Figure 2. Cross-neutralizing activity of the C4…
Figure 2. Cross-neutralizing activity of the C4 EV71 inactivated vaccines.
Note: According to Chi-square analysis, the percentage of cases with the NTAb titer changes ≤4 fold difference among all six groups was not significantly different (χ2 = 2.04, p>0.05). Comparison of the post-vaccination sera of initially seronegative and seropositive infants and children found no significant differences (χ2 = 1.89, p>0.05). In addition, comparison between vaccine A and vaccine B revealed no significant differences in their EV71 NTAb titers (χ2 = 1.26, p>0.05).
Figure 3. Correlation analyses of the NTAb…
Figure 3. Correlation analyses of the NTAb titers against B4, B5, C2, C4 and C5 by CPE and ELISpot assays.
Note: The NTAb titers against B4, B5, C2, C4, and C5, quantified by CPE assays, showed a statistically significant correlation with those detected by ELISopt assays (r2≥0.8296, p<0.0001 in both cases).

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