Primary infection with dengue or Zika virus does not affect the severity of heterologous secondary infection in macaques

Abstract

33Zika virus (ZIKV) and dengue virus (DENV) are genetically and antigenically related 34 flaviviruses that now co-circulate in much of the tropical and subtropical world. The rapid 35 emergence of ZIKV in the Americas in 2015 and 2016, and its recent associations with 36 Guillain-Barré syndrome, birth defects, and fetal loss have led to the hypothesis that 37 DENV infection induces cross-reactive antibodies that influence the severity of 38 secondary ZIKV infections. It has also been proposed that pre-existing ZIKV immunity 39 3 could affect DENV pathogenesis. We examined outcomes of secondary ZIKV infections 40 in three rhesus and fifteen cynomolgus macaques, as well as secondary DENV-2 41 infections in three additional rhesus macaques up to a year post-primary ZIKV infection. 42 Although cross-binding antibodies were detected prior to secondary infection for all 43 animals and cross-neutralizing antibodies were detected for some animals, previous 44 DENV or ZIKV infection had no apparent effect on the clinical course of heterotypic 45 secondary infections in these animals. All animals had asymptomatic infections and, 46 when compared to controls, did not have significantly perturbed hematological 47 parameters. Rhesus macaques infected with DENV-2 approximately one year after 48 primary ZIKV infection had higher vRNA loads in plasma when compared with serum 49 vRNA loads from ZIKV-naive animals infected with DENV-2, but a differential effect of 50 sample type could not be ruled out. In cynomolgus macaques, the serotype of primary 51 DENV infection did not affect the outcome of secondary ZIKV infection. 52 53 Author summary 54 Pre-existing immunity to one of the four DENV serotypes is known to increase the risk 55 of severe disease upon secondary infection with a different serotype. Due to the 56 antigenic similarities between ZIKV and DENV, it has been proposed that these viruses 57 could interact in a similar fashion. Data from in vitro experiments and murine models 58 suggests that pre-existing immunity to one virus could either enhance or protect against 59 infection with the other. These somewhat contradictory findings highlight the need for 60 immune competent animal models for understanding the role of cross-reactive 61 4 antibodies in flavivirus pathogenesis. We examined secondary ZIKV or DENV infections 62 in rhesus and cynomolgus macaques that had previously been infected with the other 63 virus. We assessed the outcomes of secondary ZIKV or DENV infections by quantifying 64 vRNA loads, clinical and laboratory parameters, body temperature, and weight for each 65 cohort of animals and compared them with control animals. These comparisons 66 demonstrated that within a year of primary infection, secondary infections with either 67 ZIKV or DENV were similar to primary infections and were not associated with 68 enhancement or reduction in severity of disease based on the outcomes that we 69 assessed. 70 71 126 an effective vaccine for ZIKV, as well as the introduction of a tetravalent DENV va...

Long-term protection of rhesus macaques from Zika virus reinfection

“…Here we demonstrate a new minimum length of protection resulting from primary ZIKV infection using Indian-origin rhesus macaques from previously published studies [44,46,47].…”

“…Using a one-way paired t-test, we compared EC50 values on day 0 to EC50 values on day and day (Fig 2B). All animals showed increased nAb titers following rechallenge as noted by a greater EC50 value on day 14 compared to day 0 (p = 0.0025, t=5.604, df=4) and on day 28 (p = throughout the duration of the study [44][45][46][47]. Animal C1 had lymphocyte levels dip below the RI (20-80% WBC) on days 4 and 7 but rebounded back to within the normal range by day 8.…”

“…Animal C1 had lymphocyte levels dip below the RI (20-80% WBC) on days 4 and 7 but rebounded back to within the normal range by day 8. Animal C5 had high platelet counts exceeding the RI (229-524 thousands of platelets/uL) present at day -3 and persisted to be above the RI throughout the study period [44][45][46][47].…”

“…Animal demographics, infection history, and naming scheme used for each animal are described in Table 1. Following these initial ZIKV infections, peak plasma vRNA load occurred between 2 and 6 days post infection (DPI) and ranged from 7.0 ✕ 10 5 to 2.8 ✕ 10 4 vRNA copies per ml [44][45][46][47]. In non-pregnant animals, vRNA load became undetectable by 10 -14 DPI.…”

“…Animals C5 and C3 were previously infected with 10 4 PFU of ZIKV-FP during their first and late second/early third trimesters of pregnancy, respectively, as described by Nguyen et al [46]. Animal C2 was previously infected with 10 6 PFU ZIKV-FP as previously described by Breitbach et al [47]. Full infection histories are described in Table 1.…”