DNA vaccination before conception protects Zika virus–exposed pregnant macaques against prolonged viremia and improves fetal outcomes

Abstract

Zika virus (ZIKV) infection of pregnant women is associated with congenital Zika syndrome (CZS) and no vaccine is available, although several are being tested in clinical trials. We tested the efficacy of ZIKV DNA vaccine VRC5283 in a rhesus macaque model of congenital ZIKV infection. Most animal vaccine experiments have a set pathogen exposure several weeks or months after vaccination. In the real world, people encounter pathogens years or decades after vaccination, or may be repeatedly exposed if the virus is endemic. To more accurately mimic how this vaccine would be used, we immunized macaques before conception and then exposed them repeatedly to ZIKV during early and mid-gestation. In comparison to unimmunized animals, vaccinated animals had a significant reduction in peak magnitude and duration of maternal viremia, early fetal loss, fetal infection, and placental and fetal brain pathology. Vaccine-induced neutralizing antibody titers on the day of first ZIKV exposure were negatively associated with the magnitude of maternal viremia, and the absence of prolonged viremia was associated with better fetal outcomes. These data support further clinical development of ZIKV vaccine strategies to protect against negative fetal outcomes.

A Combination of Two Human Monoclonal Antibodies Limits Fetal Damage by Zika Virus in Macaques

“…In addition, in the ZIKV DNA vaccine study, the presence or absence of detectable viremia in vaccinated dams correlated with the titer of neutralizing antibody responses at the time of the first ZIKV challenge (i.e., animals with antibody titers above a threshold had no detectable viremia). For vaccinated animals with detectable viremia, the reduced viremia was always early (peak viremia ≤ 5 days after ZIKV inoculation), and short in duration (≤ 14 days after the first ZIKV challenge), consistent with the observed rapid augmentation of antiviral antibody and T-cell mediated immune responses in vaccinated animals after challenge (21).…”

“…VRC5283 is a DNA vaccine that produces subviral particles with pre-membrane, membrane and envelope proteins, is immunogenic in phase 1 clinical trial and is currently being evaluated in a phase 2/2b (17,37,38). In the macaque pregnancy experiment with similar design to the present study, two doses of vaccine prior to ZIKV inoculation significantly reduced maternal viremia when animals were challenged between 4 days to 1 year after the 2 nd immunization (21). Viremia was undetectable in 5 of 13 animals (38%), a rate of protection comparable to the current antibody treatment study (37.5%; n=8).…”

“…Despite these differences in the kinetic of viremia, early versus delayed viremia in vaccinated versus antibody-treated pregnant dams, the reduced maternal viremia and associated improved fetal outcomes were similar in the two studies (21). Thus, the VRC5283 vaccine and the Z004 GRLR/LS + Z021 GRLR/LS antibodies are comparably efficacious vis-à-vis fetal protection, with each strategy having their intrinsic advantages and limitations in terms of speed of induction, potential for enhancement and durability of protective immunity.…”

“…ZIKV infection of pregnant macaques is associated with fetal demise and neuropathology (11)(12)(13). To evaluate the effect of anti-ZIKV antibodies on fetal development and health in pregnant primates, we performed timed breeding experiments and challenged the dams 3 times with 10 3 PFU of ZIKV subcutaneously on gestational days (GD) 30, GD 60 and GD 90, which corresponds to 1 st and 2 nd trimester (normal gestation of rhesus macaques is ~165 days) (21). Macaques in the treatment group received intravenous infusions of Z004 GRLR/LS + Z021 GRLR/LS antibodies 24 hours before each virus challenge ( Fig.…”

“…4 B-F). Fetal death (i.e., no heartbeat on ultrasound) was detected in 2 control animals (C03 and C07) on GD 35 and 60 (i.e., 5 and 30 days after the first ZIKV inoculation), with detectable viral RNA in placental and fetal tissues (21). Fetal death was observed on GD51 in one of the antibody-treated macaques (AB02).…”