In vivo protection against ZIKV infection and pathogenesis through passive antibody transfer and active immunisation with a prMEnv DNA vaccine

Abstract

Significant concerns have been raised owing to the rapid global spread of infection and disease caused by the mosquito-borne Zika virus (ZIKV). Recent studies suggest that ZIKV can also be transmitted sexually, further increasing the exposure risk for this virus. Associated with this spread is a dramatic increase in cases of microcephaly and additional congenital abnormalities in infants of ZIKV-infected mothers, as well as a rise in the occurrence of Guillain Barre’ syndrome in infected adults. Importantly, there are no licensed therapies or vaccines against ZIKV infection. In this study, we generate and evaluate the in vivo efficacy of a novel, synthetic, DNA vaccine targeting the pre-membrane+envelope proteins (prME) of ZIKV. Following initial in vitro development and evaluation studies of the plasmid construct, mice and non-human primates were immunised with this prME DNA-based immunogen through electroporation-mediated enhanced DNA delivery. Vaccinated animals were found to generate antigen-specific cellular and humoral immunity and neutralisation activity. In mice lacking receptors for interferon (IFN)-α/β (designated IFNAR−/−) immunisation with this DNA vaccine induced, following in vivo viral challenge, 100% protection against infection-associated weight loss or death in addition to preventing viral pathology in brain tissue. In addition, passive transfer of non-human primate anti-ZIKV immune serum protected IFNAR−/− mice against subsequent viral challenge. This study in NHP and in a pathogenic mouse model supports the importance of immune responses targeting prME in ZIKV infection and suggests that additional research on this vaccine approach may have relevance for ZIKV control and disease prevention in humans.

Modified mRNA Vaccines Protect against Zika Virus Infection

“…Three groups reported DNA plasmid vaccines encoding ZIKV M-E or prM-E genes that induced neutralizing antibodies in mice and non-human primates and protected against viremia or lethal virus challenge Dowd et al, 2016b;Larocca et al, 2016;Muthumani et al, 2016). A rhesus adenovirus-vectored vaccine encoding ZIKV M-E genes induced neutralizing antibodies after a single dose in four rhesus macaques .…”

“…Several groups have developed subunit (prM-E or M-E DNA plasmid or adenovirusvectored) or inactivated virus vaccine platforms capable of eliciting neutralizing antibodies that protect against ZIKV viremia in mice and non-human primates Dowd et al, 2016b;Larocca et al, 2016;Muthumani et al, 2016). Some of these vaccine candidates have initiated or are scheduled to begin recruitment of subjects for evaluation in humans (NCT02840487, NCT02887482, NCT02809443, NCT02937233, NCT02952833, and NCT02963909).…”

“…Potently inhibitory monoclonal antibodies (mAbs) against ZIKV target epitopes in all three E protein domains as well as quaternary structures composed of multiple domains within or across E dimers Sapparapu et al, 2016;Stettler et al, 2016;Swanstrom et al, 2016;Wang et al, 2016;Zhao et al, 2016). In addition to induction by infectious or inactivated virus particles, neutralizing antibodies against ZIKV can be produced after immunization with DNA plasmids encoding M-E protein or prM-E, which in some cases generates secreted virus-like subviral particles (SVPs) (Dowd et al, 2016b;Muthumani et al, 2016).…”

Zika virus infection of first-trimester human placentas: utility of an explant model of replication to evaluate correlates of immune protection ex vivo

“…Five have reported DNA-based vaccines expressing pre-membrane and E proteins, which enable responses to quaternary epitopes known to elicit neutralizing activity [79–83]; all were shown to confer protection in animal models after virus challenge by various measures, including suppression of viremia and indicators of pathology. Similar results were obtained in rhesus macaques using purified inactivated virus and adenovirus-based expression of pre-membrane and E proteins [81].…”

Zika Virus: Current Status, Protective Vaccine Trials, and Antiviral Treatment Alternatives

“…Fare modellerinde antijen spesifik hücresel ve hümoral bağışıklık ve nötralizasyon aktivitesi oluşturduğu bildirildi (55) .…”