**Table 1.**

*Therapeutic agents or vaccine candidates targeting virus or immunity with promisor potential to use during ZIKV infection in pregnant women.*

*Innate Immunity Modulation during Zika Virus Infection on Pregnancy: What We Still Need… DOI: http://dx.doi.org/10.5772/intechopen.94861*

Zika virus replication in placenta, and fetal infection, thus minimizing the risk of maternal-fetal transmission of ZIKV [27].

There are few studies investigating innate immunity during antiviral therapy, especially when its concern to Flaviviridae family [38, 135, 138, 139]. Scarce literature revealed knowledge about antiviral therapy immune effects only during hepatitis C infection [138, 139]. Antiviral drugs, as pegylated interferon (PEG-IFN), ribavirin, and direct-acting antiviral agents (DAA) have been related with a reduction of innate regulatory cells, as MDSC, in peripheral blood from hepatitis C chronic patients, in which T cells were increased and immune function was reestablished [138, 139]. Nevertheless, all those drugs are aimed to interrupt viral replication and any dysregulation of immune cells during pregnancy is not safe, then those drugs are not recommended to be used during gestational period [140]. Besides no immune response evaluation was related to DAA therapy, it has been known that small molecules with specific activity should not induce any immune alterations in maternal-fetal immunity [140].

Safety and effectiveness of sofosbuvir on Zika virus infection should be addressed to immune response evaluation, which is poorly explored, even more in pregnant animal models. More studies and investments are needed for non-clinical and clinical studies, to get safety therapeutic protocols aimed to pregnant women with Zika virus or other flavivirus infection.

#### **5.3 Cell death modulation during antiviral therapy**

Genetic manipulation has been proven to be a promising tool for vaccine and therapy development. Considering the type 2 of programmed death, autophagy is activated by ZIKV in placental parenchyma and is involved in poor outcome during pregnancy, this cell death pathway has been a target for therapies [112, 141–143].

Recently, a study showed the role of an autophagy gene (Atg16I1) during ZIKV infection in pregnant mice model, in which inducing a deficiency in this gene limited ZIKV vertical transmission, as well fetal damage, improving placental and fetal outcomes [112]. In addition, an antiviral compound approved to be used by pregnant women for malaria and autoimmune diseases [141], hydroxychloroquine (HCQ ), has been used to dampen autophagic activity *in vivo* [142]. Thus, Cao et al., showed that HCQ administered with a dose of 40 mg/kg/day has *in vivo* inhibitory effects on autophagy sustained lower levels of ZIKV RNA compared with saline buffer treatment [112].

Based on the knowledge of ZIKV infection that can trigger a caspase-3 activation contributing to cell death of neural progenitor cells during pregnancy, it is an extremely relevant approaches targeting cell death pathways for antiviral treatments even though for therapeutic vaccines.

#### **5.4 Recombinant viral vectors as vaccine candidate**

Recombinant viral vectors have been highlighted as therapeutic alternatives to prevent and treat infectious disease [144, 145], considering its specificity and the adverse effects of antiviral drugs and some vaccines [140, 146]. Betancourt et al., 2017 showed that a recombinant viral vector from vesicular stomatitis virus (rVSV) anti-ZIKV vaccine increased IFN-γ production by splenic CD8+ T cells as well as high neutralizing anti-ZIKV antibody titers from pregnant mice. This study also demonstrates that neonatal mouse from vaccinated dams was partially protected against neurological manifestations of ZIKV infection following wild-type virus challenge [147]. This rVSV using pre membrane and envelope region together obtained from a ZIKV strain as reference had the potential to protect from ZIKV

infection during prenatal and neonatal development, likely through the transmission of maternal IgG. Despite rVSV vaccine induces IFN-γ production in pregnant mice, this vaccine needs to be evaluated for other types of interferon, mainly its effects on placental tissues .

### **5.5 Potential DNA and mRNA vaccines**

mRNA vaccines as well as DNA-based vaccines represent a versatile vaccine platform and an alternative to conventional vaccine approaches because of their high potency, capacity for rapid development and potential for low-cost manufacture and safe administration [148]. Recent technological advances have allowed mRNA vaccines to demonstrate encouraging results in both animal and human models. Regarding prophylactic mRNA vaccines, a number of reports have demonstrated the potency and versatility of mRNA to elicited protective immunity against a variety of infectious agents in animal models against, including influenza virus, Ebola virus, Zika virus, Human Immunodeficiency virus 1 (HIV-1), herpes simplex virus, cytomegalovirus, hepatitis C and respiratory syncytial virus [149–151]. It has been noted that approximately ten mRNA vaccines programs have entered clinical trials [152].

The importance of mRNA-based vaccines and therapies is emphasized when mRNA-based biopharmaceuticals are entering the market with guidance of new biopharmaceutical companies. Modern Therapeutics, an mRNA therapy company evaluated various mRNA vaccine technologies to identify immunogenic and scalable candidates. The pipeline of this company shows different investigative stages mRNA vaccines of the following vaccines Respiratory Syncytial virus (RSV), Cytomegalovirus (CMV), human metapneumovirus (hMPV) + Parainfluenza virus Type 3 (PIV3), Influenza A subtypes H10N8, and H7N9, Zika, and Chikungunya. Curevac is the first biopharmaceutical company that developed the first prophylactic mRNA vaccine in the clinics, recently they showed that RNActive® vaccines induced long-lived and protective immunity to influenza A virus infections in various animal models [153].

Thus, big pharmaceutic companies, such as Merck & Co., have been invested in Modern Therapeutics aiming to expand the field of mRNA vaccine (https://www. modernatx.com/). Indeed, nucleic acid vaccine platform has been presented to combat the emergence of acute viral diseases, mainly to rapidly contain emerging outbreaks before they spread out of control. In this context, two vaccines were developed to combat the ZIKV outbreak (1) DNA plasmid vaccine encoding the prM-E genes of ZIKV and (VRC5283) (2) mRNA vaccine (mRNA-LNP), both vaccines mediate protection from ZIKV infection in mouse models. The DNA plasmid vaccine is in phase 2 human clinical trials (VRC-ZKADNA090–00-VP) and vaccine mRNA-LNP is in phase 1 clinical trial (NCT03014089) [154–156].

Considering that vaccine trials might not be performed in pregnant women and have not yet tested vaccines against ZIKV vertical transmission, there is a need for establishing the efficacy of ZIKV vaccines against mother-to-child transmission in animal models. In order to address those questions, it has been shown that vaccination with DNA plasmid encoding Zika virus prM-E and a lipid-encapsulated mRNA vaccine-elicited antigen-specific antibody and CD8+ T cell responses in mice, being able to generate a high level of protection against vertical transmission. Moreover, the mRNA-LNP vaccine not only inhibited vertical transmission but also ensured that fetuses are protected therefore, reinforcing its potential as promising vaccine for pregnant women [155]. Since there are few studies in the field of ZIKV vaccine candidates that evaluated vertical transmission, intrinsic maternal factors as well as fetal health, nucleic acid vaccines are pointed as a great opportunity to contain ZIKV infection.

*Innate Immunity Modulation during Zika Virus Infection on Pregnancy: What We Still Need… DOI: http://dx.doi.org/10.5772/intechopen.94861*
