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Zika virus (ZIKV) is an arbovirus first discovered in the Americas. ZIKV infection is insidious based on its mild clinical symptoms observed after infection. Currently, no specific prophylactics or therapeutics are clinically available to treat ZIKV infection. Development of a safe and effective vaccine is essential to prevent the rise of any potential pandemic.
Zika virus (ZIKV) is a small envelope, positive-strand RNA virus belonging to the Flavivirus family of Flaviviridae [1]. As shown in Figure 1, the genome-encoded polyprotein can be cleaved into three structural proteins (capsid (C), anterior membrane (prM), and envelope (E)) and seven non-structural proteins (NS1, NS2A, NS2B, NS3, NS4A, NS4B, and NS5) [2]. The mature ZIKV particles consist of 90 E homodimers and 90 M homodimers on the lipid membrane, and the genomic RNA is surrounded by C protein (Figure 2). E proteins are responsible for receptor binding, attachment, viral entry, and membrane fusion. Transmission routes are arthropod vectors (e.g., Aedes aegypti), intrauterine (perinatal), and through sex and blood-related pathways [3]. ZIKV was also found to be present in the breast milk [4][5]. When ZIKV attacks pregnant women, it is easily reproduced in the placental tissue and seriously affects the fetal central nervous system and immune system, causing congenital Zika syndrome (CZS) in infants [6][7][8]. Studies have identified the major epitopes present on ZIKV structural proteins that can induce neutralizing antibodies [9]. Owing to high structural homology, the presence of common epitopes between Dengue virus (DENV) and ZIKV were reported earlier [10]. However, it is not feasible to prepare a ZIKV vaccine based on the principle of “cross-reactivity of the neutralizing antibodies” [11]. Several in vitro experiments demonstrated an antibody-dependent enhancement (ADE) of ZIKV infection after DENV infection, which poses a challenge to the development of a safe vaccine.
Development of a safe and an effective vaccine plays an important role in preventing the potential spread and serious harm caused by of ZIKV infection.
The DNA vaccine platform has been used for over twenty-five years to develop candidate vaccines against numerous pathogens. DNA vaccines can induce both humoral and cellular immune responses and are capable of mediating long-term protection [12]. Most currently developed DNA vaccines for ZIKV contain prM and E genes coding for prM and E proteins (Table 1). Type I interferon receptor alpha-chain null mice (Ifnar1−/− mouse model) [13][14] exposed to ZIKV developed severe damage to the testes and sperm [15][16], but a DNA vaccine encoding ZIKV prM-E completely protected mice against such ZIKV-associated damage [17]. The immunogenicity of a DNA-based vaccine candidate, pVAX1-ZME, expressing the prM/E protein of ZIKV, was evaluated in maternal and post-natal protection of suckling BALB/c mice, and it was demonstrated that the administration of three doses with 50 µg of pVAX1-ZME by in vivo electroporation induced robust ZIKV-specific cellular and long-term humoral immune responses with high and sustained neutralizing activity in adult BALB/c mice. The neutralizing antibodies passively protected against ZIKV infection in neonatal mice and effectively inhibited delay in growth [18]. GLS-5700, a DNA-based vaccine that encodes the prM and E antigenic regions of ZIKV, was shown to prevent fertility loss in male IFNAR−/− mice [19]. The Vaccine Research Center (VRC) of the National Institute of Allergy and Infectious Diseases (NIAID) and National Institutes of Health (NIH) in USA have developed two DNA vaccine candidates, named VRC5288 and VRC5283, and tested them in phase I clinical trials to assess their safety, tolerability, and immunogenicity in humans [20]. Another DNA vaccine was developed by using a single tetrafunctional amphiphilic block copolymer (ABC) encoding the full sequence of prM-E, which induced a high neutralizing antibody titer against three divergent ZIKV isolates in six-week-old female C57BL/6C mice [21].
Vaccine’s Name or Component | Immunogenicity in the Induction of Immune Responses | Animal Model | Vaccine Doses | Administration Route | Virus Challenged | Ref. |
---|---|---|---|---|---|---|
prM and E | Completely protected mice against ZIKV-associated damage to the testes and sperm and prevented viral persistence in the testes | Type-I interferon knockout mice | Two doses at two-week interval | i.m. | Puerto Rico Strain PRVABC59 | [17] |
pVAX1-ZME (prM and E) | Induced robust ZIKV-specific cellular and long-term humoral immune responses with high and sustained neutralizing activity, which provided passive protection against ZIKV infection in neonatal mice | BALB/c mice | Three doses at three-week intervals | i.m. | (SMGC-1 strain, GenBank accession number: KX266255 |
[18] |
GLS-5700 (prM and E) | Prevented fertility loss in male IFNAR−/− mice | C57BL/6J mice and IFNAR−/− mice | Two doses at two-week interval | i.m. | Puerto Rico Strain PRVABC59 | [19] |
VRC5288 and VRC5283 | Induced detectable T-cell response and antibody response with neutralization activity. The immunogenicity of VRC5283 was better than that of VRC5288. | Humans | Single dose, two and three doses | i.m | No | [20] |
prM and E | Elicited protective responses against multiple diverse ZIKV isolates | C57BL/6c mice | Four doses at days 0, 24, 42, and 199 | i.m | Puerto Rico Strain PRVABC59 | [21] |
pVAX-NS1, pVAX-tpaNS1, pVAX-tpaNS1-IMX313P (NS1) | pVAX-tpaNS1 vaccination induced significantly higher NS1-specific antibody titers and CD4+, as well as CD8+, T-cell responses compared to pVAX-NS1 and pVAX-tpaNS1- IMX313P | BALB/c and IFNAR−/− mice | Three doses at two-week intervals | i.d. | ZIKVzkv2015 | [22] |
Based on their rapid, stable, and consistent production capabilities, subunit vaccines are considered as effective tools to prevent virus infection. Subunit vaccines against ZIKV have been designed and tested in animal models (Table 2). Viral structural proteins, such as E protein and its domain III (EDIII), are attractive vaccine targets. The immunogenicity of a subunit vaccine candidate comprised of ZIKV E protein and two clinical adjuvants (Alum and CoVaccine HTTM) was evaluated in Swiss Webster, BALB/c, and C57BL/6 mice [26]. These vaccine formulations induced robust IgG titers and high levels of neutralizing antibodies in all three mouse strains and protected them against viremia after ZIKV infection [26]. Another research team used a recombinant subunit platform consisting of antigens produced in Drosophila melanogaster S2 cells to develop two candidate formulations. The first formulation contained 25 µg of ZIKV E which was adjuvanted with 10 mg Co-Vaccine HTTM, and the second formulation contained 50 µg of ZIKV E protein with Alhydrogel® 85 plus 1.2 mg of elemental aluminum. High neutralizing antibody titers were induced in a non-human primate (NHP) viremia model, and passive transfer of the plasma from the macaques protected against viremia in ZIKV-infected BALB/c mice [27]. Based on this observation, another research team agreed that high anti-ZIKV titers protected against viremia, but they also suggested that low titers could provide an incremental degree of protection, albeit not sufficient to prevent viremia [26]. Purified EDIII from transformed Escherichia coli inclusions induced high titers of IgG and ZIKV neutralizing antibodies, which showed no evidence of ADE induction in C57BL/6 mice [28].
Vaccine’s Name or Component | Immunogenicity in the Induction of Immune Responses | Animal Model | Vaccine Doses | Administration Route | Virus Challenged | Ref. |
---|---|---|---|---|---|---|
E | Induced robust antigen binding IgG titers and high levels of neutralizing antibodies in the mice, which protected against viremia after ZIKV infection | Swiss Webster, BALB/c, and C57BL/6 mice | Three doses at three-week intervals | i.m. | Puerto Rico Strain PRVABC59 | [26] |
Induced high neutralizing antibody titers | Cynomolgus macaques and BALB/c mice | Three doses at three-week intervals | i.m. | Puerto Rico Strain PRVABC59 | [27] | |
EDIII | Induced high titer of IgG and ZIKV-neutralizing antibodies and showed no evidence of ADE induction in mouse serum | C57BL/6 mice | Four doses at three-week intervals | s.c. | Puerto Rico Strain PRVABC59 | [28] |
E90 (Consisting of the first 450 amino acids at the N-terminal region of E protein) | Immunization of pregnant mice with E90 protected the developing brains of offspring, both in utero and in the neonatal period, from subsequent ZIKV infection and microcephaly. E90 induced robust ZIKV-specific humoral responses in adult BALB/c mice. | ICR (CD-1 immunocompetent) mice; BALB/c mice | Two doses at two-week interval | i.p. | GZ01 and FSS13025 strains | [29][30] |
EDIII fragments (E296–406; E298–409; E301–404) | Induced sustained broad-spectrum neutralization antibodies and passive transfer of the E298–409-specific antibodies prevented ZIKV infection in newborns and immunocompromised adults. | BALB/c mice and A129 mice | Five doses at days 0, 21, 42, 210, and 300 | i.m. | R103451 and FLR strains | [31] |
A truncated subunit vaccine consisting of the first 450 amino acids at the N-terminal region of the ZIKV FSS13025 strain E protein (E90) was investigated in 7- to 8-week-old CD-1 (ICR) immunocompetent mice for both in utero and neonatal ZIKV infection. Results demonstrated that immunization of pregnant mice with E90 protected the developing brains of offspring, both in utero and during the neonatal period, from subsequent ZIKV infection and microcephaly. Most importantly, E90 vaccination protected mice from ZIKV infection, even at 140 days post-immunization [29]. Another group showed robust induction of ZIKV-specific humoral response in adult BALB/c mice by E90, and passive transfer of the antisera from these mice conferred absolute protection against lethal ZIKV challenge in a neonatal mouse model [30]. These studies demonstrated the promising nature of recombinant ZIKV E90 as a ZIKV subunit vaccine that deserves further clinical development. One study used seven-day-old male and female BALB/c pups, 6 to 8-week-old female BALB/c mice, and 5-week-old male and female type-I IFN receptor–deficient A129 mice to investigate the long-term immunogenicity and neutralizing activity of the ZIKV EDIII fragments. The results showed that ZIKV EDIII fragment, especially E298–409, could induce sustained development of neutralizing antibodies [31]. The E298–409-specific antibodies upon passive transfer prevented ZIKV infection in newborns and immunocompromised adults [31]. Thus, this subunit vaccine based on the critical fragment (E298–409) of ZIKV EDIII is one of the promising vaccine candidates for ZIKV infection. It has been proven that the recombinant ZIKV subunit vaccine is a safe and efficacious option for the prevention of ZIKV infection. However, its less immunogenic nature is the major disadvantage, requiring more doses and appropriate adjuvants [32].
Vaccine’s Name or Component | Immunogenicity in the Induction of Immune Responses | Animal Model | Vaccine Doses | Administration Route | Virus Challenged | Ref. |
---|---|---|---|---|---|---|
ZIKV-3′ UTR-10-LAV | Showed complete protection from viremia and induced a saturated neutralizing antibody response | A129 mice | Single dose | s.c. | Cambodian strain FSS13025 and Puerto Rico strain PRVABC59 | [34] |
ZIKV-3′ UTR-20-LAV | Induced strong immune responses and protected ZIKV-induced damage to testes in mice; induced sterilizing immunity in NHPs | A129 mice and rhesus macaques | Single dose | s.c. | Cambodian strain FSS13025 and Puerto Rico strain PRVABC59 | [35] |
ZIKV-NS1-LAV (NS1) | Markedly diminished viral RNA levels in maternal, placental, and fetal tissues, which resulted in protection against placental damage and fetal death | A129 mice andrhesus macaques | Single dose | s.c. | Puerto Rico strain PRVABC59 | [36] |
LAV (with 9-amino-acid deletion in the C protein) | Not only elicited protective immunity that completely prevented viremia, morbidity and mortality, but also fully prevented infection of pregnant mice and maternal-to-fetal transmission | A129 mice | Single dose | s.c. | Puerto Rico strain PRVABC59 | [37] |
Vaccine’s Name or Component | Immunogenicity in the Induction of Immune Responses | Animal Model | Vaccine Doses | Administration Route | Virus Challenged | Ref. |
---|---|---|---|---|---|---|
Ad4-prM-E and Ad5-prM-E | Ad5-prM-E vaccination induced both humoral and T-cell responses, while Ad4-prM-E induced only a T-cell response. | C57BL/6 mice | Two doses at three-week interval | i.m. | Puerto Rico strain PRVABC59 | [39] |
hAd5-prM-E | Induced both cell-mediated and humoral immune responses, which conferred protection against a ZIKV challenge | C57BL/6 mice and Ifnar1−/− mice | Single dose | i.n. | Puerto Rico strain PRVABC59 | [41] |
Ad5-Sig-prM-Env (prM-E) and Ad5-Env (E) | Both vaccines elicited robust humoral and cellular immune responses in immunocompetent BALB/c mice, as well as in A129 mice, but Ad5-Sig-prM-Env-vaccinated mice resulted in significantly higher ZIKV-specific neutralizing antibody titers and lower viral loads than Ad5-Env-vaccinated mice. | BALB/c mice and A129 mice | Single dose | i.m. | Puerto Rico strain PRVABC59 | [42] |
ChAdOx1 | Induced high levels of protective responses in challenged mice | BALB/c mice | Single dose | i.m. | Brazilian ZIKV | [43] |
RhAd52-prMEnv | Induced ZIKV-specific neutralizing antibodies in rhesus monkeys; antibodies sufficient for protection against ZIKV challenge in mice | Rhesus monkeys and BALB/c mice | Single dose | i.m. | Brazilian ZIKV and Puerto Rico strain PRVABC59 | [44] |
rVSV-prM-E-NS1 | Induced ZIKV-specific antibody and T-cell immune responses that conferred partial protection against ZIKV infection | A129 mice and BALB/c mice | Single dose | i.n. | Cambodian strain FSS13025 | [45] |
VSV-Capsid and VSV-ZikaE260-425 | Both vaccines induced strong ZIKV-specific humoral responses in immunized BALB/c mice, but VSV-Capsid immunization elicited significantly higher levels of IFN-γ+ CD8+ and CD4+ T-cells than that of VSV-ZikaE260-425 vaccine. | BALB/c mice | Single dose | i.n. | Puerto Rico strain PRVABC59 | [46] |
Vaccine’s Name or Component | Immunogenicity in the Induction of Immune responses | Animal Model | Vaccine Doses | Administration Route | Virus Challenged | Ref. |
---|---|---|---|---|---|---|
Alum-adjuvant mixed purified inactivated ZIKV vaccine (PIZV) | Two-dose vaccination of the candidates was highly immunogenic in the mouse models, which protected AG129 mice against lethal ZIKV challenge. Passive transfer of naïve mice with ZIKV-immune serum also showed full protection against lethal ZIKV challenge. | CD-1 and AG129 mice | Three doses at four-week intervals | i.m. | Puerto Rico strain PRVABC59 | [48] |
Induced robust neutralizing antibody responses and provided complete protection from homologous ZIKV strain challenge | BALB/c mice and cynomolgus macaques | Two doses at three/four-week interval | i.m. | Puerto Rico strain PRVABC59 | [49][50] | |
PIZV | Elicited a dose-dependent and long-lasting neutralizing antibody responses | Indian rhesus macaques | Two doses at four-week interval | i.m. | Puerto Rico strain PRVABC59 | [51] |
Two dose-vaccination of the Type of vaccine gave a robust protection against ZIKV challenge. | rhesus macaques | Two doses at four-week interval | s.c., i.m. |
Brazil ZKV2015 | [52] | |
Safe and well tolerated in humans up to 52 weeks of follow-up; but two doses not durable for immunogenicity required | Phase I clinical trial | Single dose and two doses at two/four-week interval | i.m. | No | [53] |
Vaccine’s Name or Component | Immunogenicity in the Induction of Immune Responses | Animal Model | Vaccine Doses | Administration Route | Virus Challenged | Ref. |
---|---|---|---|---|---|---|
prM and E (HEK293 expression system) | Induced a protective antibody response | AG129 mice | Two doses at day 0 and 32 | i.m. | Prototype Zika Nica 2-16 strain | [54] |
prM and E (Baculovirus expression system) | Stimulated ZIKV-specific IgG and neutralizing antibodies, as well as T-cell responses | BALB/c mice | Three doses at two-week intervals | i.m. | ZIKV strain SZ-WIV01 | [55] |
EDIII (Nicotiana benthamiana plant expression system) | Elicited potent humoral and cellular immune responses correlated with protective immunity against multiple strains | C57BL/6 mice | Three doses at three-week intervals | s.c. | Puerto Rico strain PRVABC59 | [56] |
prM and E | Intradermal electroporation of as little as 1 µg of this vaccine elicited potent humoral and cellular immune responses in BALB/c and IFNAR−/− C57BL/6 mice, resulting in complete protection of the latter mice against ZIKV infection. | BALB/c and IFNAR−/− C57BL/6 mice | Two doses at four-week interval | i.d. | ZIKV strain MR-766 | [57] |
Conferred protection and sterilizing immunity in immunocompetent mice against ZIKV infection and diminished ADE in vitro, as well as in vivo | AG129, BALB/c and C57BL/6 mice | Single dose and two doses at three-week interval | i.m. | African ZIKV strain (Dakar 41519) | [58] | |
Induced potent and durable protective responses in mice and non-human primates | BALB/c and C57BL/6 mice; rhesus macaques (Macaca mulatta) | Single dose | i.d. | Puerto Rico strain PRVABC59 | [59] |
Vaccine Types | Advantages | Disadvantages | Ref. |
---|---|---|---|
DNA vaccines | Chemically stable and cost effective; easy and safe to scale up; can induce both humoral and cellular immune responses and are capable of mediating long-term protection | Have the potential of integrating the exogenous gene into the host genome, leading to induction of host autoimmunity | [17][18][19][20][21][22][25] |
Subunit vaccines | Rapid, stable, and consistent production | Normally need multiple doses with appropriate adjuvants | [26][27][28][29][30][31] |
Live-attenuated vaccines | Single dose could induce high immune responses, rapid induction of durable immunity | Safety problems and need cold-chain storage facilities | [24][34][35][36][37] |
Virus-vector-based vaccines | Single dose could induce higher and faster immune responses with lasting protection | Pre-existing immunity problem | [39][41][42][43][44][45][64][65] |
Inactivated vaccines | Easy production and storage; convenient to make multivalent vaccines | Safety problems; need multiple injections; unable to deal with mutant viruses | [48][49][50][51][52][53] |
VLP-based vaccines | Noninfectious and could induce robust antibodies; multiple choices of expression systems | Application for clinical use needs further studies | [54][55][56] |
mRNA-based vaccines | Rapid and flexible production; could induce potent humoral and cellular immune responses | Need cold-chain storage facilities; new technology, lack of historical accumulation | [57][58][59] |