Ebola Virus Disease Vaccines

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1		Subham Preetam	--	3005	2023-05-24 10:15:42	\|
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This entry is adapted from the peer-reviewed paper 10.3390/vaccines11020268

The global outgoing outbreaks of Ebola virus disease (EVD) in different regions of Sudan, Uganda, and Western Africa have brought into focus the inadequacies and restrictions of pre-designed vaccines for use in the battle against EVD, which has affirmed the urgent need for the development of a systematic protocol to produce Ebola vaccines prior to an outbreak. There are several vaccines available being developed by preclinical trials and human-based clinical trials. The group of vaccines includes virus-like particle-based vaccines, DNA-based vaccines, whole virus recombinant vaccines, incompetent replication originated vaccines, and competent replication vaccines. The limitations and challenges faced in the development of Ebola vaccines are the selection of immunogenic, rapid-responsive, cross-protective immunity-based vaccinations with assurances of prolonged protection.

Ebola virus disease (EVD) Ebola vaccines Ebola outbreak

1. Introduction

It has been more than 40 years since the first Ebola outbreak occurred in 1976, which affected southern Sudan and the northern region of the Democratic Republic of Congo and lasted for almost 4 months, extending from June to September, with a mortality rate of 53% and 88.1%, respectively ^[1]. The two viruses that were later identified and held responsible for the first outbreak were Sudan ebolavirus and Zaire ebolavirus ^[2]. It is noticeable that most of the cases throughout have been predominant in central Africa. The countries that are majorly impacted by the Ebola outbreak include Sudan, Uganda, Ivory Coast, and the Democratic Republic of Congo ^[3]. Recently, on 20 September 2022, the Sudan ebolavirus-originated Ebola virus disease (EVD) outbreak desolated Uganda; the Ministry of Health reported fifty-five fatal confirmed deaths to the World Health Organization through 21 November 2022. However a similar outbreak caused by Sudan ebolavirus was previously reported in 2012 as well. In Sudan, EVD was caused due to Zaire ebolavirus that was imported from the Democratic Republic of the Congo (DROC). Recently, the DROC reported Ebola outbreaks on 23 April 2022 and 4 July 2022, which was followed by a third outbreak that occurred in 2018. Fortunately, the preparedness against these outbreaks regulated by vigorously active national authorities has dynamically restricted the transmission of the Ebola virus. However, these past outbreaks have provided present and future epidemiologists and researchers with critical situations and lessons which can infor m preparations and advisory measures against various Ebola outbreaks on a global platform. The CDC and WHO are partnering with a large number of communities from various countries at global platforms to support the rigorous reporting and examination of Ebola outbreaks and to reinforce the rapid and swift response against Ebola-mediated infectious diseases that concern a threat to public health ^[4].The pathogenesis of EVD is summarized in Figure 1.

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Figure 1. Diagrammatic representation of pathogenetic mechanism adopted by EVD.

EVD outbreaks cause mortality ranging from 50% to 90%; however, no specified antiviral drugs are required for the treatment, which indicates the control of an outbreak by earlier identification through symptoms with early medical care. The current Ebola outbreak indicates an urgent requirement for a vaccine against EVD.

2. Current Vaccines

2.1. Virus-Like Particles Vaccines

Zaire Ebolavirus (ZEBOV) matrix protein VP40 and glycoprotein (GP) make up virus-like particles (VLPs) with the occasional presence of nucleoprotein (NP). The creation of ZEBOV-like particles and cell budding is caused by the expression of VP40 in cells. The inclusion of these proteins into the VLPs is triggered by the expression of GP and/or NP. In mouse and guinea pig efficacy tests, VLPs made of VP40 and GP provided 100 percent protection from deadly ZEBOV infection ^[5]. Three vaccinations of non-human primates (NHPs) with VLPs containing glycoprotein, nucleoprotein, VP40, and an adjuvant (RIBI) resulted in immunological responses in the animals which were protective against deadly ZEBOV ^[6]^[7]^[8].

Immunogenic VLPs-based immunization triggers innate, humoral immune (HI), and cellular immune (CI) responses. Researchers turned to a baculovirus-based expression system employing insect cells to be able to expand VLP production, which was only performed in a limited amount in 293T cells. The immunogenic effect of the VLPs produced in these insect-based cell lines has been demonstrated in mice when used with the adjuvant QS-21; however, it is yet unknown if they are effective in protecting NHPs against the deadly ZEBOV challenge. ZEBOV and Marburg virus (MARV) were tested in guinea pig animal models utilizing chimeric VLPs and vice versa for the cross-protection as well as a combination of ZEBOV- and MARV-like particles on this platform. The findings confirmed the necessity of GP for protection and the efficacy of blended VLPs over chimeric VLPs ^[6]^[7]^[8].

2.2. DNA Vaccines

The first effective DNA vaccination method against ZEBOV, containing four doses of either ZEBOV-GP or ZEBOV-NP, was disclosed in 1998, demonstrating 100% protection from EBV in the vaccinated mice models. DNA vaccines have the benefit of being quickly adaptable as pathogens change, and the fact that plasmids are non-infectious and simple to create in vast quantities makes them particularly advantageous regarding new and re-emerging infections. Additionally, this strategy is reusable because pre-existing immunity is irrelevant. DNA vaccines elicit CMI and HMI, necessitating the administration of multiple doses to produce the desired immunity ^[9].

Later, it was shown that three dosages of plasmid DNA for strain 13 guinea pigs had partial protective efficacy. Notably, 50% of the mice that survived acquired viremia. Data on DNA vaccination alone in NHPs are lacking, but DNA paired with immunization using recombinant Adenovirus 5 (rAd5)-based vectors was successful. The phase I clinical trial demonstrated successful immunogenicity developed from three doses of a DNA vaccine encoding ZEBOV (GP or NP) and Sudan ebolavirus (SEBOV-GP) in human populations. The 20 individuals experienced zero side effects post vaccination, with the production of specific antibodies and CD4+ T cell responses against each vaccine component. Eight individuals confirmed the presence of vaccine-specific produced CD8+ T cells in their samples ^[10].

2.3. Recombinant Whole Virus Vaccine

The host immune system may respond more broadly and vigorously to whole virus vaccinations than to targeted vaccines that only deliver a single viral protein because they present the host immune system with many viral proteins as well as the viral genetic material. However, early attempts to create an EBOV vaccine that had been gamma-irradiated and rendered inactive failed to effectively protect nonhuman primates from a deadly dosage of EBOV challenge. An incompetent defective EBOVΔVP30 without crucial viral transcription activator from wild type VP30 (Mayinga strain of EBOV), was created by Marzi and colleagues. High titers of EBOVΔVP30 replication, genetic stability, and lack of pathogenicity in rodents all occur in cell lines that persistently express the VP30 protein. When challenged with lethal doses of EBOV that were mouse- or guinea pig-adapted, mice and guinea pigs that had received two doses of EBOVΔVP30 were completely protected ^[11]^[12].

2.4. Replication Incompetent Vaccines

The protection of non-human primates against lethal challenge with individual homologous viruses was reported to be regulated by numerous filovirus antigens comprising complex or blended vaccination ^[13]. Cross-protection against BEBOV was accomplished using ZEBOV and SEBOV GPs through rAd5-expression along with a complex or blended vaccination strategy. These findings show that it is theoretically conceivable to develop cross-protective immunity against many filovirus species.

2.5. Replication Competent Vaccines

Based on the vaccinia virus (VV), one of the first platforms used to create an EBOV vaccine, homologous DNA recombination was used to create VV-based vaccines, and in the case of EBOV, several ZEBOV genes were selected as single antigens: GP, solube GP (sGP), NP, the polymerase co-factor VP35, and VP40. VV-based vaccines administered in strain 13 guinea pigs did not cause viremia; however, the same vaccine administration in NHPs resulted in viremia, and the subjects were euthanized ^[14].

Recombinant murine cytomegalovirus (CMV) was genetically modified to express a CTL epitope found on ZEBOV-NP (amino acids 43–54) by fusing it to the ie2 gene in a “proof-of-concept” experiment. After a single mouse immunisation, CTL responses to the ZEBOVNP epitope were easily identified. After receiving two doses of recombinant murine CMV/ZEBOV-NP vaccination, C57BL/6 mice were challenged with a lethal dosage of MA-ZEBOV. The immunised mice survived the test but lacked MA-ZEBOV replication protection. These findings suggest a protective role for CTL responses against deadly ZEBOV infection, but they must be confirmed in further animal models utilising species-specific CMVs (e.g., macaques) ^[15].

Negative-stranded RNA viral vectors have been used in a number of strategies in addition to DNA virus-based vaccinations. Based on the human parainfluenza virus 3, recombinant HPIV3 (rHPIV3) has been studied as a dual vaccine strategy against HPIV3 and measles infections in babies because it is a frequent respiratory disease. ZEBOV-GP and/or ZEBOV-NP were added to rHPIV3 to enable ZEBOV vaccination. Each vector, rHPIV3/ZEBOV-GP or rHPIV3/ZEBOV-GP/NP, was administered to guinea pigs intranasally once, and this was enough to shield all the animals from deadly disease.

3. Human Clinical Trials of Ebola Vaccines

The reappearance of the Ebola virus epidemic in Guinea intensified the demand for an efficient and secure immunization to prevent further outbreaks. ^[16] The latest EVD (Ebola virus disease) vaccination strategies target EBOV, the leading variant of the Ebola virus, for which numerous phase 1 to phase 4 human clinical trials were conducted in recent years ^[17]. Phase 1 trials involve a handful of healthy individuals to analyze the detrimental impacts of the vaccine incorporation. In the phase 2 trials, a larger population is used to check the safety and immunogenicity of the vaccines formulated. Phase 3 studies evaluate the vaccine’s effectiveness during an epidemic, and phase 4 trial studies are used to monitor a vaccine’s safety after it has been released onto the market ^[18]. There are more than 70 clinical trials for vaccination against EBOV virus, out of which, only 2–3 received FDA approval by 2020. The vaccines worth mentioning that have successfully prevented further spread of the disease are the recombinant VSV-based vaccine (VSV-EBOV), Ad26-ZEBOV/MVA-BN-Filo vaccine, and GamEvac-Combi vaccine. The currently available vaccine candidates against EBOV virus include replicative vectored vaccines, non-replicative vectored vaccines, polypeptide vaccines, protein nanoparticle vaccines and DNA vaccines ^[18].

The ability of virus-vectored vaccines to direct antigens, particularly to target cells, and to establish strong, long-lasting immunity makes them the most suitable type out of all. The GamEvac-Combi vaccine is a replicative vectored vaccine having a combination of VSV-EBOV and Ad5-EBOV vaccines merged into a single immunization approach, where Ad5-EBOV serves as a stimulant to the core VSV-EBOV vaccine. Initial phase 1 and 2 human trials were conducted on healthy individuals in Russia as an accessible, heterologous prime-boost trial with dosage progression study. The two controls administered were either VSV-EBOV or Ad5-EBOV vaccine only, whereas the heterologous groups were administered either half or full dosage of both vaccines. The half-dosage homologous group had comparatively more severe reactions like fever, even though there was not much difference observed in the nature and adversity of the reaction, thus demonstrating the safety of the vaccine ^[19].

4. Animal Models for EVD Vaccine Development

Historically, vaccine prospects for EBOV, as well as other filoviruses, have been tested in rodent models such as mice, hamsters, or guinea pigs ^[20]. However, none of the experimental filovirus variants elicited infection in these rodent models. As a result, sequential acclimation is usually necessary to achieve equal lethality in rodents. Adaptation is connected with genomic alterations, which arise frequently in genes encoding interferon inhibitors, including VP24 for EBV and VP40 for Marburg viruses. Rodent species that employ modified filoviruses may not accurately replicate human clinical signs and development, particularly mice models. However, despite the fact that overall efficacy in non-human primates and humans may not be accurately predicted by them, rodents are still considered popular testing models ^[21]^[22]. Due to clinical manifestations identical to those found in humans, non-human primate models are still regarded as the benchmark for filoviruses ^[22]. Cynomolgus macaques are chosen for preventive vaccination research, although rhesus macaques are commonly employed for pharmaceutical investigations, owing to their longer duration before death, which provides for a longer timeframe for interventions ^[23]. The majority of EBOV vaccine candidates now in development have undergone rodent testing, non-human primate validation assessment, and clinical studies.

5. Challenges for Vaccine Development

5.1. Selection of Immunogen

For the development of viral vaccines, either the entire pathogens (live or attenuated) or their membrane protein subunits, polysaccharides, are used together with the adjuvants to enhance and elicit the immune reaction. The fundamental method for the choice of immunogens for the Ebola vaccine is humoral pathways (set off neutralizing antibodies) and cellular-mediated pathways (function of T cells) ^[24]. The discovery of a selectable antigen as an immunogen for Ebola vaccine development is a major challenge for disorder control. In general, for the deactivation of immunoglobins or and anti-monoclonal antibodies (ZMapp), the transmembrane glycoproteins are used to prevent and facilitate recovery of contamination in non-human primates. The Ebola virus’s surge of highly glycosylated glycoproteins (EBOV-GP-1,2) are the target for the generation of the humoral immune response in the host body. In the pre-clinical trial, Sheep were immunised with genetically engineered EBOV-GP ectodomain (EBOV-GP1,2ecto) expressed in mammalian cells, which resulted in a potent immunological response and the production of high titres of high avidity polyclonal antibodies ^[25].

5.2. Rapid-Responding Vaccination

Several vaccines have been examined in phase 1 studies and clinical trials. The two most advanced first-generation Ebola vaccine candidates are alive-replicating vesicular stomatitis virus (rVSV) and the attenuated chimpanzee adenovirus 3 (ChAd3) ^[12]. For an effective outcome and rapid immunization, the structural and functional immunogens simply need to be studied by collecting the infected and immunizing potential contacts with an experimental Ebola vaccine. Consequently, the U.S. Food and Drug Administration (FDA) permitted clinical trial of efficient Ebola vaccine ERVEBO (Ebola Zaire Vaccine): V920 (rVSVG-ZEBOV-GP or rVSV-ZEBOV), which produced a rapid antibody response within 14 days after a single dose ^[26].

The basic approaches for the fast-acting vaccines should be permanent and prime-boosters for longer-term protection. The preventive vaccination strategy is based on the populations at risk, specifically for healthcare workers and frontline workers, based on the assessment of the durability of immunity; however, limited information or records were provided for 1 year post-vaccination. In addition, the rapidity of immune response induction is an important factor for estimating the relative effectiveness of a immunization from the perspective of ring vaccination.

5.3. Cross-Protective Immunity

Through the transfer of infected individual plasma for vaccination, cross-protective immunity plays a crucial part in the development of vaccines for the common viral illnesses. Despite serological cross-reactivity, the development of EBOV countermeasures has not been impeded by findings of inter-species cross-protective immunizations ^[13]. In the pre-clinical trials, there are two recombinant viral vaccines: SEBOV-GP and -VP40 showed improvement in the rate of cross-protection in ≥90% guinea pigs’ population with survivability against the ZEBOV ^[27]. Consequently, the double dose of viral vaccine containing single rVSV vector having both SEBOV-VP40 and SEBOV-GP the inter-species pathogenic protection found in the clinical trials against the African EBOV species: Zaire strain Ebola virus (ZEBOV) and SEBOV. Future research will examine whether combining immunogens from various EBOV species with elevated expression levels of allied antigenic molecule to improve cross-species protective immunity ^[28]. The ZEBOV GP was then used for the development of recombinant viral vector for the Ebola vaccine, resulting in rVSVG-ZEBOV-GP (rVSV-ZEBOV).

5.4. Long-Term Protection

The statistic showed five distinct species of the ebola virus and specific vaccinations only offer defense to guard against all the viruses, thus to make multimode viral vaccine for the viruses currently be a difficult approach. It is difficult, costly, and requires a lot of regulatory permission to create broad vaccines with several components ^[29]. The absence of cross protection offered by currently available vaccinations against heterologous species with similar genetic divergences implies that vaccines under development will not offer protection against newly developing Ebola viruses. Thus, in order to protect persons who are in danger of encountering the virus, a vaccine that can produce long-lasting protection is required, as virus epidemics are sporadic and impulsive.

5.5. Mechanism of Protection

In vivo animal model studies or trials provided diverse platforms for genomic, protein, or viral vaccine design since the development of the first Ebola vaccine, which concentrated on efforts to inactivate the virus. The pre- and post-exposure treatment plans include a variety of techniques, including DNA immunisation, RNA interference, polymeric delivery system, virus-like particles (VLPs), Venezuelan equine encephalitis virus replicons (VEEV RPs), serotypes, attenuation, and replication-competent viral platforms, e.g., human parainfluenzavirus 3 (HPIV3) and recombinant vesicular stomatitis virus (rVSV) ^[26].

Viral infection replication is particularly successful in inducing strong, long-lasting immune responses in a host. Contrarily, numerous genetically modified antigenic molecules as subunit DNA plasmids or proteins have commonly shown low immunogenicity, despite being thought to be generally safe (depending on the adjuvant). More than ten vaccine candidates are being developed; the two progressive vaccines are chimp adenovirus 3 (cAd3)-EBO Z(NIH-GSK) and recombinant vesicular stomatitis virus (rVSV)-ZEBOV, both of which are chimeric viral genome, along with the viral immunogenic glycoprotein (Canadian Dept. Public Health-Merck) used to induce immunogenicity.

Non-human primates (NHPs) were demonstrated to be protected after exposure to EBOV by pure sheep antibodies produced in contradiction of antigen, i.e., EBOTAb. Studies on passive transmission using human recovering sera have been utilized for further clinical studies. Additionally, EBOV typically results in acute illness, which is more frequently managed by antibodies, whereas chronic infections are typically better controlled by cytotoxic T-cells ^[25]. The identification of procedures that guarantee the security and efficiency of potential vaccines is advantageous for the regulatory licensing of vaccines. The global agency WHO recommends the design of orientation resources for EBOV pathology sero-testing and molecular analysis. Since these procedures commonly include bioassays, the ability to compare the results of the tests or analyses across periods or among labs depends on the accessibility of reference components to better diagnose and complement the data.

6. Conclusions

Ebola vaccine development has shown and proven remarkable progress in preclinical and clinical phases. These vaccines emerged as multiple targeting potential candidates in their advanced stages. However, the obstructions and challenges related to the efficacy, potency, durability, and cost-effective methodologies in development of Ebola vaccines still need to be properly addressed. Contrary to the previous Ebola vaccines, the current vaccines require a relatability of immunological response of an individual, epidemiological data, and clinical trial results in the community with respect to the vaccine’s efficacy. On these bases, potential vaccines can be developed and applied to combat remerging infectious diseases that may cause future Ebola infections. This approach requires strong monitoring, observance, investigation, and preparedness among the researchers, epidemiologists, vaccine-developing pharmaceutical organisations, stake-holders, and funders on a global level.

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