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Ebola vaccine R&D: Filling the knowledge gaps
research-article
Author(s):
Donata Medaglini
1
,
2
,
* ,
Ali M. Harandi
3 ,
Tom H. M. Ottenhoff
4 ,
Claire-Anne Siegrist
5
Publication date PMC-release:
16 November 2019
Journal:
Science translational medicine
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Abstract
With an emphasis on systems analyses, the VSV-EBOVAC project harnesses state-of-the-art technologies that illuminate mechanisms behind the observed immunogenicity and reactogenicity of the rVSV-ZEBOV vaccine and ensures that such information is shared among stakeholders.
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Most cited references10
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The effect of dose on the safety and immunogenicity of the VSV Ebola candidate vaccine: a randomised double-blind, placebo-controlled phase 1/2 trial.
Angela Huttner, Julie-Anne Dayer, Sabine Yerly … (2019)
Safe and effective vaccines against Ebola could prevent or control outbreaks. The safe use of replication-competent vaccines requires a careful dose-selection process. We report the first safety and immunogenicity results in volunteers receiving 3 × 10(5) plaque-forming units (pfu) of the recombinant vesicular stomatitis virus-based candidate vaccine expressing the Zaire Ebola virus glycoprotein (rVSV-ZEBOV; low-dose vaccinees) compared with 59 volunteers who had received 1 ×10(7) pfu (n=35) or 5 × 10(7) pfu (n=16) of rVSV-ZEBOV (high-dose vaccinees) or placebo (n=8) before a safety-driven study hold.
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Vesicular Stomatitis Virus-Based Ebola Vaccine Is Well-Tolerated and Protects Immunocompromised Nonhuman Primates
Introduction Ebola virus (EBOV) has been associated with sporadic episodes of hemorrhagic fever (HF) that produce severe disease in infected patients. Mortality rates in outbreaks have ranged from 50% for Sudan ebolavirus (SEBOV) to up to 90% for Zaire ebolavirus (ZEBOV) (reviewed in [1]). A recent outbreak caused by an apparently new species of EBOV in Uganda appears to be less pathogenic than SEBOV or ZEBOV with a preliminary case fatality rate of about 25% [2]. EBOV is also considered to have potential as a biological weapon and is categorized as a Category A bioterrorism agent by the Centers for Disease Control and Prevention [3]–[5]. While there are no vaccines or postexposure treatment modalities available for preventing or managing EBOV infections there are at least four different vaccine systems that have shown promise in completely protecting nonhuman primates against a lethal EBOV challenge [6]–[12]. Of these prospective EBOV vaccines two systems, one based on a replication-defective adenovirus and the other based on a replication-competent vesicular stomatitis virus (VSV), were shown to provide complete protection when administered as a single injection vaccine [7]–[9]. Most intriguingly, the VSV-based vaccine is the only vaccine which has shown any utility when administered as a postexposure treatment [13],[14]. Of these two leading EBOV vaccine candidates that can confer protection as single injection vaccines each has advantages and disadvantages. Adenovirus vectors are highly immunogenic as documented by clinical trials evaluating gene transfer efficacy and immune responses. Because they are replication-defective adenovirus vectors are also perceived to be safer for human use than a replication-competent vaccine. The most significant challenge for the adenovirus-based vaccines is the concern that a significant portion of the global population has pre-existing antibodies against the adenovirus vector which may affect efficacy [15]–[17] and has performed poorly as a vaccine vector in recent clinical trials [18]–[19]. In contrast, pre-existing immunity against VSV in human populations is negligible [20] and efficacy is likely greater with replication-competent vectors. The main concern with the VSV vaccine vector is that replication-competent vectors may present more significant safety challenges in humans particularly those with altered immune status. Because EBOV outbreaks in man have occurred exclusively in Central and Western Africa, the populations in this region are among those that may benefit from the development and availability of an EBOV vaccine. However, populations in this region are among the most medically disadvantaged in the world. In particular, the prevalence of individuals with a compromised immune system is high and HIV infections rates range up to 10% or more in this area [21]. While the VSV vaccine vector has been enormously successful in protecting healthy immunocompetent animals against EBOV [7],[13],[14], we are uncertain as to how these vectors would behave in individuals with altered or compromised immune systems. Therefore, we conducted a study to assess the pathogenicity and protective efficacy of the recombinant VSV-based ZEBOV vaccine vector in rhesus macaques that were infected with simian-human immunodeficiency virus (SHIV) which is known to deplete the populations of naive CD4+ T cells, naive CD8+ T cells, and memory CD4+ T cells in these animals [22],[23]. In order to take into account the degree or severity of compromised immune function animals were selected with varying degrees of CD4+ T cell loss. Methods Vaccine Vectors and Challenge Virus The recombinant VSV expressing the glycoprotein (GP) of ZEBOV (strain Mayinga) (VSVΔG/ZEBOVGP) was generated as described recently using the infectious clone for the VSV, Indiana serotype [24]. ZEBOV (strain Kikwit) was isolated from a patient of the ZEBOV outbreak in Kikwit in 1995 [25]. Animal Studies Nine filovirus-seronegative adult rhesus macaques (Macaca mulatta) (5–10 kg) were used for these studies. The macaques were infected three months prior to the current study with SHIV162p3 (kindly provided by Dr. Ranajit Pal, Advanced BioScience Laboratories, Inc., Kensington, MD). These animals all had clinical laboratory evidence of SHIV infection as evidenced by reduced CD4+ T cell counts, decreased ratios of CD4+/CD8+ T cells (Table 1) and the presence of SHIV in plasma of four out of nine animals (Table 2). Six of the nine SHIV-infected animals were vaccinated by i.m. injection with ∼1×10∧7 recombinant VSVΔG/ZEBOVGP. Three animals served as placebo controls and were injected in parallel with saline. All six VSVΔG/ZEBOVGP-vaccinated animals and two of the three control animals were challenged 31 days after the single dose immunization with 1000 pfu of ZEBOV (strain Kikwit). The monkeys were challenged with the heterologous Kikwit strain of ZEBOV as our macaque models have been developed and characterized using this strain [1],[26]. Animals were closely monitored for evidence of clinical illness (e.g., temperature, weight loss, changes in complete blood count, and blood chemistry) during both the vaccination and ZEBOV challenge portions of the study. In addition, VSVΔG/ZEBOV and ZEBOV viremia and shedding were analyzed after vaccination and challenge, respectively. Animals were given physical exams and blood and swabs (nasal, oral, rectal) were collected at 2, 4, 7, 10, 14, 21, 28, and 31 days after vaccination and on days 3, 6, 10, 15, and 28 after ZEBOV challenge. The vaccination portion of the study was conducted at BIOQUAL and was approved by NIAID, BIOQUAL, and USAMRIID Laboratory Animal Care and Use Committees. The ZEBOV challenge was performed in BSL-4 biocontainment at USAMRIID and was approved by the USAMRIID Laboratory Animal Use Committee. Animal research was conducted in compliance with the Animal Welfare Act and other Federal statues and regulations relating to animals and experiments involving animals and adheres to the principles stated in the Guide for the Care and Use of Laboratory Animals, National Research Council, 1996. Both facilities used are fully accredited by the Association for Assessment and Accreditation of Laboratory Animal Care International. 10.1371/journal.ppat.1000225.t001 Table 1 Pre-vaccination hematology of SHIV-infected rhesus macaques. Animal No. Pre-SHIV CD4 Post-SHIV CD4 CD4 % Drop Pre-SHIV CD4/CD8 Post-SHIV CD4/CD8 CD4/CD8 %Change Subject 1 2610 541 79 1.17 0.45 61 Subject 2 1207 627 48 1.03 0.44 57 Subject 3 861 595 31 0.68 0.48 29 Subject 4 1380 681 51 0.64 0.26 59 Subject 5 509 83 84 0.86 0.09 89 Subject 6 1193 42 96 0.92 0.03 97 Control 1 846 329 61 1.16 0.16 86 Control 2 731 289 60 1.00 0.29 71 Control 3 651 288 56 0.59 0.25 58 10.1371/journal.ppat.1000225.t002 Table 2 SHIV load determined by a nucleic acid sequence-based amplification assay. Animal No. Day 0* Day 2 Day 7 Day 10 Day 28 Subject 1 5 fold increase; ↓ = 2–3 fold decrease. ( ) Days after ZEBOV challenge are shown in parentheses. Blood samples were analyzed after challenge for evidence of ZEBOV replication by plaque assay and RT-PCR. By day 6, both of the placebo control animals developed high ZEBOV titers in plasma as detected by plaque assay (>104.5 log pfu/ml) (Table 4). In comparison, only one of the VSVΔG/ZEBOVGP-vaccinated monkeys (Subject #6) showed a ZEBOV viremia at day 6 by plaque assay (∼102 log pfu/ml) (Table 4). ZEBOV was detected in a second VSVΔG/ZEBOVGP-vaccinated monkey (Subject #5) by day 10 (∼104.2 log pfu/ml). RT-PCR was more sensitive and showed evidence of ZEBOV in plasma of this animal (Subject #5) at day 6. In addition, RT-PCR was more sensitive in detecting ZEBOV in swabs which were positive on a number of samples derived from Subject #5 at day 6 and day 10 (Table 4). In contrast, no ZEBOV was detected in the plasma by virus isolation or RT-PCR in the four VSVΔG/ZEBOVGP-vaccinated monkeys that survived ZEBOV challenge. Moreover, no evidence for reactivation of VSVΔG/ZEBOVGP was detected from any blood or swab sample from any animal after ZEBOV challenge (data not shown). Although we failed to detect ZEBOV viremia in the two surviving animals that were clinically ill (Subject #1 and 2) at days 3, 6, 10, and 14 after ZEBOV challenge we cannot exclude the possibility that these animals had low levels of circulating ZEBOV at time points not evaluated. 10.1371/journal.ppat.1000225.t004 Table 4 Viral load in SHIV-infected rhesus monkeys after ZEBOV challenge. Animal No. Plasma PBMC Throat Nasal Rectal Vaginal D 6 D 10 D 6 D 10 D 6 D 10 D 6 D 10 D 6 D 10 D 6 D 10 Subject 1 0* 0 NT NT 0 0 0 0 NT NT NT NT (−) (−) (−) (−) (−) (−) (−) (−) (−) (−) (−) (−) Subject 2 0 0 NT NT 0 0 0 0 NT NT NT NT (−) (−) (−) (−) (−) (−) (−) (−) (−) (−) (−) (−) Subject 3 0 0 NT NT 0 0 0 0 NT NT NA NA (−) (−) (−) (−) (−) (−) (−) (−) (−) (−) NA NA Subject 4 0 0 NT NT 0 0 0 0 NT NT NA NA (−) (−) (−) (−) (−) (−) (−) (−) (−) (−) NA NA Subject 5 0 4.2 NT NT 0 2.2 0 0 NT NT NT NT (+) (+) (+) (−) (−) (+) (−) (+) (−) (+) (−) (+) Subject 6 2.0 NT 0 0 NT NT (+) (+) (−) (−) (−) (−) Control 1 5.4 NT 0 0 NT NT (+) (+) Control 2 4.9 NT 0 0 NT NT (+) (+) (−) (−) (−) (−) *, Log 10 pfu of ZEBOV per ml of plasma; (+), sample positive for ZEBOV by RT-PCR; (−), sample negative for ZEBOV by RT-PCR; NT, not tested; NA, not applicable. The four surviving VSVΔG/ZEBOVGP-vaccinated macaques (Subjects #1, 2, 3, 4) were euthanized 28 days after the ZEBOV challenge to perform a virological and pathological examination of tissues. Organ infectivity titration from these four animals showed no evidence of ZEBOV in any of the tissues examined. In comparison, ZEBOV was recovered from tissues of both VSVΔG/ZEBOVGP-vaccinated animals that succumbed (Subject #5, 6) and both SHIV-infected control animals. Organ titers of infectious ZEBOV were consistent with values previously reported for immunocompetent ZEBOV-infected rhesus macaques [27],[28]. VSVΔG/ZEBOVGP was not recovered in any of the tissues examined from any animal on this study. Pathological and immunohistochemical evaluation of tissues from the four VSVΔG/ZEBOVGP-vaccinated animals (Subjects #1, 2, 3, 4) that survived ZEBOV challenge showed no evidence of ZEBOV antigen. In contrast, ZEBOV antigen was readily detected in typical target organs (e.g., liver, spleen, adrenal gland, lymph nodes) of the two VSVΔG/ZEBOVGP-vaccinated animals that succumbed to ZEBOV challenge (Subject #5, 6) (Figure 3) and the two placebo controls. Lesions and distribution of ZEBOV antigen in these macaques was consistent with results reported in other studies [27],[29]. 10.1371/journal.ppat.1000225.g003 Figure 3 Tissues from SHIV-infected rhesus monkeys vaccinated with VSVΔG/ZEBOVGP and challenged 31 days later with ZEBOV. (Left panel) Immunohistochemical staining of liver from animal that succumbed on day 9 (Subject 6) for ZEBOV. Note abundance of EBOV antigen (brown) associated with sinusoids. (Right panel) Immunohistochemical staining of lymph node from animal that succumbed on day 13 (Subject 5) for ZEBOV. Note localization of ZEBOV antigen (brown) associated with macrophages and dendritiform cells. Original magnifications, ×20. While cellular immune responses against ZEBOV GP in macaques vaccinated with VSVΔG/ZEBOVGP vectors have been difficult to detect before challenge in previous studies [7], humoral immune responses have been more robust and consistent ([7]; TW Geisbert, unpublished observations). Therefore, we measured the antibody responses of the rhesus macaques vaccinated with VSVΔG/ZEBOVGP before vaccination (day −7), after vaccination (day 14 and day 31), and after ZEBOV challenge (day 46 and day 59 after vaccination) by IgG ELISA. None of the six VSVΔG/ZEBOVGP-vaccinated macaques developed IgG antibody titers against the ZEBOV GP by the day of ZEBOV challenge (Figure 4). Two animals (Subjects #1, 2) developed modest IgG antibody titers against ZEBOV by day 15 after ZEBOV challenge (day 46 after vaccination) while a third animal developed a titer by day 28 after ZEBOV challenge (day 59 after vaccination) (Figure 4). 10.1371/journal.ppat.1000225.g004 Figure 4 Circulating levels of IgG against ZEBOV from SHIV-infected rhesus macaques vaccinated with VSVΔG/ZEBOVGP and challenged 31 days later with ZEBOV. Discussion An often raised concern regarding the use of the recombinant VSV vaccine platform in humans is related to the fact that this is a replication-competent vaccine, and thus demonstration of safety is of paramount importance. Taking into account our previous work it is not surprising that the VSVΔG/ZEBOVGP was tolerated well in our SHIV-infected macaques. Specifically, we failed to observe evidence of any adverse events in a large cohort of over 90 macaques receiving VSV vectors expressing different GPs from viral HF agents (38 cynomolgus macaques and 3 rhesus macaques vaccinated with VSVΔG/ZEBOVGP; 12 cynomolgus macaques and 3 rhesus macaques vaccinated with VSV expressing SEBOV GP; 29 cynomolgus macaques and 3 rhesus macaques vaccinated with VSV expressing the Marburg virus GP; and 6 cynomolgus macaques vaccinated with VSV expressing the Lassa GP) ([7],[30],[31]; TW Geisbert, H Feldmann, and SM Jones unpublished observations). We have also failed to observe any adverse events in a variety of immunocompetent laboratory mice (different inbred strains), outbred guinea pigs (Hartley strain) and goats vaccinated with the above mentioned VSV vectors at doses ranging from 2×100–2×105 pfu ([24],[32]; SM Jones and H Feldmann, unpublished observations). More recently we have also demonstrated that vaccination of severely immunocompromised SCID mice with 2×105 pfu of the VSV-based ZEBOV vaccine (VSVΔG/ZEBOVGP) resulted in no clinical symptoms [32]. While transient VSV viremia in this study was only observed in surviving macaques but not in animals that had succumbed to ZEBOV challenge (Figure 1), viremia data from previous studies [7],[30],[31] do not support any correlation between VSV viremia and survival. In addition, no evidence for vaccine vector shedding was detected in this study supporting previous results [7],[30],[31] with no compelling evidence to suggest that occasional virus shedding (only detected by RT-PCR; negative on virus isolation) would lead to vaccine vector transmission. The VSV glycoprotein exchange vector that we employed in this study has also shown promise as a preventive vaccine and postexposure treatment against Marburg HF [30],[33] and as a preventive vaccine against Lassa fever in nonhuman primates [31]. Similar recombinant VSV vectors have been evaluated in animal models as vaccine candidates for a number of viruses that cause disease in humans including HIV-1, influenza virus, respiratory syncytial virus, measles virus, herpes simplex virus type 2, hepatitis C virus, and severe acute respiratory syndrome coronavirus [34]–[40]. Many of these studies have employed VSV vectors that maintained either the entire VSV glycoprotein (G) or the transmembrane and/or cytoplamic domains of this protein to facilitate more efficient incorporation of the foreign antigen. It is known that VSV G is an important VSV protein associated with pathogenicity [38],[41]. It has been shown that truncation of the cytoplasmic tail has greatly reduced vector pathogenicity in mice following intranasal inoculation indicating the importance of this domain for pathogenicity [42]. In this regard, a VSV vector including portions of the VSV G and expressing HIV genes was found to be insufficiently attenuated for clinical evaluation when assessed for neurovirulence in nonhuman primates [43]. These investigators subsequently showed that safety and immunogenicity can be improved by genetic manipulation of the VSV genome but it remained unclear whether neurovirulence was associated with the VSV G or other genome manipulations [44]. Nevertheless, our ZEBOV vaccine is a G-deficient VSV vector [24] and thus lacks G-associated pathogenicity [41] as well as the target for VSV-specific neutralizing antibodies [45]. Aside from G, the VSV matrix (M) protein has been associated with cytopathic effects in vitro including the inhibition of host gene expression, induction of cell rounding and induction of apoptosis [46],[47]. It is largely unclear to what extent M alone contributes to pathogenicity, but inoculation studies with the VSV-based vaccines in different animal species (as described above) do not suggest a major pathogenic effect of the M protein in vivo [7],[13],[32]. Currently, the mechanism by which any filovirus vaccine confers protection in nonhuman primates is not well understood. Nearly all studies have detected modest to good humoral immune responses. For the VSVΔG/ZEBOVGP vaccine a humoral response is detected in macaques by day 14 after vaccination ([7]; TW Geisbert, unpublished observations). However, in the current study and consistent with an impaired immune system, our SHIV-infected macaques did not develop a humoral immune response by the time of ZEBOV challenge. Three animals developed modest anti-ZEBOV IgG titers 14 to 28 days after ZEBOV challenge. We are uncertain as to why four of the six VSVΔG/ZEBOVGP-vaccinated macaques survived ZEBOV challenge. Regardless of any humoral immune response elicited in these animals it is unlikely that antibody alone confers protection. Specifically, passive antibody studies in nonhuman primates using a variety of anti-ZEBOV immune reagents including polyclonal equine immune globulin [25], a recombinant human monoclonal antibody [48], and convalescent monkey blood [49] have uniformly failed to provide protection and more importantly have failed to provide any beneficial effect. A number of studies have evaluated the cellular immune response in nonhuman primates vaccinated against EBOV and the results have been mixed with some studies showing a modest cellular response and other studies showing weak and/or no cellular immune responses [7],[9],[10]. However, it is likely that the intracellular cytokine assays that have been employed in some of these studies are not sensitive or thorough enough to detect a cellular immune response against ZEBOV. Indeed, it has been reported that the inability to demonstrate a robust cellular response may illustrate the limitation of the evaluation of cellular immune responses using small numbers of functional measurements (such as interferon-gamma) [50]. One interesting finding in the current study may begin to shed some light on the mechanism of protection elicited by the VSVΔG/ZEBOVGP. Notably, the two rhesus macaques that grouped together with the most severe loss of CD4+ T cells were the only animals that failed to survive ZEBOV challenge. This suggests that CD4+ T cells may play a role in mediating protective immunity in EBOV infections. CD4+ T cells have been shown to be depleted in nonhuman primate following ZEBOV infections [27],[51] and in vitro ZEBOV infection of human peripheral blood mononuclear cells causes massive bystander death of CD4+ T cells by apoptosis [52]. While rodents do not appear to faithfully reproduce ZEBOV infection of humans and nonhuman primates [53] studies have suggested that CD4+ T cells are required for protection of rodents against ZEBOV. Specifically, in a study using liposome-encapsulated ZEBOV antigens, Rao and colleagues showed that treatment of mice with anti-CD4 antibodies before or during vaccination abolished protection, while treatment with anti-CD8 antibodies had no effect, thus indicating a requirement for CD4+ T lymphocytes for successful immunization [54]. Similarly, depletion of CD8+ T cells did not compromise protection in mice indicating that CD8+ cytotoxic T cells are not a requirement for protection [32]. In conclusion, our results show that the VSV-based ZEBOV vaccine (VSVΔG/ZEBOVGP) did not cause any illness in immunocompromised SHIV-infected rhesus macaques and resulted in sufficient protective efficacy in all but the most severely compromised animals against a lethal ZEBOV challenge. Protection in the immunocompromised macaques appeared to be dependent on CD4+ T cells rather than the development of EBOV-specific antibodies. This provides strong support for the safety of the VSV-based vectors and further development of this promising vaccine platform for its use in humans. While these data are very encouraging, as the number of SHIV-infected macaques in the current study was small, additional safety studies will be needed in order to determine whether vaccines based on attenuated VSV will ultimately prove safe in immunocompromised humans.
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A review of epidemiological parameters from Ebola outbreaks to inform early public health decision-making
Maria D. Van Kerkhove, Ana I. Bento, Harriet Mills … (2015)
The unprecedented scale of the Ebola outbreak in West Africa has, as of 29 April 2015, resulted in more than 10,884 deaths among 26,277 cases. Prior to the ongoing outbreak, Ebola virus disease (EVD) caused relatively small outbreaks (maximum outbreak size 425 in Gulu, Uganda) in isolated populations in central Africa. Here, we have compiled a comprehensive database of estimates of epidemiological parameters based on data from past outbreaks, including the incubation period distribution, case fatality rate, basic reproduction number (R 0 ), effective reproduction number (R t ) and delay distributions. We have compared these to parameter estimates from the ongoing outbreak in West Africa. The ongoing outbreak, because of its size, provides a unique opportunity to better understand transmission patterns of EVD. We have not performed a meta-analysis of the data, but rather summarize the estimates by virus from comprehensive investigations of EVD and Marburg outbreaks over the past 40 years. These estimates can be used to parameterize transmission models to improve understanding of initial spread of EVD outbreaks and to inform surveillance and control guidelines.
Author and article information
Contributors
Claire-Anne Siegrist:
On behalf of
: VSV-EBOVAC Consortium
Journal
Journal ID (nlm-journal-id): 101505086
Journal ID (nlm-ta): Sci Transl Med
Journal ID (iso-abbrev): Sci Transl Med
Title:
Science translational medicine
ISSN
(Print):
1946-6234
ISSN
(Electronic):
1946-6242
Publication date
(Print):
09
December
2015
Publication date Nihms-submitted: 12
November
2019
Publication date PMC-release: 16
November
2019
Volume: 7
Issue: 317
Page: 317ps24
Affiliations
[1
]Laboratorio di Microbiologia Molecolare e Biotecnologia (LA.M.M.B.), Dipartimento
di Biotecnologie Mediche, Università di Siena, 53100 Siena, Italy
Author notes
[‡]
The VSV-EBOVAC Consortium: Selidji Todagbe Agnandji, Raf Ahmed, Jenna Anderson, Floriane Auderset, Luisa Borgianni, Jessica Brosnahan, Annalisa Ciabattini, Olivier Engler, Marielle C. Haks, Gray Heppner, Alice Gerlini, Peter Gottfried Kremsner, Stephen Leib, Thomas Monath, Francis Ndungu, Patricia Njuguna, Mark Page, Gianni Pozzi, Rino Rappuoli, Francesco Santoro, Marc Strasser.
Article
Accession ID: PMC6858855 Pmcid ID: PMC6858855 Pmc-uid ID: 6858855 Manuscript ID: ems84889DOI: 10.1126/scitranslmed.aad3106
PMC ID: 6858855
PubMed ID: 26659569
SO-VID: d81d4728-03ac-48c0-b45f-4dca28914f4c
License:
exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. The title Science Translational Medicine is a registered trademark of AAAS.
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