Species-specific immunogenicity and protective efficacy of a vesicular stomatitis virus-based Sudan virus vaccine: a challenge study in macaques

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Summary

Background

The recent Sudan virus (SUDV) outbreak in Uganda highlights the need for rapid response capabilities, including development of vaccines against emerging viruses with high public health impact. We aimed to develop a Sudan virus-specific vaccine suitable for emergency use during outbreaks.

Methods

We generated and characterised a vesicular stomatitis virus (VSV)-based vaccine, VSV- SUDV, and evaluated the protective efficacy following a single-dose vaccination against lethal SUDV infection in non-human primates (NHPs). We used male and female cynomolgus macaques (n=11) aged 6–11 years and weighing 3·8–9·0 kg. Animals received a 1 mL intramuscular injection for vaccination containing either 1 × 10 ⁷ plaque forming units (PFU) VSV-SUDV or 1 × 10 ⁷ PFU of a VSV-based vaccine against Marburg virus (control; five NHPs). NHPs were challenged intramuscularly 28 days after vaccination with 1 × 10 ⁴ TCID ₅₀ SUDV-Gulu. We assessed anaesthetised NHPs on days 28, 21, 14, and 7 before challenge; days 0, 3, 6, 9, 14, 21, 28, and 35 after challenge; and at euthanasia (day 40 for survivors). As we repurposed NHPs from a successful VSV-Ebola virus (EBOV) vaccine efficacy study, we also investigated VSV-EBOV’s cross-protective potential against SUDV challenge.

Findings

Of the six NHPs given VSV-SUDV, none showed any signs of disease in response to the challenge. Four of the five NHPs in the control group developed characteristic clinical signs of Sudan virus diseases. SUDV glycoprotein-specific IgG concentrations peaked 14 days after vaccination (titre of >1:10 000) and reached their highest concentrations at 6 days after challenge (1:25 600-1:102 400). Although the NHPs developed cross-reactive humoral responses to SUDV after VSV-EBOV vaccination and EBOV challenge, there was little cross-protection.

Interpretation

These data emphasise the need for species-specific vaccines for each human-pathogenic Ebolavirus. Furthermore, although previous VSV-EBOV immunity is boosted through VSV-SUDV vaccination, it only has a small effect on the immunogenicity and protective efficacy of VSV-SUDV vaccination against SUDV challenge.

Funding

Intramural Research Program, US National Institute of Allergy and Infectious Diseases, National Institutes of Health.

Related collections

Most cited references 22

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Ebola virus disease

Shevin T. Jacob, Ian Crozier, William A. Fischer … (2020)

Ebola virus disease (EVD) is a severe and frequently lethal disease caused by Ebola virus (EBOV). EVD outbreaks typically start from a single case of probable zoonotic transmission, followed by human-to-human transmission via direct contact or contact with infected bodily fluids or contaminated fomites. EVD has a high case–fatality rate; it is characterized by fever, gastrointestinal signs and multiple organ dysfunction syndrome. Diagnosis requires a combination of case definition and laboratory tests, typically real-time reverse transcription PCR to detect viral RNA or rapid diagnostic tests based on immunoassays to detect EBOV antigens. Recent advances in medical countermeasure research resulted in the recent approval of an EBOV-targeted vaccine by European and US regulatory agencies. The results of a randomized clinical trial of investigational therapeutics for EVD demonstrated survival benefits from two monoclonal antibody products targeting the EBOV membrane glycoprotein. New observations emerging from the unprecedented 2013–2016 Western African EVD outbreak (the largest in history) and the ongoing EVD outbreak in the Democratic Republic of the Congo have substantially improved the understanding of EVD and viral persistence in survivors of EVD, resulting in new strategies toward prevention of infection and optimization of clinical management, acute illness outcomes and attendance to the clinical care needs of patients.

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An outbreak of Ebola in Uganda.

M Lamunu, Alex A Opio, F G Omaswa … (2002)

An outbreak of Ebola disease was reported from Gulu district, Uganda, on 8 October 2000. The outbreak was characterized by fever and haemorrhagic manifestations, and affected health workers and the general population of Rwot-Obillo, a village 14 km north of Gulu town. Later, the outbreak spread to other parts of the country including Mbarara and Masindi districts. Response measures included surveillance, community mobilization, case and logistics management. Three coordination committees were formed: National Task Force (NTF), a District Task Force (DTF) and an Interministerial Task Force (IMTF). The NTF and DTF were responsible for coordination and follow-up of implementation of activities at the national and district levels, respectively, while the IMTF provided political direction and handled sensitive issues related to stigma, trade, tourism and international relations. The international response was coordinated by the World Health Organization (WHO) under the umbrella organization of the Global Outbreak and Alert Response Network. A WHO/CDC case definition for Ebola was adapted and used to capture four categories of cases, namely, the 'alert', 'suspected', 'probable' and 'confirmed cases'. Guidelines for identification and management of cases were developed and disseminated to all persons responsible for surveillance, case management, contact tracing and Information Education Communication (IEC). For the duration of the epidemic that lasted up to 16 January 2001, a total of 425 cases with 224 deaths were reported countrywide. The case fatality rate was 53%. The attack rate (AR) was highest in women. The average AR for Gulu district was 12.6 cases/10 000 inhabitants when the contacts of all cases were considered and was 4.5 cases/10 000 if limited only to contacts of laboratory confirmed cases. The secondary AR was 2.5% when nearly 5000 contacts were followed up for 21 days. Uganda was finally declared Ebola free on 27 February 2001, 42 days after the last case was reported. The Government's role in coordination of both local and international support was vital. The NTF and the corresponding district committees harmonized implementation of a mutually agreed programme. Community mobilization using community-based resource persons and political organs, such as Members of Parliament was effective in getting information to the public. This was critical in controlling the epidemic. Past experience in epidemic management has shown that in the absence of regular provision of information to the public, there are bound to be deleterious rumours. Consequently rumour was managed by frank and open discussion of the epidemic, providing daily updates, fact sheets and press releases. Information was regularly disseminated to communities through mass media and press conferences. Thus all levels of the community spontaneously demonstrated solidarity and response to public health interventions. Even in areas of relative insecurity, rebel abductions diminished considerably.

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Single-injection vaccine protects nonhuman primates against infection with marburg virus and three species of ebola virus.

Lisa Hensley, Anders Leung, Thomas W. Geisbert … (2009)

The filoviruses Marburg virus and Ebola virus cause severe hemorrhagic fever with high mortality in humans and nonhuman primates. Among the most promising filovirus vaccines under development is a system based on recombinant vesicular stomatitis virus (VSV) that expresses a single filovirus glycoprotein (GP) in place of the VSV glycoprotein (G). Here, we performed a proof-of-concept study in order to determine the potential of having one single-injection vaccine capable of protecting nonhuman primates against Sudan ebolavirus (SEBOV), Zaire ebolavirus (ZEBOV), Cote d'Ivoire ebolavirus (CIEBOV), and Marburgvirus (MARV). In this study, 11 cynomolgus monkeys were vaccinated with a blended vaccine consisting of equal parts of the vaccine vectors VSVDeltaG/SEBOVGP, VSVDeltaG/ZEBOVGP, and VSVDeltaG/MARVGP. Four weeks later, three of these animals were challenged with MARV, three with CIEBOV, three with ZEBOV, and two with SEBOV. Three control animals were vaccinated with VSV vectors encoding a nonfilovirus GP and challenged with SEBOV, ZEBOV, and MARV, respectively, and five unvaccinated control animals were challenged with CIEBOV. Importantly, none of the macaques vaccinated with the blended vaccine succumbed to a filovirus challenge. As expected, an experimental control animal vaccinated with VSVDeltaG/ZEBOVGP and challenged with SEBOV succumbed, as did the positive controls challenged with SEBOV, ZEBOV, and MARV, respectively. All five control animals challenged with CIEBOV became severely ill, and three of the animals succumbed on days 12, 12, and 14, respectively. The two animals that survived CIEBOV infection were protected from subsequent challenge with either SEBOV or ZEBOV, suggesting that immunity to CIEBOV may be protective against other species of Ebola virus. In conclusion, we developed an immunization scheme based on a single-injection vaccine that protects nonhuman primates against lethal challenge with representative strains of all human pathogenic filovirus species.

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Author and article information

Contributors

Andrea Marzi

Paige Fletcher

Friederike Feldmann

Greg Saturday

Patrick W Hanley

Heinz Feldmann

Journal

Journal ID (nlm-journal-id): 101769019

Journal ID (pubmed-jr-id): 49714

Journal ID (nlm-ta): Lancet Microbe

Journal ID (iso-abbrev): Lancet Microbe

Title: The Lancet. Microbe

ISSN (Electronic): 2666-5247

Publication date Nihms-submitted: 27 February 2023

Publication date (Print): March 2023

Publication date (Electronic): 02 February 2023

Publication date PMC-release: 13 March 2023

Volume: 4

Issue: 3

Pages: e171-e178

Affiliations

Laboratory of Virology, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rocky Mountain Laboratories, Hamilton, MT, USA

Rocky Mountain Veterinary Branch, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rocky Mountain Laboratories, Hamilton, MT, USA

Laboratory of Virology, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rocky Mountain Laboratories, Hamilton, MT, USA

Author notes

Contributors

AM and HF conceived the idea, designed the study, and secured funding. AM, FF, and PWH conducted the non-human primate study. AM, PF, and GS collected and processed samples, did assays, and analysed the data. AM and HF verified the underlying data of the study and wrote the manuscript with input from all authors. All authors had full access to all the data in the study and had final responsibility for the decision to submit for publication.

Correspondence to: Dr Andrea Marzi, Laboratory of Virology, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rocky Mountain Laboratories, Hamilton, MT 59840, USA marzia@ 123456niaid.nih.gov or Dr Heinz Feldmann, Rocky Mountain Veterinary Branch, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rocky Mountain Laboratories, Hamilton, MT 59840, USA feldmannh@ 123456niaid.nih.gov

Article

Manuscript ID: NIHMS1873504

DOI: 10.1016/S2666-5247(23)00001-0

PMC ID: 10010116

PubMed ID: 36739878

SO-VID: 788e8710-7efb-4bcf-bbd6-065669b9b28f

License:

This is an Open Access article under the CC BY-NC-ND 4.0 license.

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Species-specific immunogenicity and protective efficacy of a vesicular stomatitis virus-based Sudan virus vaccine: a challenge study in macaques

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Summary

Background

Methods

Findings

Interpretation

Funding

Related collections

Malaria vaccine development

Most cited references 22

Ebola virus disease

An outbreak of Ebola in Uganda.

Single-injection vaccine protects nonhuman primates against infection with marburg virus and three species of ebola virus.

Author and article information

Contributors

Journal

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Article

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Cited by 15

Most referenced authors 310