The Western Equine Encephalitis Lyophilized, Inactivated Vaccine: An Update on Safety and Immunogenicity

Maryam Keshtkar-Jahromi, Ronald B Reisler, Jeannine M Haller, Denise P Clizbe, Robert G Rivard, Anthony P Cardile, Benjamin C Pierson, Sarah Norris, David Saunders, Phillip R Pittman, Maryam Keshtkar-Jahromi, Ronald B Reisler, Jeannine M Haller, Denise P Clizbe, Robert G Rivard, Anthony P Cardile, Benjamin C Pierson, Sarah Norris, David Saunders, Phillip R Pittman

Abstract

Background: Western Equine Encephalitis (WEE) is a naturally acquired infection and potentially devastating bioweapon, with no specific human countermeasures. An experimental inactivated Western Equine Encephalitis Vaccine (WEEV; WEE TSI-GSD 210) has been used under an IND (investigational New Drug) protocol at the United States Army Medical Research Institute of Infectious Diseases (USAMRIID) since 1976.

Methods: Over 24 years from 1987 to 2011, 876 subjects received 3 primary vaccine doses under 3 studies with 1,537 booster doses administered (FY87-8, phase 2, laboratory workers, vaccine lots 1-81-1, 1-81-2, and 2-1-91; FY99-12, phase 2 laboratory workers, lot 2-1-91; and FY09-02, phase 1 healthy volunteer, lot 3-1-92). Post-vaccination safety and immunogenicity [plaque reduction neutralization test 80% (PRNT80) > 1:40] were analyzed.

Results: Overall PRNT80 response to the primary series in FY87-8 was 42% (326/770) but dropped to 16% (14/87) in FY99-12, prompting study FY09-02, which achieved 89% (17/19). The first booster response rate was 68% (814/1194) in FY87-8, 53% (171/324) in FY99-12, and 100% (10/10) in FY09-02. The majority of definitely related adverse reactions (AEs) were mild and local with no definitely related serious AEs. No laboratory acquired WEE infection was documented during this period despite 4 reported exposures in vaccinated subjects.

Conclusion: The TSI-GSD 210 WEE vaccine was immunogenic, safe and well tolerated. Use of this vaccine could be considered in an emergency setting. Despite decades of safe and effective use under IND, full licensure is not planned due to manufacturing constraints, and a strategic decision to develop alternatives.

Clinical trial registration: https://ichgcp.net/clinical-trials-registry/NCT01159561" title="See in ClinicalTrials.gov">NCT01159561.

Keywords: Western Equine Encephalitis; clinical trial; immunogenicity; inactivated; vaccine.

Copyright © 2020 Keshtkar-Jahromi, Reisler, Haller, Clizbe, Rivard, Cardile, Pierson, Norris, Saunders and Pittman.

Figures

Figure 1
Figure 1
CONSORT diagram of study enrollment. *Rollovers (subjects recruited from previous protocols); **No more than two boosters required within this protocol; ***Relocation (subjects moved due to new job).
Figure 2
Figure 2
In FY87-08 protocol, post primary* GMT (Geometric Mean Titers) was 23.3 [21.5, 25.2], and post booster* GMT was 72.2 [63.3, 82.4]. In FY99-12, post primary† GMT (Geometric Mean Titers) was 14.1 [12.1, 16.5], and post booster† GMT was 36.9 [30.1, 45.3]. In the FY09-02 protocol, GMT day 56‡ was 98.1 [58.6, 164.3], day 180‡ (pre-6 month boost) was 25.8 [9.7, 68.9], day 210‡ (post 6-month boost) was 557.2 [376.8, 823.8], and day 360 was 121.3 [62.1, 236.8]. Thus, prior to the 6-month boost, the average titer was <1:40, justifying the need for the 6-month boost. *Titers collected 14–56 days post vaccination. †Titers collected 23–42 days post-vaccination. ‡Titers collected 21–35 days post-vaccination.
Figure 3
Figure 3
Post-Primary series PRNT80 immune response to WEE vaccine by year within FY87-8 and FY99-12 (1987–2005). The immunogenicity of WEE TSI-GSD 210 appeared to decline from 53 to 23%.
Figure 4
Figure 4
Post-boosters PRNT80 immune response to WEE vaccine by year within FY87-8 and FY99-12 (1987–2006). Immunogenicity of WEE TSI-GSD 210 appeared to decline from 77–58%.

References

    1. Griffin DE. “Alphaviruses”. In: Knipe DM, Howley PM, editors. Fields Virology, 5th ed Philadelphia: Lippincott, Williams, and Wilkins; (2007).
    1. Meyer KF, Haring CM, Howitt B. The Etiology of Epizootic Encephalomyelitis of Horse in the San Joaquin Valley. Science (1930) 74(1913):227–8. 10.1126/science.74.1913.227
    1. Aréchiga-Ceballos N, Aguilar-Setién A. Alphaviral equine encephalomyelitis (Eastern, Western and Venezuelan). Rev Sci Tech (2015) 34(2):491–501. 10.20506/rst.34.2.2374
    1. Weaver SC, Paessler S. “Alphaviral Encephalitides”. In: Vaccines for Biodefense and Emerging and Neglected Diseases. Amsterdam: Elsevier Inc; (2009). p. 339–59.
    1. Robb LL, Hartman DA, Rice L, deMaria J, Bergren NA, Borland EM, et al. Continued Evidence of Decline in the Enzootic Activity of Western Equine Encephalitis Virus in Colorado. J Med Entomol (2019) 56(2):584–8. 10.1093/jme/tjy214
    1. Delfraro A, Burgueño A, Morel N, Gonzalez G, Garcia A, Morelli J, et al. Fatal human case of Western equine encephalitis, Uruguay. Emerg Infect Dis (2011) 17:952–4. 10.3201/eid1705.101068
    1. Bergren NA, Auguste AJ, Forrester NL, Negi SS, Braun WA, Weaver SC. Western equine encephalitis virus: evolutionary analysis of a declining alphavirus based on complete genome sequences. J Virol (2014) 88(16):9260–7. 10.1128/JVI.01463-14
    1. Hu WG, Steigerwald R, Kalla M, Volkmann A, Noll D, Nagata LP. Protective efficacy of monovalent and trivalent recombinant MVA-based vaccines against three encephalitic alphaviruses. Vaccine (2018) 36(34):5194–203. 10.1016/j.vaccine.2018.06.064
    1. Randall R, Maurer FD, Smadel JE. Immunization of laboratory workers with purified Venezuelan equine encephalomyelitis vaccine. J Immunol (1949) 63(3):313–8.
    1. Pittman PR, Plotkin SA. “Biodefense and Special Pathogen Vaccines”. In: Vaccines, 6th ed Philadelphia: Elsevier; (2013). p. 1008 – 1017.
    1. Burke DS. Protecting the Frontline in Biodefense Research: The Special Immunizations Program. Washington DC: The National Academies Press; (2011).
    1. Bartelloni PJ, McKinney RW, Calia FM, Ramsburg HH, Cole FE., Jr Inactivated western equine encephalomyelitis vaccine propagated in chick embryo cell culture: clinical and serological evaluation in man. Am J Trop Med Hyg (1971) 20(1):146–9. 10.4269/ajtmh.1971.20.146
    1. Honnold SP, Mossel EC, Dupuy LC, Morazzani EM, Martin SS, HART MK, et al. “Alphavirus Encephalitidis”. In: Textbook of Military Medicine, Medical Aspects of Biological Warfare. Fort Sam Houston, Texas: Office of The Surgeon General Borden Institute, US Army Medical Department Center and School Health Readiness Center of Excellence; (2018). p. 479–501.
    1. Mangiafico JA, Sanchez JL, Figueredo LT, LeDuc JW, Peters CJ. Isolation of a newly recognized Bunyamwera serogroup virus from a febrile human in Panama. Am J Trop Med Hyg (1988) 39(6):593–6. 10.4269/ajtmh.1988.39.593
    1. Burke DS, Ramsburg HH, Edelman R. Persistence in Humans of Antibody to Subtypes of Venezuelan Equine Encephalomyelitis (VEE) Virus after Immunization with Attenuated (TC-83) VEE Virus Vaccine. J Infect Dis (1977) 136:354–9. 10.1093/infdis/136.3.354
    1. World Health organization Information Sheet Observed Rate of Vaccine reactions; Influenza Vaccine. Available at: (Accessed Aug 5th, 2020).
    1. Helwig FC. Western equine encephalomyelitis following accidental inoculation with chick embryo virus: report of fatal human case with necropsy. JAMA (1940) 115(4):291–292). 10.1001/jama.1940.72810300005007c
    1. Fothergill LD, Holden M, Wyckoff RW. Western Equine Encephalomyelitis in a laboratory worker. JAMA (1939) 113:206–7. 10.1001/jama.1939.02800280018005
    1. Gold H, Hampil B. Equine encephalomyelitis in a lab technician with recovery. Ann Int Med (1942) 16:556–69. 10.7326/0003-4819-16-3-556
    1. Rusnak JM, Kortepeter MG, Aldis J, Boudreau E. Experience in the medical management of potential laboratory exposures to agents of bioterrorism on the basis of risk assessment at the United States Army Medical Research Institute of Infectious Diseases (USAMRIID). J Occup Environ Med (2004) 46(8):801–11. 10.1097/01.jom.0000135539.99691.4e
    1. Pittman PR, Liu CT, Cannon TL, Mangiafico JA, Gibbs PH. Immune interference after sequential alphavirus vaccine vaccinations. Vaccine (2009) 27(36):4879–82. 10.1016/j.vaccine.2009.02.090
    1. Reed DS, Glass PJ, Bakken RR, Barth JF, Lind CM, daSaliva L, et al. Combined alphavirus replicon particle vaccine induces durable and cross-protective immune responses against equine encephalitis viruses. J Virol (2014) 88(20):12077–86. 10.1128/JVI.01406-14
    1. Ko SY, Akahata W, Yang ES, Kong WP, Burke CW, Honnold SP, et al. A virus-like particle vaccine prevents equine encephalitis virus infection in nonhuman primates. Sci Transl Med (2019) 11(492):eaav3113. 10.1126/scitranslmed.aav3113

Source: PubMed

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