A new vaccine design against the West Nile Virus

Kanikah Mehndiratta, MSc, University of Glasgow

Flavivirus is a genus category that includes many emerging infectious arboviruses. Use of vaccines can potentially save many lives when an individual is exposed to a flavivirus. But the diversity of pathogens can act as a major challenge against the use of vaccines or development of new vaccines to tackle an outbreak. The continuously evolving strains also pose issues to developing one vaccine that has efficacy against most of them. Recent COVID-19 related research has shown that scientists can find difficulty in developing a single effective vaccine shot against all strains. A vaccine that at molecular level helps immune cells recognise a genetic region common to and least modifiable in all possible strains is challenging. 

A recent study published in the EMBO Molecular Medicine journal discusses a rational vaccine design for the West Nile virus (WNV) of the genus Flavivirus. They have approached it via genetic alteration of the 3’ untranslated region (UTR). It must also be noted that there is currently no vaccine available in clinical trials against WNV. 

The WNV and the genus Flavivirus 

The genus Flavivirus belongs to the family Flaviviridae and has been responsible for widespread mortality and morbidity globally. The Flaviviruses come under the vector-borne RNA viruses’ category, majorly the ones that are transmitted via arthropods. Viruses such as the Dengue virus, Zika virus, the virus causing Japanese encephalitis and the WNV are some of those deadly pathogens that have been posing global threats lately. Flaviviruses generally consist of an 11kb positive RNA genome that is single stranded and has a m7GppppAmpN1 at the 5’end but without a poly(A) adenylated tail at the 3’ end. The 5’ and 3’UTRs are highly structured flanks of the single open reading frame. The 5’UTR consists of a conserved stem-loop structure, the SL-A which acts as the promoter for recognition of viral polymerase enzymes and associated activity. The 3’UTR is about 5 times the length of the 5’UTR and constitutes multiple RNA elements involved in virulence, replication of the WNV and its transmission. 

The attenuated vaccine against WNV

The adenosine ribonucleotides are significantly higher in the 3’UTR regions of the WNV genome and are considered evolutionary remnants of the poly(A) tracts. The 3’ UTR has been targeted for the live attenuated vaccine (LAV) design due to the antigenic specificity the region holds. The entire SL and DB domains were replaced with internal poly(A) tails to develop the recombinant LAV. Two mouse models, the IFNAR and the C57BL/6 without the type-1 interferon receptors were infected via the WNV-poly(A) vaccine, LAV. An impaired efficiency of replication due to the 2 domains is effectively targeted via poly(A) tails replacement. 

The future of Flavivirus vaccine design

The study concluded the successful tolerance of WNV against replacement of the 3’UTR with a poly(A) tail. The poly(A) tail stays highly immunogenic and attenuated even after a long passage in the cell culture. The LAV despite lacking the virulence-associated SL and DB region showed no side effects in mice despite a high dose. This was confirmed via testing of genetic stability, followed by genomic sequencing of viral stock exposed to about 50 blind rounds of passage in Vero cells.

The poly(A) tail stayed intact even after 50 rounds. RT-PCR testing confirmed such stability in different passages such as 10, 30 and 50 rounds without any major effects on plaque morphology and growth kinetics of the WNV. The WNV-LAV-P50 showed 100% efficacy in the mouse models at a plaque forming virus of about 10⁷. Poly(A) sequence counters the challenge of loss of viral replication due to the deletion of SL and DB domains. Filling of the SL and DB domain gap with poly(A) sequence will act as an optimal choice when designing vaccines against many different Flaviviruses. 

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References:

1. Zhang, Y., Li, N., Zhang, Q., Liu, J., Zhan, S., Gao, L., Zeng, X., Yu, F., Zhang, H., Li, X., Deng, C., Shi, P., Yuan, Z., Yuan, S., Ye, H., & Zhang, B. (2021). Rational design of West Nile virus vaccine through large replacement of 3′ UTR with internal poly(A). EMBO Molecular Medicine. https://doi.org/10.15252/emmm.202114108

2. Khan, M. T., Islam, R., Jerin, T. J., Mahmud, A., Khatun, S., Kobir, A., Islam, M. N., Akter, A., & Mondal, S. I. (2021). Immunoinformatics and molecular dynamics approaches: Next generation vaccine design against West Nile virus. PLOS ONE, 16(6), e0253393. https://doi.org/10.1371/journal.pone.0253393 

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Author Info:

Kanikah Mehndiratta is an avid researcher in the field of Genetics with a background in Biotechnology. She is a postgraduate from the University of Glasgow in their Medical Genetics and Genomics program. Currently, based in Chandigarh as a scientific writer, she involves herself mainly in projects related to neurological disorders. Outside of academics, she likes to read novels, travel and is involved in volunteer work mostly.

LinkedIn profile– https://www.linkedin.com/in/kanikah-mehndiratta-301830171

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