Lassa Fever Vaccine

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Lassa Fever and Lassa Virus

Lassa Fever, an acute haemorrhagic disease caused by Lassa virus (LASV), was described for the first time in 1950s but identified in 1969. The disease distributes mainly in West African countries such as Benin, Guinea, Mali, Sierra Leone, and so on. The vast majority of people infected with Lassa virus do not show any symptoms, only 20% of infected people will develop into serious conditions. The multimammate rat is the host of the Lassa virus, and contact with whose feces or urine could cause the infection in humans. The incubation period of Lassa Fever ranges from 6 days to 21 days. After onset of the disease, the symptoms are gradual. The early stage is usually fever, weakness, muscle pain, etc., and later develops into nose and gastrointestinal tract bleeding. In the cases of death, death usually occurs within two weeks following the start of the illness. And 25% of survivors recovered from the infection are usually accompanied by deafness. Overall, Lassa Fever has a mortality rate of 1%.

The causative agent of Lassa Fever, Lassa virus, belongs to Arenaviridae family, and the genome of the virus is a single-stranded RNA which is responsible for the expression of 4 proteins that are zinc-binding protein, a regulator of viral transcription and replication, RNA polymerase, glycoprotein (GP), and nucleoprotein (NP). All operations related to living Lassa virus must be performed in Biosafety Level 4-Equivalent Containment.

Interactions between Lassa Virus and Host Immune System

Lassa virus enters host cells via α-dystroglycan (α-DG) receptors on the surface of target cells (mainly endothelial cells and antigen-presenting cells like dendritic cells). The recognition of this receptor by Lassa virus is dependent on the sugar modification of α-dystroglycan by some glycosyltransferases such as LARGE protein. There is evidence that the aliphatic amino acid at the position 260 in the GP1 protein is essential for the high-affinity binding of the GP protein to α-DG. In addition, the amino acid at position 259 is also important because all of Arenaviruses that can bind α-DG with high affinity have an aromatic amino acid such as phenylalanine or tyrosine at this position.

Usually, when the pathogen enters into the host, the innate immune system recognizes PAMP (pathogen-associated molecular patterns) and triggers the immune response. One of the mechanisms during the process is that the host initiates the interferon response by detecting the double-stranded RNA (dsRNA) of the virus. In the cytoplasm, dsRNA is detected by receptors RIG-1 and MDA-5 and corresponding signaling pathways are subsequently initiated, leading to a recruitment of interferon regulatory factor-3 (IRF-3) and other transcription factors to the nucleus. These transcription factors then start the expression of IFN-α and IFN-β and all these initiate an adaptive immune response. The NP protein of Lassa virus is not only related to viral replication and transcription but also suppresses IFN response of host by inhibiting migration of IRF-3. In addition, it has been reported that the NP protein of Lassa virus also has exonuclease activity on dsRNA, which can counteract the IFN response by disposing its PAMPs, so that the virus can escape from the host immune response. The results of the existing studies indicate that the recovery of Lassa Fever patients and the survival of animals in the challenge test are related to cell-mediated immune responses, but not to antibody levels.

The Development of Lassa Fever Vaccine

Some promising vaccine candidates are being under evaluation. The first vaccine candidate for Lassa Fever is a recombinant vaccinia virus (VACV) of Lister strain that expresses nucleoprotein of LASV and the candidate showed 100% protection in vaccinated guinea pigs. Two similar VACV-based vaccine candidates that express NP or GPC of LASV using NYBH strain of vaccinia virus are both complete protective while slight symptoms occurred in rhesus monkeys after challenge. Extensive studies indicate that full-length GPC is indispensable and enough for protection.

Co-infecting cells by close-related Arenaviruses like Lassa virus and non-pathogenic Mopeia virus (MOPV) could produce reassortants. So-made vaccine candidate clone ML29, a MOP/LAS virus reassortant, is safe and of high-immunogenicity in non-human primates. Studies show that a single-dose vaccination of ML29 could induce strong cell-mediated immunity and completely protect animals against lethal challenge by homologous LASV. Moreover, ML29 is also partially protective in post-exposure conditions. HIV-1 seroprevalence is high (5%-12%) among younger populations in LASV endemic areas, an important issue that must be taken into consideration when designing LASV vaccine candidates. Related studies indicate that ML29 is safe and could elicit cross-protective responses against even distantly-related LASV strains.

Vesicular stomatitis virus (VSV) is also applied as a vector to prepare LASV vaccine candidate. Evaluation of rVSV• G/LASVGP (Josiah) vaccine candidate shows a complete protection against homologous LASV challenge.

Yellow Fever 17D (YF17D) is used for expressing LASV antigens too. YF17D/LASV• SSP/GPC has a weak ability to replicate in guinea pigs but could induce specific anti-LASV antibodies. YF17D/LASV GP1 or -GP2 could protect mice and guinea pigs but had low immunogenicity and failed to protect NHPs.

Alphavirus replicon technology also provides a feasible way to prepare LASV vaccines. Previous studies including VEEV-based replicon particles could elicit a certain immune response in mice and VLPs that express nucleoprotein and glycoprotein of LASV provided full protection in vaccinated guinea pigs.

Creative Biolabs has a wealth of successful experience in the development of virulent pathogen vaccines. After more than a decade of growth, we now have a variety of proven vaccine platforms that enable the design and preparation of many types of vaccines. At the same time, we have a systematic vaccine optimization and evaluation system which make us capable of providing one-stop services for vaccine design, optimization, evaluation, and production. We have in-depth and extensive research in the Lassa Fever vaccine field, aiming to provide you with the most scientific and reliable services.

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