An article in npj vaccines in August 2024 presents research into the efficacy of a deactivated rabies virus (RABV)-based vaccine encoding the glycoprotein precursor (GPC) of Lassa fever virus (LASV): LASSARAB. In nonhuman primates (NHPs), the vaccine induced “strong” humoral responses and NHPs that had been vaccinated with LASSARAB survived to study endpoint after challenge. The authors state that their work demonstrates that LASSARAB is a “worthy candidate for continued development”.
Lassa fever virus
Lassa fever virus (LASV) is an emerging biosafety level-4 (BSL-4) haemorrhagic virus with no approved vaccine. Endemic to West Africa, the virus is maintained by a rodent reservoir, Mastomys natalensis, and is commonly transmitted to humans who come into proximity with infected rodents. Human-to-human transmission also occurs, most frequently in nosocomial settings. An estimated 300,000-500,000 people are infected with LASV each year, and the overall case fatality rate (CFR) is 1%-2%. However, this increases “significantly” for hospitalised patients.
Lassa fever (LF) is likened to other haemorrhagic fevers; it starts with flu-like symptoms, such as fever, sore throat, and headache. In severe cases it can progress to vascular leakage and multiple organ failure. Although many patients survive, some develop severe sequelae, such as sensorineural hearing loss. LASV is a high-priority pathogen.
Vaccine development
LASV has a bi-segmented, abisense RNA genome that codes for four proteins. The glycoprotein precursor (GPC) is proteolytically cleaved by a host protease into two glycoproteins (GP1 and GP2). These are present on the surface of the virion and are “used for attachment and entry into cells”.
The researchers identified the GPC gene as an “attractive target” for LASV vaccine development because of the “easy accessibility of the glycoproteins to the immune system” and the gene’s “indispensable function in the LASV lifecycle”. Although vaccine candidates targeting GPC were protective in challenge models, they have “disadvantages”. For example, DNA vaccines are “poorly immunogenic without the use of speciality delivery techniques” like electroporation. RNA-based vaccines require cold-chain storage, and live viral vectors can develop mutations.
“The need for the development of alternative vaccine strategies that mitigate these issues remains.”
Rabies virus (RABV) is a “promising” vaccine platform that has already been used with success as a platform for various pathogens. It is administered as an inactivated vaccine, has a “well-established” safety profile, and offers long-term protective immune responses to the rabies antigens. RABV also shared endemic regions with many pathogens, including LASV. Finally, an inactivated RABV vectored vaccine can by lyophilised and remains stable at various temperatures.
“The RABV platform is an excellent choice for a LASV vaccine.”
Previous research has indicated that vaccine-mediated protection against LASV can occur through “various mechanisms”, but a commonality between platforms is a poor neutralising antibody response after vaccination. However, the authors are unsurprised by this, given the “absence” of neutralising antibodies seen in many convalescent LASV patients.
When LASSARAB was administered to NHPs it elicited strong antibody responses to LASV-GPC and RABV glycoprotein (G) for “up to a year” post immunisation. Following this, the researchers sought to test the efficacy of LASSARAB in a lethal LASV NHP challenge model. They immunised NHPs with LASSARAB or CORAVAX (an irrelevant RABV-based vaccine) as a negative control. The NHPs were challenged with LASV at day 70 post immunisation.
The study
The article reveals that no neutralising antibodies were detected in LASSARAB vaccinated NHPs before day 10 post challenge (pc). After detection at day 10 pc, neutralising antibody titres peaked between days 14 and 21 pc and persisted at “varying levels” to day 28 pc in all LASSARAB vaccinates. This suggests that neutralising antibodies are produced as a result of LASV challenge, rather than vaccination with LASSARAB, therefore “not playing a main role” in vaccine-mediated protection.
All LASSARAB-immunised NHPs survived challenge; only one NHP demonstrated “minor outward clinical signs and four NHPs showed transient viraemia. LASV infection has a significant effect on the liver, revealed by a “dramatic increase in liver enzymes”. However, LASSARAB-immunised NHPs maintained normal blood chemistry levels compared to controls; this indicates protection from liver dysfunction.
Despite the “positive clinical outcome” and lack of CBC and blood chemistry changes in vaccinated NHPS, pathologic analysis revealed “significant lesions” in lymphoid tissue as well as smooth muscle layer of arteries in multiple organ systems that stained positive for LASV antigen. This resembles a systemic auto-immune vasculitis, described in NHPs and guinea pigs that survive LASV infection.
LASV in NHPs has a “somewhat protracted” disease process compared to other haemorrhagic fever viruses. The study endpoint was 28 days after virus exposure, but the authors acknowledge that “it is unknown” if the pathology observed in vaccinated survivors at day 28 would have resolved or become less prevalent with a longer endpoint. They suggest that studies with longer endpoints are necessary to determine if the severity of polyarteritis in the LASSARAB vaccinated NHPs resolves over time or can be avoided with administration to a “more mature cohort” of NHPs. Studies will also be required to verify that this pathology was not caused by the vaccine itself.
The protective efficacy of LASSARAB is “comparable” to other vaccine platforms, with 100% of LASSARAB-vaccinated NHPs surviving challenge and presenting “minimal” clinical signs. However, the inactivated RABV platform has “some advantages”. The rabies vaccine has been used for decades and is “safe to administer to a variety of patient populations”. It has been shown to elicit long-term immunity in humans, and “appears to confer this longevity to foreign antigens”.
Another advantage of the RABV platform is that it has been shown to remain stable over a variety of temperatures for “extended periods of time”. This is particularly pertinent for areas in which LASV is endemic, as they have “warm climates and limited access to cold-chain storage”. It is also already commercially available, so there is existing infrastructure for production.
Further research needed
The authors state that they are setting up a Phase I clinical trial of LASSARAB in the US but highlight that other studies should be performed to support its use in the clinic. Although the vaccine has potential for cross-protection, further studies should investigate this. Research should also determine whether LASSARAB can protect NHPs after single-dose immunisation, and how soon after immunisation it confers protection.
We look forward to hearing more about a Lassa fever vaccine candidate at the Congress in Barcelona this October and exploring priority pathogens with our experts. Get your tickets to join us there, and don’t forget to subscribe to our weekly newsletters here.
