A paper published in Nature Communications in September 2023 presents the results of an investigation into the effects of mRNA vaccines against Lassa virus. The researchers suggest that vaccination induced “strong binding antibody responses”. However, Lassa virus-neutralising antibody activity was detected in “some but not all” of the vaccinated Hartley guinea pigs. Despite this, all vaccinated animals were protected from death and severe disease following a challenge with a lethal dose of the virus. Thus, although the “definitive mechanism of protection” remains unknown, the data show that mRNA is a promising vaccine platform.
LASV
The study states that Lassa virus (LASV) is the causative agent of Lassa fever, which causes between 100,000 and 300,000 human cases each year. These cases result in around 5,000 deaths. Human infections were first described in 1969 in Lassa, Nigeria.
Infection is typically asymptomatic or presents with “mild, non-specific” symptoms in around 80% of infected patients, which means that many cases go unreported. However, severe disease is often characterised by respiratory distress, facial swelling, and haemorrhage. Less common symptoms include shock, coma, or seizures.
LASV is “most common” in areas where “public health measures are difficult to implement, access to healthcare is limited, and contact with peridomestic rodents and their secretions still occurs”. It is typically transmitted to humans via contact with the rodent reservoir, Mastomys natalensis but human-to-human transmission has also been documented. This is “particularly concerning because the diagnosis is confounded by the presence of more common endemic diseases”.
“An Old-World arenavirus, LASV is an enveloped, negative-stranded RNA virus that utilises an ambisense coding strategy.”
The authors refer to two “segments” of the genome:
- The large (L) segment that codes for the viral RNA-dependent RNA polymerase and the Z matrix protein
- The small (S) segment that codes for the NP and GPC proteins.
The primary target for virus-neutralising antibodies is LASV GPC as it is the “only membrane-anchored protein on the viral envelope”.
Top target for mRNA
LASV is on the WHO R&D blueprint list of diseases and is also a target by CEPI for vaccine development. However, amidst outbreaks of increasing severity there have been no specific treatments or vaccines approved. Thus, the authors identify in the mRNA platform “multiple advantages”. It is highly immunogenic, non-infectious, lacks a carrier that could induce “non-desirable immune responses”, and lacks a “risk of incorporation” into the host’s genome.
The vaccine used in the study is an N1-methylpseudouridine-modified RNA vaccine, encapsulated in lipid nanoparticles, that encodes either wild-type (WT) LASV GPC or the prefusion stabilised GPC. Both vaccines were “safe and well tolerated” in the outbred Hartley guinea pigs. Vaccination with either construct induced “robust binding antibody titers”. However, the prefusion stabilised construct vaccine elicited “significantly higher” levels. Contrary to the expectations of the team, prefusion GPC-specific binding antibody titers were high in both the WT and prefusion GPC vaccinated animals.
Notably, LASV-neutralising antibody responses were detected in only some animals from either group. Despite this, all vaccinated animals were protected from death and severe disease caused by LASV. Thus, the authors suggest that the protection “may be associated with the Fc-mediated effects” or conferred by the cell-mediated response.
The study aimed to compare the efficacy of the LASV GPC in WT and prefusion-stabilised form. The authors hypothesised that the use of the prefusion-stabilised conformation of the antigen would yield higher titers of virus-neutralising antibodies compared to the WT form.
“Interestingly, while there was no significant difference in efficacy between the two mRNA vaccine constructs, non-neutralising antibodies induced in both groups were specific for the prefusion-stabilised LASV GPC.”
Furthermore, they found that the prefusion stabilised GPC-based vaccine induced higher titers against both LASV Clade II and V, compared to the WT construct. This could suggest that the prefusion construct “may perform better in heterologous challenges in future studies”.
Why mRNA?
The authors suggest that the platform is “highly versatile”. Thanks to its proven efficacy against SARS-CoV-2, other applications are considered. It is also “highly flexible”, which is “imperative for combatting LASV due to its high heterogeneity”. Additional benefits include rapid manufacture and modification of the construct, to adjust to changes in the pathogen.
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