Lassa fever vaccine development: Where are we?
Lassa fever vaccine development: Where are we?
Joseph Anejo-Okopi, PhD1,2.
1Department of Microbiology, Faculty of Science, Federal University of Health Sciences Otukpo, Nigeria. 2AIDS Prevention Initiative in Nigeria, Jos University Teaching Hospital, Jos, Nigeria
Email Address: [email protected], [email protected],
December 5, 2022
Lassa virus (LASV) causes acute viral hemorrhagic fever (VHF) called Lassa fever (LF) that is endemic to West Africa (Nigeria, Liberia, Sierra-Leone, Guinea, Côte d’Ivoire, Togo, Benin, Ghana, Central African Republic, Democratic Republic of Congo, Senegal, and southern Mali) 1. LASV is a single-stranded RNA virus of the Arenaviridae family and was first identified in 1969 after the death of two missionary nurses in Nigeria from an acute VHF 2. The LASV has since spread to other parts of the world (Germany, Netherlands, Sweden, UK, USA, and Asia) through international travel 3, 4. The annual incidence of LASV infection ranges from 100,000 –300,000 cases with the mortality of about 5000 deaths 5. Lassa fever is associated with febrile illness with 80% of asymptomatic cases, and the infection is often misdiagnosed and unreported, suggesting inaccurate estimation of the disease burden, which is largely due to lack of diagnostics and standardized surveillance tools. Despite the increasing burden of LASV, there is currently no approved vaccine for human use, and the only available antiviral therapy is intravenous administration of ribavirin 6. The factors underlying this increase are yet to be known, and this raises serious public health concern among the healthcare workers about the endemic disease.
For the past few years, there have been steady increase of LASV cases in Nigeria and other parts of West Africa with reported new genetic strains garnering international attention. The virus genetic diversification and worldwide spread rodent hosts provide opportunities for the continued emergence of new LASV lineages. The recent outbreak in Nigeria in 2019 had 546 confirmed cases with case fatality rate of 25% 7, 4. Unsurprisingly, as part of its efforts to establish a global strategy to improve epidemic preparedness and response, the World Health Organization (WHO) has listed LASV as a priority pathogen in need of accelerated research and development for new diagnostics, therapeutics, and vaccines 8. This suggests the urgent need for improved LASV diagnostics to curb endemic, prompt isolation and case management, outbreak response, vaccine, and clinical trials. Also, it’s important to note that early diagnosis and treatment increases survival rate from LASV infection. This mini review provides basic understanding of LASV ecology, transmission, virology, and vaccine candidates’ efforts.
Ecology and Transmission
LASV is a typical example of a zoonotic virus that circulates in animal reservoirs with great capacity to infect humans. The virus poses a high threat to the one health agenda with concomitant environmental and genetic factors yet to be properly unraveled. Mastomys natalensis multimammate, the LASV reservoir rodents are commonly found in rural areas of the African continent 9. These rodents are largely unaffected by the disease and shed the virus in their excrement. Other rodent species including Hylomyscus pamfi and Mastomys erythroleucus have been identified as LASV hosts 10. Human transmission occurs primarily through contact with infected rodent urine or feces; handling and consumption of infected rodents is a common route of infection, also transmission may occur from aerosolized rodent excretions 11, 9, 12. The Mastomys’ species readily colonize human settlement areas where food is stored, contributing a significant risk for spillover, especially in communities with poor sanitation or crowded living conditions. Risks of sexual transmission in semen after post symptomatic infection exist 13. The one health knowledge regarding LASV reservoir rodents’ ecology and activities in relation to humans are essential for strategic prevention measures against the spread of the LASV.
LASV belongs to the Arenaviridae family; an enveloped and single stranded RNA virus, ambisense, with a two segmented genome . The L fragment encodes the RNA-dependent RNA polymerase and zinc-binding (Z) protein 14, 15, while the S RNA fragment encodes the viral glycoprotein precursor (GPC) and the nucleoprotein (NP) which is the main structural component of the ribonucleoprotein (RNP) 16. The enveloped virus has spikes and encloses the genome containing the helical nucleocapsid of 400–1300 nm in length 2. The Z protein regulates RNA synthesis and helps in viral assembly and budding. Also, the Z and NP proteins are implicated as an antagonist of the host innate immune response and in inhibiting the expression of IFN-1 17. The host immune response is modulated by degradation of virus-associated double-stranded RNAs (dsRNAs), which act as pathogen-associated molecular patterns (PAMPs), via the exoribonuclease function of NP 18. The GPC also encodes a stable signal peptide (SSP) that aids in polyprotein processing into GP1 and GP2, regulation of the pH of infectivity, and provision of chaperone functions during GP maturation 19. As the only antigen displayed on the viral surface, GP has been the focus of recent LASV antiviral and vaccine research 19. Structural analyses of GP indicates that it is a primary target for neutralizing antibody binding 20. However, the role of NP-specific T cells in controlling acute infection and mediating immunity in animal models and humans, offers some degree of justification for the inclusion of NP in LASV vaccines 21.
There is no licensed LASV vaccine approved for use in both humans and animals to reduce zoonotic transmission. However, several vaccine platforms have been developed that showed some form of efficacy in non-human primates 22. WHO made very sincere and frantic efforts by stimulating vaccine development through the Lassa fever vaccine Target Product Profile (TPP) document that was made available in June 2017 to vaccine scientists, diagnostic product developers, manufacturers and funding agencies including the Coalition for Epidemic Preparedness Innovations (CEPI) 8. It’s imperative to note that some of the vaccine platforms have been evaluated as potential LASV vaccine candidates, and these include: DNA vaccine 23; virus replicon particle vaccine 24; rabies virus 25; vaccinia virus 26; LASV virus-like particles 27; recombinant vesicular stomatitis virus (VSV-LASV vaccine) 28, 29; ML29 MOPV/LASV live reassortant 30; measles virus 31; Adenovirus vectored vaccines 32, 33 and a recombinant vesicular stomatitis virus vector (rVSV∆G-LASV-GPC) - lineage IV 34..
This vaccine is based on an attenuated, or weakened, strain of vesicular stomatitis virus (VSV) that has been modified to express a Lassa fever virus protein that plays an essential role in establishing viral infection. However, a recent study showed that vaccination with the recombinant candidate vaccine (VSV-LASV-GPC) provided rapid heterologous protection against genetically heterologous lineage II isolate of LASV from Nigeria as early as 3-7 days post-vaccination in non-human human primates. The rVSVΔG-LASV-GPC vaccine induces rapid activation of adaptive immunity and the transcription of natural killer (NK) cell-affiliated mRNAs. This rVSVDG-LASV-GPC vaccine is now being assessed in humans, phase I trial (IAVI C102) some West African countries beginning from Liberia 35. This candidate vaccine demonstrated prevention against overt disease and showed remarkable effectiveness in rapidly clearing the virus 34. Future studies are however, needed to show shorter windows between vaccination and exposure and to test longer periods of immunity to the virus. It’s also important for further studies to evaluate the durability of the vaccine vector against exposure to recent heterologous LASV lineages. This has become critical and threatening as over 180 million people are currently at risk to LASV infection. Although this news of the candidate vaccine is an exciting development, further countermeasures should continue at various fronts such as new rapid point of care (rPOC) diagnostics, single dose protective, and effective antiviral targeting the replication cycles.
The current Phase 1 clinical trials for IAVI C102 vaccine should be seen as an opportunity to further understand Lassa fever pathobiology. Clinical markers, such as high viral load, interleukins microRNAs and elevated liver enzymes should be studied to predict disease outcomes. There is still a paucity of data on some early markers during asymptomatic and severe disease phases. Also, more immunologic and clinical
finding regarding a large cohort of asymptomatic cases is required to better understand the role of both cell-mediated and humoral immune responses to LASV infection, which may give clarity of the survival correlates following infection. In addition to existing vaccine platforms, more are needed for epidemic preparedness as shown in response to Covid-19 pandemic. Also, the strengthening and repositioning of capacity for further vaccine development and extension of trials phases are key to enhancing further into LASV pathogenesis and identification of diagnostic markers using both human and the virus. Further steps to strengthen capacity of researchers in endemic regions are critical to reduce the existing knowledge gaps.
LASV infection poses a significant threat to human existence particularly in poverty ridden West Africa where transmission is associated with poor sanitary practices. There exists the risk of LASV spread to other parts of Africa and the world at large due to international travels, climate change and other environmental factors. There are no licensed vaccines despite several efforts, however, major progress has been made with a recent candidate vaccine (CEPI/IAVIC102) already in clinical trials phase 1. It has become imperative that the challenge of recent discovery of new genetic lineages must be taken into consideration for future attempts in vaccine development efforts. Before now, LF was seen as a disease of only West Africa, but the lessons from the COVID-19 pandemic suggest the urgent need for the world to be committed to vaccine development efforts to curb future outbreaks.
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