Battling Kyasanur forest disease: the race for robust and long-lasting Kyasanur forest disease vaccine

Kyasanur forest disease (KFD) is an emerging tick-borne viral hemorrhagic fever endemic to the south-western parts of India, particularly in the states of Karnataka, Maharashtra, Kerala, and Tamil Nadu. The disease was first identified in 1957 after an outbreak in the Kyasanur Forest region in Shivamogga district of Karnataka state. In recent times, the cases of KFD have been reported from the adjacent States of Karnataka such as Tamil Nadu, Kerala, Goa and Maharashtra. The causative agent of KFD is the Kyasanur Forest Disease virus (KFDV), a member of the Flavivirus genus, which includes viruses such as Dengue, Zika, and Yellow Fever. The KFDV genome consists of a positive-sense, single-stranded RNA of 10 774 nucleotides (nt) that encodes a single polyprotein cleaved into three structural proteins viz. capsid, precursor membrane protein (prM), and envelope protein (E) along with seven non-structural proteins. The prM, C, and E proteins are immunogenic and can be used for the vaccine development[1] (Figure 1). The primary mode of transmission of KFDV is through the bite of infected ticks, particularly the Haemaphysalis species. These ticks typically inhabit forest areas and can transmit the virus to humans and other animals. KFD is considered an important public health concern in the regions where it is endemic due to its potential for causing outbreaks among local populations. The disease primarily affects individuals who live or work in forest areas and come into contact with infected ticks. Figure 1.: Potential platforms for development of KFD vaccine. KFDV can cause a severe clinical syndrome with chills, fever, headache, myalgia, vomiting, gastrointestinal symptoms, and hemorrhages. In addition, a biphasic illness including recurring fever with or without neurological symptoms may also be observed in few patients. It is estimated that up to 500 human KFDV infections occur annually with a case fatality rate of 3% to 5%. Because of its life-threatening pathogenicity and the absence of effective countermeasures, KFDV is classified as a biosafety level-4 (BSL-4) pathogen. The most significant human outbreaks of KFD were reported between the years 1957 and 1981 mostly in Shivamogga, with some cases in Uttar Kannada. Since 1982, new foci of disease have been recognized, with 1984 new cases reported from Dakshina Kannada. In the following years, the disease spread geographically to Chikmagalur and Udupi districts of Karnataka State. The growth in number of cases continued in 2003. The initial human case of KFD in Kerala was reported in 2013 from the Wayanad district. Subsequently, the first major outbreak occurred in 2015. In 2014, a new center of virus activity was identified in the tribal region of Nilambur in the Malappuram district of Kerala. The recent focus occurred during 2015 to 2017[2]. In Goa, the KFD outbreak was first reported in Pali village of Sattari taluka in 2015; since then there has been a spread to other villages[3]. Since January 2024, Karnataka has reported a total of 103 positive KFD cases, resulting into two fatalities. Between 1957 and 2017, an estimated 9594 cases of KFD were reported across 16 districts in India. The most notable human outbreaks occurred in the following years: 1957–1958 with 681 cases, 1983–1984 with 2589 cases, 2002–2003 with 1562 cases, and 2016–2017 with 809 cases[4]. The cases are predominantly concentrated in the districts of Shivamogga, Uttara Kannada, and Chikmagalur. Specifically, as of February 17 a total of 40, 37, and 26 cases were recorded from Uttara Kannada, Shivamogga, and Chikmagalur, respectively. Unfortunately, both of the Shivamogga and Chikmagalur have experienced one fatality due to KFD[5]. It is indeed alarming to witness the spread of KFD beyond its initial endemic areas over the past few decades. Originally confined to the Shivamogga district in Karnataka, the disease has now extended its reach to other districts within the state. Moreover, outbreaks are currently being reported in neighboring states, including Kerala, Tamil Nadu, Maharashtra, and Goa. Recently, Government of Karnataka held a high level meeting regarding the containment of the disease. In addition, the Directorate of Public Health (DPH) and Preventive Medicine in Tamil Nadu have also issued an advisory on prevention and control of the disease in villages bordering Karnataka. This expansion can be primarily attributed to the dissemination of tick populations carrying the pathogen across various regions of the country. The emergence of diseases akin to KFD, such as Alkhurma Hemorrhagic Fever (AHF), adds another layer of concern and interest to the evolving landscape of vector-borne illnesses. Overlooking the significance of these diseases could potentially give rise to global health concerns in the near future. Factors such as temperature, humidity, and rainfall play a pivotal role in the sustained activity of ticks. Unfortunately, irregular rainfall patterns have created favorable conditions for heightened nymphal activity among ticks, resulting in an increased density of tick populations. This surge in tick numbers ultimately contributes to a rise in disease outbreaks within endemic areas. Traditionally, nymphal activity tends to decrease following summer rains. However, the tangible impact of climate change, marked by irregular rainfall patterns, is disrupting this natural cycle. The resulting fluctuations in tick activity are intricately linked to shifts in disease epidemiology, underscoring the tangible and concerning influence of climate change on the dynamics of vector-borne diseases. Furthermore, the combined effects of deforestation and intensive agricultural practices have intensified the proximity between ticks, infected monkeys, and humans. This heightened closeness significantly elevates the risk of virus transmission, facilitating the establishment of infections in human populations. Currently, there is no specific treatment available for the disease; there is only scope for supportive treatment. Prevention and control measures for containment of the KFD include public awareness campaigns about the risks of tick bites, wearing protective clothing, and using insect repellents when entering forest areas. Additionally, efforts to control tick populations and surveillance for early detection of KFD cases are important strategies in preventing outbreaks. The use of acaricides for controlling and managing tick infestations in animals can be highly effective in reducing the risk of tick-borne diseases. Before visiting forests, plantations, or farms, applying tick repellents such as DEET (N,N-diethyl-m-toluamide), DEPA (N,N-diethyl phenylacetamide), neem oil, or eucalyptus oil on exposed skin is recommended to prevent tick bites. Moreover, individuals should avoid venturing into forests where monkey deaths, a potential indicator of KFD, have been reported. Although, it seems impractical to refrain from visiting the forest or plantation because it is the source of livelihood for most of the families dwelling near the forest. The KFD is endemic in forested regions of India where the terrain is often difficult to navigate. Reaching forest workers, tribal communities, and rural populations to provide vaccinations or repellents is challenging due to poor infrastructure. Over time, ticks may develop resistance to commonly used acaricides, reducing their effectiveness and requiring the development of new tick-control strategies. The presence of various wild animals, including monkeys, which act as hosts for the virus, complicates efforts to reduce tick populations. Controlling ticks on wildlife is nearly impossible, increasing the risk of spillover to humans. Efforts to develop anti-tick vaccines have gained attention as a strategy to prevent multiple tick-borne diseases. Vaccinating individuals in endemic areas, especially high-risk groups like forest workers, is critical for preventing the spread of the disease. Additionally, mapping the vaccinated population is essential for effective disease mitigation. While a formalin-inactivated vaccine is currently available, it requires repeated doses, and its efficacy remains questionable. Therefore, there is an urgent need to develop a new-generation vaccine that provides long-lasting immunity with a single administration. Accurately mapping vaccinated individuals in remote areas is difficult, which makes it challenging to track vaccination coverage and plan for future campaigns. Effective KFD control requires coordination between health, veterinary, forestry, and environmental agencies. Ensuring smooth collaboration across these sectors can be complex and often lacks proper execution. As a result of these challenges, there is improper implementation of preventive and control measures at the ground level. Limited vaccine efficacy, difficult terrain, lack of awareness, and logistical constraints hinder effective vaccination and tick control efforts. Additionally, inadequate surveillance, resistance to acaricides, and poor coordination between agencies contribute to gaps in disease prevention. These barriers ultimately lead to an insufficient response to KFD outbreaks, especially in high-risk, rural, and forested areas. The socio-economic impact of KFD, is substantial and multifaceted. The disease disproportionately affects rural communities particularly small holders and tribal population dwelling around the forest region, especially those involved in forest-based occupations like farming, logging, and gathering forest products. The disease forces governments and families to allocate resources to health care. Costs associated with hospitalization, medical treatment, and transportation can be high, especially for low-income families. The cost of treatment for an individual towards the treatment is around Rs. 1 00 000/-. Since there is no specific antiviral treatment, symptomatic management becomes expensive over time. Since most of the families are purely dependent on farming and livestock rearing, these activities expose individuals to tick-infested areas, people may avoid or be restricted from accessing forests during outbreaks, leading to reduced agricultural output and loss of income. The closure of nature reserves during the peak period of disease occurrence results in a significant loss of income for communities dependent on tourism-related jobs. KFD outbreaks exacerbate poverty in already vulnerable rural areas. The loss of income due to health issues and restrictions on accessing forests reduces household savings and leads to financial burden.[6] Although, one indigenously manufactured formalin inactivated vaccine is available in the endemic districts through the Institute of Animal Health and Veterinary Biologicals in Bangalore, Karnataka. Two doses of vaccine over 1 month interval is required to be administered followed by first booster dose after 6–9 months of primary vaccination, thereafter annual booster doses for 5 consecutive years after the last confirmed case in that area[7]. Nevertheless, the tissue culture derived inactivated virus vaccine currently used in India requires repeated administration and has short lived immunity. In addition, according to recent reports, vaccination failure is also a major concern of this vaccine and its efficacy is questionable which further reduce the probability of usage of this vaccine in future. The live-attenuated recombinant VSV vector-based vaccine is developed by heterologous expression of immunogenic precursor membrane protein (prM) and membrane protein (VSV-KFDV) of KFDV. These vector-based vaccines showed promising results against the disease in BALB/c mice and pigtailed macaque model; it is safe and elicited both arms of the immunity like cell mediated and humoral immune response. Nevertheless, the single dose of intra-muscular vaccine is sufficient to reduce the KFD viral load after the challenge with lethal dose of the virus. Intriguingly, VSV vector-based vaccine also provided cross protection against the AHFV, humoral immune response elicited by VSV-KFDV strongly neutralized AHFV infection in vitro. Currently, this second generation of KFDV vaccine now ready to enter the clinical trials[1,8]. Considering the recurrent emergence or re-emergence of KFDV in predominantly rural areas of India, where health care coverage is inadequate and logistical challenges hinder vaccine administration, the development of a single-shot, fast-acting, second-generation vaccine would prove to be immensely beneficial. So, there is huge scope for the development of effective, long-lasting, live-attenuated or multi subunit construct DNA vaccine or mRNA vaccine for the better prevention and management of the disease (Figure 1). DNA vaccine and mRNA vaccine can be constructed targeting multiple immunogenic proteins, so that vaccine can elicit broad range of long-lasting immunity. The limited efforts to develop a second-generation vaccine pose a challenge to public health, especially in light of the expanding distribution of KFDV and its variants like AHFV. Certainly, given the concerning spread of KFD, it becomes crucial for researchers and health care workers to prioritize the early development of robust vaccines. All possible efforts in the direction of developing effective preventive measures and containment strategies are essential to curb the possible global spread of this pathogen.