Kyasanur Forest Virus Research And Vaccine Updates

Introduction

Brief overview of Kyasanur forest disease virus 

In 1957, an epizootic outbreak in the Kyasanur forest of Shimoga district’s Sagara taluk, India, led to fatalities in mammals. The virus is the highly pathogenic Kyasanur forest disease virus (KFDV), a flavivirus classified as a tick-borne viral hemorrhagic fever affecting mammals such as humans and monkeys. Reports in 2021 show 200 to 500 cases per year with a death rate of 2-10%. This virus can spread to humans and monkeys by the abundant, infective tick Haemaphysalis spinigera.¹ This virus was also found in seven other different species of Haemaphysalis, Ixodes, and Dermacentor.² With the advancement of medicine and biotechnology, researchers have been working to find cures and vaccines against this disease. However, as of 2021, the vaccine’s output has decreased from 95% to 62%, and researchers are still working further on the production of these vaccines.³ This article will walk you through the most recent findings on this disease and provide you with updates on the development of the vaccine.

Historical and geographical expansion of Kyasanur forest disease in India

The Kyasanur Forest Disease (KFD), which was initially discovered in Karnataka, has also been spotted in other regions of India, such as Tamil Nadu, Goa, Maharashtra, and Kerala. This indicates the possibility of the disease spreading to new regions and crossing state boundaries, which is alarming.

From 1957 to 2017, there have been approximately 9,594 reported cases of KFD within 16 districts in India. The most significant human outbreaks of the disease were recorded in the years 1957–1958, with an estimated 681 cases, followed by 1983–1984 with 2,589 cases, 2002–2003 with 1,562 cases, and 2016–2017 with 809 cases. There is an average of 160 cases per year across the 61-year study period.⁴

In 1995, a patient in Saudi Arabia developed bleeding and fever after slaughtering a sheep, and a variant of KFDV was discovered in their blood. This variant was named Alkhurma haemorrhagic fever virus (AHFV) and shares 89% of its genetic sequence with KFDV, indicating a common ancestral origin.⁵ However, not much is known about this virus, and a recent study published in 2022 reports that 604 cases of AHFV were reported in Saudi Arabia between 1995 and 2020.⁶

Current date of research

Surveillance and monitoring

Kyasanur Forest Disease (KDF) has been crossing state borders, and the lack of an effective disease surveillance and reporting system for KFD makes it more difficult to control. Keshavamurthy et al. addressed this issue by utilizing machine-learning models and novel data sources, which could help them predict when and where outbreaks might happen. They compared time-series models, one using weather data with Event-Based Surveillance (EBS) information, such as internet search trends and news reports. They employed Extreme Gradient Boosting (XGB) and Long Short-Term Memory to make these predictions at both national and regional levels. Furthermore, they applied transfer learning (TL) algorithms to rich data from common epidemic locations to predict KFD cases in newly discovered outbreak sites with limited surveillance.

Utilizing EBS Data significantly improved prediction performance for KFD cases across all models. They discovered that the XGB model turned out to be the best at guessing the number of cases. They concluded that novel data sources and advanced machine-learning approaches showed great potential towards increasing disease prediction capabilities. TL has proven effective in predicting outbreaks in new areas, showcasing capabilities to forecast future outbreaks.⁷ 

Transmission dynamics

The natural nidus of the Kyasanur Forest Disease is discovered to be in the monsoon rainforest of the western ghats of India, which is among the most significant spots for biodiversity in the world. Researchers are still trying to figure out its consequent transmission dynamics. They have aimed to create an ecological profile of KFD virus hosts based on life history and feeding traits to guide targeted surveillance. They discovered that body mass and forest forage were linked to host infection, except for their reproductive life history traits. These findings aided in structuring wildlife surveillance and developing epidemiological models in a region facing complex ecological challenges and growing humans.⁸ 

In a research paper published in 2020, researchers enrolled KFDV-positive patients, and performed repeated peripheral blood collections, to conduct clinical, virological and immune analysis. They observed robust T and B cell responses, notably CD8 T cells, helped in eliminating the virus and leading to the appearance of protective antibodies. They noticed an increased frequency of plasmablasts and very few activated B cells during the early stage of the disease. Researchers also found a correlation between immune response and prior vaccination against KFDV. The humoral immunity and activated B cell frequency were significant only among patients who received two or more doses of the KFDV vaccine.⁹

Genetic studies

A study has been conducted using the genetic material of the Kyasanur Forest Disease Virus (KFDV) collected from various regions between 1957 and 2017. The study included 48 whole genomes and 28 sequences of a specific gene called E-gene, which is a part of the genetic code of KFDV. The study found that the evolutionary rates of the E-gene were marginally higher than when analyzing the entire genomes of the virus. This showed that certain regions of the virus's genetic material may change at a slightly faster rate than the virus as a whole. 

A subgroup of KFDV strains from 2006-2017 showed a 2.76% genetic difference from the early Karnataka strains (1957-1972). This indicates the spread of the virus to different geographical areas around 1980. Maharashtra has been identified as a new source for transmission of KFDV since 2013. 

The study also found significant evidence of adaptive evolution at the site of 123 A/T near the envelope protein dimer interface.¹⁰ KFDV is a positive strand RNA virus, and its genome codes for one polyprotein that is cleaved post-translationally into 3 structural proteins (capsid protein, envelope glycoprotein M, and envelope glycoprotein E) and 7 non-structural proteins (NS2A, NS2B, NS4A, NS4B, NS1, NS3, and NS5).¹¹

Vaccine development

Importance of vaccines

The disease KFDV is classed as an NIAID Category C priority because of its high pathogenicity and absence of US FDA-approved vaccines and treatments. The infectious dose is also currently unknown for KFD. It is a flavivirus that causes severe hemorrhagic fever with neurological manifestations such as severe headache, mental disturbances, tremors, vision deficits and tremors in infected human beings with a fatality rate of 2-10%. It is a virus which is widely spreading across borders and having similar variants like Alkhurma virus in Saudi Arabia. 

Current vaccination

The current vaccination used in India is a formalin-inactivated KFDV tissue-culture vaccine, produced in chick embryo fibroblasts, conducted in Karnataka, South India  region since 1990. Two doses are administered to individuals from the age 7-65 years with a gap of one month, followed by a periodic booster dose after 6-9 months. According to an analysis, the effectiveness of the vaccine was 62.4% among those who received two doses and 82.9% for those who received a booster dose after the first two initial doses  as compared to unvaccinated individuals. However, the coverage of KFD vaccine in this study was low with less than 50% of the population vaccinated.¹²

Recent vaccination research updates

A recent study has found that a concentration of 0.08% formalin can effectively inactivate KFDV in vaccines, while still maintaining the vaccine's immunogenicity and potency in resisting virulent challenges. By reducing the formalin concentration in the vaccine, it may be possible to reduce the pain, swelling, and other side effects that may occur at the site of vaccination in people. This could lead to higher vaccine uptake and coverage, which would be beneficial in the prevention and control of KFD in endemic areas until a new generation of vaccines is developed.

Furthermore, real-time polymerase chain reaction (PCR) can be used to quantify non-cytopathic viruses in the intermediate stages of vaccine production. The PCR results provide an estimate of virus load, and if the individual harvests have the required cycle threshold value, a final potency test can be performed on laboratory animals. This will help to save hundreds of mice typically used for virus quantification during intermediate stages of vaccine production.¹³

According to a study conducted to determine the effectiveness of a vaccine against Kyasanur Forest disease (KFD) in pigtailed macaques. The vaccine was based on the vesicular stomatitis virus (VSV) and expressed the precursor membrane and envelope proteins of KFDV (VSV-KFDV). The results showed that VSV-KFDV was safe and triggered strong immune responses, both cellular and humoral. A single dose of the vaccine was enough to reduce KFDV loads and pathology and to protect macaques from KFD-like disease. Additionally, VSV-KFDV produced cross-reactive neutralising immune responses against the Saudi Arabian version of KFDV known as the Alkhurma hemorrhagic fever virus.¹⁴

FAQs

What are the signs and symptoms for Kyanasur Forest Disease?

Symptoms include:

• High fever with headaches
• Severe muscle pai
• Vomiting
• Chills
• Gastrointestinal Symptoms
• Abnormal low blood pressure, including low red blood cell and white blood cell count
• Vision deficits
• Tremors
• Mental disturbances

How is Kyasanur forest disease diagnosed?

Diagnosis can be done using an RT-PCR test for molecular detection

Summary

Researchers are working tirelessly to control the spread of the virus. However, despite the advancements in technology and knowledge, there is still very little known about this virus. The infectious dose of the virus is also currently unknown. It is suspected that the virus may spread from animals to humans, but human-to-human transmission is unlikely as our domestic environment does not host the ticks. To control the virus as much as possible, researchers use computer models to predict outbreaks in new areas. Although new ideas to improve vaccinations are emerging, there is still plenty to learn about this virus.