Pandemic Preparedness Strategies

Priority Pathogens

Chikungunya virus

Overview

Representative natural hosts of the Chikungunya virus include Aedes aegypti or Aedes albopictus. The infection is spread through the bite of a vector mosquito infected with the Chikungunya virus.
The Chikungunya virus (CHIKV) is an enveloped, positive, single-stranded RNA virus belonging to the Tokaviridae family and Alphavirus genus. It is one of the deadly BSL-3 pathogens that causes Chikungunya fever, a zoonotic febrile disease, when bitten by vector-borne mosquitoes infected with the virus.
Chikungunya fever can range from asymptomatic and mild headaches, fever, and rash to severe symptoms such as inflammatory joint pain and neuropathic pain. If it progresses chronically, persistent polyarthralgia may occur for several years.
Since the Chikungunya virus was first identified in Tanganyika village in the central and eastern region of Africa in 1953, its cases have occurred in various regions (e.g., Asia, Central and South America, and the Americas) and it has spread around the world.
Currently, there is no effective treatment or vaccine for the Chikungunya virus, making it one of the deadly viruses that require high caution.

View Chikungunya virus in detail

Chikungunya Fever and Chikungunya Virus

Definition	Chikungunya virus infection
Disease classification	Class 3 infectious disease (disease code: A92.0)
Pathogens	Togaviridae Alphavirus Chikungunya virus (Positive single-stranded RNA virus)
Major vaccine antigens	Chikungunya structural polyprotein (C, E3, E2, 6k, E1)
Reservoir	Aedes ( Aedes albopictus or Aedes aegypti )
Route of infection	Aedes -> People	Infection is spread through the bite of an vector mosquito infected with the Chikungunya virus (human-mosquito-human transmission).It is presumed that there is a possibility of transmission through blood in the case of blood transfusions, organ transplants, and syringe cuts. Cases of vertical infection have been reported
Domestic occurrence	Over the past five years, there are 3 cases in 2018, 16 cases in 2019, 1 case in 2020, and 6 cases in 2022 (tentative).
Overseas occurrence	First report	The first outbreak occurred in 1952 in the Makonde Plateau of Tanzinia, Africa. At that time, Chikungunya virus was isolated for the first time from the patient's serum, and it later became prevalent in sub-Saharan Africa.
	Occurrence trend	(1963-2005) More than 140,000 cases occurred in India (2006~2007) Cases occurred in Africa, Asia, and Italy (2009) Virus outbreaks reported in Indonesia, Thailand, and Malaysia (2013~) Spread to the Caribbean, North America, and South America (2020) Multiple reports from Pakistan, India, Brazil, and the Caribbean
	Risk areas	t occurs mainly endemic in Africa and Asia. In particular, countries around the Indian Ocean and Southeast Asia are considered risk areas.
	Overseas inflow	There have been many cases of infection from overseas. In particular, most cases of infection occurred after visiting Southeast Asia.
Incubation period	1-12 days (Average: 3-7 days)
Clinical symptoms	Approximately 3-28% of infected patients are asymptomatic. Acute symptoms usually disappear in 5 to 10 days. Because symptoms are mild, the infection may not be recognized or may be misdiagnosed. Main symptoms include acute fever, joint pain, and other symptoms include headache, muscle pain, joint swelling, and rash. (Fever) Lasts for 24 to 48 hours and may be accompanied by chills (Joint pain) may appear without fever and tends to get worse in the morning. It may relieve with light exercise and occur symmetrically on the hands and feet, relieving for 2-3 days and then coming back. (Rash) Appears after fever. It appears on the torso and extremities, but not on the palms, soles, or face. Chikungunya virus can cause serious complications such as myocarditis, meningitis, Guillain-Barre syndrome, cranial nerve paralysis, eye diseases (uveitis, retinitis), osteomyelitis, hepatitis, and acute kidney disease.
Fatality rate	The mortality rate is extremely low, and death cases are mainly observed in elderly people.
Diagnosis	Detection of specific genes in samples (blood, body fluids, etc.) (Real-time RT-PCR)
Treatment	There is no specific treatment commercially available worldwide. Symptom-based symptomatic treatment is best
Prevention	There is no commercially available preventive vaccine worldwide. When traveling to areas where the Chikungunya virus is prevalent, it is most important to avoid mosquito bites (mosquito repellent, long-sleeved clothes, etc.)

※ Source: Grade 3 Chikungunya fever, BUSAN Infectious Disease Control Support Group, 2023., 2023 management guidelines for viral mosquito-borne infectious diseases, Korea Disease Control and Prevention Agency(KDCA), 2023. IPion reconstruction.

Trends of domestic and overseas vaccine developers

1 Trends in development of Chikungunya vaccines and treatments

Vaccine candidates for Chikungunya virus infection

Currently, there are no approved treatments or vaccines for Chikungunya. Representative Chikungunya vaccines undergoing clinical trials include VLA1553, BBV87, MV-CHIK-202, PXVX0317, VAL-181388, CHIK001, and mRNA-1944.
Among the Chikungunya vaccines under development, the vaccine that is likely to be approved by the FDA is the VLA1553 vaccine from Valneva, a French biotechnology company specializing in vaccines.

Vaccine candidates for Chikungunya virus infection

Currently, there are no approved treatments or vaccines for Chikungunya. Representative Chikungunya vaccines undergoing clinical trials include VLA1553, BBV87, MV-CHIK-202, PXVX0317, VAL-181388, CHIK001, and mRNA-1944.
Among the Chikungunya vaccines under development, the vaccine that is likely to be approved by the FDA is the VLA1553 vaccine from Valneva, a French biotechnology company specializing in vaccines.

2 Animal models for Chikungunya virus infection

Types of animal models for Chikungunya virus infection

Representative animal models used in non-clinical experiments to develop vaccines and treatments for Chikungunya virus include mice and monkeys (primates).
Recently, animal models suitable as Chikungunya infection models are being developed. Among these animal models, there are many cases in which clinical signs similar to Chikungunya virus have been induced through some genetic modification.
Animal models each have distinct advantages and disadvantages. However, non-clinical experiments using monkeys (e.g., cynomolgus macaques and rhesus macaques), which are the most representative primate models used for Chikungunya virus, have very high experimental value.
The reason is that primates show physiological and immunological characteristics most similar to humans.

Overseas

1 Vaccine developers undergoing clinical trials

Valneva Austria Gmbh

Valneva Austria Gmbh is a vaccine specialized company focusing on the development, manufacture, and commercialization of vaccines to prevent infectious diseases.
Valneva focuses on developing vaccines for infectious diseases with great unmet medical need, such as Chikungunya. It takes a highly specialized and targeted approach to vaccine development.
Valneva's Chikungunya vaccine development program previously received FDA Fast Track and Breakthrough Therapy designations in 2018 and 2021, respectively. VLA1553 was granted PRiority MEdicine (PRIME) designation by EMA in 2020.
In particular, the live-attenuated Chikungunya vaccine ‘VLA1553’ being researched and developed by Valneva is showing positive results regarding vaccine efficacy in multiple clinical trials. Thus, it is currently considered the leading Chikungunya vaccine candidate.
VLA1553 vaccine is a live-attenuated vaccine based on the CHIKV LR2006 OPY1 infectious clone that has been attenuated by removing some sequences of nsP3, one of the non-structural proteins of Chikungunya virus.
According to the latest news, the U.S. Food and Drug Administration (FDA) announced that it would delay the approval of Valneva's Chikungunya vaccine by three months (November). However, it is expected to receive priority review as it is scheduled to be released after receiving BLA (Biological License Application) approval within this year at the latest.
Therefore, it is highly expected that the VLA1553 vaccine will be the first vaccine approved on a fast track for Chikungunya fever disease.
VLA1553 For the VLA1553 vaccine, multiple phase 1 and 3 clinical evaluations have currently been undergone and completed. (Refer to the status of clinical trials such as NCT04786444)

Title : Study to Demonstrate Consistency of Three Lots of a Live-attenuated Chikungunya Virus Vaccine Candidate in Healthy Adults
Collaborator: Themis Bioscience GmbH

Themis Bioscience GmbH

Themis Bioscience is an Austrian vaccine development pharmaceutical company developing immunomodulatory therapies for cancer and infectious diseases.
With its insight into the mechanisms of the human immune system, Themis has built a sophisticated and diverse technology platform related to the discovery, development and production of vaccines, as well as the activation mechanisms of the immune system.
In particular, Themis developed a measles virus vector platform based on a vector developed by scientists at Institute Pasteur, the world's leading European vaccine research institute. It has an extensive pipeline of vaccine candidates and immunomodulatory therapies. It was acquired by American pharmaceutical giant Merck in 2020.
The Chikungunya virus vaccine developed by Themis Bioscience is ‘MV-CHIKV’, a recombinant attenuated viral vector vaccine based on the measles virus vector. The vaccine is a Chikungunya vaccine based on a recombinant measles virus presenting pTM-MVSchw-CE3E26KE1 (C-E3-E2-6K-E1) of the CHIKV Schwartz strain.
Themis has independently conducted clinical trials to commercialize the recombinant attenuated viral vector MV-CHIKV vaccine.
For the MV-CHIKV vaccine, phase 2 clinical evaluation has currently been completed. (Refer to the status of clinical trials such as NCT05072080)

Title : Phase II Study to Evaluate Safety and Immunogenicity of a Chikungunya Vaccine (MV-CHIK-202)
Collaborator: Themis Bioscience GmbH

Bavarian Nordic

Bavarian Nordic is a Danish vaccine company focusing on the development, manufacturing and commercialization of vaccines for infectious diseases and cancer immunotherapy.
The Chikungunya virus vaccine developed by Bavarian Nordic is a virus-like particle (VLP) vaccine that consists of proteins with a self-assembling structure that are similar to virions but do not contain genomic nucleic acids.
These virion-like proteins are not infectious, but can trigger an immune response to achieve the immunogenicity required by the host.
The vaccine is CHIKV West African strain/37997 and is a VLP-based Chikungunya vaccine that expresses E1, E2, and C proteins, which are structural proteins of Chikungunya.
Currently, Bavarian Nordic has been conducting multiple clinical trials with Emergent BioSolution and NIAID to commercialize the Chikungunya VLP vaccine ‘VRC-CHKVLP059-00VP/PXVX 0317’.
For the VRC-CHKVLP059-00VP/PXVX0317 vaccine, multiple clinical evaluations have been conducted and completed (Refer to the status of clinical trials such as NCT05072080.)

Title : A Phase 3 Trial of the VLP-Based Chikungunya Vaccine PXVX0317
Collaborator: Emergent BioSolution

BHARAT BIOTECH

BHARAT BIOTECH is a pioneering Indian multinational biotechnology company known for its world-class R&D and manufacturing capabilities.
BHARAT BIOTECH's top priority is to supply affordable, safe, and high-quality vaccines and treatments to overcome infectious diseases in developing countries.
BHARAT BIOTECH's major research portfolio related to infectious diseases includes the development of vaccines against Chikungunya, rotavirus, malaria, and Staphylococcus aureus.
In 2020, CEPI (Coalition for Epidemic Preparedness Innovations) signed an agreement with BHARAT BIOTECH and the International Vaccine Institute Consortium to accelerate the development of Chikungunya vaccine and provided funding.
In addition, the consortium will receive additional research funding through the Ind-CEPI program, a CEPI cooperation project of the Indian government. The research funds will be used to build a GMP manufacturing facility for vaccine research in India and to manufacture vaccines for clinical trials.
In addition to supporting vaccine manufacturing, through this collaboration, IVI (International Vaccine Institute) provides research funds for multi-center phase 2/3 clinical trials conducted in Colombia, Panama, and Thailand to verify the safety and immunity of vaccine candidates.
Currently, BHARAT BIOTECH’s Chikungunya vaccine in clinical trials is the ‘BBV87’ vaccine, and the vaccine is an inactivated whole virus vaccine of the Chikungunya ECSA (East/Central/South African) strain.
With support from CEPI, BHARAT BIOTECH and IVI have currently been conducting two clinical trials to commercialize the Chikungunya vaccine,‘BBV87.
Currently, two clinical evaluations have been completed and recruitment is underway for the BBV87 vaccine.

Title : Clinical Trial to Evaluate the Immunogenicity of Chikungunya Vaccine, Seamless Controlled Trial To Evaluate Safety And Immuno genicity of Chikun gunya Vaccine in LatinAmerica and Asia (IVI-CHIK-001) (Refer to clinical trial status such as NCT04603131 and NCT04566484.)
Collaborator: No information provided

2 Major patent development entities

ModernaTX, Inc

Moderna is a biotechnology company founded in 2010 and has been leading the development of a new level of mRNA (messenger RNA) medicine.
Moderna has been developing vaccines for various infectious indications using the mRNA platform. In particular, it has been developing the following vaccines: varicella-zoster virus vaccine (mRNA 1278), cytomegalovirus vaccine (mRNA 1443), Apstein-Barr virus vaccine (mRNA 1195), Zika virus vaccine (mRNA 1893), and Chikungunya virus. Vaccines (mRNA-1944, VAL-181388), etc.
The Chikungunya vaccine 'mRNA-1944' being developed by Moderna is a vaccine in which human IgG antibody encoding mRNA isolated from the patient's B cells produced by Chikungunya infection is coated with Moderna's proprietary lipid nanoparticle (LNP). . When inoculated with this vaccine, it protects the host from Chikungunya infection.
In addition, the other Chikungunya vaccine ‘mRNA-1388’ being developed by Moderna is a vaccine in which a single mRNA encoding the structural polyprotein C-E3-E2-6K-E1 of Chikungunya virus is surrounded by lipid nanoparticles. When inoculated with this vaccine, it is processed in the body and assembled into VLPs, which then act as antigens to acquire immunogenicity.
Moderna has applied for a patent on the Chikungunya vaccine using the mRNA platform, and it has actively been conducting research as a major applicant.

Institut Pasteur

Institut Pasteur is a French non-profit research foundation dedicated to biology, microbiology, disease and vaccine research.
Institut Pasteur has been conducting research to respond to the threat of various infectious diseases (AIDS, diphtheria, tuberculosis, polio, influenza, yellow fever, Chikungunya, etc.) for over 100 years.
Institut Pasteur is conducting a research program on Chikungunya virus. Main research contents include research on Chikungunya virus variants, diagnostic methods, disease animal model development, and vaccine candidate design.
In fact, scientists at Institut Pasteur have applied for a patent related to the Chikungunya vaccine using a recombinant measles vector.
Themis, a joint applicant for patents related to recombinant measles vectors with Institut Pasteur, developed the ‘MV-CHIKV’ Chikungunya vaccine, a recombinant attenuated virus based on measles virus vectors, using the measles virus vector platform.
Institut Pasteur has currently been conducing a number of phase 2 clinical trials at Themis Bioscience to develop vaccines for commercialization.

Nipah Virus (NiV)

Overview

Nipah virus (NiV) is an RNA virus included in the Henipavirus genus of the Paramyxoviridae family. It is one of the deadly pathogens of biosafety level 4 that causes zoonotic Nipah virus (NiV) infections.
The representative natural host of Nipah virus (NiV) is fruit bats belonging to the Pteropus genus of the Pteropodidae family. Transmitted through ingestion of date palm sap contaminated with the urine or saliva of an infected bat, or through contact with or ingestion of a diseased pig, which is an intermediate or amplification host.¹⁾
Nipah virus (NiV) infection causes a variety of clinical symptoms ranging from acute respiratory infections to fatal encephalitis.
Since the Nipah virus (NiV) was first identified in Kampung Sungai Nipah village, Malaysia in 1998, cases have been steadily occurring in various regions every year, including Bangladesh, southeastern Asia, India, and Singapore.
Currently, there are no effective treatments or vaccines to treat Nipah virus (NiV) infection, making it one of the most lethal viruses in the world that requires high caution.

1) Nipah virus: epidemiology, pathology, immunobiology and advances in diagnosis, vaccine designing and control strategies - a comprehensive review. Veterinary Quarterly 2019.

View Nipah virus in detail

Nipah visus disease and Nipah virus

Definition	Acute, febrile and viral zoonotic infectious diseases caused by Nipah virus infection2)²⁾
WHO Disease classification	ICD-10 B33.8 (other specified viral diseases)
Pathogens	(Paramyxoviridae) (Henipavirus) (NIpah virus) (Negative single-stranded RNA virus)
Major vaccine antigens	Nipah virus glycoprotein (G, F)
Reservoir	Infected animals (fruit bats of the Pteropodidae and Pteropus genera, pigs, etc.), food contaminated with bodily fluids of infected animals, and patients in direct contact
Route of infection	Direct contact with virus-infected natural hospitals (e.g., fruit bats, pigs, etc.), direct contact with patients
Route of infection	Consuming food (e.g., palm sap or fruit) contaminated with bodily fluids from virus-infected animals
Domestic occurrence	None
Overseas occurrence	First report	The first case identified in Malaysia in 1998
	Occurrence trend	Since it first case occurred in Sungai Nipa village, Malaysia in 1998-1999, its sporadic outbreaks have occurred in the Nipa belt region, including Bangladesh, India, the Philippines, and Singapore3)³⁾
	Risk areas	Bangladesh, India, Malaysia, Philippines, Singapore, etc.
	Overseas inflow	None
Incubation period	About 4 -14 days
Clinical symptoms	Common symptoms of Nipah virus infection include fever and headache in the first 3-14 days, along with signs of respiratory illness such as cough, sore throat and difficulty breathing. A stage of brain swelling (encephalitis) may follow. Symptoms of this may include drowsiness, disorientation, and mental confusion. These symptoms can quickly progress to coma within 24-48 hours. (Mild symptoms) Fever, headache, cough, sore throat, difficulty breathing, vomiting, etc. (Serious symptoms) Disorientation, drowsiness or confusion, seizures, coma, cerebral edema (encephalitis)
Fatality rate	40-70% (depending on surveillance capacity in epidemic areas)
Diagnosis	Specific gene detection (real-time RT-PCR) and viral antigen-antibody reaction test in specimens (blood, body fluids, etc.)
Treatment	There are no specific treatments commercially available worldwide. Conservative treatment should be performed, and the antiviral drug ribavirin should be used when this virus is prevalent.
Prevention	There is no commercially available preventive vaccine worldwide. When traveling to an epidemic area, it is necessary to avoid contact with infected animals (bats, pigs, etc.), to avoid consuming date palm sap in the outbreak area, and to follow basic rules to prevent human-to-human infection.

※ Source: Weekly report on trends in domestic and international infectious diseases, Korea Centers for Disease Control and Prevention, 2018., 2023 SEOUL Infectious Disease Weekly News, SEOUL Citizen Health Bureau-Infectious Disease Research Center, 2023., IPion reconstruction.

2) Weekly report on trends in domestic and international infectious disease, Korea Centers for Disease Control and Prevention, 2018.
3) 2023 SEOUL weekly news on infectious diseases, SEOUL Citizen Health Bureau-Infectious Disease Research Center, 2023.

Domestic and international R&D trends

1 Trends in development of vaccines and treatments for Nipah virus

Vaccine candidates for Nipah virus (NiV) infection

To prevent Nipah virus (NiV) infection, there has been research on vaccination strategies using various platforms such as biocombined viral vectors, protein subunits, and virus-like particles (VLP).
Most vaccine candidates currently being developed use viral vector and protein subunit vaccine platforms.

Candidates for treatment of Nipah virus (NiV) infection

Since there are currently no effective antiviral drugs, antibodies or vaccines against Nipah virus infection, high caution is required.
Regarding treatment, when possible, adjuvant therapy for severe respiratory and neurological complications,is currently used as the standard of care for Nipah virus infection.

2 Animal models for Nipah virus (NiV) infection

Types of animal models for Nipah virus (NiV)

Nipah virus (NiV) infects a wide range of wild and domestic animals, including fruit bats, cats, pigs, and horses. The symptoms of animals are not similar to those of humans or are variable depending on the type, so any animal cannot be used as an animal model for Nipah virus.
Currently, representative animal models for Nipah virus include Syrian golden hamsters, ferrets, and African green monkeys. These animals are used as animal testing models because they most accurately represent the symptoms and pathology of Nipah virus infection in humans.

Overseas

1 Vaccine developers undergoing clinical trials

Auro Vaccines LLC

Auro Vaccines is a company that designs and develops preventive and therapeutic vaccines for infectious diseases and develops clinical-stage vaccines.
With permission from the Henry M. Jackson foundation, Auro Vaccines conducted clinical trials for a recombinant subunit vaccine (HeV-sG-V) composed of the glycoprotein (G protein, glycoprotein) of the Hendra virus to prevent Nipah virus (NiV) infection. Research is in progress.
With the support of the National Institutes of Allergy and Infectious Diseases (NIAID) and the Coalition for Epidemic Preparedness Innovations (CEPI) on the HeV-sG-V Nipah vaccine candidates, there have been studies on their immunogenicity and efficacy in small animals and IND activation safety. Aa a result, cGMP vaccine manufacturing and launch have been completed.
The vaccine has currently been undergoing phase 1 clinical evaluation (NCT04199169)

Title : Safety and Immunogenicity of a Nipah Virus Vaccine
Collaborator : PATH, Coalition for Epidemic Preparedness Innovations, Cincinnati Children's Hospital Medical Center (CCHMC)

Public Health Vaccines(PHV) LLC

PHV is a privately held biotechnology company that owns the rVSV technology platform and has been developing vaccines for other filoviruses and new variants of infectious diseases. It has successfully developed an rVSV vector-based Ebola Zaire vaccine in the past.
PHV02 (rVSV∆G-EBOV GP/NiV G), a Nipah virus vaccine being jointly developed with PHV and Crozet BioPharma, is a one-time attenuated Nipah virus vaccine using a vesicular stomatitis virus (VSV) vector.
- Source : Nipah Vaccine Target, The Nipah Vaccine Project
The rVSV-Nipah vaccine was first developed by Dr. Heinz Feldmann at the laboratory of intramural research at the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health (NIH).
PHV has received funding to advance its vaccine candidate through Phase 2 clinical testing under a partner agreement worth up to $43.6 million with the Coalition for Epidemic Prevention Innovations(CEPI).
PHV and CEPI opened a website related to Nipah vaccine development
The vaccine has currently been undergoing phase 1 clinical evaluation (NCT05178901)

Title : A Phase 1 Study to Evaluate Safety & Immunogenicity of rVSV-Nipah Virus Vaccine Candidate PHV02 in Healthy Adult Subjects
Collaborator : Coalition for Epidemic Preparedness Innovations

Moderna

Moderna is a biotechnology company focusing on developing messenger RNA treatments and vaccines. Since 2021, it uses mRNA platform technology to develop vaccines that can prevent influenza, HIV and Nipah virus.
In July 2022, Moderna began an early-stage clinical trial with the National Institute of Allergy and Infectious Diseases (NIAID) to evaluate an investigational vaccine to prevent Nipah virus infection.
The experimental vaccine has been manufactured by Moderna in Cambridge, Massachusetts, and has been developed jointly with NIAID's Vaccine Research Center.
- Source : Moderna Presentation, 2021.
The mRNA-1215 vaccine used in this clinical trial utilizes NiV's antigen (F or G glycoprotein) and mRNA platform technology.
Through this clinical trial, the vaccine's safety, tolerability, and ability to generate an immune response will be evaluated.
The vaccine has currently been undergoing phase 1 clinical evaluation (NCT05398796)

Title : Dose Escalation, Open-Label Clinical Trial to Evaluate Safety, Tolerability and Immunogenicity of a Nipah Virus (NiV) mRNA Vaccine, mRNA-1215, in Healthy Adults
Collaborator : Moderna TX, Inc, National Institute of Allergy and Infectious Diseases (NIAID)

2 Major patent development entities

Henry M. Jackson Foundation

The Henry M. Jackson Foundation (HJF) is a global non-profit organization dedicated to advancing military medical research. It serves the military, medical, academia, and government by managing and supporting scientific programs that benefit both military members and civilians.
HJF identifies infectious diseases as one of the greatest threats to the military's mission capability and operational readiness.
HJF believes that infectious diseases can affect international stability by weakening the economy, military, and government. Thus, it has been strengthening its research portfolio to promote public-private partnerships and develop new solutions.
The foundation's support and management enables military medical researchers and clinicians to maintain scientific goals and to achieve research goals effectively and efficiently.
A representative example of HJF's support is the technology transfer of the HeV-sG-V vaccine developed by the USU Broder laboratory. The technology is licensed to Auro Vaccines LLC through the USU-HJF joint technology transfer office.
Currently, the vaccine has been undergoing phase 1 clinical trials with support from the Coalition for Epidemic Preparedness Innovations(CEPI) since March 2020 (same as HeV-sG-V mentioned above).
HJF has also conducted research on Nipah virus, one of the infectious diseases. Since it holds a number of patents, it has actively conducted research.

Zoetis Services LLC

Zoetis is the world's largest veterinary pharmaceutical company, producing American medicines and vaccines for pets and livestock.
Zoetis was originally a subsidiary of Pfizer, the world's largest pharmaceutical company, but it became a completely independent company when Pfizer spun off 83% of the company's shares.
Zoetis is the world's No. 1 animal medicine company and has a portfolio of more than 300 products. Since it entered the animal health diagnosis business by acquiring Abaxis in 2018, it has built an animal health value chain ranging from prediction-prevention-diagnosis-treatment.
- Source : Joetis website
Zoetis developed a vaccine for the bat-borne Hendra virus, which is associated with a highly fatal infection in horses and humans, in November 2012.
The vaccine is a Hendra virus neutralizing subunit vaccine that can only be used in horses, and it consists of a soluble form of the G surface antigen against the virus.
In addition, Zoetis has diversified its portfolio, including treatments against various bacterial diseases for livestock, vaccines to prevent various highly contagious diseases, and virus vaccines.
Currently, Joetis holds the above Nipah virus-related vaccine technologies for livestock and a number of Nipah virus-related patents.

Curevac

CureVac is a German biopharmaceutical company developing treatments based on messenger RNA. It primarily focuses on building an mRNA-based pipeline baed on three therapeutic areas: infectious disease prevention vaccines, cancer immunotherapy, and molecular therapy.
CureVac’s pipeline include mRNA-based infectious disease prevention vaccines for Influenza, COVID-19, Rabies virus, Lassa, Yellow fever, Rotavirus, Malaria, and others (Nipah virus). It has been developing vaccines for various infectious diseases.
In addition, CureVac also holds patents on Nipah virus (NiV) using mRNA.

Domestic

GeneOne Life Science

In December 2021, GeneOne Life Science signed a technology transfer agreement with the U.S. Wistar Institute of Anatomy x-x-and Biology for a nucleic acid vaccine candidate that prevents Nipah and Powassan viruses.
GeneOne Life Science uses its nucleic acid vaccine development platform to plan clinical development of DNA vaccines and mRNA vaccines as well as licensing commercialization with vaccine companies in Southeast Asia, where the Nipah infectious disease is spreading.
Furthermore, GeneOne Life Science declared joint research with the Wistar Research Institute to develop new small molecule compounds for the prevention and treatment of Nipah virus in May 2023.
GeneOne Life Science has begun research and development of a new modality, a small molecule compound-based antiviral treatment, in addition to the vaccine against Nipah virus currently under development, as part of product portfolio diversification.

VERNAGEN

VERNAGEN, ST Pharm's U.S. subsidiary, has recently signed an agreement to jointly research and develop an mRNA vaccine for Heartland Virus (HRTV) with the U.S. Centers for Disease Control and Prevention (US-CDC).
VERNAGEN plans to discover heartland virus-related mRNA vaccine candidates using ST Pharm’s mRNA platform technology. ST Pharm plans to take charge of contract manufacturing development (CDMO), to produce samples, and to supply them to the U.S. Agency for Disease Control and Prevention.
VERNAGEN has also been focusing on research and development of mRNA-based infectious disease prevention vaccines and treatments. In addition to joint research with the US-CDC, it has been researching and developing mRNA vaccines for various infectious diseases such as Nipah virus (NiV), SFTSV, varicella-zoster virus (VZV), and respiratory syncytial virus (RSV).

Lassa virus (LASV)

Overview

Lassa virus (LASV) is an enveloped, two-segmented single-stranded RNA virus belonging to the Arenaviridae family. It is one of the BSL-4 lethal pathogens that cause Lassa fever, a zoonotic acute viral hemorrhagic disease.
The representative natural host of Lassa virus is Mastomys natalensis, a rodent native to West Africa. The virus is spread through contaminated food, water, feces, or slaughter and consumption of intermediate hosts by infected rodents.
Lassa fever can cause a variety of symptoms, from asymptomatic and mild headaches and fever to severe symptoms such as bleeding in various parts of the body.
Lassa virus has been occurring regularly in parts of West Africa since it was first identified in the town of Lassa, Nigeria, in 1969. Therefore, its cases have steadily been occurring in various regions such as Benin, Ghana, Guinea, Liberia, Mali, Nigeria, Sierra Leone, and Togo.
Currently, there are no effective treatments or vaccines for Lassa fever. Thus, Lassa virus is one of the deadliest viruses in the world that requires high caution.

View Lassa virus in detail

Lassa Fever and Lassa virus

Definition	Acute febrile and hemorrhagic disease caused by Lassa virus infection1)¹⁾
Disease classification	Class 1 infectious disease (disease code: A96.2)
Pathogens	(Arenaviridae) 라싸 (Lassa virus) (Single-stranded RNA virus divided into two segments)
Major vaccine antigens	Envelope GPC(GP1, GP2) glycoprotein
Reservoir	Mastomys natalensis among rodents
Route of infection	Animal → People	Direct or indirect contact with infected rodents (rats)/inhalation of rodent droppings (urine, feces) (Ingestion) Ingestion of food contaminated with rats or rat droppings (Contact) Exposure of broken skin or mucous membranes to rat feces absorbed into the soil (Inhalation) Inhalation of aerosols generated during cleaning of floors contaminated with rat droppings
Route of infection	People → People	Contact with blood or body fluids of Lassa fever patients or deceased (Contact) Direct contact with the patient's blood or body fluids on the wounded skin or mucous membrane (Contact) Sexual contact with an infected patient (Contact/inhalation) Infection spread through exposure during medical treatment or procedures in a medical environment
Domestic occurrence	None
Overseas occurrence	First report	An outbreak was reported in Lassa area, Borno State, Nigeria in 1969.
	Occurrence trend	In West Africa, outbreaks occur during the dry season (November to May) and occur sporadically throughout the year.
	Risk areas	Benin, Ghana, Guinea, Nigeria, Liberia, Mali, Sierra Leone, Burkina Faso, Côte d'Ivoire, Togo Central African Republic (others in West Africa)
	Overseas inflow	1969-2016, 33 cases in 9 countries (UK(13), US(8), Germany(5), Netherlands(2), Canada(1), Israel(1), Japan(1), Sweden(1), South Africa(1))
Incubation period	About 2 -21 days
Clinical symptoms	About 80% of infected people have mild symptoms or are asymptomatic. However, it is possible for symptoms to become severe and cause illness.2)²⁾ Usually, symptoms appear between 6-21 days after infection, and improve within 8-10 days if survived. - Symptoms start with fever, general weakness, malaise, headache, and sore throat. - Pain response, digestive system, and respiratory system symptoms may appear within a few days. When symptoms are severe, death may occur due to facial edema, bleeding, and multiple organ failure
Fatality rate	About 1-3% of infected people, 15-20% of hospitalized patients* Varies depending on the level of the health care system in each country (fatality rate during the 2015-2016 epidemic in Nigeria was 32.6%)
Diagnosis	Detection of specific genes in samples (blood, body fluids, etc.) (Real-time RT-PCR)
Treatment	There is no specific treatment commercially available worldwide (symptomatic treatment). However, antiviral drugs (ribavirin) are known to be effective when administered in the early stages of symptoms.
Prevention	There is no commercially available preventive vaccine worldwide. There is no commercially available preventive vaccine worldwide. - Be careful not to be exposed to rats/rat droppings, avoid eating food that is open without a lid, etc. Strictly follow infection prevention rules in medical environments. - Observe standard precautions such as use of personal protective equipment and hand hygiene when contacting blood or body fluids of all patients. - Be careful when handling blood, body fluids, and specimens from people with infection symptoms (fever, etc.) and confirmed Lassa fever patients, etc.

※ Source: Korea Disease Control and Prevention Agency (KDCA), Viral Hemorrhagic Fever Response Guidelines for Class 1 Infectious Diseases, 2023, Jeju Center for Infection Control (JeCI) website, IPion reconstruction

1) KDCA, Guidelines for Response to Viral Hemorrhagic Fever, a Class 1 Infectious Disease, 2023.
2) Jeju Center for Infection Control (JeCI) website.

Domestic and international R&D trends

1 Trends in development of vaccines and treatments for Lassa virus

Vaccine candidates for Lassa virus infection

The major vaccine platforms for Lassa virus being developed include DNA vaccines, virus-like particle vaccines (VLP), recombinant vesicular stomatitis virus (VSV), rabies, measles, vaccinia, and adenovirus vector vaccines.
There are currently the following vaccine platform types in the clinical trial stage for vaccines against Lassa fever: rVSV based, DNA based, MV-LASV, etc³⁾⁴⁾

3) Understanding Immune Responses to Lassa Virus Infection and to Its Candidate Vaccines, Vaccines, 2022.
4) ClinicalTrials.gov(2023.8)

Candidates for treatment of Lassa virus infection

There are currently no approved treatments or vaccines for Lassa fever. However, in the case of its treatment, there are observations showing that early administration of Ribavirin after Lassa fever infection shows therapeutic efficacy. In addition, there have been studies on various drugs such as Favipiravir (T-705).⁵⁾
Drugs in the clinical trial stage for treating Lassa fever include Ribavirin, Favipiravir, and ARN-75039.

5) Lassa Virus Infection: a Summary for Clinicians, ELSEVIER, 2022.

2 Animal model for Lassa virus infection

Types of animal models for Lassa virus

Representative animal models used for non-clinical experiments to develop vaccines and treatments for Lassa virus include mice, guinea pigs, and monkeys (primates).
Recently, animal models suitable as infection models for Lassa virus have been developed. Among these animal models, there are many cases in which clinical signs similar to Lassa virus have been induced through some genetic modification.

Animal models for Lassa virus

Animal modesl for Lassa virus	Pros	Cons
Murine Models Murine Models(Natalensis mastomys, IFNAR-/-, Chimeric IFNAR-/-B6, IFNαβ/γR-/-, STAT1-/-, CBA, HHD, etc)	Large-scale experiments are possible on a small scale and at low cost Useful model for early vaccine and antiviral drug screening	Mice with normal immunity possess LASV resistance → Genetic modification is required and considered Limited reagent dosage
Guinea Pig Models (Strain 13-inbred, Hartley-outbred 등)	Large-scale experiments are possible on a small scale and at low cost Useful model for early vaccine and antiviral drug screening	Difficulty obtaining inbred guinea pigs and slightly genetically modified guinea pigs Limited reagent dosage
Non-Human Primate Models (Cynomolgus macaques, Rhesus monkey, Marmoset, Squirrel monkeys 등)	Primate animal models most similar to human physiology and immune response Observation of clinical signs most similar to actual Lassa fever is possible Most useful model in vaccine/antiviral evaluation and pathogenesis research	High cost and difficulty in management Experienced researchers and assistants required Difficulties in large-scale experiments

※ The animal models indicated in bold in the table above are the animal models most frequently used in S to A class papers on Lassa virus according to the paper analysis in this report.
※ Source: Animal Models of Lassa Fever, Pathogens, 2020.

Each of the above animal models has clear advantages and disadvantages. Among them, non-clinical experiments using Cynomolgus macaques monkeys, the most representative primate model of Lassa virus, have very high experimental value.⁶⁾
This is because primates show physiological and immunological characteristics most similar to humans.

6) Animal Models of Lassa Fever, Pathogens, 2020.

Overseas

1 Vaccine developers undergoing clinical trials

INOVIO Pharmaceuticals

Inovio Pharmaceuticals is an American biotechnology company that develops synthetic DNA products for the treatment of cancer and infectious diseases based on DNA.
Inovio's technology inserts engineered DNA into cells, where it is transcribed into mRNA, translated into protein, and the protein encoded by the DNA stimulates the production of T-cells and antibodies that help in recovery, thereby providing immunity against cancer and viral antigens. Inducing a reaction.
INO-4500, a vaccine against Lassa virus being developed by Inovio, is a DNA vaccine that encodes the LASV GPC (glycoprotein precursor) gene of the LASV Josiah (type IV) strain.
The vaccine is administered by using Inovio's CELLECTRA smart device to deliver it directly to cells within the muscle/subcutaneous tissue.
Inovio has conducted two clinical trials with funding from the Coalition for Epidemic Preparedness Innovations (CEPI) to develop a DNA-based Lassa virus vaccine (INO-4500).
However, in November 2022, the vaccine showed a certain level of immune response during clinical trials, but the degree of immune response following the two-dose regimen did not meet CEPI's selection criteria for further development. Thus, the development of the vaccine was stopped.
Phase 1 clinical evaluation of the INO-4500 vaccine has now been completed (NCT04093076, NCT03805984).

Title : Dose-ranging Study: Safety, Tolerability and Immunogenicity of INO-4500 in Healthy Volunteers in Ghana, Safety, Tolerability and Immunogenicity of INO-4500 in Healthy Volunteers
Collaborator : Coalition for Epidemic Preparedness Innovations

Themis Bioscience

Themis Bioscience is an Austrian vaccine development pharmaceutical company that has been developing immunomodulatory therapies for cancer and infectious diseases.
Themis has built a sophisticated and diverse technology platform related to the discovery, development and production of vaccines as well as the activation mechanism of the immune system with outstanding insight into the mechanisms of the human immune system.
In particular, Themis developed the measles virus vector platform based on the vector developed by scientists at Institute Pasteur, the world's leading European vaccine research institute. It has an extensive pipeline of vaccine candidates and immunomodulatory therapies. Acquired by the American pharmaceutical giant Merck in 2020.
The vaccine against Lassa virus developed by Themis Bioscience is a recombinant attenuated virus vector ‘MV-LASV’ vaccine based on the measles virus vector. The vaccine is a recombinant measles virus expressing LASV GP and LASV NP of the LASV Josiah (type IV) strain.
Themis received funding from CEPI (Coalition for Epidemic Preparedness Innovations) to commercialize the recombinant attenuated virus vector MV-LASV vaccine and conducted a phase 1 clinical trial in 2019.
Phase 1 clinical evaluation of MV-LASV vaccine has been completed. (NCT04055454)

Title : A Trial to Evaluate the Optimal Dose of MV-LASV (V182-001)
Collaborator : Coalition for Epidemic Preparedness Innovations, Harmony Clinical Research Assign Data Management and Biostatistics GmbH

International AIDS Vaccine Initiative(IAVI)

The International AIDS Vaccine Initiative (IAVI) is a global non-profit scientific research organization dedicated to accelerating the development of vaccines to prevent HIV infection and AIDS.
IAVI conducted policy analysis and researched and developed vaccine candidates. It develops vaccines and antibodies not only for AIDS but also for tuberculosis, emerging infectious diseases, and neglected diseases.
In particular, IAVI promotes collaboration between academia, industry, communities, governments, and funders to identify and improve ways to address public health issues disproportionate to those living in poverty.
The Lassa virus ‘rVSV∆G-LASV-GPC’ vaccine, which IAVI is researching and developing, is a technology that IAVI secured through a non-exclusive license agreement from the Public Health Agency of Canada (PHAC) in 2018.
The rVSV∆G-LASV-GPC vaccine is a recombinant vesicular stomatitis virus vector vaccine based on the VSV (Vesicular Stomatitis Virus) virus. It is an attenuated recombinant vesicular stomatitis virus expressing the LASV glycoprotein precursor (GPC) of the LASV Josiah (type IV) strain
IAVI has been conducting phase 1 clinical trials with partial funding and cooperation from the Coalition for Epidemic Preparedness Innovations (CEPI) to commercialize the recombinant attenuated virus vector ‘rVSV∆G-LASV-GPC’ vaccine. It is also scheduled to undergo phase 2 clinical trials.
IAVI is currently recruiting volunteers to conduct phase 2 clinical trials for the vaccine in West Africa.
Phase 1 clinical evaluation is currently underway for the rVSV∆G-LASV-GPC vaccine. (NCT04794218) Its phase 2 clinical evaluation is also scheduled to be conducted. (NCT05868733)

Title : A Clinical Trial to Evaluate the Safety and Immunogenicity of rVSV∆G-LASV-GPC Vaccine in Adults in Good General Heath, A Lassa Fever Vaccine Trial in Adults and Children Residing in West Africa
Collaborator : George Washington University, Brigham and Women's Hospital, Redemption Hospital, East-West Medical Research Institute Coalition for Epidemic Preparedness Innovations

2 Major patent development entities

Curevac AG

CureVac AG is a German biopharmaceutical company developing treatments based on messenger RNA. It primarily focuses on three therapeutic areas: infectious disease vaccines, cancer immunotherapy, and molecular therapy, building an mRNA-based pipeline.
CureVac's pipeline includes mRNA-based infectious disease prevention vaccines for Influenza, COVID-19, Rabies virus, Lassa, Yellow fever, Rotavirus, Malaria, and others (Nipah virus). It has been developing vaccines for various infectious diseases.
In 2019, CureVac signed a partnership agreement worth up to $34 million with the Coalition for Epidemic Preparedness Innovations (CEPI) to develop RNA Printer™, a technology in the field of mRNA-based vaccines against multiple pathogens.
RNA Printer™ can produce mRNA (producing more than 100,000 doses) consisting of several grams of LNPs in just a few weeks. The platform can be utilized to produce mRNA vaccine candidates against multiple pathogens.
With the innovative platform, CureVac has been developing vaccines targeting known pathogens (Lassa Fever, Yellow Fever, and Rabies) under the terms of a three-year partnership agreement.
As for the status of patent applications for vaccines against Lassa virus, CureVac AG has applied for 2 patents, including 1 class S (Lassa virus vaccine) and 1 class A (NOVEL LASSA VIRUS RNA MOLECULES AND COMPOSITIONS FOR VACCINATION). Thus it has actively been conducting research as a major patent applicant.

Scripps Research Institute

The Scripps Research Institute is a medical research institute that focuses on basic biomedical research and is a non-profit medical research facility in the United States. It is the world's most influential research institute, with large-scale laboratory facilities, more than 1,100 patents, and more than 10 FDA-approved therapeutics.
Scientists at the Scripps Research Institute have been using infectious disease genomics to investigate the epidemiology and viral evolution of the most lethal pathogens, such as Zika, Ebola, Lassa, and SARS-CoV-2.
By combining results from computational biology, experiments and the field, the researchers hope to change the way vaccines and treatments are developed against pathogens and other emerging pathogens.
In 2022, Ward and his colleagues at the Scripps Research Institute discovered the mechanism by which Lassa virus glycoproteins combine into trimers using nanoparticles. In addition, they isolated glycoprotein trimers from four different Lassa virus strains and, through structural characterization and the use of nanotechnology, found that the structures of glycoproteins were very similar even in different strains.
Currently, Ward's research team plans to conduct future experiments to identify more antibodies against the Lassa virus glycoprotein and further analyze the protein structure to identify ideal sites for drug targeting on the glycoprotein.
As for the status of Lassa virus vaccine patent applications, the Scripps Research Institute has applied for 3 patents, including 1 class A (Arenavirus vaccine) and 2 class B (ARENAVIRUS MONOCLONAL ANTIBODIES AND USES, METHODS AND COMPOSITIONS RELATED TO VIRAL VACCINES WITH IMPROVED PROPERTIES). Thus, it has actively been conducting research as a major patent applicant.

The Academy of Military Medical Sciences(中国人民解放军军事科学院军事医学研究院)

Academy of Military Medical The Academy of Military Medical Sciences is a military medical research institute in Shanghai, China, and participated in the development of Ebola virus and coronavirus vaccines in 2014.
It has also shown great interest in Lassa virus research. As for vaccine patent applications for Lassa virus, the Academy of Military Medical Sciences has applied for two S-class patents(Recombinant virus expressing empty capsid of lassa fever virus and preparation method of recombinant virus, Recombinant virus strain for expressing double-copy Lassa fever virus GP gene as well as construction method and application of recombinant virus strain). Thus, it has actively been conducting research as a major patent applicant.
In addition to the three research entities above, major patent development entities include UNIVERSITY OF ROCHESTER, one of the top research universities in the United States, and INSTITUT PASTEUR, a French non-profit research organization that conducts basic and applied research on microorganisms, infectious diseases, vaccines, etc.

Dengue virus

Overview

Dengue virus (DENV) is an enveloped, positive, single-stranded RNA virus belonging to the Flaviviridae family and the Flavivirus genus. It is one of the deadly pathogens of biosafety level 3 that causes dengue fever, a zoonotic acute febrile disease, when bitten by vector-borne mosquitoes infected with the virus.
In addition, representative natural hosts of Dengue virus include Aedes aegypti or Aedes albopictus. The infection is spread by being bitten by a vector mosquito infected with the dengue virus.
Dengue fever caused by dengue virus ranges from asymptomatic and mild headache, fever, and rash to serious symptoms such as inflammatory joint pain, dengue hemorrhagic fever, and dengue shock syndrome (plasma leak, fluid retention, breathing difficulties, severe bleeding, organ failure, etc.). It appears clearly. Its complications can lead to death.
Dengue virus was distributed throughout tropical regions in the 18th and 19th centuries. However, as it spread more rapidly due to globalization in the 20th and 21st centuries, the virus of various serotypes was introduced, became endemic in most tropical regions of the world, and continues to spread.
Currently, there is no effective treatment for Dengue fever. The approved vaccine is the live-attenuated yellow fever Dengvaxia® vaccine developed by Sanofi Pasteur. However, its use is primarily recommended only for individuals who have had a previous dengue infection. It is one of the deadly viruses that still requires great caution due to its large side effects.

View Dengue virus in detail

Dengue Fever and Dengue Virus

Definition	Acute febrile illness caused by dengue virus infection1¹⁾²⁾
Disease classification	Class 3 infectious disease (disease codes: A90.0, A91.0)
Pathogens	(Flaviviridae) (Flavivirus) (Dengue virus) (Benign single-stranded RNA virus)
Major vaccine antigens	structural proteins(Premembrane(prM), Envelope(E))
Reservoir	Aedes mosquitoes (Aedes albopictus or Aedes aegypti), humans
Route of infection	Aedes mosquito ↔ People	Infection is spread through the bite of a vector mosquito infected with the dengue virus. The virus can be transmitted to vectors (mosquitoes) by sucking blood from a person infected with the dengue virus and suffering from a persistent fever.
Route of infection	People → People	Blood transfusion, sexual contact, placenta, breast milk, etc.
Domestic occurrence	It was designated as a statutory infectious disease in 2000, and there have been no domestic cases of it.
Overseas occurrence	First report	AIt is difficult to know the exact time of the outbreak of the dengue virus, but it has existed for so long that there is a book published during the Jin Dynasty (265-420) in China.
	Occurrence trend	IIt occurs in more than 100 countries around the world, and the endemic area is very widespread, mainly in tropical and subtropical regions, up to 35° north and south latitude based on the equator. Because mosquitoes that spread dengue fever mainly breed in stagnant water, the number of patients increases rapidly during the rainy season.
	Risk areas
	Overseas inflow	Domestic reporting status due to overseas inflow: 227 people on average from 2013 to 2019, 43 people in 2020, 3 people in 2021, 104 people in 2022.
Incubation period	5-7 days
Clinical symptoms	Dengue fever has a diverse disease course, and approximately 75% of infected people are asymptomatic, and when symptoms occur, most symptoms appear as non-specific symptoms or acute febrile symptoms. In general, the clinical course of dengue fever progresses into the fever phase, acute phase, and recovery phase. Febrile phase: Typically lasts 2-7 days. - Occurrence of various diseases such as headache, muscle pain, rash, joint pain, decrease in white blood cells/platelets, increase in liver function level, etc. Acute phase (Critical phase/Plasma leak phase): Lasts 1-2 days (4 days) after fever - Most patients recover during this period - Patients with severe plasma leakage may develop severe dengue fever due to increased vascular permeability. Recovery or Convalescent phase - The patient's hematocrit stabilizes and diuresis improves. - Rashes in the recovery phase cause skin peeling or itching. About 5% of all dengue fever patients show severe dengue infection. - It is also called dengue hemorrhagic fever and dengue shock syndrome. - It occurs more often in children than adults. Its main symptoms are abdominal pain, persistent vomiting, rapid breathing, plasma leakage, fluid retention, severe bleeding, and organ failure, which can lead to death. - If a previously infected patient is re-infected with a different serotype, it is likely that the patient will develop severe dengue fever.
Fatality rate	1% if treated early, about 20% if treated late
Diagnosis	Detection of specific genes in samples (blood, body fluids, etc.) (Real-time RT-PCR)
Treatment	There is no specialized treatment worldwide; thus, symptomatic treatment is best.
예방	There is an FDA-approved vaccine, Dengvaxia®, commercially available worldwide, but it is recommended only for individuals with a previous dengue infection. Its side effects are great. When traveling to an endemic area, it is most important to avoid being bitten by mosquitoes (mosquito repellent, long clothes, etc.)

Source: Overview of dengue fever disease, Korea Disease Control and Prevention Agency (KDCA), 2022., [Level 3] Dengue fever, Busan Center for Infection Desease Control & Prevention 2023, Reconstruction.

1) Overview of dengue fever disease, KDCA, 2022.
2) [Level 3] Dengue fever, Busan Center for Infection Desease Control & Prevention 2023.

Domestic and international R&D trends

1 Trends in development of treatments and vaccines for Dengue virus infection

Vaccine candidates for dengue virus infection

Currently, the only FDA-approved vaccine for dengue fever is the live-attenuated yellow fever-based Dengvaxia® vaccine developed by Sanofi Pasteur. After that, there are the live-attenuated TAK-003 vaccine from Takeda Pharmaceuticals and the live-attenuated TV003/TV005 vaccine from NIAID (National Institute of Allergy and Infectious Diseases, Butantan Institute), which are in phase 3 clinical trials.³⁾
In addition, there have ccurrently been clinical trials and preclinical studies on vaccines, including TDENV-LAV, V181, rDEN1, 2, 3, 4Δ30, TDENV-PIV, V180, DENV NS1, cED III, pNS1-tPA, TVDV, CAdVax-Den, Baculovirus-expressed NS1, MV-DEN, DSV4, etc.

3) Dengue overview: An updated systemic review, J Infect Public Health, 2023.

Candidates for the treatment of dengue virus infection

There is currently no approved treatment for dengue virus. Representative treatments being developed include dengue plasma leak inhibitors (e.g., Ketotifen, Montelukast) and antivirals (e.g., EYU688, AT-752, Ivermectin, JNJ-64281802, Atibuclimab (IC14), Chloroquine, Celgosivir, Melatonin), and they are mainly distributed in phase 1/2 clinical trials or above.⁴⁾
In addition, there have been studies on Modipafant, Dengushield, AV-1, Zanamivir, Balapiravir, Dexamethasone, Lovastatin, Single donor platelet transfusion, Recombinant human IL-11, Prednisolone, Carbazochrome sodium sulfonate, etc.⁵⁾

4) Inhibitory Potential of Chromene Derivatives on Structural and Non-Structural Proteins of Dengue Virus, Viruses, 2022.
5) Dengue: A Minireview, Viruses, 2020.

2 Animal models for Dengue virus infection

Types of animal models for dengue virus

Representative animal models used in non-clinical experiments to develop vaccines and treatments for dengue virus include mice, monkeys (primates), pigs, and tree shrews6⁶⁾
Recently, animal models suitable as dengue infection models have been developed. Among these animal models, there are many cases in which clinical signs similar to dengue fever have been induced through some genetic modification.

Animal models for Dengue virus

Animal modesl for Degue virus	Pros	Cons
Murine Models (C57BL/6 and BALB/c mice, AG129 mice, Humanized mice)	Large-scale experiments are possible on a small scale and at low cost Availability of extensive literature, tools and reagents. Easy experimentation using transgenic animals Reproducibility of high viremia and thrombocytopenia due to dengue fever	Evolutionary distance Lack of obvious clinical symptoms in some species Limitations on reagent dosage and analysis time limited immune response
NHP (Rhesus macaques, Cynomolgus macaques, Marmoset, Bonnet macaque, Chimpanzee) Models	Primate animal models most similar to human physiology and immune response evolutionarily. Clinical signs most similar to actual dengue fever can be observed, including the infection process, viremia, proliferation and spread, and viral persistence.	Large animals causing high cost and difficulty in management, Skilled researchers and assistants required Ethical constraint issues Lack of obvious clinical symptoms in some species
Swine Models (Yucatan miniature pig)	Clinical symptoms of dengue fever (e.g., viremia and skin rash) can be observed. 비교적 relatively low cost 면역학적 Availability of immunological reagents Physiological/immunological responses similar to humans can be observed in some species	Lack of obvious clinical signs
Tree shrew Models	Clinical symptoms of dengue fever (e.g., increased body temperature, thrombocytopenia, etc.) can be observed They have higher genetic similarity to primates than rodents and are suitable for evaluating dengue fever-related antiviral drugs and vaccines.	Very low viremia Lack of obvious clinical signs

※ Please refer to the source paper for specific data showing the characteristics of each species in each animal model.
※ Source: Mammalian animal models for dengue virus infection: a recent overview, Arch Virol, 2022. Reconstructed.

Each of the above animal models has clear advantages and disadvantages. Among them, non-clinical experiments using the most representative monkeys, Cynomolgus macaques and Rhesus macaques, as primate models of dengue virus have very high experimental value.
The reason is that primates show physiological and immunological characteristics most similar to humans.

6) Mammalian animal models for dengue virus infection: a recent overview, Arch Virol, 2022.

Overseas

NIAID(National Institute of Allergy and Infectious Diseases)

The U.S. National Institute of Allergy and Infectious Diseases (NIAID) is one of 27 institutions and centers that make up the National Institute of Health (NIH), an affiliate of the U.S. Department of Health and Human Services (HHS).
NIAID's main goal is the interpretation of infectious, immunological, and allergic diseases and the development of vaccines and treatments. For the purpose, it has been carrying out basic and applied research.
TV003/TV005, a dengue virus-related vaccine developed by NIAID is a chimeric herbal detoxified vaccine that provides the backbone of four dengue viruses with about 30 nucleotides deleted. The vaccine uses the live virus itself as an antigen to confer immunogenicity to the host.
The U.S. Department of Health and Human Services (HHS) mentioned above does not appear as a direct sponsor in the clinical status, but a number of clinical trials have been confirmed under the name of NIAID, a subordinate organization. In the patent field, it has applied for patents on attenuated vaccines due to chimeric nucleotide deletion (Δ30) for dengue virus serotypes 1, 2, 3, and 4. Thus, it has actively been conducting research as a major patent applicant,
Currently, multiple phase (Phrase 1/2/3) clinical evaluations for TV003/TV005 vaccines have been conducted and completed (representative clinical trial, NCT02406729, etc.)

Title : Phase III Trial to Evaluate Efficacy and Safety of a Tetravalent Dengue Vaccine
Sponsor and Collaborator : Butantan Institu

Takeda Pharmaceutical & Co.

Takeda Pharmaceutical Company is Japan's largest pharmaceutical company. Based on sales, it ranks as the world's 9th largest pharmaceutical company.
Takeda Pharmaceutical Company has been conducting innovative research for the world's most difficult infectious diseases (e.g., dengue fever, COVID-19, pandemic influenza, Zika virus, etc.) mainly in the field of anticancer drugs, gastrointestinal diseases, and treatments related to the central nervous system and global vaccine business.
TAK-003 vaccine, being developed by Takeda Pharmaceutical Company, is a live-attenuated vaccine based on serotype 2, which provides the backbone of all four engue viruses. The vaccine uses the live virus itself as an antigen to confer immunogenicity to the host.
Currently, Takeda Pharmaceutical Company has voluntarily withdrawn the US Biologics License Application (BLA) for its TAK-003 vaccine. It is in further discussions with the US Food and Drug Administration (FDA) in this regard.
It is the second vaccine closest to FDA approval after Dengvaxia®, the first vaccine for dengue fever, received the FDA approval in 2019. The vaccine has already been approved in several dengue endemic and non-endemic countries.
There have currently been clinical trial studies on Takeda Pharmaceutical Company's TAK-003 vaccine.
A number of phase 1/2/3 clinical evaluations for the TAK-003 vaccine have currently beem conducted and completed. (Representative clinical trial, NCT02747927, etc.)

Title : Efficacy, Safety and Immunogenicity of Takeda's Tetravalent Dengue Vaccine (TDV) in Healthy Children
Collaborator : No information provided

US. Army Medical Research & Development command(USAMRDC)

The U.S. Army Medical Research and Development Command (USAMRDC) has been conducting research in five areas: military infectious diseases, combat casualty care, military operational medicine, chemical biological defense, and clinical and rehabilitative medicine.
In addition, USAMRDC has been conducting the Military Infectious Diseases Research Program(MIDRP), one of the medical and R&D programs.
The primary purpose of MIDRP is to plan, coordinate and oversee for the DOD requirements-driven medical solutions that PREVENT, PREDICT, and TREAT infectious diseases threats to the total force maximizing Warfighter readiness and performance
The MIDRP supports the development of treatments and vaccines to prevent infectious disease threats to eliminate their impacts on operational readiness. It has focused on the following infectious diseases: bacterial diarrheal disease, wound infections, dengue fever, HIV, hantaviruses, and emerging infectious diseases, etc.
Currently, The USAMRDC has been supporting or developing TDEN F17/F19, live–attenuated vaccines, which use a live virus itself as an antigen to provide immunogenicity to the host.cancer,
The USAMRDC has been conducting various clinical trials to commercialize TDEN F17/F19, live-attenuated vaccines.
The USAMRDC has currently been conducting and completing multiple phase 1 and 2 clinical evaluations for TDEN F17/F19 vaccines (representative clinical trial: NCT00370682, etc.)

Title : A Phase II Trial of a Live Attenuated Virus Tetravalent Dengue Vaccine in Healthy Adults in Thailand
Collaborator : GlaxoSmithKline

Sanofi(Sanofi pasteur)

Sanofi is a French multinational pharmaceutical company that researches, develops, and provides therapeutic solutions to improve the quality of human life as a leading global pharmaceutical company.
Sanofi has diverse portfolios, including medicines (for the treatment of cancer, rare diseases, and multiple sclerosis), as well as vaccines (for the prevention of various bacterial and viral diseases).
Sanofi Pasteur is the global vaccine division of Sanofi. It is the world's largest company devoted entirely to the development of vaccines. It has diverse portfolios of high-quality vaccines for children, adolescents and adults against influenza, meningitis, dengue, travel-related and endemic diseases.
Dengvaxia®(CYD-TDV), a vaccine for dengue virus, developed by Sanofi Pasteur is a chimeric live-attenuated vaccine for four dengue virus serotypes based on the vaccine strain of Yellow Fever Virus (YFV-17D). The vaccine uses the live virus itself as an antigen to provide immunogenicity to the host.
The Dengvaxia®(CYD-TDV) vaccine is the first, but limited, FDA-approved vaccine against dengue fever. Prior to its limited FDA approval, it was already approved in Mexico in 2015 as the world's first dengue fever prevention vaccine.
The following year, in 2016, it was commercialized in 11 countries, including the Philippines, Indonesia, Brazil, El Salvador, Costa Rica, Paraguay, Guatemala, Peru, Thailand, and Singapore.
However, at the end of 2017, cases of mass deaths of pediatric patients continued to occur after vaccination, leading to the suspension of vaccination and investigation.
Sanofi has currently been conducting clinical trials on combined modality therapy with the chimeric herbal attenuated vaccine (CYD-TDV) based on Yellow Fever Vaccine strains and various types of vaccines (for Japanese encephalitis, yellow fever, human papilloma virus, etc.). It has applied for additional vaccine-related patents, and it has actively been conducting research as a major patent applicant.

Merck & Co.

Merck, a leading global biopharmaceutical company known as MSD outside the United States and Canada, has been developing medicines and vaccines for the world's most challenging diseases for over 100 years.
Merck primarily focuses on the following areas: oncology, vaccines, infectious diseases (HIV, Ebola, Dengue, etc.), COVID-19, cardiometabolic disorders. There have been its scientific discoveries and developments that can make the biggest difference now and in the future. It focuses on scientific innovation to deliver medicines and vaccines that can help millions of people around the world.
In 2019, Merck signed a cooperation agreement with Institute Butantan, a non-profit producer of immunobiologicals in Sao Paulo, Brazil, to develop a vaccine for the prevention of dengue virus, a mosquito-borne infectious disease.
TetraVax-DV (V180), a dengue virus prevention vaccine being jointly researched and developed by the two companies, is a recombinant (DEN-80E) tetravalent subunit vaccine with an adjuvant (ISCOMATRIX or Alhydrogel) added. The truncated form of the envelope protein (DEN-80E) for the four serotypes of the vaccine acts as an antigen and provides immunogenicity to the host.
Merck has currently completed two phase 1 clinical trials for TetraVax-DV (V180). It has applied for a patent on the vaccine, and it has actively been conducing research as a major applicant.