The Threats of Rift Valley Fever and Chikungunya

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The Threats of Rift Valley Fever and Chikungunya

• Mark T. Heise
• The Dept. of Genetic
• The Carolina Vaccine Institute
• The University of North Carolina

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Rift Valley Fever Virus
Chikungunya
Epizootic Cycle Large Scale
Animal Disease Associated Human
infection
Urban Epidemic Cycle Large Scale Human
Epidemics Dengue Yellow Fever Onyong-nyong Ro
ss River virus
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Rift Valley fever virus

• Floodwater Aedes sp

• The Basics
• FamilyBunyaviridae, genus Plebovirus
• Zoonotic pathogen
• Humans
• Hemorrhagic fever
• Encephaltis
• Retinitis
• Livestock
• Transmission/Maintenance
• Mosquito
• Known Vectors
• Floodwater Aedes Sp.
• Vertical Transmission
• Culex (Amplified virus)
• Potential Vectors
• North American mosquitoes
• Sand flies
• Mucosal

Culix Aedes Others
Floodwater Aedes sp.
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RVFV Disease

• Livestock Disease
• Abortion storms (sheep, cattle, goats).
• High mortality in young animals
• High Priority Pathogen for USDA
• Human Disease
• Flu like symptoms (majority of cases)
• Hemorrhagic or encephalitic forms (1)
• Hemorrhagic form has hepatic involvement
• 20-30 case fatality rate in recent outbreaks
• Retinitis

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Is RVFV a Threat to the United States?
Current Distribution of Rift Valley Fever
Virus Outbreaks of Note Isolated in
Kenya (1930) - Sporadic outbreaks at
3-10 yrs. Egypt 1977-78 -
18,000 human cases, 600 deaths East
African Epizootic (1997) - 89,000 human
cases - 500 human deaths
Saudi Arabia/Yemen (2000) -1st
documented outbreak outside of
Africa/Madagascar -13.9 mortality
among hospitalized
http//www.cdc.gov/ncidod/dvrd/spb/mnpages/dispage
s/rvf/rvfmap.htm
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Potential Impact of RVFV in U.S.

• Livestock industry
• Direct Loss due to virus induced disease
• Loss of Export Market
• Outbreak would cause OIE imposed ban on exports
  for at least 6 months, and up to 4 years if RVFV
  is considered endemic.
• 7.3 billion in beef exports in 2003
• Paralysis of Transportation System
• Human Disease
• Livestock handlers most at risk
• Vector borne exposure
• Mucosal transmission from infected animals
• Healthcare workers (diagnostic laboratories)
• General public (Limited direct risk, Panic)

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Is RVFV a Threat to the United States?

• Significant Emerging Pathogen
• OIE List A pathogen
• USDA/CDC overlap agent
• 3 agent on Animal Biological Threat Agents and
  Research Priority list.
• Several means of potential introduction
• Intentional
• Accidental
• Importation of infected mosquitoes
• Importation of infected livestock/materials
• Vector Competence?
• Multiple mosquito species can transmit
  experimentally
• North American Culex and Aedes Species
• Maintenance and Spread
• Livestock industry
• Potential for vertical transmission
• Susceptibility of North American Wildlife?

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RVFV Ongoing Questions/Needs?

• Surveillance
• United States (Limited resources for animal
  testing in U.S.)
• Worldwide
• Therapeutics
• Ribavirin
• Interferon
• Vaccines
• Livestock
• Existing live attenuated vaccines show promise
• Elicit long term immunity
• Generally safe, though contraindicated for
  pregnant animals
• Not recommended for non-endemic areas
• New vaccine alternatives
• Humans
• Inactivated vaccine is effective, but requires
  multiple boosts
• Live attenuated vaccines (MP-12)
• Others?
• Biological Questions
• Vector potential and transmission

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Developing Improved RVFV Vaccines and Diagnostic
Agents

• Develop improved RVFV vaccines for human and
  livestock use
• Goals Safe vaccines that elicit long-lived RVFV
  immunity, with minimal boost requirements, DIVA
  compatible (Heise, Ross, and Burt Labs).
• Alphavirus Replicon-based RVFV vaccines
• Elicit protective immunity against peripheral and
  mucosal RVFV challenge in mouse models
• Elicit protective immunity in vaccinated sheep
  (Neut titers of 132-164)
• DNA vaccines with RVFV Gn protein linked to C3d
  molecular adjuvant
• Elicit RVFV specific antibody responses in
  immunized mice
• Can be modified for livestock use
• RVFV virus like particles (VLPs)
• RVFV Diagnostic Assays (Doms, Burt, and Heise
  Labs)
• Goals Develop non-virus based immunology
  reagents
• Experimental RVFV cell fusion and pseudotyping
  assays developed
• Virus free RVFV specific neutralization test
  developed and validated against a standard
  virus-based RVFV neutralization assay.

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Summary I RVFV

• Potential for significant impact on livestock
  industry/economy
• Epizootic would have significant human health
  impact (potentially more severe than WNV).
• Endemic potential in Western Hemisphere?
• Need for improved diagnostics, vaccines, and
  antivirals.

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Chikungunya

• The Basics
• FamilyTogaviridae, genus Alphavirus (Semliki
  Forest virus Complex)
• Human Disease
• Rural cycle
• Ae. Africanus and Ae. Furcifer maintenance with
  wild primates
• Urban cycle
• Ae. Aegypti
• Ae. Albopictus
• Related viruses
• Onyong-nyong
• 1959 African epidemic gt2 million cases
• Re-emerged in 1996
• Anopheles mosquitoes
• Ross River virus
• Australian
• 1979 epidemic in South Pacific

Ae. Aegypti, Ae. albopictus
Ae. Aegypti, Ae. albopictus
Urban Cycle
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Chikungunya

• Human Disease
• Chikungunya (Swahili) That which bends up.
• Severe arthritis/arthralgia/myalgia
• High fever (103-104 F)
• Rash
• Hemorrhagic manifestations have been reported
• Severe incapacitating arthritis/arthralgia.
• Generalized
• Usually acute (Several days to several weeks,
  though 20 of individuals have long-term joint
  complaints)
• Rarely if ever fatal
• Apparent-to-inapparent infection ratio varies
  from 13 to 150 for CHIK and related viruses
• Reunion Island 13 or population had clinically
  apparent disease (approximately 250,000 cases).
• Infected individuals develop a high titer viremia

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Is Chikungunya a Threat to the United States?
Chikungunya Distribribution 1952-2006
http//www.cdc.gov/ncidod/dvbid/Chikungunya/index.
htm
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Are Chikungunya or Related viruses Threats to the
United States?

• Epidemic Chikungunya (2005-2007)
• Groups within Central/East African CHIK strains
• Reunion Island 266,000 cases
• Approximately 1/3 of population
• Presumed vector is Aedes albopictus
• India 1.4 million cases
• Presumed vector is Aedes aegypti
• Emergence in new regions due to infected
  travelers a concern
• United States 37 imported cases 2005-2006
• Competent vectors present
• No evidence for transmission
• Endemic Chikungunya
• Congo 2004 (re-emergence after 39 years)
• Malaysia 2007 (re-emergence after 7 years)
• Parola et al., Emerg Infect Dis 2006
  1213931399.
• Schuffenecker, et al., PLoS Med 2006 3e263.

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Threat of CHIK Introduction

• Sporadic outbreaks
• Returning Travelers
• Potential for localized spread
• Large Scale Epidemic?
• Risk in areas with competent mosquito vectors
• Possibility of endemic status?
• Dengue and YFV as examples

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What do we need?

• Surveillance
• Vaccines
• Experimental Live attenuated vaccine
• Therapeutics
• Non-steroidal anti-inflammatory drugs
• Basic Biology
• Viral vector biology
• Basic pathogenesis of virus induced disease

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Basic Biology of CHIK and Related Viruses

• Vector Biology
• Epidemic on Reunion involved Ae. Albopictus
• Genetic changes in virus?
• Other potential vectors?
• Pathogenesis of virus induced-arthritis
• Viral factors
• Host factors
• Macrophages
• Complement activation (RRV)

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Summary II Chikungunya

• Potential for large scale epidemics with
  significant human morbidity
• Experience with other viruses that use similar
  mosquito vectors suggests that large scale
  outbreaks in U.S. may not occur
• Need for improved therapeutics and vaccines

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References

• RVFV

• Chikungunya