Document text
National Center for Emerging and Zoonotic Infectious Diseases
EVIDENCE TO RECOMMENDATIONS FOR
CHIKUNGUNYA VACCINE USE AMONG
ADULT TRAVELERS
Susan Hills, MBBS, MTH
CDC Lead , Chikungunya Vaccines Work Group
Arboviral Diseases Branch
Division of Vector -Borne Diseases
Fort Collins, Colorado
ACIP meeting, October 26, 2023
Chikungunya virus and transmission
Alphavirus
Primarily transmitted by Aedes
aegypti and Aedes albopictus
Uncommon modes of
transmission
–Laboratory exposure
–Intrauterine and intrapartum
–Bloodborne transmission
through needlestick
Distribution
Tropical and subtropical
regions
Large outbreaks have occurred in most parts of
the world
–Often high attack ratesCountries and territories with current or past transmission
of chikungunya virus
https://www.cdc.gov/chikungunya/geo/index.html
Clinical features of acute chikungunya virus infection
Febrile illness with arthralgia which is often severe and debilitating
Rare serious complications (e.g., neurologic illness, myocarditis, hepatic or
renal disease)
No anti -viral treatment
Risk factors for severe disease
Age >65 years
Age <1 year
Underlying medical conditions
(e.g., diabetes, heart disease,
hypertension)
Intrapartum transmission
Chikungunya vaccine
Live attenuated vaccine manufactured by Valneva
Single dose primary schedule
Initial licensure for adults aged ≥18 years
Currently under consideration by US Food & Drug Administration
Not yet licensed anywhere in world
No existing vaccine recommendations from ACIP or other vaccine
advisory groups
Evidence to Recommendations for
chikungunya vaccination for travelers
Policy question
Should chikungunya vaccine be recommended for use in
persons aged ≥18 years traveling to areas with risk of
chikungunya virus transmission?
Domain 1. Public health problem
Is chikungunya of public health importance?
Hundreds of thousands of cases
reported annually
Risk highly variable for US travelers
100– 200 reported cases annually
Hundreds of thousands of cases
reported annually
Risk highly variable for US travelers
100– 200 reported cases annually
Hundreds of thousands of cases
reported annually
Risk highly variable for US travelers
100– 200 reported cases annually
Hundreds of thousands of cases
reported annually
Mortality <1%
Public health problem
Is chikungunya of public health importance?
oNo oProbably no oProbably yes oYes oVaries oDon’t know
Domain 2: Benefits and harms of chikungunya
vaccine
How substantial are the desirable anticipated effects?
Short -term and long -term protection from disease
No efficacy data so i mmunogenicity data reviewed
–No correlate of protection
Licensure through Accelerated Approval pathway
–Effectiveness demonstrated by clinical trials showing vaccine has effect on
surrogate endpoint reasonably likely to predict clinical benefit
–Vaccine effectiveness will need to be confirmed in post -licensure field studies
Marker of protection based on neutralizing antibody titer estimated from
validated non- human primate model
Seroresponse at 28 days after vaccination
Two studies
–One randomized controlled trial
–One lot -to-lot consistency study with no placebo group
Total of 622 subjects
Seroresponse at 28 days: ≥98%
None of 96 subjects in placebo arm of randomized controlled trial
had seroresponse
Seroresponse at 12 months after vaccination
One study with 360 subjects
Seroresponse at 12 months: 99%
How substantial are the desirable anticipated effects?
oMinimal oSmall oModerate oLarge oVaries oDon’t know
How substantial are the undesirable anticipated effects?
Serious adverse events (SAE) within 6 months
SAE
–51 (1.5% ) of 3,490 vaccinated subjects in 2 trials reported SAE
–8 (0.8% ) of 1,033 placebo recipients in randomized controlled trial reported SAE*
Related SAEs
–2 events ( 0.1% ) considered vaccine -related by study investigators
•Hospitalization for severe myalgia
•Hospitalization for myalgia, high fever, syndrome of inappropriate antidiuretic
hormone excretion, and atrial fibrillation
*No significant difference from vaccine group; 46 (1.5%) of 3,082 vaccinated subjects in randomized, controlled trial
Arthralgia and arthritis in randomized controlled trial*
Vaccinated group
(N=3082)Placebo group
(N=1033)
n(%) n(%) Risk ratio (95% CI)
Any arthralgia within 10 days#520 (17%) 50 (5%) 3.5 (2.6, 4.6)¥
Severe arthralgia within 10 days#,€9(0.3%) 0(0%) 6.0 (0.4, 104.2)
Persistent arthralgia≠9(0.3%) 4(0.4%) 0.8 (0.2, 2.4)
Arthritis within 6 months£5(0.2%) 2(0.2%) 0.8 (0.2, 4.3)
New onset or worsening osteoarthritis
within 6 months£12 (0.4%) 2(0.2%) 2(0.5, 9.0)
#Solicited adverse event ; ¥Significant difference; €Severe arthralgia defined as an event that prevented daily activity;
≠Commencing within 10 days and with duration >15 days; £Unsolicited adverse event
*Similar percentage of events in vaccinated subjects in lot -to-lot consistency study (N=408) without placebo control group
Arthralgia and arthritis in randomized controlled trial
Vaccinated group
(N=3082)Placebo group
(N=1033)
n(%) n(%) Risk ratio (95% CI)
Any arthralgia within 10 days#520 (17%) 50 (5%) 3.5 (2.6, 4.6)¥
Severe arthralgia within 10 days#,€9(0.3%) 0(0%) 6.0 (0.4, 104.2)
Persistent arthralgia≠9(0.3%) 4(0.4%) 0.8 (0.2, 2.4)
Arthritis within 6 months£5(0.2%) 2(0.2%) 0.8 (0.2, 4.3)
New onset or worsening osteoarthritis
within 6 months£12 (0.4%) 2(0.2%) 2(0.5, 9.0)
#Solicited adverse event ; ¥Significant difference; €Severe arthralgia defined as an event that prevented daily activity;
≠Commencing within 10 days and with duration >15 days; £Unsolicited adverse event
Arthralgia and arthritis in randomized controlled trial
Vaccinated group
(N=3082)Placebo group
(N=1033)
n(%) n(%) Risk ratio (95% CI)
Any arthralgia within 10 days#520 (17%) 50 (5%) 3.5 (2.6, 4.6)¥
Severe arthralgia within 10 days#,€9(0.3%) 0(0%) 6.0 (0.4, 104.2)
Persistent arthralgia≠9(0.3%) 4(0.4%) 0.8 (0.2, 2.4)
Arthritis within 6 months£5(0.2%) 2(0.2%) 0.8 (0.2, 4.3)
New onset or worsening osteoarthritis
within 6 months£12 (0.4%) 2(0.2%) 2(0.5, 9.0)
#Solicited adverse event ; ¥Significant difference; €Severe arthralgia defined as an event that prevented daily activity;
≠Commencing within 10 days and with duration >15 days; £Unsolicited adverse event
Arthralgia and arthritis in randomized controlled trial
Vaccinated group
(N=3082)Placebo group
(N=1033)
n(%) n(%) Risk ratio (95% CI)
Any arthralgia within 10 days#520 (17%) 50 (5%) 3.5 (2.6, 4.6)¥
Severe arthralgia within 10 days#,€9(0.3%) 0(0%) 6.0 (0.4, 104.2)
Persistent arthralgia≠9(0.3%) 4(0.4%) 0.8 (0.2, 2.4)
Arthritis within 6 months£5(0.2%) 2(0.2%) 0.8 (0.2, 4.3)
New onset or worsening osteoarthritis
within 6 months£12 (0.4%) 2(0.2%) 2(0.5, 9.0)
#Solicited adverse event ; ¥Significant difference; €Severe arthralgia defined as an event that prevented daily activity;
≠Commencing within 10 days and with duration >15 days; £Unsolicited adverse event
Arthralgia and arthritis in randomized controlled trial
Vaccinated group
(N=3082)Placebo group
(N=1033)
n(%) n(%) Risk ratio (95% CI)
Any arthralgia within 10 days#520 (17%) 50 (5%) 3.5 (2.6, 4.6)¥
Severe arthralgia within 10 days#,€9(0.3%) 0(0%) 6.0 (0.4, 104.2)
Persistent arthralgia≠9(0.3%) 4(0.4%) 0.8 (0.2, 2.4)
Arthritis within 6 months£5(0.2%) 2(0.2%) 0.8 (0.2, 4.3)
New onset or worsening osteoarthritis
within 6 months£12 (0.4%) 2(0.2%) 2(0.5, 9.0)
#Solicited adverse event ; ¥Significant difference; €Severe arthralgia defined as an event that prevented daily activity;
≠Commencing within 10 days and with duration >15 days; £Unsolicited adverse event
Arthralgia and arthritis in randomized controlled trial
Vaccinated group
(N=3082)Placebo group
(N=1033)
n(%) n(%) Risk ratio (95% CI)
Any arthralgia within 10 days#520 (17%) 50 (5%) 3.5 (2.6, 4.6)¥
Severe arthralgia within 10 days#,€9(0.3%) 0(0%) 6.0 (0.4, 104.2)
Persistent arthralgia≠9(0.3%) 4(0.4%) 0.8 (0.2, 2.4)
Arthritis within 6 months£5(0.2%) 2(0.2%) 0.8 (0.2, 4.3)
New onset or worsening osteoarthritis
within 6 months£12 (0.4%) 2(0.2%) 2(0.5, 9.0)
#Solicited adverse event ; ¥Significant difference; €Severe arthralgia defined as an event that prevented daily activity;
≠Commencing within 10 days and with duration >15 days; £Unsolicited adverse event
How substantial are the undesirable anticipated effects?
oMinimal oSmall oModerate oLarge oVaries oDon’t know
Do the desirable effects outweigh the undesirable effects?
Balance of desirable and undesirable effects
High seroresponse rates through at least 1 year after vaccination
No serious safety concerns identified in trials performed to date
Prevents disease that can result in severe arthralgia during acute illness,
rare serious complications, and sometimes long -term arthralgia
Healthcare provider should discuss desirable and undesirable effects of vaccination and individual risk based on disease risk at destination,
activities, and personal factors
–For some travelers, even low probability of SAE might be higher than disease risk
–Target vaccine to travelers at higher risk for disease
Do the desirable effects outweigh the undesirable effects?
oFavors
intervention oFavors
comparisonoFavors
bothoFavors
neitheroVariesoDon’t
know
What is the overall certainty of the evidence for the
critical outcomes?
What is the overall certainty of the evidence for
protection from chikungunya ?
oNo studies found oVery low oLow oModerate oHigh
No vaccine efficacy data, no immunologic correlate of protection,
protection based on surrogate endpoint reasonably likely to predict
clinical benefit and requiring confirmation by post -licensure vaccine
effectiveness studies
What is the overall certainty of the evidence for
safety of chikungunya vaccination ?
oNo studies found oVery low oLow oModerate oHigh
Number of subjects in trials insufficient to detect rare adverse events,
confidence intervals indicated potential for benefit or harm, and/or
suboptimal method for collection of specific outcome information
Domain 3. Values
Does the target population feel that the desirable
effects are large relative to undesirable effects?
Is there important uncertainty about or variability
in how much people value the main outcomes?
Perceptions among US adults aged ≥18 years of the
value of a chikungunya vaccine (CDC study)
Online survey conducted in 2022
Participants provided information on
–Risk for disease with travel during outbreak or non -outbreak
periods
–Rates of chronic arthralgia after chikungunya
–Vaccine cost
Results
42%
26%32%
Likely* Unsure Unlikely**
*Includes very and somewhat likely responses
**Includes very and somewhat unlikely responsesOutbreak period (risk of 1 in 150) Non -outbreak period (risk of 1 in 15,000)
27%
24%49%
Likely* Unsure Unlikely**N=4,146N=4,138
Variability in responses
Lower likelihood of vaccination
–Persons aged 18 –29 years
–Lower education
–Lower household income
–Black race
Important factors in decision -making
Risk of disease
Vaccine side effects Avoid risk of long -term joint pain Vaccine cost
Perceptions among US adults aged ≥18 years of value of
chikungunya vaccine (Valneva study)
Online survey conducted in 2021
2,002 US residents who had traveled internationally during last 3
years or planned to do so within next 3 years
Limited information about participants provided but anyone who self-identified as ‘anti -vaccination’ excluded
Results
After being provided basic information on chikungunya
and its sequelae
–72% were very or somewhat likely to ask healthcare provider
about a vaccine
–81% were very or somewhat likely to be vaccinated if
recommended by healthcare provider
Values
Does the target population feel that the desirable
effects are large relative to undesirable effects?
oNo oProbably no oProbably yes oYes oVaries oDon’t know
Values
Is there important uncertainty about or variability
in how much people value the main outcomes?
oImportant
uncertainty
or variabilityoProbably important
uncertainty or variabilityoProbably not important uncertainty or variabilityoNo important
uncertainty or
variabilityoNo known undesirable outcomes
Domain 4. Acceptability
Is chikungunya vaccine acceptable to key stakeholders?
Acceptability to key stakeholders
Travel medicine and other healthcare providers
–Online survey in 2021 (Valneva) among 158 US healthcare
providers who routinely provide travel health services
indicated 87% were very or somewhat likely to
recommend vaccine if recommended by ACIP
Travelers
–Option for protection from a disease that can cause
severe arthralgia and potentially long -term joint pain
Acceptability
Is the intervention acceptable to key stakeholders?
oNo oProbably no oProbably yes oYes oVaries oDon’t know
Domain 5. Resource use
Is chikungunya vaccination a reasonable and efficient
allocation of resources?
Cost -effectiveness considerations
No cost- effectiveness analysis (CEA)
–Most travel vaccines are not cost -effective
–Chikungunya vaccine for travelers is not likely to be cost -effective
CEA less relevant for travel vaccine
–Decision is for individual traveler and not for population
–Vaccine paid for by traveler and generally not covered by insurance
Vaccine recommendations targeting higher risk travelers probably reasonable
allocation of resources
–Financial implications borne by travelers most at risk and who benefit most
Resource use
Is chikungunya vaccination a reasonable and
efficient allocation of resources?
oNo oProbably no oProbably yes oYes oVaries oDon’t know
Domain 6. Equity
What would be the impact on health equity?
Health equity considerations
Vaccine primarily paid for out of pocket
–Some travelers not have resources to pay for vaccine
Travel medicine providers likely have better awareness of disease and
vaccine availability than non- specialist providers
–People with fewer resources less likely to attend travel medicine provider
Chikungunya vaccine recommendations cannot address these issues
Equity
What would be the impact on health equity?
oReducedoProbably
reducedoProbably
no impactoProbably increasedoIncreased oVariesoDon’t know
Domain 7. Feasibility
Is the intervention feasible to implement?
Feasibility considerations
Single dose primary series allows administration in pre -travel
consultation
Disease risk highest, and vaccination most of benefit, during
outbreaks
–Challenge with delay in awareness of outbreaks
–CDC will post information on website once aware of outbreaks
Feasibility
Is the intervention feasible to implement?
oNo oProbably no oProbably yes oYes oVaries oDon’t know
Balance of consequences
o Undesirable
consequence clearly
outweighdesirable consequences in most settingso Undesirable consequences probably outweigh desirable consequences in most settingso The balance between desirable and undesirable consequences is
closely balanced or uncertaino Desirable
consequences
probably
outweigh
undesirable
consequences
in most settingso Desirable
consequences clearly outweigh undesirable consequences in most settingso There is insufficient evidence to determine the balance of consequences
Draft recommendations for
ACIP’s consideration
Draft recommendations
Chikungunya vaccine is recommended for persons aged ≥18 years
traveling to a country or territory where there is a chikungunya
outbreak
In addition, chikungunya vaccine may be considered forthe following
persons traveling to a country or territory without an outbreak but
with evidence of chikungunya virus transmission among humans within
the last 5 years
–Older persons (e.g., >65 years), particularly those with underlying
medical conditions, who are likely to have at least moderate exposure to mosquitoes
–Persons staying for a cumulative period of 6 months or more during a 2-year period
Example of data supporting recommendation: Substantially higher
risk for travelers during outbreak, Paraguay 2023
<1%
Percentage of all US persons
traveling to areas with
chikungunya risk visiting Paraguay 26%*
Percentage of all reported US traveler
chikungunya cases whose travel
destination was Paraguay
*18 of 69 travelers with destination data, preliminary ArboNET data, 2023
Providing clarity on chikungunya outbreaks
For the purposes of the recommendation, an outbreak
will be defined as occurring when CDC posts information on an outbreak on CDC website
Shared clinical decision- making recommendation
Chikungunya vaccine may be considered for the following persons
traveling to a country or territory without an outbreak but with
evidence of chikungunya virus transmission among humans within the last 5 years
–Older persons (e.g., >65 years), particularly those with underlying
medical conditions, who are likely to have at least moderate exposure to mosquitoes
–Persons staying for a cumulative period of 6 months or more during a 2-year period
Older persons, particularly those with underlying medical
conditions?
Key risk factors for severe disease
–Older age
–Underlying medical conditions
Key risk factors for chronic arthralgia
–Older age
–Presence of pre- existing joint problems
Risk for higher morbidity and mortality
in older persons supported by data
from recent outbreak in Paraguay1
1. Torales M, et al. Notes from the Field: Chikungunya Outbreak - Paraguay, 2022- 2023. MMWR Morb Mortal Wkly Rep 2023; 72:636- 638
Vaccine not
available for
children
Cumulative period of ≥6 months during 2 -year period*
Key risk factor for chikungunya virus infection is intensity of
transmission
–If equivalent transmission, cumulative duration of exposure important
Transmission patterns can be unpredictable over the longer term and likely to be some seasonal variation in mosquito activity that might
impact risk
*2-year period based on immunogenicity data showing high seroresponse rate (99%) at one year after vaccination
suggesting good protection at least through second year but no longer -term data
Evidence of chikungunya virus transmission among humans
within the last 5 years
Rationale: 5 -year time frame provides interval that allows reasonable
confidence there is transmission or insufficient transmission to be concern
for travelers
Tool: Map that shows countries
with chikungunya virus
transmission among humans
reported during last 5 years,
posted on CDC website
Mock map to demonstrate transmission of chikungunya virus among
humans during last 5 years
Moderate exposure
Moderate exposure could include travelers who might have at least 2
weeks (cumulative) of exposure to mosquitoes in indoor and/or
outdoor settings. It does not include travelers who might have limited exposure to mosquitoes (e.g., those traveling for business and likely to
be mainly in mosquito -protected indoor settings)
General considerations*
All persons who travel to areas with possible chikungunya virus transmission should be advised to
take precautions to avoid mosquito bites
The risk for chikungunya for most US travelers to countries or territories with evidence of
transmission is low. However, some travelers are at increased risk for infection or more severe
disease. In the discussion between the healthcare provider and traveler on the need for vaccination,
consideration should be given to
1) whether there is a recognized outbreak or ongoing disease activity
2) the duration of travel or residence, including likelihood of future travel to an area with
chikungunya virus transmission
3) the likelihood of exposure to Aedes mosquitoes
4) older age (e.g., >65 years)
5) underlying medical conditions that increase the risk for severe disease (e.g., diabetes, cardiac disease, hypertension)
6) underlying conditions that increase the risk for chronic arthralgia after infection (e.g., existing joint disease)
7) an individual’s personal perception and tolerance of risk
*Provided in background materials
Draft recommendations
Chikungunya vaccine is recommended for persons aged ≥18 years
traveling to a country or territory where there is a chikungunya
outbreak
In addition, chikungunya vaccine may be considered forthe following
persons traveling to a country or territory without an outbreak but
with evidence of chikungunya virus transmission among humans within
the last 5 years
–Older persons (e.g., >65 years), particularly those with underlying
medical conditions, who are likely to have at least moderate exposure* to mosquitoes
–Persons staying for a cumulative period of 6 months or more during a 2-year period
*Moderate exposure could include travelers who might have at least 2 weeks (cumulative) of exposure to mosquitoes in
indoor and/or outdoor settings