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Grading of recommendations, assessment, development, and evaluation (GRADE) for 

yellow fever vaccine booster doses 

Background 

Yellow fever (YF) is a mosquito-borne viral disease that is endemic to sub-Saharan Africa and 

tropical South America. YF virus causes an estimated 200,000 cases of clinical disease and 

30,000 deaths annually [WHO 1992]. Clinical disease ranges from a mild, undifferentiated 

febrile illness to severe disease with jaundice and hemorrhage. The case-fatality ratio for severe 

YF is 20%-50% [Monath 2013]. Because no specific treatment exists for YF, prevention is 

critical to reduce disease risk. One of the most effective prevention measures against YF is 

vaccination with the live, attenuated YF 17D substrain virus vaccine. 

YF vaccine is recommended for persons aged ≥9 months who are traveling to or living in 

areas with risk for YF virus transmission [CDC 2010]. In addition, International Health 

Regulations allow countries to require proof of YF vaccination from travelers entering their 

country [WHO 2005]. These requirements are intended to minimize the potential importation 

and spread of YF virus. Proof of YF vaccination is recorded on the International Certificate of 

Vaccination or Prophylaxis (i.e., yellow card). International Health Regulations specify that the 

International Certificate of Vaccination or Prophylaxis is valid for 10 years. Therefore, if 10 or 

more years have elapsed since the last vaccination, people planning travel to a country with a YF

vaccination entry requirement need to receive a booster dose of the vaccine. 

The Strategic Advisory Group of Experts on Immunization (SAGE), the principal advisory 

group to the World Health Organization (WHO) for vaccines and immunization, concluded in 

April 2013 that a single dose of YF vaccine is sufficient to confer sustained immunity and 

lifelong protection against YF disease, and a booster dose of the vaccine is not needed [WHO 

2013]. This conclusion was based on a systematic review of published studies on the duration of 

immunity following a single dose of YF vaccine, and on data that suggest vaccine failures are 

extremely rare and do not increase in frequency with time since vaccination [Gotuzzo 2013]. 

SAGE noted that future studies and surveillance data should be used to identify specific risk 

groups, such as infants or persons infected with human immunodeficiency virus (HIV), who 

could benefit from a booster dose. In May 2014, the World Health Assembly adopted the 

recommendation to remove the 10 year booster dose requirement from the International Health 

Regulations by June 2016 [WHO 2014]. 

In the United States, the current ACIP YF vaccine recommendations note that “[International 

Health Regulations] require revaccination at intervals of 10 years to boost antibody titer. 

Evidence from multiple studies demonstrates that YF vaccine immunity persists for many 

decades and might provide life-long protection” [CDC 2010]. The ACIP Japanese Encephalitis 

Vaccine Work Group was reformed to include YF vaccine in October 2013 to discuss the need 

for booster doses of YF vaccine. 

Policy questions 

The primary policy question was “Should booster doses of YF vaccine every 10 years continue 

to be recommended for healthy travelers and laboratory workers?”

Population: Healthy travelers and laboratory workers 

Intervention: Remove current recommendation for booster doses of YF vaccine 

Current option: Continue current recommendation for booster doses of YF vaccine 

June 17, 2015

https://www.cdc.gov/vaccines/acip/recs/grade/yf-vac-boost.pdf
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An additional policy question was created for special populations for whom their initial 

immunologic response to the vaccine might be suboptimal: “Should booster doses of YF vaccine 

every 10 years continue to be recommended for travelers or laboratory workers who had a 

precaution to vaccination that might have negatively impacted their immune response to their 

primary dose of YF vaccine (e.g., age 6–8 months, asymptomatic HIV infection with moderate 

immune suppression, pregnancy, or age ≥60 years)?”

Population: Travelers or laboratory workers who have a precaution to vaccination that 

might negatively impact their immune response to their primary dose of YF vaccine 

(e.g., age 6-8 months, HIV infection, pregnancy, and age ≥60 years)

Intervention: Remove current recommendation for booster doses of YF vaccine for these 

populations 

Current option: Continue current recommendation for booster doses of YF vaccine for 

these populations 

The Work Group also discussed and examined data on booster doses for travelers and 

laboratory workers in high-risk settings for exposure to YF virus. Data for these populations and 

those with conditions that might negatively impact their response to a primary dose of YF 

vaccine were reviewed and summarized but a further evaluation of the potential benefits and 

harms of booster doses could not be performed given the limited amount of data that existed. 

Identify and rank relative importance of outcome measures 

For the GRADE evaluation of YF vaccine booster doses, the benefits considered as critical 

outcomes included vaccine efficacy, effectiveness (i.e., lack of vaccine failures), and 

seroprotection. However, there are no vaccine efficacy data or long-term seroprotection data for 

YF vaccine. Given this, seropositivity was used as a surrogate for seroprotection (Table 1). The 

harms considered critical outcomes were any vaccine-related serious adverse event, vaccine 

associated-viscerotropic disease, and vaccine associated-neurologic disease. Evidence type for 

each critical outcome was derived through a review of study design, risk of bias, inconsistency, 

indirectness, imprecision, and other considerations (i.e., publication bias, strength of association, 

dose response, or direction of all plausible confounding would reduce the effect) [Ahmed 2011]. 

Evidence retrieval

To identify published literature that contained relevant evidence, we conducted PubMed and 

Embase searches of papers in any language published as of May 19, 2014. We used the keyword 

“yellow fever vaccine” and then used additional keywords to identify articles that pertained to 

the critical outcomes. For benefits related to vaccine immunity, the following keywords were 

used: “immunogenicity”, “immunity”, or “long-term”. For harms related to adverse events, the 

following keywords were used: “adverse events”, “safety”, or “side effects”. The titles of the 

articles were first reviewed to identify potentially relevant articles and then the abstracts were 

reviewed of any article with a relevant title. If no abstract was provided, the paper itself was 

reviewed. In addition, reference lists of relevant articles were reviewed to identify any additional 

articles that might be of relevance but were not obtained through searching PubMed or Embase. 

Articles that presented data on YF vaccine were included if they met the following criteria: 

1) involved human subjects; 2) reported primary data; and 3) included data relevant to the

outcome measures being assessed. Publications that met the above criteria but represented case

reports of adverse events were excluded.
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Of 1,166 articles in PubMed identified using the terminology “yellow fever vaccine”, 560 

articles included keywords related to the critical outcomes. Of these, 263 articles included 

keywords related to benefits and 412 article related to harms. Following the removal of articles 

that did not meet the inclusion criteria, 30 articles were included in the GRADE evaluation. The 

Embase search identified 1,719 articles related to YF vaccine but no additional studies meeting 

the selection criteria were found. From the reference lists of relevant articles, two additional 

articles were identified and included in the GRADE evaluation. This search was repeated on 

February 2, 2015 to identify any literature that was recently published; no additional articles 

were identified. 

Unpublished data were also considered, including data from studies conducted by the 

Brazilian Ministry of Health on duration of immunity and vaccine safety, CDC data on antibody 

titers in vaccine recipients, and VAERS data on vaccine safety.

Summarize relevant evidence for critical outcomes

Vaccine effectiveness 

The evidence used to evaluate vaccine effectiveness was derived from eight published studies

and one unpublished study that documented YF disease in persons who reported receiving YF 

vaccine. Of the eight published studies, four were from Brazil and likely contained individuals 

who were included in more than one of the studies. In response to an inquiry regarding the 

potential overlap between studies, the Brazilian Ministry of Health provided national level data 

that covered both the populations and the time period of the four studies; these data were used in 

place of the four published studies from Brazil (Table 2).

A total of 23 vaccine failures were identified following the administration of >540 million 

doses of YF vaccine [WHO 2013]. Of the 23 cases, five occurred <10 days after vaccination and 

were excluded as most persons are not expected to develop protective titers before 10 days after 

vaccination [Monath 2013]. Of the remaining 18 cases, 16 (89%) occurred in individuals who 

reported receiving a dose of the vaccine within the previous 10 years. Two vaccine failures 

occurred ≥10 years after the last dose of YF vaccine, including one at 20 years and one at 27 

years post vaccination. Eleven cases (61%) lacked any YF laboratory testing. For seven cases, 

there was laboratory confirmation of YF virus infection; however, for some cases the only 

laboratory evidence of infection was detection of anti-YF virus IgM antibodies [Brazil 2014].

Since YF IgM antibodies can persist for several years following YF vaccination [Gibney 2012],

these cases lacked definitive evidence of a recent infection with wild-type YF virus. 

Seropositivity

The evidence used to evaluate seropositivity at ≥10 years following YF vaccination was derived 

from 12 published studies and one unpublished study (Table 3). The studies were published over 

a 60 year period (1952–2014) and included data for several different vaccines, some of which are 

no longer manufactured, and results from tests that are no longer used. 

Of the 13 observational studies, immunogenicity data were available on 1,137 persons 

vaccinated ≥10 years previously. Of these, 1,002 (88%) were seropositive for YF virus

neutralizing antibodies. Of 164 persons who reported receiving YF vaccine ≥20 years previously, 

132 (80%) had detectable levels of neutralizing antibodies (i.e., seropositive). When study size 

differences and variability between studies was accounted for using a random effects model, the 

estimate of seropositivity for persons vaccinated ≥10 years previously was 92% (95% confidence 

interval [CI] 85%–96%) and those vaccinated ≥20 years previously was 80% (95% CI 74%–
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86%).

Serious adverse events (SAE)

The evidence used to evaluate SAE following YF vaccine was derived from eight published and 

one unpublished observational studies. These studies included surveillance data from national 

authorities as well as data from vaccine manufacturers for approximately 333 million doses of

distributed vaccine. There were 1,255 subjects reported to have a SAE following YF vaccination

(Table 4). For the majority (84%) of subjects, it was unknown if the SAE occurred following a

primary or booster dose of the vaccine. Furthermore, it was not known how many of the 333

million doses of vaccine were administered as a primary or booster dose. Of the 201 subjects

with a SAE where dose type was known, 14 (7%) occurred following a booster dose of vaccine.

Viscerotropic disease

The evidence used to evaluate YF vaccine-associated viscerotropic disease (YEL-AVD) was 

derived from eight observational studies. These studies included surveillance data from national 

authorities as well as data from vaccine manufacturers for approximately 437 million doses of

distributed vaccine. There were 72 subjects reported as having YEL-AVD (Table 5). Most of 

these YEL-AVD cases likely also were reported as SAE. For 41 (57%) subjects, it was unknown 

if YEL-AVD occurred following a primary or booster dose of the vaccine. Furthermore, it was 

not known how many of the 437 million doses of vaccine were administered as a primary or 

booster dose. Of the 31 subjects where dose type was known, 1 (3%) subject had YEL-AVD

after receiving a booster dose of the vaccine; no laboratory testing was performed for that case.

Neurologic disease

The evidence used to evaluate YF vaccine-associated neurologic disease (YEL-AND) was 

derived from eight observational studies. These studies included surveillance data from national 

authorities as well as data from vaccine manufacturers for approximately 462 million doses of 

distributed vaccine. There were 218 subjects reported as having YEL-AND (Table 6). For 108

(50%) subjects, it was unknown if YEL-AND occurred following a primary or booster dose of 

the vaccine. Furthermore, it was not known for most of the 462 million doses of vaccine how 

many were administered as a primary or booster dose. Of the 110 subjects where dose type was 

known, 3 (3%) subjects reported YEL-AND after receiving a booster dose of the vaccine. All

three of these YEL-AND cases were reported as an autoimmune-mediated event rather than 

direct vaccine viral invasion of the central nervous system. With autoimmune neurologic events 

seen following YF vaccination, there is no specific laboratory testing that is available to assess 

vaccine causality.

Summary of quality of evidence across outcomes

For the benefits considered critical outcomes, there were very few vaccine failures documented 

and most [92% (95% CI 85%–96%)] primary vaccine recipients were seropositive at ≥10 years 

post vaccination. However, evidence type is 4 for both vaccine effectiveness and seropositivity 

as there were only observational studies available that were downgraded because of the risk of 

bias (i.e., incomplete case capture, no comparison group, and bias in those tested for long-term 

seropositivity) and indirectness (i.e., different populations of interest, unknown how many 

persons had received a booster dose, and indirect measure of efficacy and seroprotection) (Table 

7). For harms considered critical outcomes, very few safety concerns were reported after booster 
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doses. The evidence type is 4 for observational studies that were downgraded due to indirectness 

(i.e., unknown how many of the doses were administered as booster doses versus primary doses 

and thus the rates of adverse events for booster doses specifically could not be calculated). The 

overall quality of evidence is type 4 (Table 8).

Summary of other relevant evidence

In addition to the critical outcomes, data were reviewed on certain populations who had a 

condition that might have compromised their immune response to YF vaccine, including 

pregnant women, hematopoietic stem cell transplant recipients, HIV-infected individuals, and 

young children. 

Pregnant women: The proportion of women who develop YF virus antibodies is variable and 

might be related to the trimester in which they received the vaccine. Of 83 pregnant woman 

receiving YF vaccine predominantly in their third trimester, 32 (39%) had evidence of 

seroconversion to YF virus at 2–4 weeks post vaccination compared to 94% (89/95) in the 

general population [Nasidi 1993]. Of 433 women vaccinated predominantly in the first trimester

(mean gestational age 5.7 weeks; 95% CI 5.2–6.2), 425 (98%) developed YF virus-specific 

neutralizing antibodies at 6 weeks post vaccination [Suzano 2006].

Hematopoietic stem cell transplant recipients: There are limited safety and immunogenicity 

data (i.e., a few case reports) for YF vaccination of hematopoietic stem cell transplant recipients

[Yax 2009, Gowda 2004, Ljungman 2005]. However, data for other live virus vaccines suggest 

most recipients become seronegative following transplantation [Ljungman 1994]. Infectious 

Diseases Society of America guidelines recommend re-administering live viral vaccines, such as 

measles, mumps, and rubella (MMR) vaccine and varicella vaccine, to hematopoietic stem cell 

transplant recipients if they are seronegative and no longer immunosuppressed [Rubin 2014].

HIV-infected individuals: Published studies on the immunogenicity of YF vaccines in HIVinfected persons are limited. One retrospective cohort study found 65 (83%) of 78 HIV-infected 

persons had specific antibodies against YF virus in the first year after vaccination; however this 

was significantly lower than vaccinated persons without HIV infection (97%, 64/66) (P=0.01) 

[Veit 2009]. The rate of detectable YF virus-specific antibodies was also lower among HIVinfected persons at 1 to 10 years post vaccination (77%, 54/70) compared to uninfected controls 

(88%, 81/92) but this difference was not significant (P=0.07) [Veit 2009]. One additional study 

noted that only 3 (17%) of 18 HIV-infected infants in Cote d’Ivoire developed YF virus-specific 

neutralizing antibodies following vaccination compared to 42 (74%) of 57 HIV-uninfected 

controls matched for age and nutritional status (P<0.01) [Sibailly 1997]. The mechanisms for the 

diminished immune response in HIV-infected persons are uncertain but appear to be correlated 

with HIV RNA levels and inversely correlated with CD4+ cell counts [Veit 2010].

Young children: Twelve studies were identified that provided data on the initial immune

response to YF vaccine in children aged 4 months to 10 years (Table 9). All the studies included

children who resided in endemic areas and 10 (83%) studies included children who received at 

least one other vaccine co-administered with YF vaccine. Of the 4,675 children, 4,101 (88%) 

seroconverted 1–2 months following their primary YF vaccination. When study size differences 

and variability between studies were accounted for using a random effects model, the estimate of 

seroconversion rate was 93% (95% CI 88%–96%). Furthermore, when the random effects model 

was used to compare seroconversion rates between children aged <9 months and those aged ≥9 

months, there was no difference. For children aged <9 months, data from four studies provided 

an estimated seroconversion rate of 95% (95% CI 91%–98%). In children aged ≥9 months, data 
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from 11 studies provided an estimated seroconversion rate of 92% (95% CI 86%–96%). There 

are limited data on the persistence of YF antibodies in children; with no data available on 

seropositivity by the time since last YF vaccination.

The data for seroconversion rates in children following YF vaccination were presented to the 

American Academy of Pediatrics Committee on Infectious Diseases (COID) in November 2014. 

Upon review of these data and comparing them to seroconversion rates in adults, COID members 

agreed that the response to YF vaccine in children did not appear to be different than adults. 

Given this, they concluded that children can be included with adults regarding their need for YF 

vaccine booster doses. However, they noted the need for long-term immunogenicity data from 

persons vaccinated as children to ensure the antibody decay kinetics are similar compared to 

persons vaccinated initially as an adult.

Higher-risk exposures: Finally, the Work Group considered persons who might be in a

higher-risk setting for YF virus exposure based on season, location, activities, and duration of 

their travel. Limited epidemiologic data suggest that West Africa has the highest risk of disease 

with 90% of all YF disease cases over the preceding 20 years being reported from countries in 

West Africa [Monath 2013]. Furthermore, the Work Group considered persons traveling to an 

area with an ongoing outbreak, persons traveling for a prolonged period of time in an endemic 

area, and persons who routinely handle wild-type YF virus in the laboratory to be at higher-risk 

for YF virus exposure than other persons for whom YF vaccine is recommended. 

Assess the values related to management options and outcomes

From 1970–2014, nine cases of YF were reported in unvaccinated travelers from the United 

States (n=3) and Europe (n=6) who traveled to West Africa or South America [McFarland 1997; 

Digoutte 1981; Rodhain 1979; CDC 1999; Colebunders 2002; CDC 2002; Teichmann 1999; 

WHO 1998; WHO 2000]. Eight of these nine travelers died. Only one case of YF has been 

documented in a vaccinated traveler from Spain who received the vaccine 5 years before 

traveling to several West African countries and being diagnosed with YF; the traveler survived

[Nolla-Salas 1989]. YF vaccine has been available since the 1930s, including in the United 

States, and it is not known how many cases have been prevented due to vaccination or how many 

cases are not diagnosed or reported. Reports from U.S. travel clinics or international airports 

have documented that 91%–93% of travelers for whom YF vaccine was recommended received 

the vaccine [Jentes 2013; Lown 2014; Toovey 2004]. In one study of 3,207 travelers who 

received YF vaccine at a travel clinic visit in the United States, only 149 (5%) had reportedly

received a previous dose of YF vaccine ≥10 years previously [Jentes 2013].

A traveler’s risk of acquiring YF is determined by multiple factors, including immunization 

status, use of personal protection measures against mosquito bites, location of travel, duration of 

exposure, occupational and recreational activities while traveling, and local rate of virus 

transmission at the time of travel. In both West Africa and South America, YF virus transmission 

typically is seasonal and is associated with the mid-to-late rainy season [Monath 2002]. 

However, YF virus can be transmitted by Aedes aegypti even during the dry season in both rural 

and densely settled urban areas [Beeuwkes 1933]. Although the number of reported cases of 

human disease often is used to estimate the crude level of endemic transmission, cases might not 

be reported because of a low level of transmission, a high level of immunity in the local 

population, or cases not being detected by local surveillance systems. Therefore, a lack of human 

disease cases in an area does not equate to absence of risk for transmission.
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The risk of acquiring YF is difficult to predict because of variations in ecologic determinants 

of virus transmission. For a 2-week stay, the estimated risks for illness and death attributed to YF 

for an unvaccinated traveler traveling to an area of West Africa where the disease is endemic are 

50 and 10 per 100,000 population, respectively; for South America, the risks for illness and death 

are five cases and one case per 100,000 population, respectively [Monath 2002]. These crude 

estimates for unvaccinated travelers are based on risk to indigenous populations, often during 

peak transmission season. Thus, these risk estimates might not reflect accurately the actual risk 

to travelers, who might have a different immunity profile, take precautions against getting bitten 

by mosquitoes, and have less outdoor exposure. Furthermore, it is unknown how the potential 

risk of the disease differs in persons who have received at least one dose of YF vaccine ≥10 

years previously.

Recommendations regarding the use of YF vaccine booster doses for travelers must weigh 

the overall risk for travel-associated YF disease in persons who have previously received a dose 

of the vaccine, the lack of treatment, high mortality (80%) in travel-related cases, the low 

probability of serious adverse events following revaccination, and the cost of the vaccine (Table 

10). High value is placed on preventing this life-threatening disease. A survey performed in the 

United States in 2001 found that both parents and community members were willing to pay a 

median of $500 to reduce the risk of bacterial meningitis from 21 per 100,000 to 6 per 100,000 

[Prosser 2004]. Although the disease presentation and population used in the survey are different 

than what would be expected for YF among travelers, they establish a willingness to pay to 

prevent a serious outcome. 

Review health economic data

There are no studies of the potential cost-effectiveness of vaccinating travelers or laboratory 

workers against YF either with primary or booster doses of the vaccine. However, given the 

large numbers of travelers to endemic areas (~3 million annually of which an estimated 150,000 

could need a booster dose of vaccine), the risk for YF disease for unvaccinated travelers (5–50 

case per 100,000 unvaccinated travelers), and the cost of YF vaccine ($150–$350) [Monath 

2002; Costhelper 2014], providing a booster dose of YF vaccine to all travelers going to endemic 

areas would not be cost-effective. In addition, for some travelers with lower risk itineraries, even 

a very low probability of vaccine-related serious adverse events might be higher than the risk for 

disease. Therefore, YF vaccine booster doses should be targeted to travelers who, on the basis of 

their planned travel itinerary and activities, are at increased risk for disease. 

Travel vaccines, such as YF vaccine, are usually paid for by the travelers themselves; they 

are not covered under the Vaccines for Children (VFC) program or by most private insurance 

plans. As a result, we decided not to perform a cost-effectiveness study of removing booster 

doses of YF vaccine for U.S. travelers or laboratory workers. Furthermore, none of the Work 

Group members consider cost-effectiveness study critical to make recommendations regarding 

YF vaccine booster doses for healthy travelers and laboratory workers.

Assess the balance of risks and benefits

A primary dose of YF vaccine is effective with very few vaccine failures documented and most 

(92%) of vaccine recipients maintaining seropositive levels of neutralizing antibodies at ≥10 

years post vaccination. However, the number of persons from whom the seropositivity data are 

derived is limited and over half (59%) of the data come from persons living in YF endemic areas. 

The data also suggest that 20% (95%CI 14%–26%) of persons who received YF vaccine ≥20 
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years previously do not have detectable levels of neutralizing antibodies. For previously 

vaccinated persons without evidence of circulating neutralizing antibodies, it is not known if 

other immunologic measures (e.g., cell-mediated immunity or memory B cell response) would 

provide adequate protection against YF.

Very few serious adverse events, including vaccine-related viscerotropic and neurologic 

disease, have been reported following booster doses of the vaccine. However, for most of the 

adverse event data, it is unknown whether the patients had received a primary or booster dose 

prior to their reported event, and how many of the total doses of vaccine where given as primary 

or booster doses.

In general, there is high value placed on prevention of a serious disease with no treatment 

and substantial mortality. The overall disease risk in persons who have already received a dose of 

the vaccine is likely quite low and vaccine cost is high. 

Formulate recommendations and determine the category

Current ACIP recommendations for YF vaccine were approved in 2009 and contain the 

following wording in regards to the use of booster doses. “[International Health Regulations] 

require revaccination at intervals of 10 years to boost antibody titer. Evidence from multiple 

studies demonstrates that YF vaccine immunity persists for many decades and might provide 

life-long protection. To minimize the occurrence of adverse events and optimize the immune 

response, efforts should be taken to observe a 10-year interval between YF vaccine doses.” 

[CDC 2010]. 

The GRADE evaluation found that there are very few vaccine failures documented following 

primary doses of YF vaccine, most (92%) primary vaccine recipients maintain detectable levels 

of neutralizing antibodies ≥10 years post vaccination, and very few serious adverse events have 

been reported following booster doses of YF vaccine (Evidence type 4). However, additional 

data suggest that certain populations (e.g., pregnant women or HIV-infected person) might not 

have as robust or sustained immune response to YF vaccine compared to “healthy” persons. 

Furthermore, certain groups were felt to be at increased risk of the disease either due to their 

location and duration of travel or due to more consistent exposure to virulent virus (e.g., 

laboratory workers). 

Upon reviewing the available data, the majority of the Work Group felt that booster doses of 

YF vaccine should not be recommended for most travelers or laboratory workers. However, 

based on limited data, YF vaccine should be recommended in certain populations at increased 

risk of YF disease either due to an increased risk of exposure to YF virus or due to suboptimal 

immune response to a dose of YF vaccine. The Work Group recommends the following language 

regarding booster doses of YF vaccine:

 A single dose of YF vaccine provides long-lasting protection and is adequate for most 

travelers. (Recommendation Category A)

 Additional doses of YF vaccine are recommended for certain travelers, including*:

o Women who were pregnant when they received their initial dose of YF vaccine 

should receive one additional dose of YF vaccine prior to their next travel that 

puts them at risk for YF virus infection.

o Persons who received a hematopoietic stem cell transplant after receiving a dose 

of YF vaccine and who are sufficiently immunocompetent to be safely vaccinated 

should be revaccinated prior to their next travel that puts them at risk for YF virus 

infection.
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o Persons who were HIV-infected when they received their last dose of YF vaccine 

should receive a dose every 10 years if they continue to be at risk for YF virus 

infection. 

*Persons being considered for additional doses of YF vaccine should be assessed for 

contraindications or precautions. (Recommendation Category A)

 A booster dose may be given to travelers who received their last dose of YF vaccine at 

least 10 years previously and who will be in a higher-risk setting based on season, 

location, activities, and duration of their travel. This would include travelers who plan to 

spend a prolonged period in endemic areas or those traveling to highly endemic areas 

such as rural West Africa during peak transmission season or an area with an ongoing 

outbreak. (Recommendation Category B) 

 Laboratory workers who routinely handle wild-type YF virus should have YF virusspecific neutralizing antibody titers measured at least every 10 years to determine if they 

should receive additional doses of the vaccine. For laboratory workers who are unable to 

have neutralizing antibody titers measured, YF vaccine should be given every 10 years as 

long as they remain at risk. (Recommendation Category A)

Further study

The Work Group members prioritize the following areas of study to address gaps in our current 

knowledge regarding the need for YF vaccine booster doses in U.S. travelers and laboratory 

workers:

1. Assessing neutralizing antibody levels ≥10 years post initial vaccination in non-endemic 

populations (e.g., travelers) 

2. Evaluating anamnestic immune response to revaccination in persons from non-endemic 

YF locations who fail to have detectable levels of neutralizing antibodies years ≥10 years

following their initial YF vaccination

3. Determining seroprotective level of antibodies using a plaque reduction neutralization 

test (PRNT) by correlating to established level of seroprotective neutralizing antibodies 

by log10 neutralization index (LNI) (LNI ≥ 0.7)

4. Assessing long-term neutralizing antibody levels among certain populations, such as 

infants or HIV-infected persons, to obtain more information on the need for additional 

doses of YF vaccine

5. Establishing the role of cell-mediated immunity in long-term protection against YF 

disease in non-endemic populations

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Table 1. Summary of outcome measure ranking and inclusion for yellow fever (YF) vaccine booster doses

Outcome Importance

Include in 

evidence profile

Data 

available

Benefits

Vaccine efficacy Critical Yes No

Vaccine effectiveness1 Critical Yes Yes

Seroprotection2 Critical Yes No

Seropositivity Critical Yes Yes

Harms

Serious adverse events3 Critical Yes Yes

Viscerotropic disease Critical Yes Yes

Neurologic disease Critical Yes Yes

Anaphylaxis Important No --

Systemic adverse events Important No --

1Vaccine effectiveness was assessed as vaccine failures

2There are no long-term immunogenicity data using log10 neutralization index (LNI), the only test for which a seroprotective titer 

has been established (i.e., LNI ≥0.7). Given this, it was decided that seropositivity (i.e., having detectable YF virus-specific 

antibodies) would be used as a surrogate for seroprotection and included in the evidence profile even though seropositivity was 

originally rated as important not critical.

3Serious adverse event is an event that is plausibly related to YF vaccination and was considered to be life-threatening or 

required hospitalization.
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Table 2. Vaccine effectiveness measured by vaccine failures reported following yellow fever (YF) vaccination

Study Population Type Age Group No.

Lab 

confirmed

Timing post 

vaccination Outcome

Elliot 1944 Non-endemic Obs Adult 3 0 15 mo, 16 mo, 16 mo

Died (2), 

Survived (1)

Ross 1953 Non-endemic Obs Adult 1 0 4 yr Died

Nolla Salas 1989 Non-endemic Obs Adult 1 0 5 yr Survived

Akoua-Koffi 2001 Endemic Obs Unknown 6 0 Unknown Survived (6)

Brazil 20141 Endemic Obs Unknown 7

2 73

10 dy-10 yr (5),

20 yr (1), 27 yr (1) Unknown

All

Non-endemic/ 

Endemic Obs (5)

Adult or 

Unknown 18 7 10 dy – 27 yr

Died (3), Unknown 

(7), Survived (8)

Obs = observational study; dy = days; mo = months; yr = years

1Data were provided by the Brazilian Ministry of Health to resolve overlap and errors in four published studies regarding vaccine failures in Brazil 

(Tuboi 2007, de Filippis 2004, Saraiva 2013, and Camara 2013).

2A total of 12 vaccine failures were identified but five occurred <10 days after vaccination and were excluded. 

3Laboratory confirmation defined in the study as 1) detection of YF virus-specific IgM antibodies, 2) isolation of YF virus, 3) YF-compatible 

pathological changes in liver tissue, 4) detection of YF virus antigen by immunohistochemistry, or 5) four-fold or greater rise in YF virus-specific 

IgG antibody titers. The specific laboratory criteria used to confirm the seven cases was not noted. Due to the persistence of IgM antibodies that 

can occur following vaccination [Gibney 2012], these cases lacked definitive evidence of a recent infection with wild-type YF virus. 
GRADE tables for yellow fever vaccine booster doses Revised: June 3, 2015 

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Table 3. Seropositivity at ≥10 years following yellow fever (YF) vaccination

Study Population Type

Seropositivity

criteria1

Years post

vaccination Seropositive

No. (%)

Dick 1952 Endemic Obs Mouse protection 10 156/202 (77)

de Melo 2011 Endemic Obs PRNT50 ≥20 10 20/20 (100)

Reinhardt 1998 Non-endemic Obs PRNT90 ≥10 ≥10 5/5 (100)

Machado 2013 Endemic Obs PRNT80 ≥10 ≥10 19/19 (100)

CG YF vaccines 20142 Endemic Obs PRNT50 ≥10 10-18 307/329 (93)

Rosenzweig 1963 Non-endemic Obs Mouse protection 10-15 24/243(100)

Courtois 1954 Endemic Obs Mouse protection 12 76/79 (96)

Groot 1962 Non-endemic Obs Mouse protection 17 105/108 (97)

Gomez 2008 Endemic Obs PRNT75 ≥10 10-24 13/193(68)

Niedrig 1999 Non-endemic Obs PRNT90 >10 11-38 38/51 (75)

Coulange Bodilis 2011 Non-endemic Obs PRNT80 ≥10 10-60 80/84 (95)4

CDC 2014 Non-endemic Obs PRNT90 ≥10 10-69 68/81 (84)

5

Poland 1981 Non-endemic Obs PRNT90 ≥2 30-35 91/116 (78)

All Non-endemic/Endemic Obs (13) Multiple 10-60 1,002/1,137 (88)

Obs = observational study; PRNT = plaque reduction neutralization test 

1For mouse protection assays, vaccine recipient serum for which ≥3 of 6 mice survived are included as seropositive. PRNTx% is the reciprocal of 

the highest serum dilution at which x% of YF virus is inhibited. 

2CG YF vaccines = Collaborative group for studies on yellow fever vaccines (Brazil). 

3Numbers are estimated as some cases included in the data received their vaccination <10 years previously. 

4

88% (15/17) of subjects who received YF vaccine ≥20 years previously were seropositive [Coulange Bodilis 2011] 

5

84% (26/31) of subjects who received YF vaccine ≥20 years previously were seropositive [CDC 2014] 
GRADE tables for yellow fever vaccine booster doses Revised: June 3, 2015 

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Table 4. Serious adverse events reported following yellow fever (YF) vaccination by dose type

Study Location

Reporting

Period Type Doses

Number of cases by dose type

Primary Booster Unknown

CDC 2015 Non-endemic 2007-2013 Obs 3,631,535 96 111 0

Cottin 2013 Non-endemic/Endemic 1993-2010 Obs 276,000,0002--

3

-- 805

Schumacher 2010 Non-endemic 1991-2001 Obs 272,727 -- -- 7

Lindsey 2008 Non-endemic 2003-20064 Obs 902,500 54 1

5 0

Khromava 2005 Non-endemic 1990-2002 Obs 9,600,000 13 2

6 32

Biscayart 2014 Endemic 2008-2009 Obs 1,940,000 24 -- 9

Breugelmans 2013 Endemic 2007-2010 Obs 38,009,411 -- -- 164

Fernandes 2007 Endemic 1999-2005 Obs 499,714 -- -- 24

Fitzner 2004 Endemic 2001 Obs 2,600,000 -- -- 137

All Non-endemic/Endemic 1990-2013 Obs (9) 333,455,887 187 14 1054

Obs = observational study

1All 11 serious adverse event cases were reported in adults who were hospitalized following their second (n=10) or third (n=1) dose of YF 

vaccine. The cases included: 1) Guillain-Barré syndrome (GBS) 16 days post vaccination; 2) GBS 7 days post vaccination; 3) encephalitis 4 

days post vaccination; 4) bilateral optic neuritis 2 days post vaccination; 5) anaphylaxis with angioedema on the day of vaccination; 6) lower 

extremity cellulitis 7 days post vaccination; 7) acute appendicitis requiring surgery 2 days post vaccination; 8) fever and right lower quadrant

pain 5 days post vaccination; 9) fever and syncope 1 day post vaccination; 10) myalgia and upper extremity weakness 3 days post vaccination; 

and 11) lymphadenitis 26 days post vaccination, subsequently diagnosed as Hodgkin’s lymphoma.

2Of the 276 million doses, 16.2 million (5.8%) doses were given to non-endemic populations (e.g., travelers).

3

Indicates that cases are not reported for the specific dose type.

4The published study includes data from 2000–2006 but 2000–2002 removed to prevent overlap with data from Khromova 2005.

5One case of appendicitis requiring surgery at 1 day post vaccination.

6One case reporting numbness and weakness at 12 days post vaccination and one case with abdominal pain and yellow stools requiring 

hospitalization at 7 days post vaccination.

7Cases not explicitly defined as having serious adverse events but 13 out of 87 adverse events required hospitalization and were considered to be 

serious.
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Table 5. Yellow fever vaccine-associated viscerotropic disease (YEL-AVD) by dose type

Study Location

Reporting

Period Type Doses

Number of cases by dose type

Primary Booster Unknown

Cottin 2013 Non-endemic/Endemic 1993-2010 Obs 276,000,0001 4 1

2 7

Lindsey 2008 Non-endemic 2003-20063 Obs 902,500 6 --

4

--

Khromava 2005 Non-endemic 1990-2002 Obs 9,600,000 8 -- --

Kitchner 2004 Non-endemic 1991-2003 Obs 3,046,007 -- -- 4

Biscayart 2014 Endemic 2008-2009 Obs 1,940,000 12 -- --

Breugelmans 2013 Endemic 2007-2010 Obs 38,009,411 -- -- 5

Martins 2010 Endemic 1999-2009 Obs 107,649,393 -- -- 20

Whittembury 2009 Endemic 2007 Obs 42,742 -- -- 5

All Non-endemic/Endemic 1990-2010 Obs (8) 437,190,053 30 1 41

Obs = observational study

1Of the 276 million doses, 16.2 million (5.8%) doses were given to non-endemic populations (e.g., travelers).

2One suspect case in a 55-year-old male who had illness onset 2 days following a booster dose of yellow fever (YF) vaccine. He presented 

with polyarthralgia, and liver cytolysis; no YF specific-testing was performed. He was reported as recovering from his illness.

3The published study includes data from 2000–2006 but 2000–2002 removed to prevent overlap with data from Khromova 2005.

4

Indicates that cases are not reported for the specific dose type.
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Table 6. Yellow fever vaccine-associated neurologic disease (YEL-AND) by dose type

Study Location

Reporting

Period Type Doses

Number of cases by dose type

Primary Booster Unknown

Cottin 2013 Non-endemic/Endemic 1993-2010 Obs 276,000,0001 10 1

2 13

Lindsey 2008 Non-endemic 2003-20063 Obs 902,500 6 --

4

--

Khromava 2005 Non-endemic 1990-2002 Obs 9,600,000 10 -- --

Kitchner 2004 Non-endemic 1991-2003 Obs 3,046,007 -- -- 4

Martins 2014 Endemic 2009-20125 Obs 30,745,7436 59 2

7

--

Biscayart 2014 Endemic 2008-2009 Obs 1,940,000 12 -- --

Breugelmans 2013 Endemic 2007-2010 Obs 38,009,411 -- -- 6

Martins 2010 Endemic 2000-2008 Obs 101,564,083 -- -- 85

All Non-endemic/Endemic 1990-2010 Obs (8) 461,807,744 107 3 108

Obs = observational study

1Of the 276 million doses, 16.2 million (5.8%) doses were given to non-endemic populations (e.g., travelers).

2One suspected case in a 45-year-old female who had illness onset 13 days following a booster dose of the vaccine. Her clinical features were listed 

as a suspected “multiple sclerosis syndrome”; no yellow fever (YF) specific-testing performed. She had “favorable outcome with corticosteroids”.

3The published study includes data from 2000–2006 but 2000–2002 removed to prevent overlap with data from Khromova 2005.

4

Indicates that cases are not reported for the specific dose type.

5The study includes data from 2007–2012 but 2007–2008 removed to prevent overlap with Martins 2010.

6Approximately 13 million doses were administered as booster doses. Total number of booster doses was derived by dividing the total number of 

booster doses administered by the number of years and assumed roughly the same number of doses delivered each year.

7One probable case in a 62-year-old female who was diagnosed with Guillain Barre syndrome at an unknown time post vaccination; one probable 

case in a 20-year-old male who became symptomatic 14 days post vaccination and was diagnosed with acute disseminating encephalomyelitis. 
GRADE tables for yellow fever vaccine booster doses Revised: June 3, 2015 

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Table 7. Evidence type for benefits and harms for yellow fever (YF) vaccine booster doses in healthy travelers and 

laboratory workers

Outcome

Design

(# studies) Risk of bias Inconsistency Indirectness Imprecision Other1 Evidence type2

Benefits

Vaccine effectiveness Obs (5) Yes3 No serious Yes4 No serious None 4

Seropositivity Obs (13) Yes5 No serious Yes6 No serious None 4

Harms

Serious adverse events Obs (9) No serious No serious Yes7 No serious None 4

Viscerotropic disease Obs (8) No serious No serious Yes7 No serious None 4

Neurologic disease Obs (8) No serious No serious Yes7 No serious None 4

Obs = observational study

1Publication bias, strength of association, dose response, or direction of all plausible confounding would reduce the effect.

2Evidence type:

1 = Randomized control trials (RCTs) or overwhelming evidence from observational studies

2 = RCTs with important limitations, or exceptionally strong evidence from observational studies

3 = Observational studies, or RCTs with notable limitations

4 = Clinical experience and observations, observational studies with important limitations, or RCTs with several major limitations

3Risk of bias because of incomplete case capture and no comparison group.

4

Indirectness due to different population (majority of data are from endemic areas) and it is unknown how many persons at risk of YF would not 

receive a booster dose of the vaccine.

5Risk of bias among those tested for long-term seropostivity.

6

Indirectness due to different population (majority of data are from endemic areas). No efficacy data are available, no correlate of protection 

established for the assays used to assess long-term immunity, and different assays and antibody levels were used to assess either seropositivity or 

“seroprotection”.

7

Indirectness as it is not known for all but one study the number of doses that were administered as booster doses versus primary doses and thus 

rates for the adverse events could not be calculated.
GRADE tables for yellow fever vaccine booster doses Revised: June 3, 2015 

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Table 8. Overall quality of evidence for yellow fever (YF) vaccine booster doses in healthy travelers and laboratory workers

Outcome

Study design 

(# studies) Finding

Evidence

1 type

Overall quality 

of evidence

Vaccine effectiveness

Seropositivity

Serious adverse events

Viscerotropic disease

Neurologic disease

Obs (5)

Obs (13)

Obs (9)

Obs (8)

Obs (8)

Very few vaccine failures documented

Most (92%) seropositive at ≥10 years post vaccination

Very few events reported after booster doses

Very few events reported after booster doses

Very few events reported after booster doses

4

4

4

4

4

4

Obs = observational study

1

Evidence type:

1 = Randomized control trials (RCTs) or overwhelming evidence from observational studies

2 = RCTs with important limitations, or exceptionally strong evidence from observational studies

3 = Observational studies, or RCTs with notable limitations

4 = Clinical experience and observations, observational studies with important limitations, or RCTs with several major limitations
GRADE tables for yellow fever vaccine booster doses Revised: June 3, 2015 

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Table 9. Seroconversion rates following a primary dose of yellow fever (YF) vaccine in young children

Study Population YF Vaccine Other vaccine(s)1 Age Assay used Seroconverted2

No. (%)

Belmusto-Worn 2005 Endemic 17D-204 None 9 mo-10 yo LNI 917/981 (93)

Nascimento 20113 Endemic 17DD/17D-213 None

MMR 12-23 mo PRNT50

718/819

552/792

(88)

(70)

Yvonnet 1986 Endemic 17D-204 BCG, DTP, HepB, M, Polio 9-36 mo PRNT90 170/183 (93)

Coursaget 1995 Endemic 17D-204 HepB, M 9 mo PRNT90 165/172 (96)

Lhuillier 1989 Endemic 17D-204 M 6-9 mo HIA 122/135 (90)

Mouchon 1990 Endemic 17D-204 M 6-10 mo PRNT80 131/139 (94)

Stefano 1999 Endemic 17DD M 9 mo PRNT50 228/294 (78)

Adu 1996 Endemic 17D-204 M 6-12 mo ELISA 379/400 (95)

Soula 1991 Endemic 17D-204 M 4-24 mo PRNT 158/167 (95)

Ruben 1973 Endemic 17D-204 M, DPT, S 6-24 mo PRNT90 158/165 (96)

Gateff 1973 Endemic 17D-204 BCG, M, S, T 1-5 yo HIA 119/139 (86)

Osei-Kwasi 2001 Endemic 17D-204 None 6-9 mo PRNT 284/289 (98)

BCG = Bacillus Calmette-Guerin vaccine; DTP = diphtheria, tetanus, and pertussis combined vaccine; ELISA = enzyme-linked immunosorbent 

assay; HepB = hepatitis B vaccine; HIA = hemagglutination inhibition assay; LNI = log10 neutralization index; M = measles vaccine; MMR= 

measles, mumps, and rubella combined vaccines; mo = months old; PRNT = plaque reduction neutralization test; S = Smallpox; T = tetanus; yo = 

years old 

1Except for Nascimento, serocoversion rates following concurrent administration of YF vaccine with other vaccines compared to administration 

alone was not significantly different so the proportion are for all children who received YF vaccine. For Nascimento, a significant difference was 

seen between seroconversion rates when YF vaccine was co-administered with MMR vaccine versus given 30 days post MMR vaccine; these data 

are presented individually. 

2Measured 30–90 days post YF vaccination. 

3Percent seroconversion is for per protocol population; numerator and denominator data estimated from total numbers in each cohort.
GRADE tables for yellow fever vaccine booster doses Revised: June 3, 2015 

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Table 10. Considerations for formulating recommendations for use of yellow fever (YF) vaccine booster doses in healthy 

travelers and laboratory workers at increased risk of exposure to YF virus

Key factors Comments

Evidence type for benefits and harms  Overall evidence type 4 for vaccine effectiveness, seroprotection, and serious

adverse events

 Downgraded due to risk of bias (incomplete case capture, those tested for longterm seropositivity), and indirectness (data from endemic populations, no efficacy

data, and unknown rates of adverse events with booster doses)

Balance between benefits and harms  Very few vaccine failures identified following YF vaccine

 Most (92%) of primary vaccine recipients are seropositive at ≥10 years post

vaccination

 Serious adverse events are uncommon following booster doses of the vaccine

Value  Prevent a serious disease with no treatment and poor outcomes

 Inform decisions about YF vaccination based on a traveler’s planned itinerary

Cost-effectiveness  Not evaluated

 Likely low risk of disease in persons receiving a dose of YF vaccine

 High vaccine cost for vaccines that is usually paid for by the travelers

themselves; YF vaccine is not covered under the Vaccines for Children program

or most insurance plans.