Statement on the Use of Booster Doses of Yellow Fever Vaccine

An Advisory Committee Statement (ACS)

Committee to Advise on Tropical Medicine and Travel (CATMAT)

Table of Contents

Preamble

The Committee to Advise on Tropical Medicine and Travel (CATMAT) provides the Public Health Agency of Canada with ongoing and timely medical, scientific, and public health advice relating to tropical infectious disease and health risks associated with international travel. The Agency acknowledges that the advice and recommendations set out in this statement are based upon the best current available scientific knowledge and medical practices, and is disseminating this document for information purposes to both travellers and the medical community caring for travellers.

Persons administering or using drugs, vaccines, or other products should also be aware of the contents of the product monograph(s) or other similarly approved standards or instructions for use. Recommendations for use and other information set out herein may differ from that set out in the product monograph(s) or other similarly approved standards or instructions for use by the licensed manufacturer(s). Manufacturers have sought approval and provided evidence as to the safety and efficacy of their products only when used in accordance with the product monographs or other similarly approved standards or instructions for use.

Key Points

  • Yellow fever is a vaccine-preventable, vector-borne illness caused by a virus from the family Flaviviridae. Recent changes in the World Health Organization’s (WHO’s) international regulations no longer require proof of revaccination or a booster dose of yellow fever vaccine as a condition of entry into a country, based on that organization’s determination that a single dose confers lifelong immunity.
  • The Committee to Advise on Tropical Medicine and Travel (CATMAT) does not recommend the use of a booster dose of the yellow fever vaccine for travellers to endemic regions except for certain groups at increased risk and for whom it is safe to administer the vaccine. Use of a one-time booster dose is recommended for travellers who may have received a primary dose of yellow fever vaccine during a period of reduced immunocompetence. This includes those who were pregnant, taking immunosuppressive medication, received a previous dose which may be inadequate for long term protection, and individuals diagnosed with an illness associated with an immunocompromised state. Individuals who underwent a hematopoietic stem cell transplant after having received yellow fever vaccine are included in this category (see Recommendations for expanded discussion.)
  • A booster dose of yellow fever vaccine every 10 years is recommended for HIV-positive individuals prior to travel to endemic regions.
  • Individuals who travel frequently to areas with higher risk of yellow fever, particularly to areas experiencing a major outbreak of yellow fever may consider obtaining a one-time booster dose if 10 years have elapsed since the primary dose.
  • Those working with the yellow fever virus in a laboratory setting are candidates for 10-year boosters.
  • Proof of yellow fever vaccination entered on the International Certificate of Vaccination or Prophylaxis (ICVP) should notate the duration of validity as “For the lifetime of the person vaccinated” as suggested by the WHO. Individuals who may require a booster dose in the future and are deemed safe to immunize should be provided with supplemental documentation to serve as a reminder and to be kept separate from the ICVP.

Purpose

This statement developed by the Committee to Advise on Tropical Medicine and Travel (CATMAT) is intended to review evidence and to provide recommendations and guidance to Canadian health care professionals on the need for a booster dose of yellow fever vaccine.

Introduction

In May 2014, recommendations from the World Health Organization’s (WHO’s) Strategic Advisory Group of Experts (SAGE) on immunization stated that a single dose of yellow fever vaccine confers life-long immunity Footnote 1. The World Health Assembly adopted this resolution to update and amend Annex 7 of the International Health Regulations (IHR). As of 11 July 2016, revaccination or a booster dose of yellow fever vaccine is not required of international travellers as a condition of entry into a country Footnote 2 . This applies to both existing and new international certificates of vaccination. The WHO stated in 2013: “Data suggest that the majority of vaccine recipients will develop a protective antibody titer against yellow fever virus within 28 days of vaccination and will maintain protective antibody titers for potentially several decades, or possibly life-long, following vaccination” Footnote 3. The WHO statement is based to a large extent on the findings of a systematic review by Gotuzzo et al. Footnote 4,Footnote 5.

In the United States, the Advisory Committee on Immunization Practices (ACIP) undertook a separate systematic review to evaluate the evidence for recommending a booster dose every 10 years Footnote 6. The published statement from ACIP agreed with the need for only primary immunization but also specified certain groups for whom booster doses should still apply. In ACIP’s wording, a single dose provides “long-lasting protection and is adequate for most travelers” Footnote 7.

CATMAT formed a working group to review the evidence and make recommendations on the need for a booster dose of the yellow fever vaccine.

Methods

This statement was developed by a working group of CATMAT. Each member was a volunteer, and none declared a relevant conflict of interest.

To evaluate the need for a booster dose of yellow fever vaccine, CATMAT reviewed the evidence used to inform the recommendations made by the WHO Footnote 3 and ACIP Footnote 7. The WHO evidence derives in large part from the systematic review of Gotuzzo et al. Footnote 5. Given that much of the available evidence has been previously reviewed and was used to inform the WHO Advisory Group of Experts (SAGE) statement on Yellow Fever Vaccines Footnote 3 and the ACIP Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) for Use of Yellow Fever Vaccine Booster Doses Footnote 6, CATMAT considered that conducting another GRADE review was not necessary. Most referenced papers were retrieved and reviewed.

CATMAT also studied the particular cases of The Gambia and Senegal which provided relevant epidemiologic data not included in the WHO or ACIP reviews.

Additional evidence was retrieved by performing searches in electronic databases to obtain the literature pertaining to the immunogenicity and duration of protection of yellow fever vaccine in immunocompromised states (Embase, Ovid MEDLINE, and Global Health). The search spanned the initial date for each database up to April 2016. The literature search produced 96 search results. Titles of these results were reviewed and 10 articles were selected for abstract review. Of the 10, five were selected for full review based on relevancy to the research question.

Results

We present the data on the duration of protection of yellow fever vaccination and reports on vaccine failure described in the two systematic reviews which informed the WHO and ACIP recommendations. We have grouped the evidence in a hierarchical manner: clinical, serologic and ancillary.

The findings of the CATMAT literature review on the immunogenicity of yellow fever vaccine in immunocompromised individuals are also presented. The case of The Gambia is presented.

WHO and ACIP reviews

A. Epidemiologic Evidence

The epidemiologic data are sparse, consisting primarily of case reports. Gotuzzo’s systematic review includes 10 cases of yellow fever disease occurring among immunized people Footnote 5. The ACIP review found eighteen cases of yellow fever disease occurring among immunized people more than 10 days after receipt of the vaccine Footnote 6. In a number of these, the diagnosis was uncertain. During this time, over 540 million doses Footnote 7 were administered.

Six cases of yellow fever disease in unimmunized travellers are discussed in the Gotuzzo review Footnote 5.

Though formal published studies were not found, the WHO paper observes that yellow fever epidemics appear to have been stopped by mass immunization and that immunized individuals seem to be spared during epidemics. WHO notes as well the reduction in cases where there is high vaccine coverage Footnote 3, again without citing published reports.

B. Serologic Evidence

A summary of the studies identified in the WHO and ACIP reviews with intermediate (11–19 years) Footnote 8,Footnote 9,Footnote 10,Footnote 11,Footnote 12 and long-term (20 years or more) Footnote 6,Footnote 13,Footnote 14,Footnote 15,Footnote 16 post-immunization follow-up on immunogenicity are presented in Table 1. These studies generally analyze antibody titres, and do not examine the potential role of other immunologic mechanisms of protection against disease. It is possible that presence of antibody does not protect against disease, and conversely that some subjects without any given measure of antibody titres remain protected in vivo.

Gotuzzo’s systematic review Footnote 5 presents eight studies demonstrating seroprotection, six of these in the intermediate and longer term. ACIP interpreted the same studies as providing evidence of seropositivity (meaning detectable yellow fever-virus specific antibodies) but not seroprotection (a protective level of antibodies), regardless of the titre reported. This is because none of the presented serologic studies used the Log Neutralization Index (LNI), the only test for which a seroprotective titer had been established through testing in primates. Notwithstanding this, ACIP does appear to treat seropositivity at a titre of 1:10 or greater as a surrogate for seroprotection. In doing so, ACIP appropriately downgraded the quality of this evidence as per GRADE requirements.

ACIP used seropositivity as a surrogate for protection and we are using the terms “protection” and “sero-protection” in this document with this important caveat.

To further clarify the duration of protection, we reviewed the original papers and concluded the following:

Short-term protection
(up to 10 years post-immunization): Two studies Footnote 17,Footnote 18. Given the short duration, we consider that this data provides little evidence for long-term or lifelong protection (not included in Table 1).
Intermediate-term protection
(11–19 years post-immunization): Two studies Footnote 8,Footnote 9. These show 97% and 100% seropositivity (unclear as to whether these results are considered seropositive or seroprotective).
Longer-term protection
(20 years or more post-immunization): Four studies, the longest follow-up being 60 years post-immunization Footnote 13,Footnote 14,Footnote 15,Footnote 16. Results range from 60% to 97% seropositive or seroprotective levels of antibody.

ACIP’s systematic review presents 13 serologic studies Footnote 6. Immunogenicity data were available on 1,137 persons vaccinated ≥10 years previously. Of these, 1,002 (88%) were seropositive for yellow fever virus neutralizing antibodies. These are presented in Table 1 excluding two studies that did not exceed a 10 year duration. Of 164 persons who reported receiving yellow fever 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 ACIP 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%-86%).

Table 1: Serologic studies after immunization with yellow fever vaccine – WHO and ACIP
Follow-up period Study Sample size Time since last Yellow Fever immunization Results

Intermediate (11–19 years post-immunization)

Groot and Riberiro, 1962
(ACIP, WHO) Footnote 8
108 17 years 76% strongly positive (presumably meaning seroprotective levels) and 21% weakly positive (presumed meaning seropositive but not seroprotective)
Rosenzweig et al., 1963
(ACIP, WHO) Footnote 9
24 16–19 years 100% seropositive (uncertain if this was interpreted as seroprotective)
Courtois, 1954
(ACIP) Footnote 10
79 12 years 96% seropositive
Machado et al., 2013
(ACIP) Footnote 11
19 10+ years 100% seropositive; In the entire group (n= 383), 25% had been immunized once, the rest twice or more. Nineteen of the 383 individuals were immunized 10 yrs or more previously.
Collaborative group, 2014
(ACIP) Footnote 12
329 10–18 years 93% seropositive

Long-term
(20 years or more post-immunization)

Poland et al., 1981
(ACIP, WHO) Footnote 13
149 30-35 years 97% navy/air force seropositive; 60% of army personnel seropositive. Authors speculate that army personnel not all immunized as planned; Difficult to discern if titres are protective or are only seropositive.
Niedrig et al., 1999
(ACIP, WHO) Footnote 14
51 11–38 years 74.5% seroprotected; unclear how many are >30 yrs
Gomez and Ocazionez, 2008
(ACIP, WHO) Footnote 15
19 4–24 years 13 of 19 of people (68.4%) immunized 4 or more years previously were seroprotected. Unclear how many were long term.
Coulange et al., 2011
(ACIP, WHO) Footnote 16
84 10–60 years 95.2% seroprotected; 9 of 10 seroprotected after >25 years
CDC 2014 Footnote 6 31 10–69 years 84% (26/31) of subjects who received yellow fever vaccine ≥20 years previously were seropositive
Comment: We do not see an indication if titres were seroprotective by CDC standard. This appears to be unpublished data from CDC Arbovirus testing laboratory.
ABBREVIATIONS:  WHO, World Health Organization; ACIP, Advisory Committee on Immunization Practices; CDC, Centers for Disease Control and Prevention

C. Ancillary Evidence

It has been noted both that booster doses of yellow fever vaccine do not often lead to dramatic increases in antibody titre and it is theorized that cell-mediated immunity is more important for protection against natural infection.  Studies demonstrate that the yellow fever vaccine activates various toll-like receptors on natural killer cells and dendritic cells, induces a broad cellular response and as such, innate and cellular immunity may play a role in the long lasting protection conferred by the vaccine Footnote 19,Footnote 20,Footnote 21,Footnote 22. Furthermore, chronic persistent infection with the vaccine virus or storage of antigen in vivo, possibly in follicular dendritic cells, may also explain the durability of the human immune response Footnote 23,Footnote 24.

D. Special groups

WHO does not identify any groups that should be exempted from the recommendation that a single lifetime dose should be sufficient to confer long-term immunity. However, their statement notes the possible reduced immunogenicity of the vaccine in young children, among pregnant women, and in HIV-positive individuals. Eight of the studies cited by WHO included immunogenicity data for infants and children in the shorter term. There is no information on longer-term immune response in children. Results are varied. WHO concludes that children may not develop an immunologic response as effectively as adults or may lose immunity more rapidly. They also note that some of these studies have methodologic limitations.

In contrast, the ACIP recommendations identify special groups of travellers for whom booster doses may be considered following appropriate assessments for contraindications and precautions. These include women who were pregnant when they received their initial dose of yellow fever vaccine, those who received a hematopoietic stem cell transplant after receiving a dose of yellow fever vaccine, and those who were infected with HIV when they received their last dose of yellow fever vaccine Footnote 6.

A booster dose is also suggested for travellers who received their last dose of yellow fever 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. ACIP recommends that laboratory workers with exposure to wild yellow fever virus be boosted or tested for immunity at 10 year intervals. Young children are not considered a special group in the ACIP statement, despite the fact that there are no studies that have followed individuals vaccinated in infancy over the longer term. CATMAT notes that four papers that pertain to yellow fever vaccine in children are referenced in the Gotuzzo systematic review but are not mentioned in the ACIP review (Appendix A) Footnote 15,Footnote 25,Footnote 26,Footnote 27.

CATMAT review of additional data

Epidemiologic

In response to a yellow fever epidemic in 1978–79, the small West African nation of The Gambia initiated mass immunization reaching 95% of the population within a six month period. Additionally, yellow fever vaccine was incorporated into the childhood immunizations schedule with coverage of children maintained at over 80% to the present time. Since then, The Gambia has only reported a single case involving an unimmunized tourist Footnote 28.

This is to be contrasted with the epidemiology of yellow fever in its larger neighbour, Senegal, which almost completely surrounds The Gambia. Senegal had lower coverage of its population during this same period of almost 40 years and has experienced several yellow fever outbreaks Footnote 28.

Immunogenicity of Yellow Fever Vaccine in Immunocompromised Travellers

CATMAT undertook a literature review of the evidence on the effectiveness of yellow fever vaccine in immunocompromised individuals. Ninety-six papers were found in the search. Titles of these results were reviewed and 10 articles were selected for abstract review. Of these, five were selected for full review Footnote 29,Footnote 30,Footnote 31,Footnote 32,Footnote 33. These ranged in study design from a case report of a kidney transplant recipient to a systematic review on yellow fever immunization in people infected with HIV. None reported on persistence of antibody in the longer term; consequently, results of these studies are insufficient to draw clear conclusions about the immune response to yellow fever vaccine in immunocompromised individuals over the long term.

Evaluation of the evidence base

Epidemiologic

Given the hundreds of millions of doses of yellow fever vaccine administered globally, the small number of vaccine failures is impressive and lends support to the premise that vaccine protects for the long term. However, given its nature, this data provides only weak evidence as it is impossible to ascertain how many vaccine failures were not diagnosed, not reported, not published, or otherwise escaped notice; yellow fever is most common in regions that are less likely to devote resources to viral diagnostics and where high-quality medical care is less easily accessed.

The observations regarding the apparent effectiveness of yellow fever vaccine in epidemics is important but it can be considered as indirect supporting evidence only Footnote 24.

The comparison of The Gambia and Senegal represents a unique geographic situation facilitating an ecologic study that provides indirect evidence that a single dose without boosters appears to have provided long term protection against outbreaks. However, since completeness of reporting is known to be problematic in many instances, this otherwise impressive contrast does not provide high level epidemiologic evidence.

In total, the epidemiological data pertaining to long-term or lifelong protection from one dose of yellow fever vaccine are sparse. The supporting evidence deriving from this most important category of data is consequently weak.

Serologic

Overall, studies show high rates of seropositivity or seroprotectivity in the medium and longer term. WHO interprets the results as demonstrating seroprotection. ACIP does not accept plaque reduction neutralization test (PRNT) threshold titres as a valid indicator of seroprotection. ACIP has interpreted all the published seroconversion data of intermediate and longer-term as representing seropositivity only.

ACIP’s reported seropositivity rates for those immunized ≥10 years previously are 92% (95% CI 85%–96%) and for those vaccinated ≥20 years previously, 80% (95% CI 74%–86%). There is limited data on very long-term immunity.

Serologic studies provide surrogate evidence of efficacy and therefore provide weaker evidence. If one adopts the more stringent ACIP requirements for evidence of seroprotection, this surrogate evidence is again weaker since no studies were done using the log neutralization index testing. An additional concern is that more recent work in hamsters raises the possibility that the PRNT seroprotective threshold titre used in many of the referenced papers is too low to protect against viscerotropic manifestations of yellow fever Footnote 34. It is not known if this finding can be extrapolated to humans.

Special groups

There is weak evidence of a reduced immune response to yellow fever vaccine in young children, a matter that requires further investigation.

The lack of literature on the long-term response to yellow fever vaccine in immunocompromised individuals does not allow a conclusion to be drawn. It is assumed that most individuals in this category will have a poorer immune response.

Summary of Evidence Base

CATMAT concludes that the paucity of high-quality data found in both the WHO (Gotuzzo Footnote 5) and ACIP systematic reviews does not provide strong evidence for long-term protection from yellow fever vaccine. We believe that insufficient information exists to confidently state the duration of protection afforded by a single dose. There is some weak evidence of a poorer immunogenic response in young children and there are no data relating to the duration of protection in these individuals. There are sparse data in immunosuppressed individuals, a group known to respond more poorly to other vaccines.

Recommendations

1. Notwithstanding the paucity of evidence for lifelong protection from one dose, CATMAT recommends that no booster dose of yellow fever vaccine be routinely given except for three special groups (Table 2).

  • Individuals in whom response to prior vaccination may be diminished
  • Individuals at particularly high risk of exposure
  • Individuals with regular and ongoing risk of exposure

This recommendation rests on the following considerations:

Considerations which support a recommendation FOR continued 10-year repeat doses of yellow fever vaccine

  • The epidemiologic data indicating long-term immunity from one dose is sparse and provides only very low quality evidence
  • The serologic data indicating long-term immunity from one dose provides only very low quality evidence

Considerations which support a recommendation AGAINST repeat doses of yellow fever vaccine

  • Yellow fever is extremely rare in Canadians.Footnote 35,Footnote 36
  • Epidemiologic and serologic evidence, albeit very low quality, that the vaccine confers long-term protection from a single dose
  • The possibility that innate and cellular immune responses play a role in long term protection
  • The rarity of documented vaccine failures
  • There are known adverse events of the vaccine which can be serious, including the very rare risk of yellow fever vaccine-associated neurologic disease in previously immunized individuals Footnote 37
Table 2: Recommendations for Yellow Fever Vaccine Booster in Special Groups
Group Recommendation
Individuals in whom response to prior vaccination may be diminished or for whom long term protection data is lacking:
  • Individuals previously immunized with yellow fever vaccine exclusively during a period of presumed reduced immunocompetence. This includes pregnancy, individuals taking immunosuppressive medication, and those diagnosed with an immunocompromising illness, including HIV-positivity.
  • Individuals who underwent a hematopoietic stem cell transplant after receiving their last dose of yellow fever vaccine.
  • Individuals who received a previous dose which may have been inadequate for long term protection (fractional dose, undocumented or improperly documented dose, dose administered by non-accredited providers etc)

Travellers recommended to receive a one-time booster dose of yellow fever vaccine prior to travel to an area with risk of yellow fever.

For HIV-positive travellers, a booster dose of yellow fever vaccine every 10 years is recommended prior to such travelTable 2 - Footnote *. Note: the vaccine is contraindicated for people with symptomatic HIV, including people with CD4 T lymphocyte values <200/mm3 or <15% of total lymphocytes for children aged <6 years.

Travellers who received a dose considered to be inadequate for long term protection should receive a one-time full dose of yellow fever vaccine prior to travel to an area with risk of yellow fever.

These recommendations assume that an assessment deems it safe to immunize the traveller.

Individuals at particularly high risk of exposure:
  • Individuals travelling to an area experiencing an epidemic or major outbreak.
  • Individuals travelling frequently or for prolonged periods to areas of high endemicity particularly West Africa. Risk will be greater with occupations and activities that involve more mosquito exposure and rural stays. Current protection may be less certain if the primary dose was administered during infancy. 
Consider a one-time booster dose of yellow fever vaccine prior to such travel if 10 years have elapsed since the primary dose and no previous booster doses administered.
Individuals with regular and ongoing risk of exposure:
  • Laboratory personnel working with yellow fever virus.
A booster is recommended every 10 years unless measured neutralizing antibody titre to yellow fever virus confirms ongoing protection.

CATMAT does not make specific recommendations for a booster dose of the yellow fever vaccine in young children. More research is needed to determine the duration of immunity in this group. Individual assessment of risks and benefits should be done when considering re-immunization of children who received their first dose prior to one year of age.

2. The International Certificate of Vaccination or Prophylaxis (ICVP) for yellow fever immunizations should be completed as follows:

  1. For newly immunized individuals, duration of validity of the vaccine certificate should be entered as “For the life of the person vaccinated”. This applies as well to immunocompromised individuals who are deemed safe to immunize. However, the possible need for additional doses for future travel should be discussed with such travellers and ideally supplemental documentation of this information should be provided as a reminder, to be kept separate from the ICVP.
  2. For individuals immunized more than 10 years previously, it is recommended that their existing certificate continue to be used. CATMAT suggests that such travellers also carry a copy of the WHO statement announcing lifelong protection from one dose. This may be presented in the event of difficulties at a border. Note that WHO advises that any change made to an existing certificate may render it invalid.

Conclusions

There is a paucity of data providing evidence for long-term protection from yellow fever vaccine.

Based on a consideration of the historical rarity of yellow fever cases in Canadians, the risk of adverse events from vaccination and the existence of evidence (though weak) of long-term vaccine effect, CATMAT recommends that no booster dose of yellow fever vaccine be given except for special groups.

Further studies addressing the issue of long-term protection in the general population, in children and in immunosuppressed individuals are needed. CATMAT’s recommendations are subject to change based on the future publication of such data.

Appendices

APPENDIX A

Papers pertaining to response to yellow fever vaccine in children included in the WHO review but absent from the ACIP review:

APPENDIX A
Study Results
Gomez SY, Ocazionez RE, 2008 Footnote 15 Results showed reduced immunity in children but parents’ memory of children having been immunized was accepted as sufficient documentation
Guerra HL, Sardinha TM, da Rosa AP, Lima e Costa MF, 1997 Footnote 25 75% seropositivity in primary school children n=173, 6 months after immunization; Conclusion: lower seroconversion than expected
Fox JP, Fonseca Da Cunha J, Kossobudzki SL, 1948 Footnote 26 For children age 5–14 yrs, n=79, tested 2 yrs later, 81% seropositive pointing to reduced immune response but the difference vs older age group was not statistically significant.
Veras MA, Flannery B, de Moraes JC, da Silva Teixeira AM, Luna EJ, 2010 Footnote 27 This paper is a population survey of yellow fever vaccine coverage.

Acknowledgements

This statement was developed by the Yellow Fever Working Group: Teitelbaum P (Chair), Bui Y, Libman M, and Pernica J, and approved by CATMAT.

CATMAT acknowledges and appreciates the contribution of Mona Abdel-Motagally and Elspeth Payne to this statement.

CATMAT members: McCarthy A (Chair), Acharya A, Boggild A, Brophy J, Bui Y, Crockett M, Greenaway C, Libman M, Teitelbaum P and Vaughan S.

Liaison members: Angelo, K (United States Centers for Disease Control and Prevention), Audcent T (Canadian Paediatric Society), and Pernica J (Association of Medical Microbiology and Infectious Disease Canada).

Ex officio members: Marion D (Canadian Forces Health Services Centre, Department of National Defence), McDonald P (Bureau of Medical Sciences, Health Canada), Rossi C (Medical Intelligence, Department of National Defence), and Schofield S (Pest Management Entomology, Department of National Defence).

Conflict of interest

None declared.

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