Evidence to Recommendations for Use of Tetanus Toxoid, Reduced Diphtheria Toxoid and Acellular Pertussis (Tdap) Vaccines in Adolescents and Adults

About

  • The Evidence to Recommendations (EtR) frameworks describe information considered in moving from evidence to ACIP vaccine recommendations.

Summary

Question: Should recommendations be changed to allow either tetanus toxoid, reduced diphtheria toxoid and acellular pertussis (Tdap) vaccine or tetanus and diphtheria toxoids (Td) vaccine be used in situations where only Td vaccine is recommended?

Population: Persons aged ≥7 years who have previously received at least one dose of Tdap vaccine and who are recommended to receive Td for the decennial Td booster, for tetanus prophylaxis in the setting of wound management or for the catch-up immunization schedule

Intervention: Tdap or Td

Comparison: Td

Outcome: Safety and immunogenicity; programmatic considerations, including flexibility for providers and ease of implementation

Background

Background: Two Tdap vaccines are licensed for use in the United States. Boostrix (GSK) is approved for a single dose in persons ≥10 years. Adacel (Sanofi) is approved for persons 10–64 years. Since 2005, a single booster dose of Tdap vaccine has been recommended for adolescents 11–18 years and adults 19–64 years12 to increase protection against tetanus, diphtheria and pertussis. Decennial doses of Td vaccine have been recommended every 10 years to ensure continued protection against tetanus and diphtheria. These recommendations were expanded to include a single dose of Tdap for adults ≥65 years in 2012 (only one Tdap product is approved for use in individuals ≥65 years of age, although either vaccine administered to a person adults ≥65 years is considered valid)3. If a tetanus toxoid–containing vaccine is indicated for tetanus prophylaxis in the setting of wound management, Td has been recommended for nonpregnant persons ≥7 years of age who had previously received Tdap. For pregnant women, Tdap is recommended in this setting. For previously unvaccinated persons ≥7 years of age, a 3-dose catch-up immunization schedule included only one dose of Tdap, preferably the first (off-label use in children 7–9 years), and two subsequent Td doses at specified intervals.4

No further doses of Tdap are routinely recommended, with two exceptions. Pregnant women should receive Tdap during each pregnancy (off-label use) and children aged 7–10 years who received Tdap as part of the catch-up schedule were recommended to receive the routine adolescent Tdap booster dose at 11–12 years.12 Note that in 2010, ACIP evaluated the safety of administering Tdap at intervals <5 years after Td,56 and recommended that the dose of Tdap, when indicated, should not be delayed. It should be administered regardless of the interval since the last tetanus or diphtheria toxoid-containing vaccine.

In 2013, ACIP reviewed the latest safety and immunogenicity data at that time to inform their recommendations regarding a second routine dose of Tdap. ACIP concluded that a second dose of Tdap would be safe and immunogenic at 5- or 10-year intervals.7891011 However, anti-pertussis antibodies decline rapidly after the first year91213141516171819 and vaccine effectiveness studies indicate that pertussis protection begins to decline within 2 to 4 years after receipt of a single dose of Tdap.202122 This likely limits the impact of second dose of Tdap on the overall burden of pertussis in the United States.23 In addition, Tdap vaccines have an uncertain role in prevention of transmission and herd protection.2425 ACIP concluded that the data did not support a general recommendation for a routine second dose of Tdap, given its public health impact would be limited.26

In January 2019, the FDA approved Adacel for a second dose if administered ≥8 years after the first Tdap dose and for use for tetanus prophylaxis when indicated for wound management if at least 5 years have elapsed since the previous receipt of any tetanus toxoid-containing vaccine.27 In light of the new indication for a second dose of Adacel and evidence of Tdap being used in place of Td,28 the ACIP Pertussis Vaccines Work Group assessed data related to potential benefits and harms of allowing either Td or Tdap to be used in situations where previously only Td had been recommended. Because the previous Pertussis Vaccines Work Group had assessed the evidence available on safety and immunogenicity of repeat Tdap vaccination and its impact on pertussis disease burden, a Grading of Recommendations, Assessment, Development and Evaluation (GRADE) was not completed for these recommendations. Additional factors related to repeat Tdap vaccination were assessed as part of the Evidence to Recommendations Framework (EtR), summarized below, with a focus on programmatic considerations.

Additional background information supporting the ACIP recommendations on the use of Tdap can be found in the relevant publication of the recommendation referenced on the ACIP website.

Problem

References in this table: 28

Criteria Work Group Judgments Evidence Additional Information
Is the problem of public health importance? Probably yes Current ACIP recommendations lack flexibility for providers to use Tdap in place of Td for the decennial booster, tetanus prophylaxis for wound management and for additional doses of the catch-up immunization schedule.

 

The lack of flexibility for providers was judged to probably be of public health importance in the context of a recent FDA label change allowing >1 dose for one licensed Tdap product and evidence that many providers are using Tdap in place of Td despite current recommendations, described in detail below. [28]

Benefits and harms

References in this table:7891011282930313233

Criteria Work Group Judgments Research Evidence Additional Information
How substantial are the desirable anticipated effects? Moderate Note that ACIP had previously concluded that data do not support a general recommendation for a routine second dose of Tdap, as the public health impact of routinely recommending a second dose of Tdap on the burden of disease in the United States would likely be limited. [29] As the focus of the intervention for this Evidence to Recommendations Framework was on programmatic considerations and not on pertussis control, disease burden data were not reviewed in detail.

 

Benefits to providers: Survey data and other data are lacking on provider attitudes and the benefits of the intervention to providers and patients. Based on expert opinion, allowing Td or Tdap to be used in place of Td would have moderate benefits to providers by increasing ease of vaccine administration and flexibility.

  • It can be challenging to determine patient history and receipt of previous Tdap. Allowing repeat doses of Tdap would simplify administration of tetanus- and diphtheria-toxoid containing vaccines.
  • It is cumbersome to stock both Td and Tdap vaccines. This change may simplify vaccine ordering and supply.
How substantial are the undesirable anticipated effects Minimal Use of Tdap for the decennial Td booster:
  • Multiple studies, including those reviewed previously by ACIP, indicate that a second dose of Tdap at 5- and 10-year intervals are safe when compared with Td. [7-11]
  • Since repeat Tdap vaccination was last reviewed by ACIP, three additional clinical trials found no significantly increased risk of serious adverse events among adults who received Tdap compared with those who received Td at a 10-year interval after receipt of initial Tdap dose [30,31] or among persons received a second dose of Tdap 9 years after an initial Tdap dose who were compared with persons receiving Tdap for the first time. [32]
  • A retrospective study by the Vaccine Safety Datalink (VSD) identified 68,915 persons who had received an initial dose of Tdap and then received another Td-containing vaccine. There was no elevated risk of medical visits for adverse events among those who received a subsequent dose of Tdap compared with Td. [28]
  • Data is lacking on >2 doses of Tdap at 5- and 10- year intervals.

There are no substantive safety concerns in allowing either Tdap or Td to be used for the decennial Td booster and for tetanus prophylaxis in the setting of wound management in persons who had previously received Tdap.

 

Use of Tdap in the catch-up immunization schedule
Data were limited for the use of multiple Tdap doses in the catch-up immunization schedule, including for pregnant women. Safety data from one clinical trial33 and unpublished and published data on closely spaced Tdap vaccines were reviewed (see Appendix for details). These data do not suggest any substantive safety concerns regarding the use of either Td or Tdap in the catch-up immunization schedule in settings where Td would be recommended, including in pregnant women.
Do the desirable effects outweigh the undesirable effects? Favors intervention Allowing providers to use either Tdap or Td in settings where Td only was previously recommended is favored as an intervention due to:
  • The desirable effects of increased flexibility to providers and immunization programs.
  • Acceptable safety profile with no substantive safety concerns identified for the substitution of Tdap in place of Td.
What is the overall certainty of this evidence for the critical outcomes? Effectiveness of the intervention is Level 2 (Moderate)

Safety of the intervention is Level 3 (Low)

 Because the previous Pertussis Vaccines Work Group had assessed the evidence available on safety and immunogenicity of repeat Tdap vaccination and its impact on pertussis disease burden, a Grading of Recommendations, Assessment, Development and Evaluation (GRADE) was not completed for these recommendations. The judgements on the certainty of evidence were made based on expert opinion.

 

Effectiveness of intervention as relates to programmatic benefits
The certainty of the evidence of the programmatic benefits of increasing flexibility for providers and patients is moderate.

 

Safety:
The certainty of evidence for safety for use of Tdap for the decennial Td booster and for tetanus prophylaxis in the setting of wound management is based on multiple clinical trials compared the use of a 2nd Tdap dose to Td at 5- and 10-year intervals. The certainty of the evidence for the safety of multiple doses to replace Td in the catch-up immunization schedule, including in pregnant women, is low.

Values

References in this table:28

Criteria Work Group Judgments Research Evidence Additional Information
Does the target population feel that the desirable effects are large relative to undesirable effects? Uncertain No data are available on the values of the target population towards the use of Tdap or Td in in situations where only Td vaccine is recommended.
Is there important uncertainty about or variability in how much people value the main outcomes? Probably no important uncertainty or variability No direct data are available on how much people value the main outcomes.  However, there is considerable evidence that Tdap is already being used in settings where Td only is recommended.

 

Published data suggests that providers give Tdap to persons who previously received Tdap.

  • A retrospective study by the Vaccine Safety Datalink (VSD) identified 68,915 persons who had received an initial dose of Tdap and then received another Td-containing vaccine. The majority (n=61,394, 89%) received a second Tdap; 7,521 (11%) received Td. [28]

 

Unpublished data indicates that Tdap administration in adults is more frequent than Td administration.

  • Analysis of commercial insurance claims indicated that in 2017 in adults aged 19 to 64 years, Tdap claims (n=716,638) were 12-fold more frequent than Td claims (n=61,468) (Truven Health Analytics, unpublished data).
  • In 2017, there were 441,075 doses of Tdap ordered by providers for adults for public sector purchases compared with 41,881 doses of Td ordered (CDC unpublished data).

These data suggest that key stakeholders, including providers and immunization programs, value the programmatic benefits of increased flexibility and ease of administration.

Acceptability

Criteria Work Group Judgments Research Evidence Additional Information
Is the intervention acceptable to key stakeholders? Yes Key stakeholders include patients, healthcare providers and immunization programs. No direct data are available on the acceptability of this intervention to these stakeholders.  However, as noted above, there is considerable evidence that Tdap is already being used in settings where Td only is recommended.

 

These data suggest that key stakeholders, including providers and immunization programs, value the programmatic benefits of increased flexibility and ease of administration, and that the intervention is acceptable to key stakeholders.

Resource use

References in this table:23293435

Criteria Work Group Judgments Research Evidence Additional Information
Is the intervention a reasonable and efficient allocation of resources? Probably yes Tdap costs more than Td.
  • As of April 19, 2019, per the CDC Vaccine Price List, the CDC cost per dose of generic Td (TDVAX™) was $13.96. The two Tdap products, Boostrix® and Adacel® cost $24.65 and $24.49 respectively. The cost difference was greater for private sector purchases. [34]

Population-level effectiveness and economic impact of replacing Td with Tdap vaccine has been modeled and was previously reviewed by ACIP. [23,29]
Estimates of economic impact are dependent on values for parameters for which there is a high degree of uncertainty, including pertussis incidence, illness severity, initial vaccine effectiveness, duration of protection, and the impact of Tdap on herd immunity.

  • An updated model of economic impact of substituting Tdap for the decennial Td booster was presented to the Pertussis Vaccines Work Group.35 The analysis suggested that replacing Td with Tdap for the decennial booster would result in high cost per Quality Adjusted Life Year (QALY) saved based on the number of cases reported to the Nationally Notifiable Diseases Surveillance System. It was noted that programmatic benefits from using a single tetanus-toxoid containing vaccine could result in cost-savings that were not accounted for in the model.


Conclusion: Given the uncertainty in the results from economic models, and evidence for the already widespread use of Tdap vaccine in place of Td, programmatic issues were the main consideration in the decision-making process. Allowing providers to use either Tdap or Td in place of Td is probably a reasonable and efficient allocation of resources.

Feasibility

Criteria Work Group Judgments Research Evidence Additional Information
Is the intervention feasible to implement? Yes As noted above, there is evidence that the use of Tdap in place of Td is already implemented in many clinical settings.


Conclusion: The intervention is feasible to implement.

Balance of consequences

Desirable consequences probably outweigh undesirable consequences in most settings

Is there sufficient information to move forward with a recommendation? Yes

Policy option for ACIP consideration

ACIP recommends the intervention

Recommendation (text)

Routine recommendations:
Persons aged 11–18 years should receive a single dose of Tdap, preferably at a preventive care visit at ages 11–12 years. To ensure continued protection against tetanus and diphtheria, booster doses of either Td or Tdap should be administered every 10 years throughout life.

Persons aged ≥19 years who previously have not received a dose of Tdap should receive a single dose of Tdap regardless of the interval since their last tetanus or diphtheria toxoid–containing vaccine. To ensure continued protection against tetanus and diphtheria, booster doses of either Td or Tdap should be administered every 10 years throughout life.

Tetanus prophylaxis for wound management recommendations
A tetanus toxoid–containing vaccine is indicated as part of wound management when more than five years has passed since the last tetanus toxoid–containing vaccine dose. If a tetanus toxoid–containing vaccine is indicated for persons aged ≥11 years, Tdap is preferred for persons who have not previously received Tdap or whose Tdap history is unknown. If a tetanus toxoid–containing vaccine is indicated for a pregnant woman, Tdap should be used. For nonpregnant persons with documentation of previous Tdap vaccination, either Td or Tdap can be used if a tetanus toxoid–containing vaccine is indicated. For complete information on tetanus prophylaxis and the use of tetanus immunoglobulin when indicated for wound management, please see: [insert link to previous guidance].

Catch-up immunization recommendations
Persons aged 7–18 years who have never been vaccinated against pertussis, tetanus, or diphtheria should receive a series of three tetanus and diphtheria toxoid-containing vaccines, which includes at least 1 dose of Tdap. The preferred schedule is a dose of Tdap, followed by a dose of either Td or Tdap at least 4 weeks afterward and another dose of either Td or Tdap 6 to 12 months later.

Persons aged 7–18 years who are not fully immunized against pertussis, tetanus or diphtheria should receive 1 dose of Tdap (preferably the first) in the catch-up series; if additional tetanus toxoid–containing doses are required, either Td or Tdap vaccine can be used. The vaccine series does not need to be restarted for those with incomplete DTaP vaccine history, regardless of the time that has elapsed between doses. The catch-up schedule and minimum intervals between doses are available.

Persons aged ≥19 years who have never been vaccinated against pertussis, tetanus, or diphtheria should receive a series of three tetanus and diphtheria toxoid-containing vaccines, which includes at least 1 dose of Tdap. The preferred schedule is a dose of Tdap, followed by a dose of either Td or Tdap at least 4 weeks afterward and another dose of either Td or Tdap 6 to 12 months later.

Persons aged ≥19 years who are not fully immunized against pertussis, tetanus or diphtheria should receive 1 dose of Tdap (preferably the first) in the catch-up series; if additional tetanus toxoid–containing doses are required, either Td or Tdap vaccine can be used.

No change has been made to the recommendations for routine Tdap immunization during each pregnancy.429 The risk of neonatal tetanus is minimal if a previously unvaccinated woman has received at least 2 properly spaced doses of a tetanus toxoid–containing vaccine during pregnancy; at least one of the doses administered during pregnancy should be Tdap, administered according to published guidance.29 If more than one dose is needed, either Td or Tdap can be used. She should complete the 3-dose primary series at the recommended intervals.

Final deliberation and decision by the ACIP

Final ACIP recommendation

ACIP recommends the intervention

Appendix: Summary of safety data on the use of >1 Tdap dose for the catch-up immunization schedule

For previously unvaccinated persons ≥7 years of age, a 3-dose catch-up immunization schedule included only one dose of Tdap, preferably the first (off-label use in children 7–9 years), and two subsequent Td doses at specified intervals.4 There is limited data for use of Tdap instead of Td for >1 dose in the catch-up immunization schedule in persons ≥7 years, including in pregnant women. Both published and unpublished data were reviewed.

  • One double-blind, randomized controlled clinical trial of 460 adults ≥40 years without diphtheria or tetanus vaccination for 20 years or with an unknown vaccination history were vaccinated at 0, 1 and 6 months. Subjects were randomized to receive three doses of Tdap (non-U.S. formulation), one Tdap-IPV dose (vaccine not licensed in the U.S.) followed by two Td doses, or 3 Td doses.33
    • There was no evidence of increased risk of adverse events for adults receiving three Tdap doses compared with those receiving three Td doses.
    • There was no significant differences in tetanus and diphtheria seroprotection rates between the three groups.

Because there were few studies examining the use of Tdap in the catch-up immunization schedule, recent data on the safety of closely spaced (interval of <12 months) Tdap vaccines was examined to see if any concerning safety signals were reported.

  • A review of the Vaccine Adverse Event Reporting system found that among 34,804 Tdap reports in non-pregnant and pregnant persons of all ages from January 1, 1990 to June 30, 2019, 88 (0.3%) involved multiple Tdap doses spaced <12 months apart. Among these, 18 (23%) were associated with adverse events (CDC unpublished data).
  • An analysis of data collected as part of a published retrospective study28 by the Vaccine Safety Datalink (VSD) identified 13,599 persons who had received an initial dose of Tdap and then received another Td-containing vaccine within 12 months of prior Tdap dose, either a second Tdap (n=11,687, 86%) or Td (n=1,912, 16%). There was no elevated risk of medical visits for adverse events among those who received a subsequent dose of Tdap compared with Td (unpublished data).

There are no published data comparing rates of adverse events among previously unimmunized pregnant women who receive multiple doses of Tdap during pregnancy with those who received a single Tdap dose and also additional Td doses for catch-up vaccination. Given this, we examined published and unpublished data on the receipt of multiple Tdap doses administered during a single pregnancy or at least 2 doses administered <12 months apart in pregnant women.

  • A cohort study examining reactogencity of Tdap in pregnant women included data on eight study participants who had >1 Tdap dose within a 12-month period. None experienced severe reactions or fever.36

A VSD study examining safety of Tdap during pregnancy identified 187 women who had received more than 1 dose of Tdap during a single pregnancy among 633,542 singleton pregnancies screened for potential study inclusion.37 Although these 187 women were excluded from the published study, the authors found similar rates of adverse birth outcomes (i.e., small for gestational age, preterm delivery, and low birth weight) in these women compared with women had received a single Tdap dose in pregnancy (N=29,155). When evaluating acute reactions, only 1 out of 187 women receiving >1 Tdap dose had a medically attended acute adverse event diagnosed as limb pain and swelling 7 days after receipt of vaccine; this timing corresponded to the date of her delivery. Furthermore, there was one woman who received 3 Tdap vaccines without acute adverse events during a single pregnancy; her baby was born at term (unpublished data).

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