Skip directly to search Skip directly to A to Z list Skip directly to navigation Skip directly to page options Skip directly to site content

Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) for Third Dose of Mumps Virus-Containing Vaccine in Persons at Increased Risk for Mumps Disease During an Outbreak

Printer friendly version of this page [9 pages, HTML]

Introduction

In 1977, the Advisory Committee on Immunization Practices (ACIP) recommended one dose of mumps vaccine for all children aged ≥12 months (1).  In 1989, in response to multiple measles outbreaks in the late 1980s, ACIP recommended routine administration of two doses of measles, mumps, rubella (MMR) [M-M-R II, Merck & Co., Inc] vaccine for children, with the first dose administered at ages 12 through 15 months and the second at ages 4 through 6 years (2). In addition to improved measles control, this policy led to substantial reduction in the number of mumps cases in the United States during the 1990s, which was sustained through 2005 (3).  However, mumps outbreaks, primarily affecting populations with high coverage with two doses of MMR vaccine in midwestern states and colleges, occurred in 2006, prompting ACIP to formally recommend a routine 2-dose mumps vaccination policy for school-aged children (i.e., Kindergarten–grade 12) and adults at high risk (i.e., students at post-high school educational institutions, health care personnel, and international travelers) in 2006 (4). Despite this recommendation, mumps outbreaks continued to be reported throughout the United States. To assist state and local health departments in responding to mumps outbreaks, CDC issued guidance on use of a third dose of MMR vaccine in 2012 in specifically identified target populations.

As more evidence has accumulated after 2012, in October 2017 the Advisory Committee on Immunization Practices (ACIP) reviewed the evidence on vaccination with a third dose of mumps virus-containing vaccine. The policy question was “Should a third dose of mumps virus-containing vaccine be administered to persons at increased risk for mumps because of an outbreak?” Evidence of benefits and harms was evaluated in accordance with Grading of Recommendations, Assessment, Development and Evaluation (GRADE) methods (5).
Top of Page

Methods

The ACIP Mumps Work Group proposed beneficial and harmful outcomes of vaccination to consider, as well as the importance of these outcomes (critical vs. important).

A systematic review of Medline, Embase, Cochrane Library, CINAHL, Scopus and ClinicalTrials.gov, was conducted for studies in any language published from January 2000 to August 2017. The start date of January 2000 was selected because a large outbreak among persons with two doses of MMR vaccine was first reported in 2006 by the United States (6) and use of a third dose of mumps virus-containing vaccine was not considered before this and other large mumps outbreaks that occurred around the same time. We added five years as an additional capture period. Search terms are described in Table 1. Articles were included if they presented data on a third dose of mumps virus-containing vaccine and 1) reported primary data; 2) included data relevant to the outcome(s) being assessed; and 3) were not animal studies. The work group also pursued available unpublished data.

After review of the titles and abstracts (n=478), 50 studies were identified for further review. Of these, 34 studies did not report data on a third dose, 5 did not report on outcomes of interest, 1 study on a third dose was conducted only in immunocompromised children and 3 studies had results not yet reported or not found. We identified an additional 3 studies that were unpublished at the time of the work group assessment. A total of 10 studies reporting on critical and important outcomes were considered in the GRADE analysis. In this document, we summarize evidence from 7 studies that reported on critical outcomes (7–13).  Studies included in the evaluation of important outcomes are provided in Supplementary Table 1 (7, 11–16). In all studies, MMR vaccine was used as the third dose of mumps virus-containing vaccine.

Top of Page

Results

The benefits outcomes considered critical were preventing mumps disease and preventing complications of mumps disease and the harms outcome considered critical was occurrence of serious adverse events (SAEs) after vaccination (Table 2). Important outcomes included duration of protection, immune response, and reactogenicity.

Benefits outcomes

Three cohort studies reported on the outcome of preventing mumps disease. Characteristics and results of these studies are presented in Table 3. All studies were conducted in outbreak settings among populations with high two-dose coverage (i.e. >95%) and reported a lower attack rate in three dose MMR vaccine recipients compared with two dose recipients. Incremental vaccine effectiveness (VE) at 21 to 28 days post-vaccination ranged from 61% to 88% but only one estimate (78%, 95% CI 61%–88%) was significant (p<0.001). The GRADE evidence type for preventing mumps disease was 4 (Table 4).

For the outcome of preventing mumps complications, no studies reported on VE against mumps complications and the evidence type was not determined for this outcome (Table 4). However, it was considered that complications from mumps disease also are prevented when mumps disease is prevented by a third dose of MMR vaccine.

Harms outcome

One pre- and post- study and 4 case series studies reported on serious adverse events (SAE) of a third dose of MMR vaccine. Characteristics and results of these studies are presented in Table 3. SAE is defined as death, life-threatening illness, hospitalization or prolongation of existing hospitalization, or permanent disability. No SAEs were reported in 14,368 children and young adults vaccinated with a third dose. Two studies were based on passive reporting and 3 studies actively surveyed vaccine recipients. In addition, no healthcare visits for vaccination-related symptoms were reported in any of the studies. The GRADE evidence type for serious adverse events was 3 for the pre- and post- study and 2 for the cases series studies, and therefore the overall evidence type for this outcome was 2 (Table 4).

Top of Page

Summary

The evidence types supporting critical outcomes for use of third dose of mumps virus-containing vaccine in persons at increased risk for mumps disease because of an outbreak was determined to be 4 for preventing mumps, not determined for preventing mumps complications, and 2 for serious adverse events (Table 5). A third dose of MMR vaccine is effective in preventing mumps and no serious adverse events were reported in more than 14,000 third dose recipients. Together, the benefit of added protection of a third dose of mumps virus-containing vaccine outweighs the low risk for vaccine adverse events. After reviewing the results of the GRADE analysis and other data related to burden of disease, values attributed to benefits and harms from a third dose of MMR vaccine, acceptability, and implementation, the ACIP recommended that persons previously vaccinated with two doses of a mumps virus-containing vaccine who are identified by public health authorities as being part of a group or population at increased risk for acquiring mumps because of an outbreak should receive a third dose of a mumps virus-containing vaccine to improve protection against mumps disease and related complications. Although studies evaluated for the GRADE analysis only assessed MMR vaccine, mumps virus-containing vaccine was used in the recommendation to include the measles, mumps, rubella, and varicella (MMRV) vaccine [ProQuad, Merck & Co., Inc] as an option for children aged 12 years or younger when a third dose mumps vaccination is indicated. The full recommendations for the use of mumps virus-containing vaccine in persons at increased risk for mumps because of an outbreak have been published in MMWR.

Top of Page

Tables

Table 1. Use of a Third Dose of Mumps Virus-Containing Vaccine During Outbreaks: Literature Search Terms by Database

Literature Search Terms by Database
Database Strategy
Medline
(OVID)
1946-
[Mumps OR parotitis] AND [Vaccin* OR immuni?ation* OR MMR*] AND

[(third ADJ5 (Dose* OR dosage)) OR (three ADJ5 (Dose* OR dosage)) OR (outbreak* ADJ5 (dose* OR dosage)) OR (additional ADJ5 (dose* OR dosage)) OR (booster* AND (outbreak* OR epidemic*)) OR (booster ADJ5 (dose* OR dosage)) OR military]

Embase
(OVID)
1947-
[Mumps OR parotitis] AND [Vaccin* OR immuni?ation* OR MMR*] AND

[(third ADJ5 (Dose* OR dosage))  OR (three ADJ5 (Dose* OR dosage)) OR (outbreak* ADJ5 (dose* OR dosage)) OR (additional ADJ5 (dose* OR dosage)) OR (booster* AND (outbreak* OR epidemic*)) OR (booster ADJ5 (dose* OR dosage)) OR military]

Cochrane Library [Mumps OR parotitis] AND [Vaccin* OR immuni?ation* OR MMR*] AND

[(third N5 (Dose* OR dosage))  OR (three N5 (Dose* OR dosage)) OR (outbreak* N5 (dose* OR dosage)) OR (additional N5 (dose* OR dosage)) OR (booster* AND (outbreak* OR epidemic*)) OR (booster N5 (dose* OR dosage)) OR military]

Clinical Trials.gov [mh mumps] OR (Mumps OR parotitis):ti,ab AND (Vaccin* OR immuni?ation* OR MMR*) AND (third NEAR/5 (Dose* OR dosage))  OR (three NEAR/5 (Dose* OR dosage)) OR (outbreak* NEAR/5 (dose* OR dosage)) OR (additional NEAR/5 (dose* OR dosage)) OR (booster* AND (outbreak* OR epidemic*)) OR (booster NEAR/5 (dose* OR dosage)) OR military
Scopus

1960-

TITLE-ABS-KEY(Mumps OR parotitis) AND TITLE-ABS-KEY(Vaccin* OR immuni?ation* OR MMR*) AND TITLE-ABS-KEY((third W/5 Dose*) OR (third W/5 dosage) OR (three W/5 Dose*) OR (three W/5 dosage) OR (outbreak* W/5 dose*) OR (outbreak* W/5 dosage) OR (additional W/5 Dose*) OR (additional W/5 dosage) OR (booster* AND (outbreak* OR epidemic*)) OR (booster W/5 dose*) OR (booster W/5 dosage) OR military) AND NOT INDEX(medline) AND NOT INDEX(embase)
Clinicaltrials.gov (Mumps OR parotitis)

Top of Page

Table 2. Use of a Third Dose of Mumps Virus-Containing Vaccine During Mumps Outbreaks: Outcomes, Importance, and Data Availability

Outcomes, Importance, and Data Availablity
Outcome Importance Data available
Benefits
Prevent mumps disease Critical Yes
Prevent mumps disease complications Critical No
Duration of protection Important No
Immune response Important Yes
Harms
Serious adverse events Critical Yes
Reactogenicity Important Yes

Top of Page

Table 3. Use of a Third Dose of MMR Vaccine During Mumps Outbreaks: Characteristics and Results of Included Studies for Critical Outcomes

Literature Search Terms by Database
Author, year Study design Study population; setting Comparison group Benefit outcome (results) Harm outcome (results)
Cardemil, 2017 Cohort University students; outbreak Two MMR dose vaccinated Prevention of mumps disease (incremental VE=60%, 95% CI: 38%–74%) None
Nelson, 2013* Cohort School children aged 9–14 yrs; outbreak One or two MMR dose vaccinated Prevention of mumps disease (incremental VE=61%, 95% CI: -243–95%) Serious adverse events (0/533 doses administered)
Ogbuanu, 2012* Cohort School children aged 11–17 yrs; outbreak Two MMR dose vaccinated Prevention of mumps disease (incremental VE=88%, 95% CI: -32–99%) Serious adverse events (0/1,597 doses administered)
Albertson, 2016 Case series University students and staff; outbreak None None Serious adverse events (0/11,500 doses administered)
Aasheim, 2014 Case series School children aged 12–19 years; outbreak None None Serious adverse events(0/76 doses administered)
Abedi, 2012 Case series School children aged 11–17 years; outbreak None None Serious adverse events (0/1,597 doses administered)
Routh, unpublished Pre- and post-intervention Young adults; non-outbreak Pre-third MMR dose symptoms None Serious adverse events (0/662 doses administered)

VE=vaccine effectiveness; CI=confidence interval

*Considered case series studies for the outcome serious adverse events because the outcome was reported only for persons that received a third dose and not the comparison group

Studies reported survey data from the same study for the outcomes serious adverse events and are considered in the analysis as one study for this outcome

Top of Page

Table 4. Use of a Third Dose of MMR Vaccine During Mumps Outbreaks: Evidence Table for Critical Outcomes

Evidence Table for Critical Outcomes
Outcome Design (# studies) Initial Evidence Risk of Bias Inconsistency Indirectness Imprecision Other considerations Final Evidence type Overall Evidence Type
Benefits
Prevent mumps disease Cohort (3) 3 Serious* (-1) No serious No serious Serious (-1) None 4 4
Prevent complications of mumps disease No studies ND ND ND ND ND ND ND ND
Harms
Serious adverse events Pre- and post- (1) 3 No serious No serious No serious Unable to assess None 3 2
Case series (4) 3 No serious No serious No serious Unable to assess Yes 2

ND=Not determined

*Selection bias; downgraded by 1

The CI around the effect estimate are large or include both effect and non-effect; downgraded by 1

Strong strength of association. No reported serious adverse events in over 13,000 vaccinated persons; upgraded by 1

Top of Page

Table 5. Considerations for Use of a Third Dose of Mumps Virus-Containing Vaccine During Mumps Outbreaks

Considerations for Use of a Third Dose of Mumps Virus-Containing Vaccine During Mumps Outbreaks
Key factors Comments
Balance between benefits and harms A third dose of MMR vaccine is effective in preventing mumps. No evidence available but complications of mumps disease are prevented when mumps disease is prevented. There are no concerns for serious adverse events after vaccination with a third dose of MMR vaccine.
ACIP considered that this evidence also would pertain to MMRV vaccine.
Evidence type for benefits and harms Benefits:
Prevent mumps disease: evidence type 4
Prevent complications of mumps disease: evidence type not determined
Harms:

Serious adverse events: evidence type 2

Top of Page

Supplementary Table 1. Use of a Third Dose of MMR Vaccine During Mumps Outbreaks: Characteristics of Included Studies for Important Outcomes

Characteristics of Included Studies for Important Outcomes
Author, year Study design Study population; setting Comparison group Benefit outcome Harm outcome
Routh, unpublished Pre- and post-intervention Young adults; non-outbreak Pre-third MMR dose symptoms None Reactogenicity
Latner, in press* Repeated measures Young adults; non-outbreak Pre-third MMR dose titers Immune response (IgG against whole virus, hemagglutinin-neuraminidase (HN) and nucleoprotein) None
Fiebelkorn, 2014* Repeated measures Young adults; non-outbreak Pre-third MMR dose titers Immune response (plaque reduction neutralization (PRN) neutralizing antibody titers) None
Nelson, 2013 Cohort School children aged 9–14 yrs; outbreak One or two MMR dose vaccinated None Reactogenicity
Abedi, 2012 Case series School children aged 11–17 years; outbreak None None Reactogenicity
Ogbuanu, 2012†‡ Cohort School children aged 11–17 yrs; outbreak Two MMR dose vaccinated None Reactogenicity
Date, 2008 Repeated measures University students seronegative for mumps; post-outbreak Pre-third MMR dose titers Immune response (IgG against whole virus) None

*Studies used serum samples from same cohort but different antibody detection methods

Considered case series studies for the outcome reactogenicity because the outcome was reported only for persons that received a third dose and not the comparison group

Studies reported survey data from the same study for the outcome reactogenicity and are considered in the analysis as one study for this outcome

Top of Page

References

  1. Centers for Disease Control and Prevention. Mumps vaccine. MMWR 1977;26(48):393–4.
  2. Centers for Disease Control and Prevention. Measles prevention. MMWR 1989;38:1–18.
  3. Centers for Disease Control and Prevention. Prevention of measles, rubella, congenital rubella syndrome, and mumps, 2013: summary recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR 2013;62:1–34.
  4. Centers for Disease Control and Prevention. Updated recommendations of the Advisory Committee on Immunization Practices (ACIP) for the control and elimination of mumps. MMWR Morb Mortal Wkly Rep 2006;22:629–30.
  5. Ahmed F, Temte J, Campos-Outcalt D, Schunemann H, ACIP Evidence Based Recommendations Work Group. Methods for developing evidence-based recommendations by the Advisory Committee on Immunization Practices (ACIP) of the U.S. Centers for Disease Control and Prevention (CDC). Vaccine 2011;29:9171–6.
  6. Centers for Disease Control and Prevention. Mumps epidemic—Iowa, 2006. MMWR 2006;55:366–8.
  7. Routh J. MMR3 Adverse Events. ACIP Workgroup presentation, May 25, 2017. Unpublished data.
  8. Cardemil C, Dahl RM, James L, Wannemuehler K, Gary HE, Shah M, Marin M, Riley J, Feikin DR, Patel M, Quinlisk P. Effectiveness of a Third Dose of MMR Vaccine for Mumps Outbreak Control. N Engl J Med, 2017;377:947–956.
  9. Albertson JP, Clegg WJ, Reid HD, Arbise BS, Pryde J, Vaid A, Thompson-Brown R, Echols F. Mumps Outbreak at a University and Recommendation for a Third Dose of Measles-Mumps-Rubella Vaccine – Illinois, 2015-2016. MMWR, 2016;65(29):731–734.
  10. Aasheim ET, Inns T, Trindall A, Emmett L, Brown KE, Williams CJ, Reacher M. Outbreak of mumps in a school setting, United Kingdom, 2013. Hum Vaccin Immunother, 2014;10(8): 2446–2449.
  11. Nelson GE, Aguon A, Valencia E, Oliva R, Guerrero ML, Reyes R, Lizama A, Diras D, Mathew A, Camacho EJ, Monforte MN, Chen TH, Mahamud A, Kutty PK, Hickman C, Bellini WJ, Seward JF, Gallagher K, Fiebelkorn AP. Epidemiology of a mumps outbreak in a highly vaccinated island population and use of a third dose of measles-mumps-rubella vaccine for outbreak control–Guam 2009 to 2010. Pediatr Infect Dis J, 2013. 32(4):374–80.
  12. Abedi GR, Mutuca JD, Lawlerd J, Leroyb ZC, Hudsond JM, Bloge DS, Schultee CR, Rausch-Phunge E, Ogbuanuc IU, Gallaghera K, Kuttya PK. Adverse events following a third dose of measles, mumps, and rubella vaccine in a mumps outbreak. Vaccine, 2012. 30(49):7052–
  13. Ogbuanu IU, Kutty PK, Hudson JM, Blog D, Abedi GR, Goodell S, Lawler J, McLean HQ, Pollock J, Rausch-Phung E, Schulte C, Valure B, Armstrong GL, Gallagher K. Impact of a third dose of measles-mumps-rubella vaccine on a mumps outbreak. Pediatrics, 2012. 130(6):e1567–74.
  14. Latner DR, Fiebelkorn AP, McGrew M, Williams NJ, Coleman LA, McLean HQ, Rubin S, Hickman CJ. Mumps Virus Nucleoprotein and Hemagglutinin-Specific Antibody Response Following a Third Dose of Measles Mumps Rubella (MMR) Vaccine. Open Forum Infectious Diseases, in press.
  15. Fiebelkorn AP, Coleman LA, Belongia EA, Freeman SK, York D, Bi D, Zhang C, Ngo L, Rubin S. Mumps antibody response in young adults after a third dose of measles-mumps-rubella vaccine. Open Forum Infectious Diseases, 2014. 1(3); 1–9.
  16. Date AA, Kyaw MH, Rue AM, Klahn J, Obrecht L, Krohn T, Rowland J, Rubin S, Safranek TJ, Bellini WJ, Dayan GH. Long-term persistence of mumps antibody after receipt of 2 measles-mumps-rubella (MMR) vaccinations and antibody response after a third MMR vaccination among a university population. J Infect Dis, 2008. 197(12):1662–8.

Top of Page

TOP