Centers for Disease Control and Prevention (1/12/2018)

Grading of Recommendations Assessment, Development, and Evaluation (GRADE): Use of 

a Third Dose of Mumps Virus-Containing Vaccine in Persons at Increased Risk for Mumps 

Disease During an Outbreak

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 viruscontaining 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).

Methods for GRADE

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. 

https://www.cdc.gov/vaccines/acip/recs/grade/mumps-h.pdf
Centers for Disease Control and Prevention (1/12/2018)

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.

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). 

Summary
Centers for Disease Control and Prevention (1/12/2018)

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 Advisory Committee on Immunization 

Practices (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 and are available at ... 

(link to MMWR policy note).

Table 1. Use of a Third Dose of Mumps Virus-Containing Vaccine During Outbreaks: 

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)

1996-

[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]

CINAHL

(Ebsco)

1982-

[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)) 
Centers for Disease Control and Prevention (1/12/2018)

OR (booster* AND (outbreak* OR epidemic*)) OR (booster N5 (dose* OR 

dosage)) OR military]

Cochrane

1800- [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)

Table 2. Use of a Third Dose of Mumps Virus-Containing Vaccine During Mumps 

Outbreaks: Outcomes, Importance, and Data Availability

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

Table 3. Use of a Third Dose of MMR Vaccine During Mumps Outbreaks: Characteristics 

and Results of Included Studies for Critical Outcomes

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
Centers for Disease Control and Prevention (1/12/2018)

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 

postintervention

Young adults; nonoutbreakPre-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
Centers for Disease Control and Prevention (1/12/2018)

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

Outcome Design 

(# 

studies) 

Initial 

Evidenc

e 

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

Footnotes

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 
Centers for Disease Control and Prevention (1/12/2018)

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

During Mumps Outbreaks

Supplementary Table 1. Use of a Third Dose of MMR Vaccine During Mumps Outbreaks: 

Characteristics of Included Studies for Important Outcomes

Author, 

year

Study 

design

Study 

population; 

setting

Comparison 

group Benefit outcome Harm outcome

Routh, 

unpublished

Pre- and 

postintervention

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, 

hemagglutininneuraminidase 

(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

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
Centers for Disease Control and Prevention (1/12/2018)

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

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