Third vaccine dose shows short-term benefits in Iowa mumps outbreak

Giving students a third dose of the measles, mumps and rubella vaccine during a large mumps outbreak at the University of Iowa lowered their risk of getting the disease by 78% compared with students who had received the standard two doses, according to research published today in The New England Journal of Medicine.

Furthermore, researchers found that students who had received a second dose of the MMR vaccine 13 or more years before the outbreak in 2015 had a much greater risk for infection than those who had gotten it more recently, which is a sign of waning immunity.

The findings were previously presented during a June meeting of the Advisory Committee on Immunization Practices (ACIP), which makes vaccine recommendations to the CDC. They come at a time when the ACIP is considering the benefits of adding a third dose of the MMR vaccine to the standard two-dose series to address a surge in mumps cases in the U.S., including some large outbreaks that have occurred among fully immunized populations.

The ACIP recommended the current two-dose schedule in 1989. According to the CDC, it is 88% effective at preventing mumps. The CDC previously issued guidance in 2012 for using a third dose of the MMR vaccine as a control measure during mumps outbreaks in settings with more than 90% coverage with two doses, in outbreaks that occur in close quarters, and in settings with high attack rates and with ongoing transmission. However, the committee has made no formal recommendation on the subject.

The authors of the new study, which was funded by the CDC, said their findings are best interpreted in the short-term context of stemming a mumps outbreak and may be helpful to health departments in that context but that more studies are needed on the long-term effects.

It is unclear what impact the findings will have on the ACIP’s recommendation, expected in February 2018, on whether to add a third dose of the MMR vaccine to the immunization schedule. The issue may be clarified at the next ACIP meeting in October, which will feature a session on mumps.

Manisha Patel, MD, who leads the measles, mumps and rubella team in the CDC’s Division of Viral Diseases and was one of the authors of the study, said the findings will be “critical” to deliberations over whether to add a third dose of the MMR vaccine to the current two-dose series, but that other factors such as safety and immunogenicity will need to be part of the discussion.

“It’s almost like a constellation of different features that the ACIP looks at to make the decision,” Patel said in an interview. “I think we’ll have a better idea as we get closer to the October ACIP meeting what the exact agenda will be in terms of the mumps presentation.”

Kelly Moore, MD, MPH, who chairs the ACIP’s mumps work group, told Infectious Disease News that findings from the Iowa outbreak were “informing our work.” But Moore was not able to comment on the group’s specific plans or how it was weighing the available evidence because the deliberations of ACIP work groups are confidential.

The longer term benefits of adding a third dose of the MMR vaccine have not been extensively studied. One previous study, cited in the new paper, examined the immunological protection of a third dose of the MMR vaccine by checking antibody titers in study subjects at 1 month and then 1 year. Titers were higher at both intervals, but had declined at 1 year compared with 1 month.

“What would be really helpful are studies that look at the longer-term effectiveness of the third dose,” Cristina V. Cardemil, MD, MPH, medical epidemiologist in the CDC’s Division of Viral Diseases and lead author of the new study, said in an interview. “We know from that study is that there is potentially immunological protection in the short term, but the question is what happens at 1 year and what happens beyond 1 year?”

2015 outbreak

The University of Iowa outbreak began in the summer of 2015 and involved 259 of the 20,496 students who were enrolled for that upcoming academic year. Among those who were infected, 98.1% had received at least two doses of the MMR vaccine, which is required for incoming students. During the outbreak, 4,783 students received a third dose.

Cardemil and colleagues compared unadjusted attack rates according to dose status and years since receipt of the second dose. They estimated risk-adjusted vaccine effectiveness in students who received three doses vs. two doses, and two doses vs. no doses.

According to the results, the attack rate in students who received a third dose was much lower compared with those who had received two doses — 6.7 vs. 14.5 cases per 1,000 population. When a second dose had been given within the past 12 years, the attack rate was between 1.6 and 3.9 cases per 1,000 population. It jumped to between 11.3 and 17.6 cases per 1,000 population if the second dose was given between 16 and 23 years earlier.

Students who received a third vaccine dose during the outbreak had a 78.1% lower risk for mumps after 28 days. Compared with students who had received a second dose within the past 2 years, the risk for mumps was 9.1 times higher in those who received it 13 to 15 years before the outbreak and 14.3 times higher in those who got it 16 to 24 years earlier.

Cardemil and colleagues estimated that the vaccine effectiveness of a third dose of the MMR vaccine compared with two doses was 60% at 7 days and 78.1% at 28 days. They estimated that getting a second dose of the MMR vaccine less than 13 years before the Iowa outbreak was 89% effective at preventing mumps, which is in line with previous estimates of the effectiveness of two doses vs. no doses. However, they said receiving a second dose 13 or more years before the outbreak was 32% effective and had confidence intervals that crossed zero.

Coverage levels

Because students involved in the outbreak were born after a switch to the two-dose schedule in 1989, Cardemil and colleagues said they probably had minimal opportunity to boost their immunity through natural exposure to wild-type mumps virus.

According to the report, in 2015, 90.7% of adolescents between the ages of 13 and 17 years in the U.S. had received at least two doses of MMR vaccine.

“If the current coverage levels continue, there may be even fewer opportunities for boosting of immunity from natural exposure, which could result in breakthrough mumps cases even in highly vaccinated populations,” the researchers wrote. – by Gerard Gallagher

References:

Cardemil CV, et al. N Engl J Med. 2017;doi:10.1056/NEJMoa1703309.

Fiebelkorn AP, et al. Open Forum Infect Dis. 2014;doi:10.1093/ofid/ofu094.

Disclosure: The researchers and Moore report no relevant financial disclosures.

Editor’s note: This story was updated to clarify when the CDC previously issued guidance for using a third dose of the MMR vaccine as a control measure during mumps outbreaks.

Giving students a third dose of the measles, mumps and rubella vaccine during a large mumps outbreak at the University of Iowa lowered their risk of getting the disease by 78% compared with students who had received the standard two doses, according to research published today in The New England Journal of Medicine.

Furthermore, researchers found that students who had received a second dose of the MMR vaccine 13 or more years before the outbreak in 2015 had a much greater risk for infection than those who had gotten it more recently, which is a sign of waning immunity.

The findings were previously presented during a June meeting of the Advisory Committee on Immunization Practices (ACIP), which makes vaccine recommendations to the CDC. They come at a time when the ACIP is considering the benefits of adding a third dose of the MMR vaccine to the standard two-dose series to address a surge in mumps cases in the U.S., including some large outbreaks that have occurred among fully immunized populations.

The ACIP recommended the current two-dose schedule in 1989. According to the CDC, it is 88% effective at preventing mumps. The CDC previously issued guidance in 2012 for using a third dose of the MMR vaccine as a control measure during mumps outbreaks in settings with more than 90% coverage with two doses, in outbreaks that occur in close quarters, and in settings with high attack rates and with ongoing transmission. However, the committee has made no formal recommendation on the subject.

The authors of the new study, which was funded by the CDC, said their findings are best interpreted in the short-term context of stemming a mumps outbreak and may be helpful to health departments in that context but that more studies are needed on the long-term effects.

It is unclear what impact the findings will have on the ACIP’s recommendation, expected in February 2018, on whether to add a third dose of the MMR vaccine to the immunization schedule. The issue may be clarified at the next ACIP meeting in October, which will feature a session on mumps.

Manisha Patel, MD, who leads the measles, mumps and rubella team in the CDC’s Division of Viral Diseases and was one of the authors of the study, said the findings will be “critical” to deliberations over whether to add a third dose of the MMR vaccine to the current two-dose series, but that other factors such as safety and immunogenicity will need to be part of the discussion.

PAGE BREAK

“It’s almost like a constellation of different features that the ACIP looks at to make the decision,” Patel said in an interview. “I think we’ll have a better idea as we get closer to the October ACIP meeting what the exact agenda will be in terms of the mumps presentation.”

Kelly Moore, MD, MPH, who chairs the ACIP’s mumps work group, told Infectious Disease News that findings from the Iowa outbreak were “informing our work.” But Moore was not able to comment on the group’s specific plans or how it was weighing the available evidence because the deliberations of ACIP work groups are confidential.

The longer term benefits of adding a third dose of the MMR vaccine have not been extensively studied. One previous study, cited in the new paper, examined the immunological protection of a third dose of the MMR vaccine by checking antibody titers in study subjects at 1 month and then 1 year. Titers were higher at both intervals, but had declined at 1 year compared with 1 month.

“What would be really helpful are studies that look at the longer-term effectiveness of the third dose,” Cristina V. Cardemil, MD, MPH, medical epidemiologist in the CDC’s Division of Viral Diseases and lead author of the new study, said in an interview. “We know from that study is that there is potentially immunological protection in the short term, but the question is what happens at 1 year and what happens beyond 1 year?”

2015 outbreak

The University of Iowa outbreak began in the summer of 2015 and involved 259 of the 20,496 students who were enrolled for that upcoming academic year. Among those who were infected, 98.1% had received at least two doses of the MMR vaccine, which is required for incoming students. During the outbreak, 4,783 students received a third dose.

Cardemil and colleagues compared unadjusted attack rates according to dose status and years since receipt of the second dose. They estimated risk-adjusted vaccine effectiveness in students who received three doses vs. two doses, and two doses vs. no doses.

According to the results, the attack rate in students who received a third dose was much lower compared with those who had received two doses — 6.7 vs. 14.5 cases per 1,000 population. When a second dose had been given within the past 12 years, the attack rate was between 1.6 and 3.9 cases per 1,000 population. It jumped to between 11.3 and 17.6 cases per 1,000 population if the second dose was given between 16 and 23 years earlier.

PAGE BREAK

Students who received a third vaccine dose during the outbreak had a 78.1% lower risk for mumps after 28 days. Compared with students who had received a second dose within the past 2 years, the risk for mumps was 9.1 times higher in those who received it 13 to 15 years before the outbreak and 14.3 times higher in those who got it 16 to 24 years earlier.

Cardemil and colleagues estimated that the vaccine effectiveness of a third dose of the MMR vaccine compared with two doses was 60% at 7 days and 78.1% at 28 days. They estimated that getting a second dose of the MMR vaccine less than 13 years before the Iowa outbreak was 89% effective at preventing mumps, which is in line with previous estimates of the effectiveness of two doses vs. no doses. However, they said receiving a second dose 13 or more years before the outbreak was 32% effective and had confidence intervals that crossed zero.

Coverage levels

Because students involved in the outbreak were born after a switch to the two-dose schedule in 1989, Cardemil and colleagues said they probably had minimal opportunity to boost their immunity through natural exposure to wild-type mumps virus.

According to the report, in 2015, 90.7% of adolescents between the ages of 13 and 17 years in the U.S. had received at least two doses of MMR vaccine.

“If the current coverage levels continue, there may be even fewer opportunities for boosting of immunity from natural exposure, which could result in breakthrough mumps cases even in highly vaccinated populations,” the researchers wrote. – by Gerard Gallagher

References:

Cardemil CV, et al. N Engl J Med. 2017;doi:10.1056/NEJMoa1703309.

Fiebelkorn AP, et al. Open Forum Infect Dis. 2014;doi:10.1093/ofid/ofu094.

Disclosure: The researchers and Moore report no relevant financial disclosures.

Editor’s note: This story was updated to clarify when the CDC previously issued guidance for using a third dose of the MMR vaccine as a control measure during mumps outbreaks.