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The Wide World of Vaccines

June 2019

Should We Accelerate the MMR Schedule as the Measles Outbreak Continues to Expand?          

Dr. Harrison.jpg            

Christopher J. Harrison, MD, FAAP, FPIDS
 | Director, Infectious Diseases Research Laboratory | Director, Vaccine and Treatment Evaluation Unit | Professor of Pediatrics, UMKC School of Medicine

The 2019 measles outbreak appears to be heading toward more than 1,000 cases (currently near 900). The current recommended schedule has a first MMR at 12 to 15 months old followed by a second MMR at 4 to 6 years old. Age 12 to 15 months was chosen to allow disappearance of maternal antibody, which would otherwise blunt the child’s response to live measles vaccine. Age 4 to 6 years was chosen to trigger responses in primary vaccine failures (~5% failing to respond to the first measles vaccine dose), and also to boost mumps vaccine responses. Mumps titers are known to wane by school age, and more recent data indicate waning after the preschool dose by mid to late teens.

But now clusters of measles non-immune children in many parts of the United States have allowed a few imported cases to spread given the high contagion of measles. For each new measles case 12 to 15 additional cases can be expected in an exposed non-immune population. These 12 to 15 new cases also can produce 12 to 15 new cases each if they expose additional non-immune populations. Non-immune individuals include those:

• Not-yet-age-eligible
• Individuals with true MMR contraindications
• Patients late getting vaccines by choice or by circumstance
• Families who refuse vaccines

The result: 1/12 of U.S. children fail to get MMR on time.

Practitioners have asked if the outbreak has become sufficiently severe that we should consider immunizing 6 to 12-month-old infants to reduce the vulnerable population (better herd immunity) so new cases would not produce the full 15 additional cases. Early dosing has blunted prior outbreaks.1

Accelerated schedules also could apply to toddlers, i.e., give second doses sooner. Current recommendations allow the second MMR dose as soon as 28 days after the first dose. This would “catch up” the ~5% of primary measles immunization failures right away, instead of at 4 to 6 years old. During non-outbreak times, chances of exposure are so small that accelerated dosing is limited to those traveling to endemic areas. Could the U.S. now be considered an endemic area?

But is there a downside to early or accelerated dosing? One downside is that we could end up with larger populations with waning mumps titers at school age and in teen years, creating larger vulnerable populations to mumps later on if no 4 to 6-year dose is given.

A second downside is suggested by recent Dutch data2 evaluating MMR given initially at 6 to 8 months (N=44), 9 to 12 months (N=31), or 14 months (N=40: controls). Second MMRs were given at 14 months to the 6 to 8 and 9 to 12-month groups. Measles neutralizing antibody was assayed just before 14-month MMR doses, as well as 6 weeks, one year, and three years after the 14-month doses.

Those immunized at 6 to 8 months responded less well, both short term and long term. Just before the 14-month dose, titers were lower in the 6 to 8-month versus 9 to 12-month group; also 4/44 among 6 to 8-month-old children had titers below the threshold for protection versus 0/31 among 9 to 12-month-old children.

Six weeks after the 14-month doses, titers were significantly higher in controls (first immunized at 14 months) versus 6 to 8-month or 9 to 12-month groups; note: one primary failure (2.5%) occurred in controls.

Comparing titers pre- versus post-14-month doses (Figure 1), titers:

1. Increased the most in controls (pre titers were zero, rising briskly 6 weeks post MMR)
2. Rose the least in the 9 to 12-month group (were fairly high pre-14-month dose with minimal rise post dose)
3. Rose modestly in 6 to 8-month group (more than 9 to 12-month and less than the controls). Interestingly the primary failures in the 6 to 8-month group (column 3-Figure 1) responded just like controls to the 14-month dose.

Wide World of Vaccines Measles Graphic.jpg
One year after the 14-month MMR dose, titers in all groups had dropped, but only one 6 to 8-month subject dropped below the protective cut-off. The 6 to 8-month group titers were also significantly lower than both other groups. Three years after the 14-month MMR, all controls and 9 to 12-month subjects stayed above the protective cut-off, whereas three more 6 to 8-month subjects (11%) fell below the cut-off. Projections out to six years suggest that up to 50% of the 6 to 8-month group might be below the cut-off.

So a universal recommendation for accelerated MMR vaccine is not a slam dunk. On the plus side, it would likely blunt the outbreak, but at a considerable expense. Even with accelerated dosing, data suggest, a 4 to 6-year dose would still be needed. There also could be a backlash against MMR, already under assault by misguided anti-vaccine groups. Finally, if early dosing (6 to 12-month-old children) is recommended soon, those 6 to 8 months old may not respond as well as we like, so limiting accelerated schedules to 9 to 12-month-olds may be best. As we are at 900 cases and counting, we await the next recommendation by the CDC.  

References

1. Effectiveness of Vaccination at 6 to 11 months of Age During an Outbreak of Measles. de Serres G1, Boulianne N, Ratnam S, Corriveau A. Pediatrics. 1996 Feb;97(2):232-5.

2. Early Measles Vaccination During an Outbreak in The Netherlands: Reduced Short and Long-Term Antibody Responses in Children Vaccinated Before 12 Months of Age. Brinkman ID, de Wit J, Smits GP, et al. J Infect Dis. 2019 Apr 11. pii: jiz159. doi: 10.1093/infdis/jiz159.