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Non-specific effects of measles, mumps, and rubella (MMR) vaccination in high income setting: population based cohort study in the Netherlands

BMJ 2017; 358 doi: https://doi.org/10.1136/bmj.j3862 (Published 30 August 2017) Cite this as: BMJ 2017;358:j3862

Re: Non-specific effects of measles, mumps, and rubella (MMR) vaccination in high income setting: population based cohort study in the Netherlands

The sequence of vaccinations to test the non-specific effects of vaccines

There is growing evidence that vaccines may modify susceptibility to unrelated infections with implications for hospital admissions patterns in high-income countries (1,2) and mortality levels in low-income countries (3). Ideally, such potential non-specific effects of vaccines (NSEs) should be tested in randomised clinical trials (RCTs). However, that is unlikely to happen due to the ethical challenges related to randomising children to recommended vaccines. Hence, we need other ways of testing whether vaccines are likely to have important NSEs.

The disease-specific effects of vaccines are likely to be the same irrespective of the sequence in which the vaccines were provided; for example, children vaccinated with diphtheria-tetanus-pertussis (DTP3) and measles-mumps-rubella (MMR) vaccines are likely to be protected against pertussis and measles infections irrespective of whether they got MMR before or after DTP3. However, many observational studies (3) and RCTs (4) have shown that the sequence may matter for the NSEs of vaccines, the most recent vaccination having the strongest effect.

Studies from low-income countries suggest that it is better to have measles vaccine (MV) after DTP3 rather than to have DTP3 after MV (3,4). Similarly, in the Danish register based studies of hospital admission (1), MMR was associated with 14% (12-16%) lower risk of admission than children still having DTaP-IPV-Hib-3 as their most recent vaccination, whereas getting the vaccines in the opposite sequence, i.e. DTaP-IPV-Hib3 after MMR, was associated with a 62% (28-105%) increase in the risk of admission. The increase was particularly strong for upper respiratory infections (89% (31-74%)) and lower respiratory infections (64% (6-154%)).

The recent paper on the potential NSEs of vaccines in the Netherlands did not report the admission risk for children receiving DTaP-IPV-Hib-4+PCV after MMR+MenC (5). However, in the response to reviewers (available at the BMJ website), Tielemans et al. mention that the adjusted HR was 0.85 (0.70-1.03) for DTaP-IPV-Hib-4+PCV (after MMR+MenC) compared with having MMR+MenC (after DTaP-IPV-Hib-3+PCV) as last vaccination. It is not indicated whether this estimate refer exclusively to the >1 day admissions or to all admissions. In the main paper, compared with children who still had DTaP-IPV-Hib-4+PCV as their last vaccination, MMR+MenC (after DTaP-IPV-Hib-4+PCV) was associated with HRs of 0.62 (0.57-0.67) for >1 day admissions and 0.40 (0.38-0.41) for all admissions (5).

This would suggest that the differential effect of having DTaP-IPV-Hib-4+PCV after MMR+MenC rather than MMR+MenC after DTaP-IPV-Hib-4+PCV as the last vaccine was a 37% (11-69%) (0.85/0.62=1.37 (1.11-1.69)) increase in the relative risk of admission if the 0.85 estimate referred to >1 day admissions. [The differential effect would be 113% (75-159%) (0.85/0.40=2.13 (1.75 -2.59)) increase in the relative risk of admission if the 0.85 estimate referred to all admissions].

Hence, the data suggest that DTaP-IPV-Hib-4+PCV after MMR+MenC is associated with an increase in relative risk of admissions compared to MMR+MenC after DTaP-IPV-Hib-4+PCV. This is similar to the pattern in Denmark (1) and low-income countries (3,6). Unless it can be shown that healthy vaccinee bias works differently in the two situations, the pattern is likely to reflect that MMR+MenC and DTaP-IPV-Hib-4+PCV are associated with completely different NSEs.

To test our observation that the negative effect of the reverse sequence was strongest for respiratory infections, we would appreciate if Tielemans et al. would report the results for DTaP-IPV-Hib-4+PCV after MMR+MenC also for the four admission groups used in the main paper (lower respiratory infections, upper respiratory infections, gastrointestinal infections, other infections) (5).

The sequence of vaccinations have received relatively little attention (3,4,6). This is unfortunate since analysing the sequence may help to assess the relative importance of NSEs of different vaccines, even in situations with severe healthy vaccinee bias.

So far the results have been consistent in indicating that it is better to receive a live vaccine after a non-live vaccine than a non-live after a live vaccine (1,3,4,6). Hence, it could have major effects on mortality and morbidity and health care costs if immunisation programmes implemented a “live-vaccine-last” policy.

References
1. Sørup S, Benn CS, Poulsen A, Krause TG, Aaby P, Ravn H. Live vaccine against measles, mumps, and rubella and the risk of hospital admissions for nontargeted infections. JAMA 2014;311:826-35
2. Bardenheier BH, McNeil MM, Wodi AP, McNicholl J, DeStefano F. Risk of nontargeted infectious disease hospitalizations among U.S. children following inactivated and live vaccines, 2005-2014. Clin Inf Dis 2017;epub
3. Higgins JPT, Soares-Weiser K, López-López JA, Kakourou A, Chaplin K, Christensen H, Martin NK, Sterne JAC, Reingold AL. Association of BCG, DTP, and measles containing vaccines with childhood mortality: systematic review. BMJ 2016;355:i5170
4. Aaby P, Ravn H, Benn CS, Rodrigues A, Samb B, Ibrahim SA, Libman MD, Whittle HC. Randomized Trials Comparing Inactivated Vaccine After Medium- or High-titer Measles Vaccine With Standard Titer Measles Vaccine After Inactivated Vaccine: A Meta-analysis. Pediatr Infect Dis J. 2016 Nov;35(11):1232-1241
5. Tielemans SMAJ, de Melker HE, Hahné SJM, Boef AGC, van der Klis FRM, Sanders EAM, van der Sande MAB, Knol MJ. Non-specific effects of measles, mumps, and rubella (MMR) vaccination in high income setting: population based cohort study in the Netherlands. BMJ 2017;358:j3862
6. Welaga P, Oduro A, Debpuur C, Aaby P, Ravn H, Andersen A, Binka F, Hodgson A. Fewer out-of-sequence vaccinations and reduction of child mortality in Northern Ghana. Vaccine 2017;35:2496-2503

Competing interests: No competing interests

16 November 2017
Christine S Benn
Center Leader, Professor
Signe Sorup, Peter Aaby
Research Centre for Vitamins and Vaccines (CVIVA), Bandim Health Project, Statens Serum Institut, Artillerivej 5, 2300 Copenhagen S; OPEN, Department of Clinical Research, and Danish Institute for Advanced Study, University of Southern Denmark/Odense University Hospital, Denmark
Research Centre for Vitamins and Vaccines (CVIVA), Bandim Health Project, Statens Serum Institut, Artillerivej 5, 2300 Copenhagen S; OPEN, Department of Clinical Research, and Danish Institute for Advanced Study, University of Southern Denmark/Odense University Hospital, Denmark