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

Beneficial non-specific reduction in hospital admissions for respiratory infections following MMR and MenC vaccinations in the Netherlands

We appreciate that Tielemans et al.(1), using Dutch population data on vaccinations and hospital admission for infectious diseases, tested our findings of non-specific effects (NSEs) of the live attenuated measles-mumps-rubella (MMR) vaccine in Denmark(2). We found the transition from the third DTaP-IPV-Hib (DTP3) to MMR to be associated with a hazards ratio (HR) of 0.86 (95%CI=0.84-0.88). The Dutch study finds much stronger beneficial effect estimates for the transition from the fourth DTaP-IPV-Hib-PCV (DTP4) to MMR+MenC (HR for all admissions of 0.40 (0.38-0.41); for >1 day admissions 0.62 (0.57-0.67)), but also strong beneficial effect estimates for the previous transition from DTP3-to-DTP4 (HR all admissions 0.48 (0.46-0.51); >1 day 0.69 (0.63-0.76)). The authors conclude that healthy vaccinee bias at least partly explains the lower rates of admission after MMR and add that though NSEs cannot be excluded, NSEs cannot be distinguished from bias. The authors therefore emphasise the importance of caution in the interpretation of observational studies on the NSEs of vaccines.

There are several important contextual differences between the Danish and the Dutch studies. For instance, Denmark provides MMR at 15 months, whereas the Netherlands provides MMR+MenC vaccines at 14 months, and the NSEs of a live vaccine vs. co-administration of a live vaccine and a non-live vaccine have been shown to differ(3).

Most important in relation to healthy vaccinee bias is the difference in the organisation of vaccination. In the Netherlands, all children have pre-scheduled vaccination appointments, so 99.6% of all children had received MMR+MenC vaccine by 24 months of age. Judged by Figure 2(1), it was the sick children, who were delayed, since the admission rate increased in the unvaccinated children after 14 months. If almost all are vaccinated except sick children, this creates a strong healthy vaccinee bias, or maybe rather “unhealthy non-vaccinee bias”. In Denmark, parents have to schedule the vaccination appointments themselves; less than 90% had received MMR by 24 months; therefore the group of delayed children is more diverse and the admission rate did not increase in the unvaccinated children after 15 months(2).

It could be discussed whether it is meaningful to compare vaccinated versus unvaccinated children in settings like the Dutch, with severe healthy vaccinee bias. Tielemans et al. propose one way to control for healthy vaccinee bias: if we assume that the HR associated with the transition from DTP3–to-DTP4 is due to healthy vaccinee bias, then the relative difference in the HRs for DTP3-to-DTP4 and DTP4-to-MMR+MenC could be ascribed to the NSEs of MMR+MenC(1). The authors do not present the calculation, but if we use the HR for all admissions for the transition from DTP3-to-DTP4 as an indication of the “baseline” healthy vaccinee bias, then an adjusted HR for all admissions for the transition from DTP4-to-MMR+MenC can be estimated as 0.40/0.48=0.83 (95% CI=0.78-0.89). The correction of a HR for a vaccine by adjustment for the HR of another vaccine represents one way to deal with healthy vaccinee bias. It cannot be excluded that healthy vaccinee bias could be different in different age groups and the true estimate of the NSEs of MMR+MenC might well be larger or smaller than 17% (11-22%).

Are there other ways to control for healthy vaccinee biases? We have previously used triangulation methods to examine whether NSEs are the most logical explanation for all the data available. In the Danish study, we showed that DTP administered after MMR was associated with increased risk of admission, a tendency which cannot be explained by healthy vaccinee bias. Furthermore, both observational studies and RCTs(4) from low-income countries have suggested that measles vaccine is associated particularly with lower risk of respiratory infections. We therefore tested whether the reduction in admissions differed by disease category, or was similar for all categories as would be expected if healthy vaccinee bias were the main explanation. Corroborating the findings from low-income countries, the effect of MMR was smallest for gastrointestinal infection admissions (HR=0.93 (0.87-1.00)), being stronger for lower respiratory infections (HR=0.80 (0.76-0.84); p=0.001 for same effect as for gastrointestinal infections) and for upper respiratory infections (HR=0.86 (0.82-0.89); p=0.058).

In the Dutch study, MMR+MenC was likewise associated with the smallest reduction in gastrointestinal infection admissions (0.69 (0.61-0.78)) whereas the reductions were significantly stronger for lower respiratory infections (HR=0.57 (0.49-0.65); p<0.046) and for upper respiratory infections (HR=0.36 (0.34-0.37); p<0.001). In contrast, DTP4 was associated with the same reductions in gastrointestinal (HR=0.70 (0.61-0.79)), lower respiratory (HR=0.79 (0.67-0.82)) and upper respiratory infection admissions (HR=0.72 (0.62-0.82)) (p=0.299 for same effect; estimates for >1 day admissions, as no estimates for all admissions were reported)). Thus, relative to the reduction for gastrointestinal infections, MMR+MenC was associated with stronger reductions in admissions for lower respiratory infections (HR=0.80 (0.65-0.98)) and upper respiratory infections (HR=0.77 (0.64-0.93)), and the effect on lower respiratory infections and upper respiratory infections differed significantly between MMR+MenC vaccination and DTP4 vaccination.

Thus, there are two observations from this triangulation analysis, which cannot be explained by healthy vaccinee bias: First, the pattern of stronger reductions for respiratory infections than for gastrointestinal infections after MMR(+/-MenC) vaccinations seen in both the Netherlands and Denmark. Second, the effect of MMR(+MenC) and DTP3/4 on respiratory infections differed significantly in both the Netherlands and Denmark, with beneficial effect estimates of MMR(+MenC) but the opposite tendency for DTP4. Thus, in spite of severe healthy vaccinee bias, there was still important information supporting beneficial NSEs of MMR+MenC on respiratory infections in the Dutch study. Reassuringly, a beneficial effect of MMR on respiratory infections has also recently been reported by studies from USA(5) and Italy(6).

There is increasing epidemiological and immunological evidence that NSEs of vaccines are important(2-7). The number of RCTs testing NSEs is going to be limited for ethical and financial reasons. Hence, we rely largely on observational studies to assess NSEs. As shown here, using triangulation methods it is possible to distinguish NSEs from bias, even in settings with severe healthy vaccinee bias. Hence, we hope the Dutch call for caution is not interpreted as a call for caution against observational studies of the NSEs of vaccines.

Christine S Benn, Signe Sørup, 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

References
1. 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
2. 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
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. Martins CL, Benn CS, Andersen A, Balé C, Schaltz-Buchholzer F, Do VA, Rodrigues A, Aaby P, Ravn H, Whittle H, Garly ML. A randomized trial of a standard dose of Edmonston-Zagreb measles vaccine given at 4.5 months of age: effect on total hospital admissions. J Inf Dis 2014;209;1731-8
5. 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
6. La Torre G, Saulle R, Unim B, Meggiolaro A, Barbato A, Mannocci A, Spadea A. The effectiveness of measles-mumps-rubella (MMR) vaccination in the prevention of pediatric hospitalizations for targeted and untargeted infections: a retrospective cohort study. Human Vaccines & Immunotherapeutics 2017; 13: 1879-83
7. Benn CS, Netea MG, Selin LK, Aaby P. A small jab - a big effect: nonspecific immunomodulation by vaccines. Trends Immunol. 2013 Sep;34(9):431-9.