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Contradictory mortality results in early 2-dose measles vaccine trials: interactions with oral polio vaccine may
Sebastian Nielsen1, Ane B Fisker1, Ali Sie2
1Bandim Health Project, Indepth Network, Bissau, Guinea-Bissau; OPEN, Odense Patient Data Explorative Network, Institute of Clinical Research, Odense University Hospital/University of Southern Denmark, Odense, Denmark.
Objectives:
Between 2003 and 2019, three trials (randomised controlled trials [RCTs]) in Guinea-Bissau randomised infants to an early 2-dose measles vaccine (MV) schedule at 4 and 9 months vs standard MV at 9 months. The RCTs produced contradictory mortality results; the effect being beneficial in the 2-dose group in the first but tending to have higher mortality in the last two RCTs. We hypothesised that increased frequency of campaigns with oral polio vaccine (C-OPV) explained the pattern.
Methods:
We performed per-protocol analysis of individual-level survival data from the three RCTs in Cox proportional hazards models yielding hazard ratios (HR) for the 2-dose vs the 1-dose MV group. We examined whether timing of C-OPVs and early administration of OPV0 (birth to day 14) affected the HRs for 2-dose/1-dose MV.
Results:
The combined HR(2-dose/1-dose) was 0.79 (95% confidence interval: 0.62-1.00) for children receiving no C-OPV-before-enrolment, but 1.39 (0.97-1.99) for those receiving C-OPV-before-enrolment (homogeneity, P = 0.01). C-OPV-before-enrolment had a beneficial effect in the 1-dose group but tended to have a negative effect in the 2-dose group, especially in females. These effects were amplified further by early administration of OPV0.
Conclusion:
In the absence of C-OPVs, an early 2-dose MV strategy had beneficial effects on mortality, but frequent C-OPVs may have benefitted the 1-dose group more than the 2-dose MV group, leading to varying results depending on the intensity of C-OPVs.
Insights
An early 2-dose measles vaccine (MV) schedule showed benefits without oral polio vaccine (OPV) campaigns. However, frequent OPV campaigns may have altered MV effectiveness, impacting infant mortality differently based on vaccination schedules.
Area of Science:
- Immunization strategies
- Pediatric infectious diseases
- Public health interventions
Background:
- Three randomized controlled trials (RCTs) in Guinea-Bissau investigated early (4 and 9 months) versus standard (9 months) 2-dose measles vaccine (MV) schedules.
- Conflicting mortality outcomes were observed across the RCTs, with initial benefits in the 2-dose group followed by increased mortality in later trials.
- A hypothesis emerged suggesting that the frequency of oral polio vaccine (OPV) campaigns influenced the observed mortality patterns.
Purpose of the Study:
- To analyze individual-level survival data from three RCTs to determine the impact of an early 2-dose measles vaccine (MV) schedule on infant mortality.
- To investigate the potential confounding effect of oral polio vaccine (OPV) campaigns, specifically the timing of campaigns (C-OPV) and early OPV administration (OPV0), on the mortality outcomes associated with different MV schedules.
Main Methods:
- Per-protocol analysis of individual-level survival data from three randomized controlled trials (RCTs).
- Cox proportional hazards models were employed to calculate hazard ratios (HR) comparing the 2-dose MV group to the 1-dose MV group.
- Subgroup analyses were conducted to assess the influence of C-OPV timing and early OPV0 administration on the MV HRs.
Main Results:
- The combined hazard ratio (HR) for 2-dose vs. 1-dose MV was 0.79 (95% CI: 0.62-1.00) in children without prior C-OPV exposure, indicating a potential mortality benefit.
- In contrast, children who received C-OPV before enrollment showed an HR of 1.39 (95% CI: 0.97-1.99), suggesting a potential negative impact of the 2-dose MV schedule in this context (homogeneity P = 0.01).
- The negative effect of C-OPV was more pronounced in the 2-dose MV group, particularly in females, and was further amplified by early OPV0 administration.
Conclusions:
- An early 2-dose measles vaccine (MV) strategy demonstrates beneficial effects on infant mortality in settings without frequent oral polio vaccine (OPV) campaigns.
- The results suggest that frequent OPV campaigns may have differentially benefited the 1-dose MV group compared to the 2-dose MV group.
- The observed variability in mortality outcomes across studies is likely attributable to the intensity and timing of concurrent OPV vaccination campaigns.
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