The WHO estimated that 750 000 measles deaths occurred worldwide in 2000 and decreased to 197 000 in 2007.53
This substantial reduction is largely due to intense efforts from WHO/UNICEF and other programmes to provide vitamin A supplementation and treatment as well as increase coverage of measles vaccine including offering a second opportunity for vaccination in countries with a high measles burden.
Live attenuated measles vaccine was first introduced in the United States and many developed countries during the 1960s; licensure was based on prevention of measles disease and immunologic correlates of immunity as the primary outcomes.54–56
Our systematic review identified three RCTs identifying measles-specific mortality as an endpoint. Only 14 measles deaths occurred in the three trials combined (all in the unvaccinated group) and following the CHERG Rules for Evidence Review, we were not able to determine a direct effect estimate.57
Observational studies, in addition to RCTs, were included in the all-cause mortality analysis to address the hypothesis that measles vaccine has an effect on non-measles mortality.58
Our meta-analysis found that measles vaccine reduced all cause mortality by 43% (29–54), but the quality of evidence is graded low per CHERG rules due to a majority of data arising from observational studies, which are prone to survival bias and possibly other forms of unrecognized bias. Due to inconclusive evidence for a non-specific effect of measles vaccine on all cause mortality, this assessment will not be included in this edition of LiST. We included three RCTs and two QE studies in the meta-analysis of vaccination effect on measles disease. These studies found that measles vaccine reduced measles disease by 85% (95% CI 83–87) and per Rule 7, this effect size will be used in the LiST tool as a proxy for prevention of measles mortality. Numerous methodologically sound observational studies have also been published with data on the effectiveness of measles vaccine; however, per LiST rules these studies are graded as ‘low’ and are considered weaker sources of evidence in comparison to RCTs. Furthermore, a pooled estimate of well-conducted observational studies would likely underestimate the true efficacy of measles vaccine. A substantial proportion of published observational studies were conducted during measles outbreaks which can occur as a result of decreased vaccine efficacy attributable to improper vaccine storage or vaccination of children before recommended age.5
Our effect estimate is consistent with the Cutts serology review which estimated seroconversion rates of 85% when vaccine is administered prior to one year and the Singh review which estimated effectiveness of 85–90% based on feasibility studies conducted in India.10
Our effect findings and corresponding uncertainty are applicable to real world vaccine programmes in developing countries as children are vaccinated at a wide range of ages. The studies included in our analysis vaccinated children between 6 months and 5 years. However, this estimate is likely conservative for the effect of vaccination on measles mortality since several studies have documented that previously vaccinated children who develop measles have reduced rates of complications compared with unvaccinated children.59–61
None of the trials in our meta-analysis specifically address current vaccination programmes in developed countries, where the recommended age of vaccination is usually at ≥12 months of age. Measles vaccine is more effective when administered to older children as maternal antibodies that can interfere with development of immunity are usually absent.62
The WHO SAGE recently recommended that countries with low levels of measles transmission increase the age at administration of the first dose of vaccine from 9 to 12 months in addition to providing a routine second dose during the second year of life.3
Approximately, 95% of individuals seroconvert when measles vaccine is administered at one year of age or older.63
Therefore, if the LiST tool is used to estimate measles mortality effect in countries vaccinating at one year or greater, the user may want to increase the effect estimate for measles vaccine. In addition, we chose not to include herd immunity in the default LiST estimates for single dose vaccine. The reproductive number (R0
) for measles is 15–20 and >95% of a population is needed to be immune in order to stop endemic transmission.65
Furthermore, these immune individuals will have to be equally dispersed in the population, an assumption we are not willing to make especially since most developing countries have not reached >90% coverage. However, LiST users have the capacity to adjust the effectiveness of measles vaccination by coverage level, and we support users adjusting country specific effect estimates to 100% if strong surveillance data indicate no measles transmission.
The effect of a second dose of measles vaccine on measles disease or mortality compared with no vaccination has not been evaluated on individual children in prospective randomized studies as this type of trial would be unethical. Therefore, the best estimate of the effect of a two-dose measles vaccine schedule on measles mortality must be extrapolated from serology data, studies looking at effectiveness of two dose vs one-dose measles vaccination, and observational studies. Caution should be taken when using serology data to estimate the impact on mortality. A recent WHO review of serology studies determined that a median 97% [inter-quartile range (IQR) 87–100%] of children that failed to seroconvert to first dose measles vaccine developed immunity after a second dose.64
If 85% efficacy is assumed for single dose measles vaccine, these serology results would correlate to an efficacy of 99.6% for two dose measles vaccine with a range of 98.1–100% based on the IQR of the review. In addition, the effectiveness of two doses of measles vaccine will vary by setting based on the age of vaccination. Epidemiologic studies comparing the effectiveness of early two dose vaccination vs single dose have found varying results in developing country settings; a study in Niger found two doses (first dose at 6–8 months and second at 9 months) was 23% less effective than single dose whereas studies in India (first dose at 9–12 months and second at 15–18 months) and Guinea Bissau (first dose at 6–8 months and second at 9–12 months) determined two doses of vaccine were respectively 83 and 90% more effective than one dose of measles vaccine.66–69
In order to produce a conservative estimate of the efficacy of two dose measles vaccine per LiST rules, we felt an input of 98% based on the lower quartile of the WHO two dose measles vaccine serology review was reasonable.
Vitamin A deficiency is a recognized risk factor for severe measles and since 1987 the WHO and UNICEF have recommended vitamin A treatment of children with measles.70
We performed a meta-analysis of six vitamin A treatment RCTs with measles-specific mortality data and found no significant reduction in measles morality [RR 0.63; 95% CI (0.37–1.08)]. However, when stratifying the analysis by vitamin A treatment dose, at least two doses of 200 000 IU for children ≥1 year of age and 100 000 IU for infants was found to reduce measles mortality by 62% [RR 0.38; 95% CI (0.18–0.81)]. These results support the current recommendation that two doses of vitamin A be offered to children with measles.7
An exception to Rule 0 (at least 50 deaths needed) was deemed appropriate with support of CHERG due to the high quality evidence from three RCTs. As a result, a 62% effect estimate with corresponding uncertainty will be used in the LiST tool.
The results of our review, which are the default effectiveness values included in LiST, are summarized in . Our results support the current strategy of WHO/UNICEF to reduce measles mortality in priority countries, which includes increasing coverage of measles vaccine and vitamin A in addition to offering a second opportunity for vaccination to all children. The GIVS 2010 goals for measles seem to be within reach and hopefully with offering two dose measles vaccine in the South-East Asian region a 90% reduction in measles mortality will be accomplished.
Application of standard rules to measles interventions for LiST