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Reduced All-cause Child Mortality After General Measles Vaccination Campaign in Rural Guinea-Bissau

Fisker, Ane B. PhD*†; Rodrigues, Amabelia PhD*; Martins, Cesario PhD*; Ravn, Henrik PhD*†‡; Byberg, Stine MSc*†‡; Thysen, Sanne BMed*†; Storgaard, Line BMed*; Pedersen, Marie BMed*; Fernandes, Manuel*; Benn, Christine S. DMSc*†‡; Aaby, Peter DMSc*†‡

The Pediatric Infectious Disease Journal: December 2015 - Volume 34 - Issue 12 - p 1369–1376
doi: 10.1097/INF.0000000000000896
Vaccine Reports
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SDC

Background: Randomized trials have shown that measles vaccine (MV) prevents nonmeasles deaths. MV campaigns are conducted to eliminate measles infection. The overall mortality effect of MV campaigns has not been studied.

Methods: Bandim Health Project (BHP) surveys children aged 0–4 years in rural Guinea-Bissau through a health and demographic surveillance system. A national MV campaign in 2006 targeted children aged 6 months to 15 years. In a Cox proportional hazards model with age as the underlying timescale, we compared mortality of children aged 6–59 months after the campaign with mortality in the same age group during the 2 previous years.

Results: Eight thousand one hundred fifty eight children aged 6–59 months were under BHP surveillance during the 2006 campaign and 7999 and 8108 during similar periods in 2004 and 2005. At least 90% of the eligible children received MV in the campaign. There were 161 nonaccident deaths in 12 months after the campaign compared with 203 and 206 deaths in the 2 previous years, the adjusted mortality rate ratio (aMRR) comparing all children in 2006 with all children in 2004 to 2005 being 0.80 (95% confidence interval: 0.66–0.96). Censoring deaths caused by measles infection, the aMRR was 0.83 (0.69–1.00). The mortality reduction was separately significant for girls [aMRR = 0.74 (0.56–0.97)] and for children who also had received routine MV [MRR = 0.59 (0.36–0.99)].

Conclusions: Mortality levels were stable during 2004 and 2005, but a significant drop occurred after the 2006 MV campaign and was not explained by the prevention of measles deaths. If MV campaigns reduce nonmeasles-related mortality, the policies for measles vaccination should take this into account.

Supplemental Digital Content is available in the text.

From the *Bandim Health Project, INDEPTH Network, Bissau, Guinea-Bissau; Research Center for Vitamins and Vaccines (CVIVA), Bandim Health Project, Statens Serum Institut, Copenhagen, Denmark; and OPEN, Institute of Clinical Research, University of Southern Denmark/Odense University Hospital, Odense, Denmark.

Accepted for publication June 25, 2015.

Supported by Danish Council for Independent Research (DFF-1333-00192), DANIDA (grant: 104.Dan.8-920), European Union FP7 support for OPTIMUNISE (grant: Health-F3-2011-261375). The Bandim Health Project received support from Danish National Research Foundation via support to CVIVA (grant: DNRF108). P.A. holds a research professorship grant from the Novo Nordisk Foundation. C.S.B. holds a starting grant from the European Research Council (grant ERC-2009-StG-243149). The funding agencies had no role in the collection, analysis, and interpretation of data; in the writing of the report; and in the decision to submit the article for publication.

The authors have no other funding or conflicts of interest to disclose.

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website (www.pidj.com).

Address for correspondence: Ane B. Fisker, PhD, Research Center for Vitamins and Vaccines (CVIVA), Bandim Health Project, Statens Serum Institut, 2300 Copenhagen S, Denmark. E-mail: a.fisker@bandim.org.

To eliminate measles infection, the Measles and Rubella Initiative funds measles vaccination campaigns targeting children in low-income countries.1 These measles vaccination campaigns, also known as supplementary immunization activities, provide a second opportunity for measles vaccination.2 Supplementary immunization activities can be discontinued when the routine vaccination coverage of a second dose of measles vaccine (MV) exceeds 90%–95%.2

Despite the many MV campaigns that have been conducted to eliminate measles infection in low-income countries, no study has evaluated the overall effect on mortality. Studies on campaigns have focused on coverage,3–53–53–5 risk factors for nonparticipation,3,5,6 adverse events4 and specific protection against measles infection.4,7,8 The estimated mortality reduction due to measles vaccination is based on assumptions about the incidence and case fatality of measles. For example, in Niger which has circulating measles infection, the anticipated reduction in under-5 mortality due to MV is 5%.9 However, MV campaigns may do more than protect against measles infection and thus be even more important for the overall survival.

In 1979, when MV was first introduced in Guinea-Bissau, mortality declined to a third from the year before the campaign to the following year,10 a much larger reduction than could be explained by preventing measles infection. There was no indication of improved nutritional status in the year when the vaccine was given compared with the previous year,10 and the decline was not explained by MV preventing long-term excess mortality after measles infection11 but indicated that MV may confer protection against nonmeasles-related infections.12,13 The introduction of MV at other demographic surveillance sites was associated with similar large reductions in mortality,14–1614–1614–16 suggesting that MV has beneficial nonspecific effects on child mortality.12 Subsequent randomized trials of the effect of MV on all-cause mortality have supported this.17,18 Studies indicate that MV has a stronger beneficial effect for females than for males14,17–1917–1917–19 and suggest that 2 MVs may provide even stronger beneficial effect than 1 MV.17,20 A recent WHO-commissioned review of the nonspecific effects of vaccines concluded that there was consistent evidence of a beneficial effect of MV and that girls seemed to benefit more.21

In May 2006, a general measles vaccination campaign was conducted in Guinea-Bissau. We examined the effect of this MV campaign on the overall mortality and estimated the number needed to vaccinate to prevent 1 death. We furthermore examined whether the effect differed by sex and routine vaccination status.

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MATERIALS AND METHODS

Setting

To obtain high-quality data on maternal and child mortality, the Bandim Health Project (BHP) has followed 100 randomly selected clusters of 100 women of fertile age and their children younger than 5 years in rural Guinea-Bissau since 1990.13,22 The clusters were originally selected using the methodology of the Expanded Programme on Immunizations for immunization surveys, sampling 20 clusters of 100 women of fertile age in each of the 5 most populous regions that cover 83% of the rural population in Guinea-Bissau.

The clusters are visited every 6 months, and all pregnancies, births, deaths and migrations are recorded at these visits. New women are included when they move into the area or reach fertile age. At the time of registration, information on age, ethnicity and schooling is collected. Children are followed from the date the pregnancy of their mothers is registered, or alternatively, if the pregnancy has not been captured, from the date of first registration as infants or toddlers. At all visits, the child’s nutritional status is assessed by measuring the mid-upper arm circumference, and it is recorded whether the child has a vaccination card, whether the card was seen; if seen, the dates of all vaccinations are noted.

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Intervention

As part of the global efforts to eliminate measles infection, a national MV campaign targeting children aged 6 months to 15 years was conducted between May 15 and May 29, 2006, in Guinea-Bissau. Children were given a standard dose of MV and vitamin A (100,000 IU vitamin A if aged 6–11 months/200,000 IU vitamin A if aged 12–59 months), and children aged 12–59 months received mebendazole (500 mg). Information on participation in the 2006 MV campaign was collected at the first home visit after the campaign. Mothers/caretakers were asked whether their children had received MV during the campaign, and if so, the date of vaccination was recorded.

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Design

To assess the effect of the MV campaign on the overall child mortality, overall and by sex and previous MV, we took advantage of the BHP routine surveillance system to conduct this retrospective study. Thus, the sample size was based on availability. We compared survival in the year immediately after the campaign (after May 29, 2006) with survival in the same period during the previous years (after May 29, 2004, and after May 29, 2005). The dates for initiating follow-up are henceforth referred to as the index dates. The same criteria for being part of the cohort were used for all 3 cohorts: date of registration before index date, alive at the index date and having turned 6 months before the May 15, the same year. In 2004, Guinea-Bissau experienced a measles epidemic23; there has been no circulating measles infection since. We therefore also compared mortality in 2006 to 2005 only.

We examined whether the effect of MV campaign differed according to whether the children had or had not yet received routine MV; to do that we compared survival among children aged 1–4 years (at the index date) according to vaccination status at the first visit after the index date and to the end of the 12-month follow-up period. In all analyses, we investigated whether the effect of MV campaign varied by sex.

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Other Interventions During the Study Period

The Expanded Programme on Immunization provided vaccines to Guinean infants since 1984.24 The vaccination schedule in 2004 to 2007 in Guinea-Bissau was Calmette-Guérin bacillus and oral polio vaccine (OPV) at birth, 3 doses of diphtheria-tetanus-pertussis vaccine (DTP) and OPV at 6, 10 and 14 weeks of age and MV at 9 months of age, but many children received the vaccines much later.25 Annual vitamin A supplementation (VAS) campaigns have been conducted in November/December since 2001. Campaigns of OPV either in combination with VAS or as OPV alone were also conducted in 2004 and 2005. In 2006, the VAS campaigns became biannual; and VAS (to children 6–59 months) and mebendazole (children 12–59 months) were provided both during the MV campaign and in November 2006 when bed nets were also distributed (Table, Supplemental Digital Content 1, http://links.lww.com/INF/C266).

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Statistical Methods

Distribution of background variables in the 3 cohorts were compared by χ2 tests, Kruskal-Wallis test and linear regression. In the survival analyses, children aged 6–59 months on the May 15 in the years 2004, 2005 and 2006 entered the analysis on the 29th of May 2004, 2005 and 2006 and were followed to the 15th of May the subsequent year. All children were included, irrespective of whether their vaccination status had been ascertained and irrespective of whether it was recorded that they took part in the MV campaign or not (intention-to-treat). Deaths due to accidents (based on postmortem interviews) were censored at the date of death. A Cox proportional hazards model with age as the underlying time was used to compare mortality rates between the 2006 cohort and the 2004 and 2005 cohorts stratified by village cluster. The proportional hazards assumption was evaluated by log-log plots and Schoenfeld residuals. Previous studies have indicated that MV is particularly beneficial for girls,17,18,26,27 that the effect of MV is neutralized by subsequent DTP vaccine19 and that 2 doses may be better that 1 dose.17,20 We had prespecified analyses by sex and vaccination status and evaluated these potential effect modifiers using Wald statistics. Data were analyzed using Stata12.1 (StataCorp, College Station, TX).

To assess whether the effect varied during 1 year of follow-up, we assessed the effect separately during the first 6 months after the index date and 6–12 months after the index date. We furthermore analyzed the data using time since the index date as the underlying timescale adjusted for age and stratified for cluster and age in years at the index date.

In the analysis of whether the effect of MV campaign was influenced by routine measles and DTP-3 vaccination, children entered the analysis at the first surveillance visit, where the vaccination card was seen after the index date, and remained under study to the end of the 12-month follow-up period.

To investigate the robustness of our estimates, we conducted several sensitivity analyses: (1) we censored all deaths due to measles infections; (2) we compared the postcampaign mortality only to the mortality during the previous year (2005 and 2006) in which no measles epidemic took place and (3) 86% of deaths were only known with the precision of a month. To investigate how the missing precision of date of death affected the estimate, we also applied a statistical model for interval censored data. The model assumes a constant hazard rate (exponential distribution). We ran 2 models: (1) using the 15th of the month as an exact date of death and (2) treating deaths with the precision of a month as interval censored using the 1st and the 30th as the interval in which the death could have occurred.

We estimated the risk of death within the year after the index date using the estimates from the stratified Cox model adjusted for age. Using these risks estimates, we calculated the number needed to vaccinate to prevent 1 death within the year as 1/the risk difference. Confidence intervals were estimated based on the 2000 bootstrap samples.28

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RESULTS

A total of 8158 children aged 6 months to 5 years were under surveillance at the time of the 2006 campaign and 7999 and 8108 during the 2 previous years. Four children were lost to follow-up (1 in 2005, 3 in 2006; Fig. 1). Background factors (age, sex, maternal age, ethnicity and maternal education) were similar across the years, although more children were found at home and had higher DTP-3 coverage in the later cohorts and lower MV coverage (Table 1). If the comparison was made only between 2006 and 2005, there was no difference in DTP-3 coverage but still a lower MV coverage before the campaign in 2006. The distribution of background factors by cohort was similar for boys and girls (Table, Supplemental Digital Content 2, http://links.lww.com/INF/C267).

Table 1

Table 1

FIGURE 1

FIGURE 1

Campaign participation in 2006 was high. Among the 5600 children (69%) present at the first visit after the campaign, 90% were said to have participated (5015/5600).

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Mortality Analyses

In the primary analysis with follow-up for 12 months, 579 children died during the year after index dates, 164 after the campaign and 208 and 207 during the same period the previous years. Censoring 9 deaths due to accidents retained 161 deaths after the campaign (mortality rate = 23.8 per 1000 person-years) and 409 in the 2 precampaign years (mortality rate = 30.7 per 1000 person-years; Fig. 1). The mortality rate ratio (MRR) comparing the year after the campaign with the 2 previous years was 0.78 (0.65–0.93) (Table 2). Adjusting for maternal education and maternal age had little effect on the estimate, the adjusted MRR (aMRR) being 0.80 (0.66–0.96). The reduction was statistically significant in girls [aMRR = 0.74 (0.56–0.97)] but not in boys [aMRR = 0.86 (0.66–1.11)]; the interaction between sex and campaign was not statistically significant (P = 0.44). In children aged 6–11 months, the aMRR after the campaign was 0.92 (0.63–1.34); in children aged 1–4 years of age, it was 0.76 (0.61–0.94), the effect being similar in children aged 1–2 years [aMRR = 0.77 (0.60–1.00)] and children aged 3–4 years [aMRR = 0.75 (0.49–1.13)].

Table 2

Table 2

During the first 6 months of follow-up, the aMRR was 0.79 (0.63–0.98) for all eligible children; from 6–12 months, aMMR was 0.86 (0.60–1.24) (data not shown). Changing the timescale to time since the index date yielded essentially the same estimates when mortality rates were compared in a Cox proportional hazards model: aMRR = 0.79 (0.66–0.95); 0.84 (0.65–1.08) in boys and 0.74 (0.57–0.97) in girls (Fig. 2).

FIGURE 2

FIGURE 2

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Cause of Death

Guinea-Bissau experienced a measles epidemic in 2003 and 2004.23 On the basis of interviews conducted after the death of the child, 15 deaths in the 2004 cohort were classified as due to measles. No child was said to have died from measles in the 2005 and 2006 cohorts. Censoring follow-up time of the children who died from measles on the date of death, the aMRR comparing the 2006 cohort with the 2004 and 2005 cohorts was 0.83 (0.69–1.00). When limiting the analyses to the 2006 and 2005 cohorts in which no measles deaths were registered, the aMRR comparing the 2006 cohort with the 2005 cohort was 0.79 (0.64–0.98) (Table, Supplemental Digital Content 3, http://links.lww.com/INF/C268). Nonmeasles febrile illness was reported as the main symptom for 68% of the deaths (Table, Supplemental Digital Content 4, http://links.lww.com/INF/C269), the MMR being 0.82 (0.66–1.03). Diarrheal disease was the second most common cause, accounting for 10% of the deaths and was associated with an MRR of 0.71 (0.40–1.26).

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Effect of MV Campaign by Routine MV and DTP-3 Status

Among children aged 1–4 years at the time of the index date, 5946 (84%), 6134 (85%) and 6276 (86%) had a visit within the follow-up period in the 2004, 2005 and 2006 cohorts, respectively. The vaccination cards were seen for 42% (2487/5946), 41% (2535/6134) and 44% (2775/6276) in the 3 cohorts, respectively; the coverage for routine MV was 91%, 91% and 84%, respectively. Among children whose vaccination card was seen, the aMRR was 0.59 (0.36–0.99) for children who had received both routine and MV campaign and 0.97 (0.38–2.52) for children who had received no routine MV and only MV campaign (P for interaction = 0.37; Table 3). The effect was particularly strong among children who had received DTP-3 and therefore were unlikely to receive DTP during follow-up, the MRR being 0.49 (0.28–0.87) in the unadjusted and 0.50 (0.28–0.88) in the adjusted model (Table, Supplemental Digital Content 5, http://links.lww.com/INF/C270). In routine measles-vaccinated children, the effect of the campaign tended to differ by DTP-3 vaccination status for girls [MRR = 0. 40 (0.17–0.91) among DTP-3-recipients, but MRR = 1.81 (0.40–8.18) in girls who had not received DTP-3 (P = 0.07 for same effect)] while there was no difference in boys (Table, Supplemental Digital Content 5, http://links.lww.com/INF/C270).

Table 3

Table 3

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Sensitivity Analyses

Deaths with only the month of death known were coded as having occurred on the 15th of the month. The proportion of deaths occurring on the 15th were 91% (190/208), 83% (172/207) and 83% (136/163) in the 3 cohorts. The estimated mortality reduction indicated no difference as to whether the 15th of the month was considered an exact date of death or whether deaths registered to have occurred on the 15th were treated as interval censored using the 1st and the 30th as the interval in which the death could have occurred. These 2 approaches both estimated MRRs as 0.78 (0.65–0.93). Including deaths classified as being due to accidents did not change the reduction in mortality, with the aMMR being 0.80 (0.67–0.96).

The under-5 mortality level has declined from approximately 300/1000 in 2000 to 150/1000 in 2006 (Fig., Supplemental Digital Content 6, http://links.lww.com/INF/C271). In none of the years was the mortality decline as large as between 2005 and 2006.

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Number Needed to Vaccinate

Mortality during the year following the index dates in the precampaign years was 2.5% (2.3%–2.7%) and 1.9% (1.7%–2.2%) during the year after the campaign. The risk difference was 0.6 percentage point (0.2–0.9) and consequently the number needed to vaccinate to avoid 1 death was 179 (106–526).

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DISCUSSION

Main Findings

We found a 20% (4%–34%) reduction in mortality the year following the 2006 MV campaign compared with the 2 previous years. The lower mortality was not explained by protection against measles infection. Consistent with many other studies, the beneficial effect of MV was most marked in girls and it was also strongest among children who had received routine MV previously, although none of the interactions was statistically significant.

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Strengths and Weaknesses

In a before-and-after study, observed differences could be caused by other factors varying at the same time. However, the observed tendencies are consistent with the hypotheses regarding the beneficial nonspecific effects of MV: the drop in mortality between 2004 to 2005 and 2006 appeared larger than declines observed in previous years (Fig., Supplemental Digital Content 6, http://links.lww.com/INF/C271), and it tended to be stronger during the first 6 months of follow-up, excluding the period after November 2006 when bed nets were distributed. The drop in mortality also tended to be stronger for girls than for boys and for children who had previously received MV. By stratifying the analysis for village cluster, children in the same village were compared, and the distribution of risk factors for death therefore should be similar for children compared in the post- and precampaign years. Hence, we would expect little effect of adjusting for background factors, as observed for maternal education and age.

Guinea-Bissau has higher mortality in the rainy season (June to November) than in dry season29; we therefore compared the mortality during the months after the campaign, with mortality during the same period the previous years. The duration of the nonspecific effect of MV is unknown. We limited postcampaign follow-up to 1 year since vaccination strategies changed in 2007 when the BHP started offering vaccines at the 6 monthly routine visits30 and the national program discontinued the DTP booster dose at 18 months of age, as we expected both changes to lower mortality.

The analysis had to be made as an intention-to-treat analysis as it otherwise would have been impossible to know with whom to compare in the years before the campaign. We confirmed reception of MV campaign for at least 90% of the children. Coverage figures provided by the Measles and Rubella Initiative indicate 92% coverage. Hence, the before-after comparison is likely to resemble a comparison of children who received MV in a campaign and children who did not. Still an intention-to-treat analysis will be conservative because some children did not receive the intervention. A before-after study rather than a comparison of participants and nonparticipants was chosen because the small group of nonparticipant is likely to differ from the participants and because the follow-up could only start after classifying participation status at a visit after the campaign.

In addition to MV, the children received VAS and mebendazole during the 2006 campaign and the effects of the 3 interventions are difficult to disentangle. VAS had also been distributed in campaigns in the previous years although only once per year, whereas the post-MV campaign cohort received VAS twice (Table, Supplemental Digital Content 1, http://links.lww.com/INF/C266). In a randomized trial of VAS administered with vaccines, we recently found that VAS compared with placebo had no overall effect on child survival but increased the mortality in boys and reduced it in girls.31 Similarly, a recent trial from India of one million children found no overall effect of biannual distribution of VAS.32 Hence, it seems unlikely that VAS should be the major driver in the mortality decline after the 2006 campaign although it may amplify a beneficial effect in girls and counteract it in boys.31 It also seems unlikely that deworming would have such a strong effect on child survival.33,34 In the years before the MV campaign (but not during the year after the campaign), children aged 0–59 months received OPV that may also have beneficial nonspecific effects35,36 and would therefore tend to mask a benefit of MV campaign. No single cause of death seemed to explain the lower mortality after the campaign (Table, Supplemental Digital Content 4, http://links.lww.com/INF/C269).

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Consistency With Previous Studies

Despite the huge investment in delivering MV in campaigns, the effect on survival has not been assessed previously. From a disease-specific perspective, measles revaccination campaigns should have a limited effect on child mortality because most children are already protected against measles infection. Several studies have compared mortality of measles-vaccinated and measles-unvaccinated children. In 10 cohort studies from the 1970s to 1980s, the estimated MMRs ranged from 0.14 to 0.70.12 In a previous study from the same village clusters, children were followed between 1990 and 1996; measles-vaccinated children aged 6–17 months had an MRR of 0.51 (0.28–0.95) during 6 months of follow-up (excluding measles deaths).13 In the late 1990s, children in Guinea-Bissau were randomized to an early MV or a control group receiving inactivated polio vaccine at 6 months. Both groups should receive an MV at 9 months. When the war broke out in 1998, a group of children had not received their 9 months’ vaccination. Among these, the MRR for measles-vaccinated children compared with inactivated polio vaccine-vaccinated children was 0.30 (0.08–0.87).18 In these studies, the mortality in the unvaccinated group was considerably higher than that in the present study. With the decline in mortality since the 1990s, presumably because of fewer infectious disease deaths, we would expect a lower nonspecific effect on mortality.

We found a stronger beneficial effect for girls than for boys. As shown in Table (Supplemental Digital Content 2, http://links.lww.com/INF/C267), no sex-differential distribution of background factors could explain this difference. Stronger beneficial nonspecific effects of MV for girls have been observed consistently in both randomized trials and observational studies in Guinea-Bissau, which does not have sex-differential treatment,26,30 as well as in settings with sex-differential treatment.37

Interestingly, when assessing survival after inspection of a vaccination card after the index dates, the effect of MV in campaign on all-cause mortality was only seen in children who had already received routine MV and hence were protected against measles infection already. In a quasi-experimental study from the early 1980s when the first MV campaigns were conducted and before DTP was introduced in the rural areas in Guinea-Bissau, children who happened to be younger than 9 months at the time of the first MV campaign were also offered MV after 9 months of age. Children who received 2 doses of MV had significantly lower mortality between 9 and 59 months of age than children who received only 1 dose of MV between 9 and 11 months of age, the reduction in mortality being 59% (15%–81%).20 More recently, in a randomized trial of early measles vaccination, children who received MV at 4.5 and 9 months had 29% (−1% to 50%) lower mortality between 9 and 36 months of age than children who received 1 dose of MV at 9 months of age.17 Hence, the beneficial nonspecific effects of MV seem to be amplified by a booster MV as also supported by the present study, and the 20% reduction observed in the present study is comparable with the result from a randomized trial.

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Interpretation and Implications

We observed 20% lower mortality during 12 months of follow-up. Like in previous studies,12,13,17 excluding measles deaths did not alter the estimated beneficial effect of MV. Hence, the reduction in child mortality cannot be explained by the prevention of measles infection. Six monthly visits took place throughout the study period, and we know of no other disease outbreaks during 2004 to 2006, which could explain the mortality pattern. The effect tended to be strongest for those who had received both routine and MV campaign, corroborating that beneficial nonspecific effects of MV were the main drivers of the mortality reduction. Noteworthy, if a booster MV is associated with strong additional survival benefits, the program for a second dose of MV in the second year of life, which is currently being rolled out with funding from GAVI, the Vaccine Alliance,38 may have a much larger effect on child survival than assumed. Future cluster randomized studies of MV campaigns should seek to measure the effect of MV campaign on all-cause mortality and whether the effect differs by number of prior MVs.

Few studies on the biological mechanisms underlying nonspecific effects of MV have been undertaken,39,40 and the mechanisms are largely unknown. Recent studies have shown that Calmette-Guérin bacillus vaccination induces epigenetic changes that affect the responses to unrelated pathogens.41 MV also may induce such changes. Within a randomized trial, we recently observed that children randomized to early MV versus no MV at 4–6 months of age had higher levels of monocyte chemoattractant protein-1, 6 weeks postrandomization.39 In the present study, the second dose of MV seemed to carry additional beneficial nonspecific effects. It has been shown previously that providing MV in the presence of maternal measles-specific antibodies results in the lower attained antibody levels but at the same time in stronger beneficial nonspecific effects.42 We have speculated that the high-affinity maternal measles-specific antibodies may (1) bind to the most dominant epitopes and thereby lead to a broader response to other epitopes on the MV virus, resulting in protective cross-reactivity memory responses or (2) result in rapid formation of antibody-antigen complexes, which may lead to enhanced T-cell responses.42 Such mechanisms also could explain the beneficial effect of the second dose of MV observed in the present study because the first MV induces high-affinity measles-specific antibodies, and the second vaccination occurs in the presence of these antibodies. If vaccination in the presence of measles antibodies is responsible for the beneficial effect, children would benefit from receiving the first vaccine early rather than later as is recommended when measles infection is better controlled.2 The second dose is provided to improve immunity against measles,2 but the benefit may even be stronger in children who have seroconverted already.

The number needed to vaccinate to prevent one death during the first year after vaccination was only 179 (106–526), and thus, the cheap MV has the potential to prevent many nonmeasles-related deaths. The effect was evident in our study in which three-quarters of the children had already received routine MV before the campaign and particularly strong among these children. Hence, cutting routine MV immunization services, the number of MV doses or MV campaigns in connection with approaching measles elimination and eventual eradication could have negative effects on child survival.

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CONCLUSIONS

Mortality levels were stable during 2004 and 2005, but a mortality drop was observed after the 2006 measles campaign. Corroborating findings from previous observational studies and randomized trials, the beneficial effect of MV was significant in its own right for girls. Furthermore, contrary to assumptions about specific effects, the beneficial effect of MV campaign was also significant in its own right among children who had received routine MV but not among measles-unvaccinated children. Both findings support that the mortality decline was due to nonspecific effects of MV rather than protection against measles infection or uncontrolled confounding.

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ACKNOWLEDGMENTS

Author contributions: A.B.F., H.R., C.S.B. and P.A. designed the study; A.B.F., C.M., S.B., S.T., L.S., M.P., M.F. and P.A. supervised data collection, data entry and/or data cleaning; A.B.F., P.A. and H.R. analyzed the data and A.B.F. had full access to the data, wrote the first manuscript draft and had primary responsibility for its final content. All authors contributed to and approved the final manuscript.

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REFERENCES

1. Measles and Rubella Initiative 2013. Available at: http://www.measlesrubellainitiative.org/. Accessed January 11, 2015
2. . Measles vaccines: WHO position paper. Wkly Epidemiol Rec. 2009;84:349–360
3. Zuber PL, Conombo KS, Traoré AD, et al. Mass measles vaccination in urban Burkina Faso, 1998. Bull World Health Organ. 2001;79:296–300
4. Chuang SK, Lau YL, Lim WL, et al. Mass measles immunization campaign: experience in the Hong Kong Special Administrative Region of China. Bull World Health Organ. 2002;80:585–591
5. Goodson JL, Kulkarni MA, Vanden Eng JL, et al. Improved equity in measles vaccination from integrating insecticide-treated bednets in a vaccination campaign, Madagascar. Trop Med Int Health. 2012;17:430–437
6. Hu X, Xiao S, Chen B, et al. Gaps in the 2010 measles SIA coverage among migrant children in Beijing: evidence from a parental survey. Vaccine. 2012;30:5721–5725
7. Munyoro MN, Kufa E, Biellik R, Pazvakavambwa IE, Cairns KL. Impact of nationwide measles vaccination campaign among children aged 9 months to 14 years, Zimbabwe, 1998–2001. J Infect Dis. 2003;187(suppl 1):S91–S96
8. Lowther SA, Curriero FC, Kalish BT, et al. Population immunity to measles virus and the effect of HIV-1 infection after a mass measles vaccination campaign in Lusaka, Zambia: a cross-sectional survey. Lancet. 2009;373:1025–1032
9. Amouzou A, Habi O, Bensaïd KNiger Countdown Case Study Working Group. . Reduction in child mortality in Niger: a Countdown to 2015 country case study. Lancet. 2012;380:1169–1178
10. Aaby P, Bukh J, Lisse IM, et al. Measles vaccination and reduction in child mortality: a community study from Guinea-Bissau. J Infect. 1984;8:13–21
11. Aaby P, Simondon F, Samb B, et al. Low mortality after mild measles infection compared to uninfected children in rural West Africa. Vaccine. 2002;21:120–126
12. Aaby P, Samb B, Simondon F, et al. Non-specific beneficial effect of measles immunisation: analysis of mortality studies from developing countries. BMJ. 1995;311:481–485
13. Kristensen I, Aaby P, Jensen H. Routine vaccinations and child survival: follow up study in Guinea-Bissau, West Africa. BMJ. 2000;321:1435–1438
14. Desgrees du Lou A, Pison G, Aaby P. Role of immunizations in the recent decline in childhood mortality and the changes in the female/male mortality ratio in rural Senegal. Am J Epidemiol. 1995;142:643–652
15. . Influence of measles vaccination on survival pattern of 7-35-month-old children in Kasongo, Zaire. The Kasongo Project Team. Lancet. 1981;1:764–767
16. Koenig MA, Khan MA, Wojtyniak B, et al. Impact of measles vaccination on childhood mortality in rural Bangladesh. Bull World Health Organ. 1990;68:441–447
17. Aaby P, Martins CL, Garly ML, et al. Non-specific effects of standard measles vaccine at 4.5 and 9 months of age on childhood mortality: randomised controlled trial. BMJ. 2010;341:c6495
18. Aaby P, Garly ML, Balé C, et al. Survival of previously measles-vaccinated and measles-unvaccinated children in an emergency situation: an unplanned study. Pediatr Infect Dis J. 2003;22:798–805
19. Aaby P, Jensen H, Samb B, et al. Differences in female-male mortality after high-titre measles vaccine and association with subsequent vaccination with diphtheria-tetanus-pertussis and inactivated poliovirus: reanalysis of West African studies. Lancet. 2003;361:2183–2188
20. Aaby P, Andersen M, Sodemann M, et al. Reduced childhood mortality after standard measles vaccination at 4-8 months compared with 9-11 months of age. BMJ. 1993;307:1308–1311
21. Higgins JPT, Soares-Weiser K, Reingold A Systematic review of the non-specific effects of BCG, DTP and measles containing vaccines. Available at: http://www.who.int/immunization/sage/meetings/2014/april/3_NSE_Epidemiology_review_Report_to_SAGE_14_Mar_FINAL.pdf?ua=1. Accessed October 12, 2015
22. Høj L, da Silva D, Hedegaard K, et al. Factors associated with maternal mortality in rural Guinea-Bissau. A longitudinal population-based study. BJOG. 2002;109:792–799
23. Balé C, Garly ML, Martins C, et al. Risk factors for measles in young infants in an urban African area with high measles vaccination coverage. Pediatr Infect Dis J. 2011;30:689–693
24. Aaby P, Jensen H, Gomes J, et al. The introduction of diphtheria-tetanus-pertussis vaccine and child mortality in rural Guinea-Bissau: an observational study. Int J Epidemiol. 2004;33:374–380
25. Hornshoj L, Benn CS, Fernandes M, et al. Vaccination coverage and out-of-sequence vaccinations in rural Guinea-Bissau: an observational cohort study. BMJ open. 2012;2:e001509
26. Martins CL, Benn CS, Andersen A, et al. 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 Infect Dis. 2014;209:1731–1738
27. Veirum JE, Sodemann M, Biai S, et al. Routine vaccinations associated with divergent effects on female and male mortality at the paediatric ward in Bissau, Guinea-Bissau. Vaccine. 2005;23:1197–1204
28. Austin PC. Absolute risk reductions and numbers needed to treat can be obtained from adjusted survival models for time-to-event outcomes. J Clin Epidemiol. 2010;63:46–55
29. Veirum JE, Biai S, Jakobsen M, et al. Persisting high hospital and community childhood mortality in an urban setting in Guinea-Bissau. Acta Paediatr. 2007;96:1526–1530
30. Fisker AB, Hornshøj L, Rodrigues A, et al. Effects of the introduction of new vaccines in Guinea-Bissau on vaccine coverage, vaccine timeliness, and child survival: an observational study. Lancet Glob Health. 2014;2:e478–e487
31. Fisker AB, Bale C, Rodrigues A, et al. High-dose vitamin A with vaccination after 6 months of age: a randomized trial. Pediatrics. 2014;134:e739–e748
32. Awasthi S, Peto R, Read S, et al. Vitamin A supplementation every 6 months with retinol in 1 million pre-school children in north India: DEVTA, a cluster-randomised trial. Lancet. 2013;381:1469–1477
33. Awasthi S, Peto R, Read S, et al.DEVTA (Deworming and Enhanced Vitamin A) Team. Population deworming every 6 months with albendazole in 1 million pre-school children in North India: DEVTA, a cluster-randomised trial. Lancet. 2013;381:1478–1486
34. Donnen P, Brasseur D, Dramaix M, et al. Vitamin A supplementation but not deworming improves growth of malnourished preschool children in eastern Zaire. J Nutr. 1998;128:1320–1327
35. Aaby P, Hedegaard K, Sodemann M, et al. Childhood mortality after oral polio immunisation campaign in Guinea-Bissau. Vaccine. 2005;23:1746–1751
36. Aaby P, Rodrigues A, Biai S, et al. Oral polio vaccination and low case fatality at the paediatric ward in Bissau, Guinea-Bissau. Vaccine. 2004;22:3014–3017
37. Hirve S, Bavdekar A, Juvekar S, et al. Non-specific and sex-differential effects of vaccinations on child survival in rural western India. Vaccine. 2012;30:7300–7308
38. GAVI Alliance. Measles Vaccine Support. Available at: http://www.gavialliance.org/support/nvs/measles/. Accessed January 11, 2015
39. Jensen KJ, Søndergaard M, Andersen A, et al. A randomized trial of an early measles vaccine at 4½ months of age in Guinea-Bissau: sex-differential immunological effects. PLoS One. 2014;9:e97536
40. Bertley FM, Ibrahim SA, Libman M, et al. Measles vaccination in the presence of maternal antibodies primes for a balanced humoral and cellular response to revaccination. Vaccine. 2004;23:444–449
41. Kleinnijenhuis J, Quintin J, Preijers F, et al. Bacille Calmette-Guerin induces NOD2-dependent nonspecific protection from reinfection via epigenetic reprogramming of monocytes. Proc Natl Acad Sci U S A. 2012;109:17537–17542
42. Aaby P, Martins CL, Garly ML, et al. Measles vaccination in the presence or absence of maternal measles antibody: impact on child survival. Clin Infect Dis. 2014;59:484–492
Keywords:

child mortality; measles vaccination; vaccination campaigns; nonspecific/heterologous effects of vaccines

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