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

Summary

Background

Females given high-titre measles vaccine (HTMV) have high mortality; diphtheria-tetanus-pertussis (DTP) vaccination might be associated with increased female mortality. We aimed to assess whether DTP or inactivated poliovirus (IPV) administered after HTMV was associated with increased female-male mortality ratio.

Methods

In three trials from West Africa, 2000 children were randomised to HTMV or control vaccine at 4–5 months of age; a second vaccination was given at age 9–10 months (standard measles vaccine). Children in high-titre groups were given IPV or DTP-IPV. Another 944 children received HTMV as routine vaccination in Senegal.

Findings

When we compared high-titre and control groups, no difference in mortality between the first and the second vaccination was noted. After the second vaccination, the female-male mortality ratio was 1·84 (95% CI 1·19–2·84) in children in the high-titre groups who received DTP-IPV or IPV, and 0·59 (0·34–1·04) in controls who received standard measles vaccine (p=0·007). Children who received HTMV but no additional DTP-IPV or IPV had a female-male mortality ratio of 0·83 (0·41–1·67). This ratio was 2·22 (1·04–4·71) for children who received DTP-IPV after routine HTMV and 1·00 (0·68–1·47) for those who did not. When we combined the results from all trials, the female-male mortality ratio was 1·93 (1·33–2·81) for those who received DTP or IPV after HTMV, and 0·96 (0·69–1·34) for those who did not (p=0·006).

Interpretation

A change in sequence of vaccinations, rather than HTMV itself, may have been the cause of increased female mortality in these trials.

Introduction

In 1989, WHO recommended use of high-titre Edmonston-Zagreb (EZ-HT) measles vaccine at age 6 months for children living in countries in which the incidence of measles before age 9 months was high.¹ In 1992, after results of studies in Guinea-Bissau, Senegal, and Haiti had shown raised female mortality in recipients of high-titre measles vaccine (HTMV),2, 3, 4 recommendation for this vaccine was rescinded.⁵ Since high-titre vaccines protect against measles infection, the results of the high-titre trials had shown that vaccines might reduce survival in geographical areas with high mortality from this infection.

In areas of high mortality, various vaccines might have non-specific effects on mortality; for example, measles6, 7, 8, 9 and BCG9, 10, 11 vaccines reduce mortality from diseases other than measles and tuberculosis. On the other hand, inactivated vaccines such as diphtheria-tetanus-pertussis (DTP) and inactivated poliovirus (IPV) might amplify mortality from diseases other than diphtheria, tetanus, pertussis, and polio.7, 9, 11, 12 Non-specific effects are strongest in the first 3–6 months after immunisation¹³ and in girls,2, 3, 6, 12, 14 and they are largely determined by the most recent vaccine received; for example, in Guinea-Bissau, the female-male mortality ratio was 3·08 (95% CI 1·11–8·56) for children who received DTP as their last vaccine, but only 0·63 (0·28–1·40) for those who received measles vaccine last.¹² Results of several studies from West Africa have shown that BCG could enhance the response to unrelated antigens.10, 15

The greatly reduced mortality after measles vaccination has been attributed to prevention of long-term effects of measles infection. However, although morbidity might be raised for a few months after measles infection,¹⁶ results of studies from Burundi,1⁷ Ghana,¹⁸ Bangladesh,13, 16 and Senegal¹⁹ have shown no increase in mortality after the acute phase of infection. Mild measles infection might be associated with lower mortality,13, 19 thus both measles infection and measles vaccination might provide beneficial stimulation of the immune system, which enhances resistance to other infections.

HTMVs seem to result in a high female-male mortality ratio⁶ and an increased mortality when compared with female recipients of standard-titre measles vaccine.²⁰ In a meta-analysis of West African studies, girls who received HTMV had a mortality ratio of 1·86 (95% CI 1·28–2·70) compared with those who received standard measles vaccine, whereas boys had a mortality ratio of only 0·91 (0·61–1·35). The effect was not seen immediately, but several months later. Two different hypotheses have been proposed to account for these surprising observations.

Initially, HTMV was postulated to have come too close to the natural disease, thus inducing immune suppression, as happens in natural measles infection.4, 21 This hypothesis does not account for the delayed increase in mortality and why later, the effect was noted for girls only. Although measles mortality might be raised in older girls and women,22, 23 it is usually not higher in girls in the first 3 years of life, which is the period when high-titre vaccines are associated with increased female mortality. If anything, boys have higher measles mortality in this age range.²³ More importantly, measles infection is usually not associated with long-term excess mortality.16, 17, 18, 19 Hence, HTMV does not mimic natural measles disease. Furthermore, contradictory to the hypothesis, results of one large trial of HTMV in Zaire showed no increase in mortality of high-titre recipients when compared with recipients of medium-titre measles vaccine, and no increase in female-to-male mortality.²⁴

Second, we noted in geographical areas with high childhood mortality that standard measles vaccine was associated with a non-specific benefit on survival, which was especially strong for girls.6, 7 We therefore suggested that the detrimental effect of HTMV would only be seen in areas with high mortality,⁸ for high-titre vaccine did not provide the non-specific and sex-specific benefits of the standard measles vaccine.3, 8, 20 The mortality difference would only be seen when girls in the control groups had received the standard measles vaccine, and it would not be noted in areas with low mortality since children in these areas had no non-specific survival benefit from standard measles vaccine. However, in the time before vaccination, girls did not have higher mortality than boys.⁶ Thus, our hypothesis did not fully explain why girls had a higher mortality than boys in the high-titre group6, 8 and why these effects did not arise in the HTMV trial in Zaire.²⁴

Since both of these interpretations are unable to account for all observations, we propose an alternative hypothesis. In the high-titre trials, many children received DTP or IPV after measles vaccination. Since DTP has been reported to be associated with an increase in female mortality,12, 14 we aimed to find out whether vaccination with DTP or IPV after high-titre measles vaccination might have contributed to the increased female-male mortality ratio. If excess female mortality was indeed caused by subsequent administration of DTP or IPV vaccines, these three deductions should hold. First, there should be no excess mortality for high-titre recipients compared with controls in the period between enrolment and subsequent reception of DTP or IPV vaccines. Second, recipients of high-titre vaccine, after being given DTP or IPV, should have a higher female-male mortality ratio than controls receiving standard measles vaccine at age 9–10 months, and a higher female-male mortality ratio than high-titre recipients who did not receive additional DTP or IPV. Finally, the hypothesis should account for contradictions encountered by the other two hypotheses.