The specific aims were to examine in Guinea-Bissau
- whether the standard titre Schwarz (SW) or standard-titre Edmonston-Zagreb (EZ) measles vaccine will be the best vaccine strain for use in a routine one-dose measles vaccination schedule and a two dose measles vaccination schedule in terms of antibody response, protection against measles
- Whether the standard-titre Edmonoston-Zagreb (EZ) vaccine will be suitable for use in a very early age two-dose schedule vaccinating at 4½ and 9 months of age
Newborn infants were identified in the BHP registration system. To make sure that study children had received the third dose of diphtheria-tetanus-pertussis (DTP) four weeks before inclusion, we contacted the mothers of 6, 10, and 14 week-old children, and reminded them to go one of the health centres to receive DTP and OPV vaccinations. Enrolment in the measles vaccination study took place at 4½ months of age. At 4½ months children were randomized to one of three equally large groups, using block randomisation with 24 envelopes per bag. One of the three arms received vaccination with the standard-titre EZ measles vaccine at 4½ months of age and the other two groups received nothing at enrolment. At 9 months of age, all children were invited back to the health centre, the early EZ measles vaccination received second dose of standard-dose EZ vaccine. The other two groups received a standard dose of either Schwarz or Edmonston-Zagreb vaccine.
A measles outbreak swept through the country between November 2003 and May 2004 shortly after we had started the trial. Given the marked efficacy of early measles vaccination, we presented an interim study reports the efficacy of early EZ measles vaccination in an outbreak situation. During the outbreak, 19% of unvaccinated children contracted measles before 9 months of age. The vaccine efficacy in the children who received measles vaccine at early age was 94% (95% CI 77 - 99%) for serologically confirmed; the efficacy against admission to hospital with measles was 100% (46 – 100%) and the efficacy against measles death was 100% (-42-100%). In the same period, the children who had received measles vaccine had a reduction in overall mortality, the MR being 0.18 (0.02-1.36). At 4½ months of age girls were less likely to have protective maternal antibody levels, the male-female ratio for protective antibody level being 1.23 (1.00-1.51). At 9 months, girls were more likely to have protective levels, the male-female ratio having protective antibody levels being 0.60 (0.36-1.01) (p=0.053) and GMT was significantly higher for girls (p=0.007).
Among the two different strains of standard-titre measles vaccine Schwarz (SW) and Edmonston-Zagreb(EZ) measles vaccine used at 9 months of age, only 1% had non-protective antibody levels for either vaccines. SW vaccine was associated with significantly higher levels of measles antibodies (geometric mean titre (GMT)=2114 mIU/mL (1153-2412) than EZ measles vaccine (GMT=807 mIU/mL (722-908)) (p=0.001). We did not find any significant difference in antibody level for boys or girls after SW vaccination but EZ measles vaccine induced a higher level of antibodies in girls than boys. Antibody levels were higher during the rainy season. At 24 months of age there was no indication that a booster dose at 18 months increased the antibody level for children who had received a second dose at 18 months of age for either vaccine.
The maternal antibody level of children declined significantly with age in days (p<0.01) and was significantly lower in the rainy season than in the dry season. An early two-dose schedule was found to provide good protective antibody levels against measles among children below the normal age of vaccination (9 months). The prevalence of protected after the first dose vaccination at 4½ months of age was 77% (316/408). At 24 months of age, following the second dose, 97% (286/294) had protective levels. The height of the response at both 9 and 24 months of age was inversely correlated with the level of maternal antibodies at the time of initial measles vaccination. In the EZ-at-9-month group, 99% (341/344) had protective levels at 24 months of age after first or second dose of measles vaccination. The geometric mean titre (GMT) was significantly lower in the early measles vaccination group than in the EZ-at-9- month group (p=0001). A second dose of vaccine provided a significant boost in antibody level particularly to children who had an antibody level of less than 1000 mIU/mL.
Conclusion and future perspectives
In low-income countries, maternal antibodies level may be low and severe outbreak of measles can occur in infants before 9 months of age. Outbreaks of measles may be curtailed given Edmonston-Zagreb measles vaccine in an early two dose regimen, in which the primary dose is given at 4½ months. This schedule has the potential to provide earlier protection against measles in a susceptible population that is expected to grow in Africa as more mothers of childbearing age have vaccine-induced measles immunity.
This study showed that girls lost maternal measles antibodies more rapidly than boys and well before 9 months of age. They may therefore also be more likely to contract subclinical measles infection before the current age of measles vaccination.
During the two year follow-up after vaccination, the antibody level in the early measles vaccination group was still high. We will continue to follow the cohort in Bissau to assess long-term maintenance of antibody levels. If early measles vaccination is associated with maintaining measles antibody levels to 3-4 years of age, it should be considered to recommend an early two–dose measles vaccination for all children in our country since then we would have shown that this strategy protected against measles infection through the critical period of high measles mortality. This evaluation is based on measles antibody levels but we have also collected data on mortality. If the mortality data suggests that early measles vaccination tends to be associated with lower mortality there is every reason to recommend this strategy more generally. Because measles vaccine have been shown to have beneficial non-specific effects on morbidity and mortality, particularly for the youngest children, it is important to vaccinate as early as possible.