Clinical trial NCT00168558: Early Two-dose Measles Vaccination Trial
Official title: Measles Vaccination in Guinea-Bissau. Strategies to Reduce Disease Burden and Improve Child Survival
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Measles
Keywords: Non-specific effects of vaccines
Infant mortality
Child mortality
Mortality
Morbidity
Diphtheria-tetanus-pertussis vaccine
Measles vaccine
Measles
Immunisation
Low income country
Guinea-Bissau
Bandim Health Project
Immunology
Lead sponsor: Bandim Health Project
Sponsor class: OTHER
Collaborators: name: Danish Council for Development Research
name: Novo Nordisk A/S
name: AP Moeller Foundation
name: Medical Research Council Unit, The Gambia
First posted: 2005-09-15
Enrollment: 5879
Sex: ALL
Minimum age (years): 4
Maximum age (years): 6
Standard ages: CHILD
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

Brief summary: The specific aims are 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 and child survival, and
* whether the standard-titre Edmonston-Zagreb (EZ) vaccine will be suitable for use in a very early two-dose schedule vaccinating at 4½ and 9 months of age

Detailed description: BACKGROUND:

Two dose schedules:

After the failure of the high-titre measles vaccine, which was to be administered at 6 months of age it was suggested to perform trials of early two-dose measles vaccination schedules to lower the age of vaccination. The standard titre SW measles vaccine has been shown to be associated with a non-specific beneficial effect on child mortality that cannot be ascribed to the protection against measles. The two measles vaccines most commonly used in the Expanded Programme on Immunization (EPI) are the standard titre SW and the standard titre EZ vaccine. Surprisingly, these two vaccines have never been compared in a randomised trial with child mortality as end-point, and it is not clear which would be most suitable for use in a two-dose vaccination schedule.

From 1995 to 2002, all children in the BHP study area were included in an early two-dose measles vaccination trial from 6 months of age. The children were randomised to either a one-dose group receiving an inactivated polio vaccine (IPV) at 6 months of age and a measles vaccine at 9 months of age, or a two-dose group receiving two doses of measles vaccine at 6 and 9 months of age. For the first 6 months of the trial, the standard-titre EZ measles vaccine was used, for the rest of the trial the standard-titre SW vaccine was used. Results from the trial showed that an early two-dose schedule increased coverage considerably and provided better protection against measles among infants than the recommended one-dose at 9 months of age schedule. The EZ and the SW vaccine were used in two different cohorts - so a direct comparison was not possible, but the EZ vaccine seemed to boost a secondary immune response better than the SW vaccine. Further, the SW vaccine was less able to induce a protective level of antibodies when used from 6 months of age than the EZ vaccine. The preliminary data that we have on long-term vaccine efficacy supports that the SW vaccine might be less suitable than the EZ vaccine for use in very early measles vaccine schedules (unpublished data). On the other hand, trials performed during the 1980's in Mexico and Bangladesh have shown that administration of the standard-titre EZ vaccine to infants as young as 4-6 months of age gave good seroconversion results.

The Global Measles Strategic Plan 2001-2005 developed by the WHO and UNICEF states that all children should be guaranteed a second opportunity for measles vaccination either through campaigns or routine immunisation. The best strategy for protection of infants living in overcrowded urban African societies and who run a great risk of contracting measles before the recommended age of immunisation, will probably be early vaccination followed by a second vaccination later in childhood. If, in a vaccination campaign strategy, administration of the first vaccine is postponed this could dramatically increase the measles incidence in children below the age of vaccination. To this add that vaccination campaigns have not yet been evaluated in Africa in terms of childhood mortality relative to the routine schedule. Some children might get two, three or even more measles vaccines in an uncontrolled and not necessarily beneficial manner. Thus finding the best schedule and vaccine strain for use in a routine two-dose schedule seems a better approach for this region.

We thus propose to conduct a study comparing the standard-titre SW measles vaccine and the standard-titre EZ measles vaccine in a one- or two-dose schedule providing the first dose at 9 months of age, and then randomising the children at 18 months of age to receive either an additional dose of vaccine or nothing. The groups will be compared in terms of seroconversion-rate, proportion with an non-protective antibody level, geometric mean titer antibody level, vaccine efficacy, and child mortality. Further we plan to test the standard-titre EZ vaccine in a very early two-dose schedule providing the first dose at 4½ months of age and the second dose at 9 months of age (see also non-specific effect of vaccination).

It is likely that measles elimination vaccination campaigns will take place in the study area during the trial. The date of vaccination and the type of measles vaccine used in such campaigns will be noted, as well as simultaneous vitamin A supplementation; and the information will be included in the final data-analyses.

Non-specific effect of vaccination:

The measles vaccine has in several community studies from different parts of the world been shown to have a non-specific beneficial effect on child mortality. That means that the protection against death mediated by the vaccine exceeds the disease specific effect, ie the vaccine not only prevents deaths caused by measles, but also other deaths, presumably due to a non-specific immune stimulation providing protection from other infections than measles. For example, during the war in Guinea-Bissau that broke out on June 7, 1998, the population fled and the health care system broke down. There was no routine vaccination for at least a 3 months period. Hence, when the war started there was a group of infants who had been randomised to early SW measles vaccination at 6 months or IPV and who did not receive the standard-titre SW measles vaccine at 9 month that they would otherwise have been given. This natural experiment represents the first randomised study of the mortality effect of SW measles vaccine. The mortality ratios for measles vaccinated children were 0.29 (0.08-1.03, p=0.041) and 0.31 (0.10-0.94) over the first 3 and 7 months of the war.

Contrary to measles vaccination, diphtheria-tetanus-pertussis (DTP) vaccination has been associated with a negative effect on child mortality. Current studies indicate that the negative effect of DTP may be neutralized by a subsequent measles vaccination. The design of the proposed trial will allow us to test whether the negative effect of the DTP vaccine, which is administered by the EPI-programme at 6, 10 and 14 weeks of age, can be reverted by administration of a measles vaccine 4 weeks after the last DTP vaccination at around 4½ months of age.

Non-specific effects of vaccination are sex-specific. Girls benefit most from beneficial non-specific effects, and suffer most from apparently harmful non-specific effects of vaccination. Non-specific effects of measles vaccination may also show interaction with season, the beneficial effect of measles vaccination being largest in the dry season (unpublished), suggesting that some unknown immunological factors play a role. Season has a large influence on health in West Africa, and both morbidity and mortality, as well as immunologic parameters such as delayed-type hypersensitivity, T-cells, thymus size and measles antibody levels which are associated with season.

We intend to investigate the interactions of sex and season with measles vaccination and will assure that data on morbidity and immunologic parameters will be collected both in the dry as well as in the rainy season.

Time table:

The study began in July 2003, and with a sample size of 5.755 and a possible 2.000 children included per year, the inclusion period for the trial will be about 3 years.

Eligibility criteria: Inclusion Criteria:

* Infants of 4½ months of age registered in the Bandim Health Project registration system and currently living in the Bandim Health Project areas: Bandim I, Bandim II, Belem, Mindará and Cuntum; and who received all three diphtheria-tetanus-pertussis vaccinations at least 4 weeks before enrollment

Exclusion Criteria:

* Severe illness requiring immediate hospitalisation

Primary outcomes:
measure: Vaccine efficacy
timeFrame: Assessed by study completion
measure: Measles specific mortality
timeFrame: Assessed by study completion
measure: All cause sex-specific mortality until 3 years of age
timeFrame: Assessed by study completion
Secondary outcomes:
measure: Measles antibody level at 4½, 9, 18 and 24 months of age
timeFrame: Assessed by study completion
measure: Morbidity from 4½ to 12 months of age
timeFrame: Assessed by study completion
measure: Anthropometric measures at 4½, 9, 18 and 24 months of age
timeFrame: Assessed by study completion
Other outcomes:
Locations:
city: Bissau
country: Guinea-Bissau
facility: Bandim Health Project
state: Apartado 861
Study officials:
affiliation: Bandim Health Project
name: Peter Aaby, MSc, Dr. Med
role: STUDY_DIRECTOR
affiliation: Bandim Health Project
name: May-Lill Garly, PHD, DTM&H
role: PRINCIPAL_INVESTIGATOR
References:
citation: Brond M, Martins CL, Byberg S, Benn CS, Whittle H, Garly ML, Aaby P, Fisker AB. Randomized Trial of 2 Versus 1 Dose of Measles Vaccine: Effect on Hospital Admission of Children After 9 Months of Age. J Pediatric Infect Dis Soc. 2018 Aug 17;7(3):226-233. doi: 10.1093/jpids/pix042.
citation: Rasmussen SM, Biering-Sorensen S, Byberg S, Andersen A, Bjerregaard-Andersen M, Rodrigues A, Benn CS, Martins CL, Aaby P. The effect of early measles vaccination at 4.5 months of age on growth at 9 and 24 months of age in a randomized trial in Guinea-Bissau. BMC Pediatr. 2016 Dec 3;16(1):199. doi: 10.1186/s12887-016-0738-z.
citation: Benn CS, Martins CL, Fisker AB, Diness BR, Garly ML, Balde I, Rodrigues A, Whittle H, Aaby P. Interaction between neonatal vitamin A supplementation and timing of measles vaccination: a retrospective analysis of three randomized trials from Guinea-Bissau. Vaccine. 2014 Sep 22;32(42):5468-74. doi: 10.1016/j.vaccine.2014.07.090. Epub 2014 Aug 13.
citation: Aaby P, Martins CL, Garly ML, Andersen A, Fisker AB, Claesson MH, Ravn H, Rodrigues A, Whittle HC, Benn CS. Measles vaccination in the presence or absence of maternal measles antibody: impact on child survival. Clin Infect Dis. 2014 Aug 15;59(4):484-92. doi: 10.1093/cid/ciu354. Epub 2014 May 14.
citation: Martins C, Garly ML, Bale C, Rodrigues A, Njie-Jobe J, Benn CS, Whittle H, Aaby P. Measles virus antibody responses in children randomly assigned to receive standard-titer edmonston-zagreb measles vaccine at 4.5 and 9 months of age, 9 months of age, or 9 and 18 months of age. J Infect Dis. 2014 Sep 1;210(5):693-700. doi: 10.1093/infdis/jiu117. Epub 2014 Mar 31.
citation: Martins CL, Benn CS, Andersen A, Bale C, Schaltz-Buchholzer F, Do VA, Rodrigues A, Aaby P, Ravn H, Whittle H, Garly ML. 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 Jun 1;209(11):1731-8. doi: 10.1093/infdis/jit804. Epub 2014 Jan 16.
citation: Martins C, Garly ML, Bale C, Rodrigues A, Benn CS, Whittle H, Aaby P. Measles antibody levels after vaccination with Edmonston-Zagreb and Schwarz measles vaccine at 9 months or at 9 and 18 months of age: a serological study within a randomised trial of different measles vaccines. Vaccine. 2013 Nov 19;31(48):5766-71. doi: 10.1016/j.vaccine.2013.08.044. Epub 2013 Aug 28.
citation: Aaby P, Martins CL, Garly ML, Bale C, Andersen A, Rodrigues A, Ravn H, Lisse IM, Benn CS, Whittle HC. Non-specific effects of standard measles vaccine at 4.5 and 9 months of age on childhood mortality: randomised controlled trial. BMJ. 2010 Nov 30;341:c6495. doi: 10.1136/bmj.c6495.
citation: Martins CL, Garly ML, Bale C, Rodrigues A, Ravn H, Whittle HC, Lisse IM, Aaby P. Protective efficacy of standard Edmonston-Zagreb measles vaccination in infants aged 4.5 months: interim analysis of a randomised clinical trial. BMJ. 2008 Jul 24;337:a661. doi: 10.1136/bmj.a661.