Non-Specific Effects of Standard Titre Measles Vaccination

• ClinicalTrials.gov Identifier: NCT00168662
• Recruitment Status: Completed
• First Posted: September 15, 2005
• Last Update Posted: February 26, 2008
• Sponsor: Bandim Health Project
• Collaborators: International Cooperation with Developing Countries; Danish Council for Development Research; Medical Research Council Unit, The Gambia
• Information provided by: Bandim Health Project

Study Description

Brief Summary:

The general objectives of the proposed research work are:

A1) to reduce childhood mortality in developing countries through better control of measles infection by finding the best immunization strategy, and A2) to investigate the hypothesis that standard titre measles immunization is associated with non targeted beneficial effects on childhood morbidity and mortality in developing countries.

The measurable, specific objectives of the present proposal are:

B1) to examine whether a two-dose strategy for measles immunization at 6 and 9 months of age can reduce measles incidence by 50% through better coverage or improved seroconversion, and B2) to examine whether a two-dose strategy for measles immunization at 6 and 9 months of age can reduce childhood mortality by 20% through better coverage, better protection against measles or non targeted beneficial effects, and B3) to determine the magnitude and duration of non-measles related changes in morbidity patterns after standard titre measles immunization, in particular to test whether measles immunization is associated with a 15% reduction in the risk of diarrhoea, and B4) to determine non-measles related immunological changes among recipients of measles vaccine in order to establish possible pathways for the non targeted effects of standard titre measles immunization.

Condition or disease	Intervention/treatment	Phase
Measles	Biological: Measles and inactivated polio vaccine	Phase 4

Detailed Description:

Background. Measles is the major killer among vaccine preventable diseases with an estimated one million deaths/year in developing countries. Though a good vaccine exists, the current immunization strategy of one dose at 9 months is far from optimal; too many children get measles before the age of immunization, coverage is too low when immunization has to wait until 9 months of age, and the protective efficacy is insufficient with the current vaccine given at 9 months of age. There is therefore a need for alternative immunization strategies or new vaccines.

Evaluations of vaccines have usually been based on a disease specific perspective; i.e. evaluation of specific immunity, and protective efficacy against the specific disease, its complications and mortality. However, our research from Guinea-Bissau, Senegal and Bangladesh has indicated that measles immunization and measles infection may have non-specific beneficial effects. The present protocol is an attempt to assess the magnitude and possible mechanisms of the non targeted beneficial effects of measles immunization and measles infection as well as an attempt to assess some of the practical implications of the hypothesis about non-specific beneficial effects.

Approach and methodologies. We tested a two dose measles immunization strategy at 6 and 9 months compared with the currently recommended strategy of one dose at 9 months. The children were be randomized to receive measles immunization at 6 and 9 months of age or inactivated polio at 6 months and measles at 9 months of age.

The non targeted effects of measles immunization on mortality and morbidity are best studied within a randomized trial comparing immunized and unimmunized children. In order to study the impact on non-measles related morbidity, some children recruited for the immunization trial will be included in weekly morbidity surveillance for diarrhoea, respiratory infections and malaria which are the most important disease complexes for childhood mortality in Guinea-Bissau.

Possible immunological differences between measles immunized and unimmunized children will be examined through measurements of T-lymphocyte levels, neopterin, beta2-microglobulin, delayed hypersensitivity (Multitest), allergic reactions (skin prick tests), antibody responses to other antigens (tetanus) and thymus growth (by sonography). Functional differences will be tested by response to a second vaccine antigen (HBV) at 7½ and 9 months of age when only one group has received measles vaccine.

Study Design

• Study Type: Interventional (Clinical Trial)
• Enrollment: 7800 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Prevention
• Official Title: Trial of Two-Dose Standard Measles Vaccination Schedule: Long-Term Impact on Morbidity and Mortality of a Two-Dose Vaccination Schedule at 6 and 9 Months of Age Compared With a Standard Regimen of One Dose at 9 Months of Age
• Study Start Date: March 1995
• Actual Primary Completion Date: January 2006
• Actual Study Completion Date: January 2006

Arms and Interventions

Outcome Measures

Primary Outcome Measures :

1. Vaccination coverage
2. Vaccine efficacy
3. Measles specific mortality
4. All cause mortality until 3 years of age

Secondary Outcome Measures :

1. Measles antibodies at 6, 7½, 9, 10½ and 18 months of age
2. T-cells at 6, 7½, 9, 10½ and 18 months of age
3. Thymus size at 6, 7½, 9, 10½ months of age
4. Neopterin level at 7½ months of age
5. Beta-2-microglobulin level at 7½ months of age
6. Hepatitis B antibodies at 7½, 9 and 10½ months of age
7. Tetanus antibodies at 9 months og age
8. Delayed type hypersensitivity at 7½ months of age
9. Skin prick test (allergy) at 7½ months of age
10. Morbidity from 6 to 18 months of age
11. Anthropometric measures at 6, 7½, 9, 10½ and 18 months of age

Eligibility Criteria

• Ages Eligible for Study: 6 Months to 8 Months (Child)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Criteria

Inclusion Criteria: Infants of 6 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 and Mindará

Exclusion Criteria: Severe illness requiring hospitalisation

Contacts and Locations

Locations

Guinea-Bissau

Bandim Health Project

Bissau, Apartado 861, Guinea-Bissau, 1004 Bissau Codex

Sponsors and Collaborators

Bandim Health Project

International Cooperation with Developing Countries

Danish Council for Development Research

Medical Research Council Unit, The Gambia

Investigators

• Study Director: PETER AABY, MSc, Dr. Med; Bandim Health Project

More Information

Additional Information:

Statens Serum Institut, Denmark 

Publications of Results:

Garly ML, Martins CL, Balé C, da Costa F, Dias F, Whittle H, Aaby P. Early two-dose measles vaccination schedule in Guinea-Bissau: good protection and coverage in infancy. Int J Epidemiol. 1999 Apr;28(2):347-52.

Garly ML, Balé C, Martins CL, Monteiro M, George E, Kidd M, Dias F, Aaby P, Whittle HC. Measles antibody responses after early two dose trials in Guinea-Bissau with Edmonston-Zagreb and Schwarz standard-titre measles vaccine: better antibody increase from booster dose of the Edmonston-Zagreb vaccine. Vaccine. 2001 Feb 28;19(15-16):1951-9.

Garly ML, Balé C, Martins CL, Baldé MA, Hedegaard KL, Whittle HC, Aaby P. BCG vaccination among West African infants is associated with less anergy to tuberculin and diphtheria-tetanus antigens. Vaccine. 2001 Nov 12;20(3-4):468-74.

Aaby P, Jensen H, Garly ML, Balé C, Martins C, Lisse I. Routine vaccinations and child survival in a war situation with high mortality: effect of gender. Vaccine. 2002 Nov 22;21(1-2):15-20.

Garly ML, Martins CL, Balé C, Baldé MA, Hedegaard KL, Gustafson P, Lisse IM, Whittle HC, Aaby P. BCG scar and positive tuberculin reaction associated with reduced child mortality in West Africa. A non-specific beneficial effect of BCG? Vaccine. 2003 Jun 20;21(21-22):2782-90.

Aaby P, Garly ML, Balé C, Martins C, Jensen H, Lisse I, Whittle H. Survival of previously measles-vaccinated and measles-unvaccinated children in an emergency situation: an unplanned study. Pediatr Infect Dis J. 2003 Sep;22(9):798-805.

Aaby P, Jensen H, Rodrigues A, Garly ML, Benn CS, Lisse IM, Simondon F. Divergent female-male mortality ratios associated with different routine vaccinations among female-male twin pairs. Int J Epidemiol. 2004 Apr;33(2):367-73.

Garly ML, Jensen H, Martins CL, Balé C, Baldé MA, Lisse IM, Aaby P. Hepatitis B vaccination associated with higher female than male mortality in Guinea-bissau: an observational study. Pediatr Infect Dis J. 2004 Dec;23(12):1086-92.

Roth A, Gustafson P, Nhaga A, Djana Q, Poulsen A, Garly ML, Jensen H, Sodemann M, Rodriques A, Aaby P. BCG vaccination scar associated with better childhood survival in Guinea-Bissau. Int J Epidemiol. 2005 Jun;34(3):540-7. Epub 2005 Jan 19.

Other Publications:

Veirum JE, Sodemann M, Biai S, Jakobsen M, Garly ML, Hedegaard K, Jensen H, Aaby P. Routine vaccinations associated with divergent effects on female and male mortality at the paediatric ward in Bissau, Guinea-Bissau. Vaccine. 2005 Jan 19;23(9):1197-204.

• Responsible Party: May-Lill Garly, Bandim Health Project
• ClinicalTrials.gov Identifier: NCT00168662
• Other Study ID Numbers: IC18-CT95-0011-Twodose1; EU grant: IC18-CT95-0011
• First Posted: September 15, 2005
• Last Update Posted: February 26, 2008
• Last Verified: February 2008

Keywords provided by Bandim Health Project:

Non-specific effects of vaccines; Infant mortality; Child mortality; Mortality; Morbidity; Measles vaccine; Measles; Immunisation; Low income country; Guinea-Bissau; Bandim Health Project; Immunology

Additional relevant MeSH terms:

Measles; Morbillivirus Infections; Paramyxoviridae Infections; Mononegavirales Infections; RNA Virus Infections; Virus Diseases