PhD Dissertations

Campaign with a measles vaccine – overall effect on mortality and morbidity in children aged 9-59 months from Guinea-Bissau

Campaign with a measles vaccine –  overall effect on mortality and morbidity in children aged 9-59 months from Guinea-Bissau
Published in:

Health

CVIVA, Bandim Health Project
University of Southern Denmark, Department of Clinical Research (OPEN)


2020

In the last decades, worldwide, numerous measles vaccine campaigns have been implemented to control and eventually eradicate measles. During the same decades, mortality in children aged under- five has decreased tremendously. Meanwhile, accumulating evidence suggests that the measles vaccine protects against other infections than measles, also termed, beneficial non-specific-effects. Thus, measles vaccine campaigns may have efficiently contributed to decreasing the under-five child mortality beyond our common understanding. However, no randomized trial has assessed the beneficial non-specific-effects of a measles vaccine campaign. The trial, RECAMP-MV, presented in this PhD thesis, assessed the overall effect of a measles vaccine campaign among children aged 9– 59 months on mortality and morbidity, in a setting with limited measles. The overall effect would capture any potential specific effect and non-specific-effect, and even adverse events, thereby providing a complete risk-benefit profile of a measles vaccine campaign. RECAMP-MV used the data collection platform of the Bandim Health Project in rural Guinea-Bissau, West Africa. In a cluster-randomized trial, 222 village-clusters were randomly assigned to receive a measles vaccine campaign (intervention) or to not receive a measles vaccine campaign (control). This PhD thesis compiles three articles based on RECAMP-MV: Article 1 presented the methodology, rationalities behind choices made, and analysis plans, to facilitate future assessments of measles vaccine campaigns. Article 2 assessed the overall effect of a measles vaccine campaign on outpatient consultation. We observed that the measles vaccine campaign tended to reduce outpatient consultations by 16% (relative risk, 0.84; 95% confidence interval, 0.65-1.11) within 1-2 months from enrolment in a sub-group of 8,319 children (4,437 intervention/3,882 control). This estimate was robust to restrictions on the definition of outpatient consultations. Article 3 assessed the overall effect of a measles vaccine campaign on mortality or hospital admission in a composite outcome. Contrary to our hypothesis, we observed that the measles vaccine campaign did not reduce the composite outcome by 30% (hazard ratio, 1.12; 95% confidence interval, 0.88-1.41) during a median follow-up period of 22 months among 18,411 children (9,636 intervention /8,775 control). This estimate was similar in intention-to-treat analyses. Thus, in the short-term, the measles vaccine campaign was safe an even tended to reduce outpatient consultations. However, in the long-term, the measles vaccine campaign did not reduce mortality or hospital admission. An explanation for this may be its interaction with oral polio vaccine campaigns, as we observed that the measles vaccine campaign increased mortality or hospital admission after oral polio vaccine campaigns but not before after oral polio vaccine campaigns, especially in girls

BCG vaccination policy in Guinea-Bissau – cost and impact on mortality

BCG vaccination policy in Guinea-Bissau – cost and impact on mortality
Published in:

Health
Aarhus University Center for Global Health, Department of Public Health Bandim Health Project, Statens Serum Institut


2019

Bacillus Calmette-Guérin (BCG) vaccination is recommended at birth in countries with high TB burden. Increasing evidence supports that BCG may have beneficial non-specific effects in addition to the protection against TB. Despite BCG being recommended at birth, local practices of not opening a 20-dose vial of BCG unless a sufficient number of children are present for BCG vaccination have arisen to reduce vaccine wastage. However, this may cause delays in BCG vaccination. In this PhD thesis, the impact andconsequences of the current BCG vaccination policy in Guinea-Bissau were evaluated.

Paper I demonstrated that the current BCG vaccination policy was associated with delayed BCG vaccination; at 1 month of age, only 38% of children had received BCG. Factors associated with delayedBCG vaccination included socio-economic status. When BCG vaccine was provided at monthly visits, socio-economic factors were no longer associated with delayed BCG and BCG coverage at 1 month of age was 88%.

Paper II showed that mothers on average sought BCG vaccination 1.26 times before getting their child vaccinated. The average household cost of seeking BCG vaccination was USD 1.89, equivalent to the UNICEF prices of a BCG vial. Thus, some of the costs saved by reducing vaccine wastage are transferredto mothers seeking BCG in vain.

In paper III, the effect of BCG on neonatal mortality and morbidity was evaluated in a natural experiment. Contrary to our hypothesis, there was no beneficial effect of BCG on neonatal mortality. The hazard ratio comparing BCG-vaccinated children with BCG-unvaccinated children was 1.26. The results were robust to sensitivity analyses.

Paper IV evaluated the effect of neonatal BCG on child mortality between 1 month and 3 years of age inTB-exposed and TB-unexposed children. Neonatal BCG was associated with 65% (95% CI: 29-83%) reduced mortality in TB-exposed children, and 45% (95% CI: 33-54%) reduced mortality in TB-unexposed children. The results were robust to sensitivity analyses.

In paper V, the impact and cost-effectiveness of disregarding the restrictive vial-opening policy was estimated to reduce TB mortality by 11.0% (95% UR: 0.5-28.8%), equivalent to 4 (UR: 0-15) averted TB deaths per annual birth cohort in Guinea-Bissau during the first 5 years of life. The estimated reduction in all-cause mortality was 8.1% (UR: 3.3-12.7%), corresponding to 392 (UR: 158-624) averted deaths per birth cohort.

In conclusion, this thesis presents important consequences of the current BCG vaccination practice in Guinea-Bissau: current BCG policy is associated with delays in BCG vaccination at increased costs for mothers seeking BCG. There was no beneficial effect of BCG on neonatal mortality, but neonatal BCG was associated with lower mortality in both TB-exposed and TB-unexposed children. Finally, disregarding the restrictive vial-opening policy was estimated to reduce both TB mortality and all-cause mortality. Based on this thesis and existing evidence, delays in BCG should be removed as it is highlycost-effective to open a vial of BCG for every child and no mother should seek BCG in vain.

Neonatal vaccination with Bacille Calmette-Guérin strains: Effects in infancy

Neonatal vaccination with Bacille Calmette-Guérin strains: Effects in infancy
Published in:

University of Southern Denmark


2020

This thesis examines the non-specific effects associated with vaccination at birth with different BCG strains. We assessed the overall effects on hospital admission risk and in-hospital case-fatality of providing early BCG-Denmark versus delayed BCG, and of providing different strains of BCG.

Neither early BCG nor the different strains of BCG affected the risk of hospitalization, but BCG-Denmark versus no-BCG was associated with a substantial 42% reduction in in-hospital deaths, primarily due to a 54% reduction in cases of fatal neonatal sepsis.

It is documented in a large-scale RCT that different strains of BCG have different immunogenic profiles; BCG-Denmark and BCG-Japan thus induces more 2-month BCG skin reactions that are also larger, more 6-month TST conversions and more adverse events when compared to BCG-Russia. Across five trials providing BCG-at-birth, infants presenting a 2-month BCG skin reaction had a 50% lower subsequent all-cause mortality up to one year of age than infants presenting no 2-month reaction, and larger reaction sizes were associated with the greatest mortality reduction. In a meta-analysis of data regarding BCG-vaccinated infants from Guinea-Bissau, having a TST reaction at 2- or 6-months of age was associated with 44% and 37% reduced all-cause mortality compared to having no reaction.

 

Full dissertation in pdf form here

List of thesis papers:
I. F Schaltz-Buchholzer, HN Frankel, CS Benn: The real-life number of neonatal doses of Bacille Calmette-Guérin vaccine in a 20-dose vial. Glob Health Action. 2017;10(1):1-4

II. F Schaltz-Buchholzer, S Biering-Sørensen, N Lund, I Monteiro, P Umbasse, AB Fisker, A Andersen, A Rodrigues, P Aaby, CS Benn: Early BCG Vaccination, Hospitalizations, and Hospital Deaths: Analysis of a Secondary Outcome in 3 Randomized Trials from Guinea-Bissau. J Infect Dis. 2019 Jan 29;219(4):624-632.

III. F Schaltz-Buchholzer, M Bjerregaard-Andersen, CB Øland, C Golding, EB Stjernholm, I Monteiro, P Aaby, CS Benn: Early vaccination with BCG-Denmark or BCG-Japan versus BCG-Russia to healthy newborns in Guinea-Bissau: A randomized controlled trial. Clin Infect Dis. 2019 Nov 3. pii: ciz1080.

IV. F Schaltz-Buchholzer, M Berendsen, A Roth, KJ Jensen, M Bjerregaard-Andersen, MJ Sørensen, I Monteiro, P Aaby, CS Benn: BCG skin reactions by 2 months of age are associated with better survival in infancy: A prospective observational study (Submitted, BMJ Global Health)

V. F Schaltz-Buchholzer, S Biering-Sørensen, LCJ de Bree, A Roth, CAG Timmermann, I Monteiro, P Aaby, CS Benn: Neonatal Bacille Calmette-Guérin vaccination and tuberculin skin test reactions at 2- and 6-months: effects on mortality up to 1 year of age. (Manuscript)

PhD dissertations before 2018

Najaaraq Lund 2013 Lund, Najaaraq. 2013. Investigating the Non-Specific Mortality and Morbidity Impact of Oral Polio Vaccine at Birth. Bandim Health Project, INDEPTH NETWORK. Research Center for Vitamins and Vaccines, Statens Serum Institut. Faculty of Health Sciences, University of Copenhagen.
Bjerregaard-Andersen, Morten. 2013. Establishing a twin cohort in Guinea-Bissau. Bandim Health Project, Statens Serum Institut. Faculty of Health Sciences, University of Southern Denmark. Odense University Hospital.
Rudolf, Frauke. 2013. The Bandim TBscore- reliability, further development and evaluation of potential uses. Health Aarhus University, Department of Infectious Medicine Skejby University Hospital, Institute of Clinical Medicine Projecto Saúde Bandim, INDEPTH Network, Guinea-Bissau.
Brander Eriksen, Helle. 2013. Determinants of Thymic Size in Guinea-Bissau and the Impact of Routine Vaccinations. Bandim Health Project, Statens Serum Institut. Faculty of Health and Medical Sciences, University of Copenhagen.
Andersen 2012 Andersen, Andreas. 2012. Statistical Analysis of Population-Based Immunological Studies. Bandim Health Project, Statens Serum Institut. Faculty of Health and Medical Sciences, University of Copenhagen. 131 p.
Fisker 2012 Fisker, Ane Bærent. 2011. Evaluation of the WHO vitamin A supplementation policy in Guinea-Bissau. Bandim Health Project, Statens Serum Institut. Department of Biostatistics, Institute of Public Health, Aarhus University.
Martins 2011 Martins, Cesário Lourenço. 2011. Measles Vaccination in Guinea-Bissau. Strategies to Reduce Disease Burden and Improve Child Survival. Bandim Health Project, Statens Serum Institut. Faculty of Health Sciences, University of Copenhagen.
Biai 2011 Biai, Sidu. 2011. Evaluation of Interventions to Reduce Hospital and Community Mortality. Bandim Health Project, Statens Serum Institut. Faculty of Health Sciences, University of Copenhagen.
Jorgensen 2010 Jørgensen, Mathias Jul. 2010. Understanding the immunological effects of vitamin A supplementation. Bandim Health Project, Statens Serum Institut. Faculty of Health Sciences, University of Copenhagen.
Souto 2010 Souto, Inês M. Oliveira. 2010. Implementation of HIV Programme in Guinea-Bissau. Setting up the West African Retrovirus and Aquired Immune Deficiency Cohort Study. Bandim Health Project, Statens Serum Institut. Clinical Research Center Copenhagen University Hospital Hvidovre. 119 p.
da Silva 2009 da Silva, Zacharias José. 2009. Trends in Retroviral Infections in Guinea-Bissau, West Africa. Cross-sectional surveys and longitudinal community-based studies. Bandim Health Project, Statens Serum Institut. Faculty of Health Sciences, University of Copenhagen.
Agergaard 2009 Agergaard, Jane. 2009. Randomised study of not providing diphtheria-tetanus-pertussis vaccine together with or after measles vaccination: Impact on morbidity and growth. Bandim Health Project, Statens Serum Institut. Faculty of Health Sciences, Aarhus University.
Gomes 2009 Gomes, Victor. 2009. Children exposed to tuberculosis at home: impact on mortality and the effect of using chemoprophylaxis on Guinea-Bissau, West-Africa. Bandim Health Project, Statens Serum Institut. Faculty of Health Sciences, University of Copenhagen.
Rabna 2008 Rabna, Paulo. 2008. Soluble Urokinase Plasminogen Activator Receptor (suPAR) as a Marker of Tuberculosis Treatment Efficacy and Potential Prognostic marker for Survival in individuals with a TB negative diagnosis. A prospective, Longitudinal Cohort Study in Suspected Pulmonary Tuberculosis patients in Guinea-Bissau. Bandim Health Project, Statens Serum Institut. Faculty of Health Sciences, University of Copenhagen.
Diness 2007 Diness, Birgitte Rode. 2007. High-dose vitamin A supplementation with Bacille Calmette-Guérin vaccine at birth. Bandim Health Project, Statens Serum Institut. Danish Gradual School in Public Health Science, University of Copenhagen.
Wejse 2007 Wejse, Christian. 2007.The role of vitamin D in the pathogenesis and treatment of tuberculosis. Bandim Health Project, Statens Serum Institut. Department of Infectious Diseases, Aarhus University Hospital, Skejby. Faculty of Health Sciences, Aarhus University.
Poulsen 2005 Poulsen, Anja. 2005. Determinants of severity of acute viral disease and their long-term consequences. Bandim Heatlh Project, Department of Epidemiology Research, Statens Serum Institut. University of Copenhagen.
Stensballe 2005 Stensballe, Lone Graff. 2005. Risk Factors for Severe Respiratory Syncytial Virus Infection. Bandim Heatlh Project, Department of Epidemiology Research, Statens Serum Institut. University of Copenhagen.
Nielsen 2005 Nielsen, Jens. 2005. Mortality pattern and interventions during the war in Guinea-Bissau 1998-99. Statistical methods and inference in complex emergency situations. Bandim Health Project, Danish Epidemiology Science Centre, Statens Serum Institut. University of Copenhagen.
No picture-x Dræbel, Tania. 2004. Public Health Response in a Complex Political Emergency and its aftermath: the role of National Health Professionals in Conflict and Health systems change in Guinea-Bissau. Bandim Health Project, Division of Epidemiology, Statens Serum Institut. Department of Public Health, University of Copenhagen.
Roth 2004 Roth, Adam. 2004. Specific and non-specific effects of BCG – implications for routine immunisation. Bandim Health Project, Division of Epidemiology, Statens Serum Institut. University of Copenhagen.
Kæstel 2004 Kæstel, Pernille. 2004. Nutrition and reproductive health in Guinea-Bissau. Bandim Health Project, Statens Serum Institut. The Royal Veterinary and Agricultural University, Copenhagen.
Steenhard 2003 Steenhard, Nina Ruth. 2003. Concurrent infection with intestinal worms and bacteria in man and domestic animals. Epidemiological studies in children in Guinea-Bissau and experimental model studies in pigs. Bandim Health Project, Statens Serum Institut. Danish Centre for Experimental Parasitology, Faculty of Life Sciences, The Royal Veterinary and Agricultural University. 176 p.
Veirum 2003 Veirum, Jens Erik. 2003. Childhood hospitalisations in a West African city. Bandim Health Project, Department of Epidemiology Research, Danish Epidemiology Science Centre, Statens Serum Institut. University of Copenhagen.
Benn 2003 Benn, Christine Stabell. 2003. Early life exposures and risk of allergy. Bandim Health Project, Department of Epidemiology Research, Danish Epidemiology Science Centre, Statens Serum Institut. University of Copenhagen.
Vigh 2003 Vigh, Henrik. 2003. Navigating terrains of war: youth and soldiering in Guinea Bissau. Bandim Heatlh Project, Division of Epidemiology, Statens Serum Institut. Institute of Anthropology, University of Copenhagen.
Jensen 2002 Jensen, Henrik. 2002. Analysis of Multivariate Survival Data from Longitudinal Epidemiological Studies – with special reference to the impact of routine immunisation in infancy. Bandim Health Project, Danish Epidemiology Science Centre, Department of Epidemiology Research, Statens Serum Institut. University of Copenhagen. 162 p.
Lars Høj 2002 Høj, Lars. 2002. Maternal mortality in rural Guinea Bissau: level, causes and determinants. Bandim Health Project, Division of Epidemiology, Statens Serum Institut. Aarhus University.
Holmgren 2002 Holmgren, Birgitta. 2002. Age and gender patterns of HIV-1, HIV-2, and HTLV-1 in Guinea-Bissau. Epidemiological and Behavioural Aspects. Bandim Health Project, Department of Epidemiology Research, Danish Epidemiology Science Center, Statens Serum Institut. University of Copenhagen.
Rodrigues 2001 Rodrigues, Amabélia. 2001. The pattern of cholera disease in Guinea-Bissau: Risk factors and local preventive measures. Bandim Health Project, Department of Epidemiology Research, Statens Serum Institut. University of Copenhagen. Ministry of Health, Guinea-Bissau.
Garly 1999 Garly, May-Lill. 1999. Specific and non-specific effects of standard-titre measles vaccine and the BCG vaccine, Bandim Health Project, Statens Serum Institut. University of Copenhagen.
Valentiner-Brandt 1999 Valentiner-Branth, Palle. 1999. Diarrhoea in early childhood: Control, management and long-term consequences. Bandim Health Project, Department of Epidemiology Research, Danish Epidemiology Science Centre, Statens Serum Institut. University of Copenhagen.
Nete Munk Nielsen 1999 Nielsen, Nete Munk. 1999. Poliomyelitis: Acute Severity and Long-term Consequences. A Study Based on Hospital Records from the Blegdamshospital. Bandim Health Project, Department of Epidemiology Research, Statens Serum Institut. University of Copenhagen.
Larsen 1998 Larsen, Olav Ditlevsen. 1998. Epidemiology of Retroviral Infections in Guinea-Bissau. Bandim Heatlh Project, Department of Epidemiology Research, Statens Serum Institut. University of Copenhagen.
Marc Andersen 1997 Andersen, Marc. 1997. Anthropometric Measurements in Health Programmes: Epidemiological and Statistical Aspects. Bandim Health Project, Statens Serum Institut. University of Copenhagen.
Sodemann 1996 Sodemann, Morten. 1996. Management of severe childhood illness in suburban West Africa, with special reference to diarrhoea. Implications for health education and improved quality of care in developing countries. Bandim Health Project, Statens Serum Institut. Aarhus University.
No picture-x Jakobsen, Marianne Skytte. 1996. Breast feeding in developing countries. Promotion and impact on child health. Bandim Health Project, Statens Serum Institut. Department of Epidemiology and Social Medicine, Aarhus University.
Knudsen 1994 Knudsen, Kim Mark. 1994. Analysis of Event History Data in Measles and Diarrhea Epidemiology. Bandim Health Project, Statens Serum Institut. Biostatistical Department, University of Copenhagen. 93 p.