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

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.

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)