Live-attenuated Mycobacterium #tuberculosis #vaccine MTBVAC versus #BCG in #adults and #neonates: a randomised controlled, double-blind dose-escalation trial (Lancet Resp Med., abstract)

[Source: The Lancet Respiratory Medicine, full page: (LINK). Abstract, edited.]

Live-attenuated Mycobacterium tuberculosis vaccine MTBVAC versus BCG in adults and neonates: a randomised controlled, double-blind dose-escalation trial

Michele Tameris, MBChB *, Helen Mearns, PhD *, Adam Penn-Nicholson, PhD, Yolande Gregg, NDip, Nicole Bilek, PhD, Simbarashe Mabwe, BSc, Hennie Geldenhuys, MBChB, Justin Shenje, MBChB, Angelique Kany Kany Luabeya, MBChB, Ingrid Murillo, BD, Juana Doce, PhD, Nacho Aguilo, PhD, Dessislava Marinova, PhD, Eugenia Puentes, PhD, Esteban Rodríguez, VD, Jesús Gonzalo-Asensio, PhD, Bernard Fritzell, MD, Jelle Thole, PhD, Prof Carlos Martin, MD, Prof Thomas J Scriba, DPhil †, Prof Mark Hatherill, MD  † and theMTBVAC Clinical Trial Team

Published: August 12, 2019 / DOI: https://doi.org/10.1016/S2213-2600(19)30251-6

 

Summary

Background

Infants are a key target population for new tuberculosis vaccines. We assessed the safety and immunogenicity of the live-attenuated Mycobacterium tuberculosis vaccine candidate MTBVAC in adults and infants in a region where transmission of tuberculosis is very high.

Methods

We did a randomised, double-blind, BCG-controlled, dose-escalation trial at the South African Tuberculosis Vaccine Initiative site near Cape Town, South Africa. Healthy adult community volunteers who were aged 18–50 years, had received BCG vaccination as infants, were HIV negative, had negative interferon-γ release assay (IGRA) results, and had no personal history of tuberculosis or current household contact with someone with tuberculosis were enrolled in a safety cohort. Infants born to HIV-negative women with no personal history of tuberculosis or current household contact with a person with tuberculosis and who were 96 h old or younger, generally healthy, and had not yet received routine BCG vaccination were enrolled in a separate infant cohort. Eligible adults were randomly assigned (1:1) to receive either BCG Vaccine SSI (5 × 10 5colony forming units [CFU] of Danish strain 1331 in 0·1 mL diluent) or MTBVAC (5 × 10 5 CFU in 0·1 mL) intradermally in the deltoid region of the arm. After favourable review of 28-day reactogenicity and safety data in the adult cohort, infants were randomly assigned (1:3) to receive either BCG Vaccine SSI (2·5 × 10 5 CFU in 0·05 mL diluent) or MTBVAC in three sequential cohorts of increasing MTBVAC dose (2·5 × 10 3 CFU, 2·5 × 10 4 CFU, and 2·5 × 10 5 CFU in 0·05 mL) intradermally in the deltoid region of the arm. QuantiFERON-TB Gold In-Tube IGRA was done on days 180 and 360. For both randomisations, a pre-prepared block randomisation schedule was used. Participants (and their parents or guardians in the case of infant participants), investigators, and other clinical and laboratory staff were masked to intervention allocation. The primary outcomes, which were all measured in the infant cohort, were solicited and unsolicited local adverse events and serious adverse events until day 360; non-serious systemic adverse events until day 28 and vaccine-specific CD4 and CD8 T-cell responses on days 7, 28, 70, 180, and 360. Secondary outcomes measured in adults were local injection-site and systemic reactions and haematology and biochemistry at study day 7 and 28. Safety analyses and immunogenicity analyses were done in all participants who received a dose of vaccine. This trial is registered with ClinicalTrials.gov, number NCT02729571.

Findings

Between Sept 29, 2015, and Nov 16, 2015, 62 adults were screened and 18 were enrolled and randomly assigned, nine each to the BCG and MTBVAC groups. Between Feb 12, 2016, and Sept 21, 2016, 36 infants were randomly assigned—eight to the BCG group, nine to the 2·5 × 10 3 CFU MTBVAC group, nine to the 2·5 × 10 4 CFU group, and ten to the 2·5 × 10 5 CFU group. Mild injection-site reactions occurred only in infants in the BCG and the 2·5 × 10 5 CFU MTBVAC group, with no evidence of local or regional injection-site complications. Systemic adverse events were evenly distributed across BCG and MTBVAC dose groups, and were mostly mild in severity. Eight serious adverse events were reported in seven vaccine recipients (one adult MTBVAC recipient, one infant BCG recipient, one infant in the 2·5 × 10 3 CFU MTBVAC group, two in the 2·5 × 10 4 CFU MTBVAC group, and two in the 2·5 × 10 5 CFU MTBVAC group), including one infant in the 2·5 × 10 3 CFU MTBVAC group treated for unconfirmed tuberculosis and one in the 2·5 × 10 5 CFU MTBVAC group treated for unlikely tuberculosis. One infant died as a result of possible viral pneumonia. Vaccination with all MTBVAC doses induced durable antigen-specific T-helper-1 cytokine-expressing CD4 cell responses in infants that peaked 70 days after vaccination and were detectable 360 days after vaccination. For the highest MTBVAC dose (ie, 2·5 × 105 CFU), these responses exceeded responses induced by an equivalent dose of the BCG vaccine up to 360 days after vaccination. Dose-related IGRA conversion was noted in three (38%) of eight infants in the 2·5 × 10 3 CFU MTBVAC group, six (75%) of eight in the 2·5 × 10 4 CFU MTBVAC group, and seven (78%) of nine in the 2·5 × 105 CFU MTBVAC group at day 180, compared with none of seven infants in the BCG group. By day 360, IGRA reversion had occurred in all three infants (100%) in the 2·5 × 10 3 CFU MTBVAC group, four (67%) of the six in the 2·5 × 10 4 CFU MTBVAC group, and three (43%) of the seven in the 2·5 × 10 5 CFU MTBVAC group.

Interpretation

MTBVAC had acceptable reactogenicity, and induced a durable CD4 cell response in infants. The evidence of immunogenicity supports progression of MTBVAC into larger safety and efficacy trials, but also confounds interpretation of tests for M tuberculosis infection, highlighting the need for stringent endpoint definition.

Funding

Norwegian Agency for Development Cooperation, TuBerculosis Vaccine Initiative, UK Department for International Development, and Biofabri.

Keywords: Tuberculosis; Vaccines; BCG.

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Boosting #BCG with proteins or #rAd5 does not enhance #protection against #tuberculosis in rhesus macaques (npj Vaccines, abstract)

[Source: npj Vaccines, full page: (LINK). Abstract, edited.]

Article | OPEN | Published: 28 May 2019

Boosting BCG with proteins or rAd5 does not enhance protection against tuberculosis in rhesus macaques

Patricia A. Darrah, Robert M. DiFazio, Pauline Maiello, Hannah P. Gideon, Amy J. Myers, Mark A. Rodgers, Joshua A. Hackney, Thomas Lindenstrom, Thomas Evans, Charles A. Scanga, Victor Prikhodko, Peter Andersen, Philana Ling Lin, Dominick Laddy, Mario Roederer, Robert A. Seder & JoAnne L. Flynn

npj Vaccines 4, Article number: 21 (2019)

 

Abstract

Tuberculosis (TB) is the leading cause of death from infection worldwide. The only approved vaccine, BCG, has variable protective efficacy against pulmonary TB, the transmissible form of the disease. Therefore, improving this efficacy is an urgent priority. This study assessed whether heterologous prime-boost vaccine regimens in which BCG priming is boosted with either (i) protein and adjuvant (M72 plus AS01E or H56 plus CAF01) delivered intramuscularly (IM), or (ii) replication-defective recombinant adenovirus serotype 5 (Ad5) expressing various Mycobacterium tuberculosis (Mtb) antigens (Ad5(TB): M72, ESAT-6/Ag85b, or ESAT-6/Rv1733/Rv2626/RpfD) administered simultaneously by IM and aerosol (AE) routes, could enhance blood- and lung-localized T-cell immunity and improve protection in a nonhuman primate (NHP) model of TB infection. Ad5(TB) vaccines administered by AE/IM routes following BCG priming elicited ~10–30% antigen-specific CD4 and CD8 T-cell multifunctional cytokine responses in bronchoalveolar lavage (BAL) but did not provide additional protection compared to BCG alone. Moreover, AE administration of an Ad5(empty) control vector after BCG priming appeared to diminish protection induced by BCG. Boosting BCG by IM immunization of M72/AS01E or H56:CAF01 elicited ~0.1–0.3% antigen-specific CD4 cytokine responses in blood with only a transient increase of ~0.5–1% in BAL; these vaccine regimens also failed to enhance BCG-induced protection. Taken together, this study shows that boosting BCG with protein/adjuvant or Ad-based vaccines using these antigens, by IM or IM/AE routes, respectively, do not enhance protection against primary infection compared with BCG alone, in the highly susceptible rhesus macaque model of tuberculosis.

Keywords: Tuberculosis; BCG; Vaccines; Animal models.

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#Outcomes of controlled #human #malaria infection after #BCG #vaccination (Nat Commun., abstract)

[Source: Nature Communications, full page: (LINK). Abstract, edited.]

Article | OPEN | Published: 20 February 2019

Outcomes of controlled human malaria infection after BCG vaccination

Jona Walk, L. Charlotte J. de Bree, Wouter Graumans, Rianne Stoter, Geert-Jan van Gemert, Marga van de Vegte-Bolmer, Karina Teelen, Cornelus C. Hermsen, Rob J. W. Arts, Marije C. Behet, Farid Keramati, Simone J. C. F. M. Moorlag, Annie S. P. Yang, Reinout van Crevel, Peter Aaby, Quirijn de Mast, André J. A. M. van der Ven, Christine Stabell Benn, Mihai G. Netea & Robert W. Sauerwein

Nature Communications, volume 10, Article number: 874 (2019)

 

Abstract

Recent evidence suggests that certain vaccines, including Bacillus-Calmette Guérin (BCG), can induce changes in the innate immune system with non-specific memory characteristics, termed ‘trained immunity’. Here we present the results of a randomised, controlled phase 1 clinical trial in 20 healthy male and female volunteers to evaluate the induction of immunity and protective efficacy of the anti-tuberculosis BCG vaccine against a controlled human malaria infection. After malaria challenge infection, BCG vaccinated volunteers present with earlier and more severe clinical adverse events, and have significantly earlier expression of NK cell activation markers and a trend towards earlier phenotypic monocyte activation. Furthermore, parasitemia in BCG vaccinated volunteers is inversely correlated with increased phenotypic NK cell and monocyte activation. The combined data demonstrate that BCG vaccination alters the clinical and immunological response to malaria, and form an impetus to further explore its potential in strategies for clinical malaria vaccine development.

Keywords: Malaria; BCG; Vaccines.

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Early #BCG #vaccination, #hospitalizations and hospital #deaths: Analysis of a secondary outcome in three #RCTs from Guinea-Bissau (J Infect Dis., abstract)

[Source: Journal of Infectious Diseases, full page: (LINK). Abstract, edited.]

Early Bacille Calmette-Guérin vaccination, hospitalizations and hospital deaths: Analysis of a secondary outcome in three randomized trials from Guinea-Bissau

F Schaltz-Buchholzer, MD, PhD, S Biering-Sørensen, PhD, N Lund, MD, PhD, I Monteiro, P Umbasse, A Bærent Fisker, MD, PhD, A Andersen, PhD, A Rodrigues, MD, PhD, P Aaby, DMSc, C S Benn, DMSc

The Journal of Infectious Diseases, jiy544, https://doi.org/10.1093/infdis/jiy544

Published: 18 September 2018

 

Abstract

Objective

To examine effects of early Bacille Calmette-Guérin (BCG) vaccination on the risk, cause and severity of infant hospitalizations.

Design

Analysis of three trials randomizing low-weight neonates to early-BCG(intervention) versus no-BCG(usual practice in low-weight neonates, control), with hospitalizations as secondary outcome.

Methods

Hospitalization data was collected at the pediatric ward of the National Hospital. Effects of BCG on hospitalization risk were assessed in Cox-models providing overall and major disease-group incidence rate ratios(IRRs). Severity was assessed by in-hospital case-fatality rates and compared by group as cohort study risk ratios(RRs).

Results

Among 6,583 infants (3,297 BCG; 3,286 controls), there were 908 infant hospitalizations (450 BCG; 458 controls) and 135 in-hospital deaths (56 BCG; 79 controls). The neonatal(28days), 6-week and infant(1year) BCG versus control hospitalization IRRs were 0.97(95% CI 0.72-1.31), 0.95(0.73-1.24) and 0.96(0.84-1.10). Corresponding BCG versus control case-fatality RRs were 0.58(0.35-0.94), 0.56(0.35-0.90) and 0.72(0.53-0.99). BCG tended to reduce neonatal and infant sepsis hospitalization rates, IRRs being 0.75(0.50-1.13) and 0.78(0.55-1.11), and reduced in-hospital neonatal sepsis mortality, RR=0.46(0.22-0.98). There were no confirmed tuberculosis hospitalizations.

Conclusion

BCG did not affect hospitalization rates but reduced in-hospital mortality significantly, primarily by preventing fatal cases of sepsis. The observed beneficial effects of BCG on in-hospital mortality were entirely non-specific.

Bacille Calmette-Guérin, infant mortality, infant morbidity, in-hospital case-fatality, neonatal mortality, neonatal morbidity, non-specific (heterologous) effects of vaccines, sepsis, tuberculosis

Issue Section: Major Article

© The Author(s) 2018. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.

This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model)

Keywords: BCG; Vaccines; Guinea-Bissau.

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#BCG-Induced Trained #Immunity Is Not Protective for Experimental #Influenza A/Anhui/1/2013 (#H7N9) Infection in Mice (Front Immunol., abstract)

[Source: US National Library of Medicine, full page: (LINK). Abstract, edited.]

Front Immunol. 2018 Apr 30;9:869. doi: 10.3389/fimmu.2018.00869. eCollection 2018.

Bacillus Calmette-Guérin-Induced Trained Immunity Is Not Protective for Experimental Influenza A/Anhui/1/2013 (H7N9) Infection in Mice.

de Bree CLCJ1,2,3,4, Marijnissen RJ5, Kel JM5, Rosendahl Huber SK5, Aaby P3, Benn CS3,4, Wijnands MVW5, Diavatopoulos DA2,6, van Crevel R1,2, Joosten LAB1,2, Netea MG1,2,7, Dulos J8.

Author information: 1 Department of Internal Medicine, Radboud University Medical Center, Nijmegen, Netherlands. 2 Radboud Centre for Infectious Diseases (RCI), Radboud University Medical Center, Nijmegen, Netherlands. 3 Research Center for Vitamins and Vaccines, Bandim Health Project, Statens Serum Institut, Copenhagen, Denmark. 4 Odense Patient Data Explorative Network, University of Southern Denmark, Odense University Hospital, Odense, Denmark. 5 Department of Immunology, Triskelion B.V., Zeist, Netherlands. 6 Laboratory of Pediatric Infectious Diseases, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, Netherlands. 7 Department for Genomics and Immunoregulation, Life and Medical Sciences Institute (LIMES), University of Bonn, Bonn, Germany. 8 Aduro Biotech Europe, Oss, Netherlands.

 

Abstract

Avian influenza A of the subtype H7N9 has been responsible for almost 1,600 confirmed human infections and more than 600 deaths since its first outbreak in 2013. Although sustained human-to-human transmission has not been reported yet, further adaptations to humans in the viral genome could potentially lead to an influenza pandemic, which may have severe consequences due to the absence of pre-existent immunity to this strain at population level. Currently there is no influenza A (H7N9) vaccine available. Therefore, in case of a pandemic outbreak, alternative preventive approaches are needed, ideally even independent of the type of influenza virus outbreak. Bacillus Calmette-Guérin (BCG) is known to induce strong heterologous immunological effects, and it has been shown that BCG protects against non-related infection challenges in several mouse models. BCG immunization of mice as well as human induces trained innate immune responses, resulting in increased cytokine responses upon subsequent ex vivo peripheral blood mononuclear cell restimulation. We investigated whether BCG (Statens Serum Institut-Denmark)-induced trained immunity may protect against a lethal avian influenza A/Anhui/1/2013 (H7N9) challenge. Here, we show that isolated splenocytes as well as peritoneal macrophages of BCG-immunized BALB/c mice displayed a trained immunity phenotype resulting in increased innate cytokine responses upon ex vivo restimulation. However, after H7N9 infection, no significant differences were found between the BCG immunized and the vehicle control group at the level of survival, weight loss, pulmonary influenza A nucleoprotein staining, or histopathology. In conclusion, BCG-induced trained immunity did not result in protection in an oseltamivir-sensitive influenza A/Anhui/1/2013 (H7N9) challenge mouse model.

KEYWORDS: avian influenza A/Anhui/1/2013 (H7N9); bacillus Calmette–Guérin; innate immune memory; oseltamivir; trained immunity

PMID: 29760700 PMCID: PMC5936970 DOI: 10.3389/fimmu.2018.00869

Keywords: Avian Influenza; H7N9; Immunotherapy; BCG; Animal Models.

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The #duration of #protection of school-aged #BCG #vaccination in #England: a population -based case–control study (Int J Epidem., abstract)

[Source: International Journal of Epidemiology, full page: (LINK). Abstract, edited.]

The duration of protection of school-aged BCG vaccination in England: a population -based case–control study

Punam Mangtani Punam Mangtani, Patrick Nguipdop-Djomo, Ruth H Keogh, Jonathan AC Sterne, Ibrahim Abubakar, Peter G Smith, Paul EM Fine, Emilia Vynnycky, John M Watson, David Elliman, Marc Lipman, Laura C Rodrigues

International Journal of Epidemiology, dyx141, https://doi.org/10.1093/ije/dyx141

Published: 31 August 2017 – Revision Received: 18 June 2017  – Accepted: 13 July 2017

Citation: Punam Mangtani, Patrick Nguipdop-Djomo, Ruth H Keogh, Jonathan AC Sterne, Ibrahim Abubakar, Peter G Smith, Paul EM Fine, Emilia Vynnycky, John M Watson, David Elliman, Marc Lipman, Laura C Rodrigues; The duration of protection of school-aged BCG vaccination in England: a population -based case–control study, International Journal of Epidemiology, , dyx141, https://doi.org/10.1093/ije/dyx141

 

Abstract

Background:

Evidence of protection from childhood Bacillus Calmette-Guerin (BCG) against tuberculosis (TB) in adulthood, when most transmission occurs, is important for TB control and resource allocation.

Methods:

We conducted a population-based case–control study of protection by BCG given to children aged 12–13 years against tuberculosis occurring 10–29 years later. We recruited UK-born White subjects with tuberculosis and randomly sampled White community controls. Hazard ratios and 95% confidence intervals (CIs) were estimated using case–cohort Cox regression, adjusting for potential confounding factors, including socio-economic status, smoking, drug use, prison and homelessness. Vaccine effectiveness (VE = 1 – hazard ratio) was assessed at successive intervals more than 10 years following vaccination.

Results:

We obtained 677 cases and 1170 controls after a 65% response rate in both groups. Confounding by deprivation, education and lifestyle factors was slight 10–20 years after vaccination, and more evident after 20 years. VE 10–15 years after vaccination was 51% (95% CI 21, 69%) and 57% (CI 33, 72%) at 15–20 years. Subsequently, BCG protection appeared to wane; 20–25 years VE = 25% (CI –14%, 51%) and 25–29 years VE = 1% (CI –84%, 47%). Based on multiple imputation of missing data (in 17% subjects), VE estimated in the same intervals after vaccination were similar [56% (CI 33, 72%), 57% (CI 36, 71%), 25% (–10, 48%), 21% (–39, 55%)].

Conclusions:

School-aged BCG vaccination offered moderate protection against tuberculosis for at least 20 years, which is longer than previously thought. This has implications for assessing the cost-effectiveness of BCG vaccination and when evaluating new TB vaccines.

BCG vaccine, Bacillus Calmette-Guerin, effectiveness, duration, tuberculosis, epidemiology, prevention and control, England

Topic: smoking – bacille calmette-guerin – bacille calmette-guerin vaccine – cost effectiveness – adult – child – life style – tuberculosis – vaccination – vaccines – drug usage – homelessness – cox proportional hazards models – school-age child – tuberculosis vaccines – correctional facilities – multiple imputation – missing data

Issue Section: Original Article

 

Key Messages

  • It is unclear whether protection by school-aged Bacillus Calmette-Guerin (BCG) vaccination against TB continues into adulthood, when most transmission occurs.
  • Using a case–control study design based on 677 cases and 1170 controls, we found about 50% protection that lasted 20 years and then waned.
  • That BCG attributable protection against tuberculosis lasts longer than previously thought affects its cost-effectiveness and has implications for the evaluation of new TB vaccines.

Keywords: TB; Vaccines; England.

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#Association of #BCG, #DTP, and #measles containing #vaccines with #childhood #mortality: systematic review (BMJ, abstract)

[Source: British Medical Journal, full page: (LINK). Abstract, edited.]

Research

Association of BCG, DTP, and measles containing vaccines with childhood mortality: systematic review

BMJ 2016; 355 / doi: http://dx.doi.org/10.1136/bmj.i5170 (Published 13 October 2016)  / Cite this as: BMJ 2016;355:i5170

Julian P T Higgins, professor of evidence synthesis1, Karla Soares-Weiser, deputy editor in chief2, José A López-López, research associate1, Artemisia Kakourou, research associate3, Katherine Chaplin, research associate1, Hannah Christensen, lecturer in infectious disease mathematical modelling1, Natasha K Martin, senior lecturer1 4, Jonathan A C Sterne, professor of medical statistics and epidemiology,1, Arthur L Reingold, professor and head of epidemiology5

Author affiliations: 1School of Social and Community Medicine, University of Bristol, Bristol BS8 2PS, UK; 2Cochrane, St Albans House, London SW1Y 4QX, UK; 3Department of Hygiene and Epidemiology, University of Ioannina School of Medicine, Ioannina, Greece; 4Department of Global Health and Development, London School of Hygiene and Tropical Medicine, London WC1E 7HT, UK; 5Division of Epidemiology, School of Public Health, University of California, Berkeley, CA 94720-7358, USA

Correspondence to: J Higgins julian.higgins@bristol.ac.uk

Accepted 16 September 2016

 

Abstract

Objectives 

To evaluate the effects on non-specific and all cause mortality, in children under 5, of Bacillus Calmette-Guérin (BCG), diphtheria-tetanus-pertussis (DTP), and standard titre measles containing vaccines (MCV); to examine internal validity of the studies; and to examine any modifying effects of sex, age, vaccine sequence, and co-administration of vitamin A.

Design 

Systematic review, including assessment of risk of bias, and meta-analyses of similar studies.

Study eligibility criteria 

Clinical trials, cohort studies, and case-control studies of the effects on mortality of BCG, whole cell DTP, and standard titre MCV in children under 5.

Data sources 

Searches of Medline, Embase, Global Index Medicus, and the WHO International Clinical Trials Registry Platform, supplemented by contact with experts in the field. To avoid overlap in children studied across the included articles, findings from non-overlapping birth cohorts were identified.

Results 

Results from 34 birth cohorts were identified. Most evidence was from observational studies, with some from short term clinical trials. Most studies reported on all cause (rather than non-specific) mortality. Receipt of BCG vaccine was associated with a reduction in all cause mortality: the average relative risks were 0.70 (95% confidence interval 0.49 to 1.01) from five clinical trials and 0.47 (0.32 to 0.69) from nine observational studies at high risk of bias. Receipt of DTP (almost always with oral polio vaccine) was associated with a possible increase in all cause mortality on average (relative risk 1.38, 0.92 to 2.08) from 10 studies at high risk of bias; this effect seemed stronger in girls than in boys. Receipt of standard titre MCV was associated with a reduction in all cause mortality (relative risks 0.74 (0.51 to 1.07) from four clinical trials and 0.51 (0.42 to 0.63) from 18 observational studies at high risk of bias); this effect seemed stronger in girls than in boys. Seven observational studies, assessed as being at high risk of bias, have compared sequences of vaccines; results of a subset of these suggest that administering DTP with or after MCV may be associated with higher mortality than administering it before MCV.

Conclusions 

Evidence suggests that receipt of BCG and MCV reduce overall mortality by more than would be expected through their effects on the diseases they prevent, and receipt of DTP may be associated with an increase in all cause mortality. Although efforts should be made to ensure that all children are immunised on schedule with BCG, DTP, and MCV, randomised trials are needed to compare the effects of different sequences.

Keywords: Vaccines; BCG; Measles; DTP.

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