Elsevier

Tuberculosis

Volume 89, Issue 4, July 2009, Pages 248-251
Tuberculosis

Non-tuberculous mycobacteria: General
Mapping the global use of different BCG vaccine strains

https://doi.org/10.1016/j.tube.2009.03.002Get rights and content

Summary

Bacille Calmette–Guérin (BCG) vaccine is one of the oldest and most commonly administered vaccines worldwide. Different BCG vaccine strains exist as a result of genetic changes that occurred during repeated subculture in different countries before lyophilisation was introduced for storage of seed lots in the 1960s. Increasing evidence suggests that these genetically divergent BCG vaccine strains are associated with different protective efficacy against tuberculosis (TB), different rates of adverse events and variable susceptibility to anti-tuberculous drugs. Information on which BCG vaccine strains are used in each country worldwide has not previously been collated. This report summarises data from the EuroTB network and from WHO/UNICEF in the first map depicting the BCG vaccine strains used globally. In 83 (44%) of 188 countries, more than one BCG vaccine strain was used during the five year period. In the countries that used only one strain, BCG Denmark was used in 32, BCG Russia/Bulgaria in 30, BCG Japan in eight, BCG Connaught in two. Twelve countries used their locally-produced BCG vaccine strains. The considerable variation in BCG vaccine strains used worldwide highlights the importance of documenting the particular vaccine strain used on an individual, local and national level. This is important for the interpretation of changes in the epidemiology of adverse events after BCG immunisation, for the management of adverse events after BCG immunisation, to interpret differences in the protective efficacy of BCG, and to inform the design of trials investigating novel TB vaccines.

Introduction

Bacille Calmette–Guérin (BCG) vaccine is one of the oldest and most commonly administered vaccines worldwide. After attenuation of Mycobacterium bovis over a 13-year period the vaccine was first used in humans in 1921 in France.1 Thereafter the vaccine was distributed to different laboratories worldwide where further repeated subculture of BCG led to the emergence of phenotypically different vaccine strains.2 Subsequently, the different BCG vaccine strains that had evolved were stored in each country as seed lots for future vaccine production (Table 1).2 Phenotypic characteristics of these different vaccine strains were reviewed in the early 1980s3 and underlying genetic differences were investigated soon thereafter.4, 5, 6 The advent of DNA microarrays and the sequencing of the genome of Mycobacterium tuberculosis enabled the first comparative analysis of genomic diversity amongst BCG vaccine strains in 1999.7 Since then, several studies have further detailed the genetic variation amongst BCG vaccine strains used worldwide.8, 9, 10, 11, 12, 13

The importance of the genetic differences between BCG vaccine strains has been highlighted by several animal and human studies.11 These strongly support the notion that genetically different BCG vaccine strains induce a quantitatively and qualitatively different immune response that leads to differences in protective efficacy against tuberculosis (TB).14, 15 The differences between BCG vaccine strains have other important implications. Different strains have been associated with different rates of adverse events.16, 17 In addition, susceptibility to anti-tuberculous drugs varies between different BCG vaccine strains.18 Some BCG vaccine strains are also administered via different routes (for example percutaneously as well as intradermally), also potentially influencing protection and rate of adverse events.19, 20

Currently there is insufficient evidence to determine which BCG vaccine strain provides better protection or which is associated with less adverse events. The particular BCG vaccine strain chosen for use in different countries worldwide is therefore based on a number of other factors, including historical precedent, logistic or cost considerations and local production. In most developed countries this results in the use of one particular BCG vaccine strain. In contrast, in the majority of countries with a high TB incidence, the vaccine is supplied through UNICEF/WHO and the Global Alliance for Vaccines and Immunisation (GAVI) who use a number of different BCG vaccine suppliers.

Although there is much information on BCG immunisation policies and coverage rates worldwide,21, 22, 23 data on which BCG vaccine strains are used in different countries is very limited. We have previously reported the particular BCG vaccine strains used in European countries.14 An online resource called the “BCG World Atlas” was launched in October 2008 and aims to collect information about BCG immunisation policies.21 This currently has limited information on BCG vaccine strains from information collected using an online questionnaire.

Documenting the use of different strains is important to interpret changes in the epidemiology of adverse events after BCG immunisation and for selecting anti-tuberculous drugs for the treatment of BCG-related local or disseminated complications.18 Accurate information about the particular BCG vaccine strains used in different countries is also important to inform the design of trials investigating novel TB vaccines and to interpret differences in the protective efficacy of BCG. It may also inform potential changes in the future use of particular BCG vaccine strains based on the results of studies comparing the immune response to different BCG vaccine strains.24

Section snippets

Methods

Information about BCG vaccine strains used in different countries worldwide was collected from three sources: (i) the most recent data available from the WHO/UNICEF Joint Reporting Form on Immunisation (2007 for WHO Western Pacific Region; 2003–2006 for all other countries); (ii) personal communications with representatives of all member states of the EuroTB network (a WHO collaborating centre) in 2007; and (iii) Sanofi Pasteur (for Australia and Canada only). A colour coded world map was

Results

Data specifying the BCG vaccine strain used was available for 188 countries (Figure 1). This data was available for a mean of three (range 1–5) years per country from the WHO/UNICEF database. For 16 countries, data for only one year was available from this database, and these were therefore categorised as ‘insufficient data’ and left blank in the map (Figure 1). More than one BCG vaccine strain was used in 83 (44%) countries during the five years (Figure 1). In countries that used only one

Discussion

Differences between BCG vaccine strains have previously attracted only limited attention and the various strains manufactured worldwide are generally considered interchangeable. However, the increasing recognition of the influence of vaccine strain on the immune response and protective efficacy induced by BCG immunisation as well as on adverse events and antibiotic susceptibility means it is important to document the strains currently used in each country.

To our knowledge this is the first time

Acknowledgments

We thank Dr Ulrich Fruth from WHO Initiative for Vaccine Research for providing the data from the ‘WHO/UNICEF Joint Reporting Form on Immunization’ and for helpful comments on the manuscript. We thank Dr Sigrun Roesel from EPI of the WHO Regional Office for Western Pacific for providing data. We thank Dr Vanessa Clifford for translating data from Russian.

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