Most of the research projects of the department fall within
the broad area of ”Infection and Immunity and Vaccine development” .
There are active research programs in the following areas:
immunity and vaccine development in various gastro-intestinal, respiratory
and genital tract infections
• Mucosal immunology (including research on
the induction, expression and regulation of immune responses to mucosal
immunization by different routes as well as on oral tolerance and mucosal
immunotherapy in autoimmune, allergic and other inflammatory diseases)
• Cancer immunology and dendritic cell vaccination
• Innate immunity and
adjuvants Viral vectors for gene therapy and cancer treatment
research Water, infection and health program
The department has a broad
range of international collaboration on a project basis with laboratories
in many countries both within and outside Europe (incl. Africa, America,
Asia and Australia). Several scientists also have active roles in various
governing bodies, expert committees etc. of national and international
research organisations including e.g. the World Health Organisation (WHO),
the Global Alliance for Vaccines and Immunisation (GAVI), the International
Vaccine Institute (IVI), and EU programs. Several projects have collaborative
links with the pharmaceutical and/or biotechnology industry. An important collaboration partner is ICDDR,B – Centre
for Health and Population Research, Dhaka, Bangladesh. Read a SASNET Report from a visit to ICDDR,B
in December 2005.
Several of the researchers are connected to the Mucosal Immunobiology and Vaccine Center (MIVAC) at Göteborg University, a strategic research center that in 2005 was granted 5 years financial support from the Swedish Foundation for Strategic Research. Director for MIVAC is Professor
The overall aim of the center is to foster basic and applied science in the field of mucosal immunobiology and vaccine development. MIVAC represents an important effort to bring together a critical mass of highly renowned research groups in one geographical location to expand Swedish international scientific excellence in the field. An important asset to MIVAC is the ability to take advances in pre-clinical research to clinical testing and commercial exploitation together with our group of collaborating industrial partners. The center has 19 research groups comprising 120 people at all academic levels with expertise in basic immunology, cell biology, protein chemistry, glycobiology, gastroenterology, microbiology and vaccinology.
Several of the research groups are connected to the Dept. of Microbiology and Immunology:
• Cholera toxin, mucosal immunity and development of mucosal vaccines and immunotherapies.
Group leader: Jan Holmgren. More information.
• NK cells and Regulatory T cells in Helicobacter pylori infection.
Group leader: Samuel Lundin. More information.
• Infection and immunity studies of ETEC and Helicobacter pylori.
Group leader: Ann-Mari Svennerholm. More information
To provide better resources
and a clearer identity for its vaccine research, Göteborg University has also, with financial
support from the Knut and Alice Wallenberg foundation, established a specific
vaccine research institute, GUVAX – Gothenburg
University Vaccine Research Centre. GUVAX focuses on vaccine development against selected mucosal infections; research
to develop anti-immunopathological vaccines/immunotherapies against
autoimmune and allergic diseases based on mucosally induced tolerance;
and research to develop therapeutic vaccination strategies against certain
forms of cancer. An important generic research line is the elucidation
of cells and mechanisms involved in steering the mucosal immunization
outcome towards immunity or tolerance and the development of immunomodulating
adjuvants for such purposes. GUVAX collaborates actively with many research
groups and units in Sweden and abroad, including active collaboration
with many international organisations and institutions engaged in vaccine
research, not the least ICDDR,B – Centre
for Health and Population Research in Dhaka, Bangladesh.
GUVAX is headed by Prof. Jan Holmgren (Director) and Prof. Svennerholm (Associate Director).
Ongoing research connected to South Asia
Holmgren has carried out research on
cholera for more than 30 years. His interest for the cholera bacteria
was originally raised by his predecessor as professor, Örjan
Ouchterlony. On a shocking visit to what is now Bangladesh in 1969/70
he was reminded of the severe cholera epidemics that flourished in Asia
and Africa. The department decided to set aside resources for this kind
of research. Along with the then new PhD candidate Ann-Mari
Svennerholm Holmgren (now also professor at the department), Jan Holmgren
could finally after several years of research and tests performed in
Bangladesh 197081 be able to present an effective oral vaccine
Another clinical field test was carried out in collaboration with the
ICDDR,B in Bangladesh in
198588. Approximately 90 000 people were involved in the test study
which gave a positive result. The vaccine, registered in 1993, is nowadays
widely manufactured by the pharmaceutical industry under the name Dukoral.
The prestigious Nordic Fernström Prize
for outstanding performances in Medicine for 2004 was awarded to Prof.
The prize delivered by the Faculty of Medicine at Lund University, Sweden, was
given to him for his research on cholera resulting in an effective vaccine. Jan
Holmgren received the award at a ceremony at Lund University on Wednesday 3 November
Professor Holmgren has later been involved
with the research project Cholera, mucosal
immunity and development of mucosal vaccines and oral tolerizing agents. Project description: The project adresses central problems in
mucosal infection, immunity and vaccine development: 1. Mechanisms of
disease and immunity in cholera and other enteric infections and development
of protective vaccines. 2. Mucosal immunity and vaccine development
against respiratory and genital tract infections. 3. Mucosal vaccines
by coupling or gene-fusing specific antigens/epitopes to the cholera
toxin B-subunit (CTB). 4. Methods for inducing specific immunological
tolerance) and development of specific immunotherapies (anti-inflammatory
vaccines) for use in autoimmune diseases, transplantation, allergies,
and immunopathologic complications to infections.
In October 2006, Prof. Holmgren received SEK 1.2 million as a two-years
grant from Sida’s Developing Country Research Council for a project
titled ”Development of an oral vaccine protecting
against both O1 and O139 cholera”. More
information about Sida’s 2006 grants.
Earlier in 2006 Prof. Holmgren also received SEK 1.4 million as a two-years
grant from Sida’s Support to HIV/Aids research programme, for a project
”Role of infant feeding peer counsellors
in prevention of mother-to-child-transmission of HIV”.
The vaccine research with large-scale field
trials in Bangladesh has not been totally uncontroversial. A
number of times over the years, criticism has been raised
by individuals in Bangladesh against the project on moral grounds. Read
an extremely critical article titled ”What is for the ICDDR,B
?” by Mahmood
Ali in the Bangladeshi monthly bilingual webzine Megh
leader of a research group working on a project titled Infection
and immunity studies of ETEC and Helicobacter pylori”.
Other members of the group are Dr.
Lundgren, Dr. Joshua
Tobias, Dr. Åsa Sjöling (more information), Dr. Matilda
Nicklasson (more information), and
the PhD candidates Tafuiq Bhuiyan, Anders Janzon, Claudia Rodas, and others. Project abstract: Enteroxigenic
Escherichia coli (ETEC) is the most common cause of diarrhea in developing
countries and in travelers to these areas. We study the prevalence of
such bacteria and their virulence factors in different countries and
populations, using specific monoclonal antibody and molecular diagnostic
methods (e.g. gene probes and PCR). We also analyze the expression of
different ETEC virulence factors during clinical infection as compared
to during growth in vitro, and we try to identify protective immune mechanisms
against ETEC both in animal studies and by studying infections and re-infections
with ETEC in birth cohort studies, e.g. in Bangladesh. Work is also in
progress to develop an effective ETEC vaccine. Studies are in progress
to evaluate the influence of different nutritional factors including
breastfeeding for vaccine efficacy. These studies are conducted in close
collaboration with scientists in different developing countries, e.g.
in Bangladesh, Egypt, Guatemala, Mexico and Bolivia. Since H. pylori
is one of the most common gastrointestinal infections that primarily
infect young children, in particular in developing countries, we are
studying infection with these bacteria and development of immune responses
during the first years of life in a high endemic area. This includes
studies to evaluate the role of maternal immunity and also if protective
immunity can develop in young infants that may explain spontaneous eradication.
We are also comparing mucosal immune responses in Swedish and Bangladeshi
asymptomatic carriers and duodenal ulcer patients as a background for
development of an H. pylori vaccine that can be used worldwide.
from research carried out in Bangladesh (supported by grants from Sida/SAREC
and the United States Agency for International Development, USAID) were
published in the journal Vaccine in
October 2005. The article is called ”Reduced
doses of oral killed enterotoxigenic Escherichia coli plus cholera toxin
B subunit vaccine is safe and immunogenic in Bangladeshi infants 6-17
months of age: dosing studies in different age groups”,
and was authored by Ann-Marie Svennerholm in collaboration with Dr. Tahmeed
Qadri; F. Ahmed; Y.A.
and Prof. David Sack, all researchers based
at ICDDR,B in Dhaka, Bangladesh. Read
a summary of the research results.
Earlier, during the 1990s Prof. Svennerholm was also involved in a research
collaboration with Indian, European and Guinean universities, studying
ETEC and EAEC-Agg surface proteins, developing diagnostic methods and participating
in epidemiological studies of childhood diarrhea in India and Guinea Bissau.
In India the collaboration partner institution was the Department
of Pediatrics, All India Institute of Medical Sciences, New Delhi.
A Sida/SAREC grant in 2001 resulted in a study jointly by ICDDR,B and
Göteborg University on ”Enterotoxigenic
Escherichia coli and Vibrio cholerae Diarrhea, Bangladesh 2004 ”,
presented in an article the Emerging Infectious
no 7/2005. Read
In 2003 the Division received SEK
1.05 Million as a three-years project grant from Sida/SAREC for the project ”Comparision
of Immune responses against Helicobacter pylori in developed and developing
countries as a basis for vaccine development”,
to be carried out in Bangladesh. The researchers involved in the project
were besides Ann-Marie Svennerholm also PhD Samuel
Lundin, PhD candidates Anna Lundgren and Erika
Strömberg, and finally Professor Lars
Engstrand at the Dept. of Clinical Bacteriology, Uppsala University.
Dr. Firdaus Qadri from the Laboratory Sciences Division at ICDDR,B in Dhaka,
participated in the Sixth
Global Vaccine Research Forum, held in Salvador
da Bahia, Brazil, 12–15 June 2005. In a panel about ”New vaccines against
Shigella and ETEC”, Qadri made a presentation about the global ETEC
disease burden. Abstract: Enterotoxigenic
E. coli (ETEC) is a common cause of watery diarrhoea in all ages, in particular
in children one to four years of age. It is estimated to cause some 280
million episodes of disease and some 400 000 deaths annually. Moreover,
it is believed to account for some 20–25%
of all cases of diarrhoea in children, and up to 40% of cases of traveller
diarrhoea. Repeated episodes of disease in children are associated with
long-term morbidity, manifested by malnutrition and growth faltering.
prevalence of ETEC in diarrhoeal patients has been demonstrated in case–control
studies. However, ETEC isolated from patients in various geographic areas
differ by toxin profile. Isolates produce either heat labile toxin or heat
stable toxin (ST) or both (LT/ST); in addition more than 25 colonizing
factors (CF) have been identified. More than 100 different ETEC O-antigen
serogroups can be differentiated, out of which some seven to eight are
common, and this diversity has hampered inclusion of O antigens in the
vaccine development pipeline.
In Bangladesh, ETEC disease burden studies
have been conducted in conjunction with studies on V. cholerae. Birth cohort
studies of natural ETEC infection at Mirpur field site revealed some 6.6
diarrhoea-days per child and per year, and a prevalence of ETEC diarrhoea
of 19%, higher than for any other enteric pathogen isolated from diarrhoeal
stools. Stratification by hospital and community setting, however, shows
the highest prevalence of rotavirus in hospitalized cases, whereas ETEC
remains highest in community cases, pointing towards greater severity of
rotavirus disease. Prospective data has revealed that, at least for some
CFs, protection is conferred against symptomatic reinfection with ETEC
expressing the homologous CF.
ETEC can be a major cause of watery diarrhoea
in disease epidemics associated with flooding, and the environment has
been established as a critical source for perpetuation of ETEC infections.
Increased antimicrobial resistance has been observed in ETEC isolates with
some 50% of isolates being resistant to ampicillin and 16% to cyprofloxacin.
Other control measures, in particular improved sanitation and vaccines,
are thus urgently needed.
Prof. Svennerholm was interviewed by the Swedish newspaper
Dagens Nyheter and an article published on 19 March 2005. It written
by the journalist Gunilla Eldh and focused on the research work on
vaccine development in Bangladesh. Read the article, titled ”En
världsmästare på vaccin”.
In November 2005 Prof. Svennerholm received SEK 300 000 as continued
funding for the year 2006 from Sida/SAREC, for a project titled ”Development
of an ETEC vaccine for use in infants in developing countries”,
and one year later, in Nov. 2006, she got another SEK 600 000 as an
extension with two years for the same project. More
information about Sida’s 2006 grants.
In November 2006 Prof. Svennerholm also received SEK 1 410 000 as a
three-years (2007-09) project grant from the Swedish Research Council
for a project titled ”Development
of vaccines against ETEC and Helicobacter pylori”. Read
the abstract (in Swedish only).
In November 2009, Prof. Svennerholm was awarded SEK 1.2 m as a three-years research grant (2010–12) from the Swedish International Development Cooperation Agency, Sida, for a a new project entitled ”Improving Immunogenicity of Oral Vaccines in Children in Developing Countries”. More information about the 2009 Sida grants.
PhD Matilda Nicklasson, a member of the research group, defended her doctoral dissertation titled ”Studies on the expression and regulation of enterotoxins and colonization factors in enterotoxigenic escherichia coli (ETEC)” on Thursday 31 January 2008. The results are based on studies of ETEC bacterias from patients at the International Centre for Diarrhoeal Disease Research (ICDDR,B) in Dhaka, Bangladesh. Abstract: Enterotoxigenic Escherichia coli (ETEC) is one of the most common causes of acute watery diarrhoea in developing countries, particularly among local children less than five years and is also the most common cause of diarrhoea in travellers to ETEC enemic areas. The infection is transmitted by ingestion of contaminated food and water and the disease is established in the small intestine Colonization factors (CFs) on the bacterial surface mediate adhesion to the intestinal epithelium and diarrhoea is manifested by the actions of a heat-stable (ST) and / or a heat-labile (LT) enterotoxin. Two of the most common CFs in strains isolated world-wide are coli surface antigens 5 (CS5) and 6 (CS6). In this thesis the expression and regulation of these important virulence factors as well as the genetic variability among ETE strains have been studied. More information.
In November 2008, Dr. Nicklasson was awarded SEK 600 000 as a one-year grant from Sida/SAREC’s Developing Country Research Council for a project titled ”Molecular epidemiology of enterotoxigenic Escherichia coli (ETEC) in the context of virulence, patient group, spread, and seasonality in Bangladesh”.
In October 2010, she was again awarded a grant from Sida/SAREC’s Developing Country Research Council, this time SEK 1 m for a project over two years (2011-12). The project, in reality a continuation of her earlier research focusing on Bangladesh but this time extending the project also to other countries, is entitled ”Transmission, infection patterns, and antibiotic resistance profiles of enterotoxigenic Escherichia coli (ETEC) in Asia, Africa and Latin America”. More information.
The main collaboration partner on the Bangladeshi side is Dr Firdaus
Qadri, Senior Scientist at the Laboratory Sciences Division/Immunology, International Centre for Diarrhoeal Disease Research (ICDDR,B) in Dhaka. Project abstract: According to the World Health Organization (WHO), acute infectious diarrhoeal disease is the number two killer of children living in developing countries, accounting for approximately one-fifth of all deaths in children under the age of five every year. One of the most common causes of acute diarrhoeal disease among children and adults in developing countries is Enterotoxigenic Escherichia coli (ETEC), which causes an estimated 400 million diarrhoeal cases and up to 400 000 deaths in young children every year. ETEC produce two main groups of virulence factors; colonization factors (CFs) and enterotoxins (ST and/or LT).
This project will investigate the global transmission, infection patterns, and antibiotic resistance of ETEC strains in different parts of the world in order to facilitate the design of appropriate intervention and prophylaxis measures. More specifically, the aim is to study the genetic variability, infection patterns and antibiotic resistance of ETEC from several countries in Asia, Africa and Latin America, focusing on emerging toxin/CF profiles.
The genetic findings and antibiotic resistance profiles will be correlated to severity of disease, patient age, seasonality, and socioeconomic factors. Better means of controlling the transmission of ETEC may decrease childhood mortality, and may result in an improved nutrition status of children in developing countries by decreasing the number of childhood diarrhoeal episodes per year. The results of the project may also lead to increased understanding of the transmission of antibiotic resistance among ETEC strains, which is important in developing countries where extensive antibiotic resistance is common.
Strains from child and adult patients in several countries in Asia, Africa and Latin America will be investigated in the project, but the main collaboration partners are research institutes in Bolivia, Mozambique, and Bangladesh, i.e. the International Centre for Diarrhoeal Disease Research (ICDDR,B). These are all poor countries where diarrhoeal disease is endemic, and where measures to control the transmission of ETEC and antibiotic resistance may have a great impact on society and on child development
PhD Tanvir Ahmed, another member of the research group, defended his doctoral dissertation titled ”Vaccination against cholera and ETEC diarrhea and interventions to improve vaccine immune responses” on 10 June 2009. Dr. Ahmed is working at ICCR,B in Dhaka. Abstract: Vibrio cholerae O1 and enterotoxigenic Escherichia coli (ETEC) together account for the majority of bacterial causes of acute dehydrating diarrhea in children in Bangladesh. Vaccines should be considered as an important public health tool for prevention of these diarrheal diseases. The results of Dr. Ahmed’s studies give important background information regarding the possibility of inducing effective immune responses to oral inactivated enteric vaccines in young children in developing countries. More information.
also involved in a research project on ”Gastrointestinal
infections, water and health”. The research group also includes
Bölin, Dr. Åsa Sjöling,
and the PhD candidates Anders
Janzon and Åsa Lothigius. Project description: The purpose
of this project is to identify environmental and ecological factors that
may facilitate spread of waterborne gastrointestinal infections, i.e.
enterotoxigenic E. coli (ETEC), Vibrio cholerae and Helicobacter pylori,
both in developing and developed countries. To achieve this goal we will
develop suitable methods for identification of the causative bacterial
pathogens in water samples and identify different environmental conditions
that may promote/counteract contamination of different water sources
with these pathogens as well as their transmission and capacity to induce
severe diseases both in populations in industrialized and in developing
countries. This project is a multidisciplinary project and it is part
of an international network for ”Research
and education in infectious diseases, water and health” with
Colwell, University of
Maryland, USA, Dr Firdaus
Centre for Diarrheal Disease Research (ICDDR, B), Dhaka, Bangladesh and
Marine Research Station, the Swedish Royal Academy of Science, and others.
PhD Stephen Attridge is
leader of a research group working on the project ”Development
of an improved cholera vaccine”.
Other members of the group include Prof.
Jan Holmgren, Prof. Ann-Marie
Svennerholm, and PhD candidate Erik
Nygren. In 2003 Sida/SAREC funded this
project with SEK 500 000 for one year. Project description: The ultimate aim of this
project is the development of a bivalent vaccine able to protect against
the two Vibrio cholerae serogroups with demonstrated epidemic potential
(O1 and O139). This is most conveniently achieved by preparing an inactivated
vaccine against the O139 serogroup strains, and adding this to the present
inactivated vaccine against V. cholerae O1. Initial attempts to prepare
an inactivated O139 vaccine component have been discouraging, as the
formulations’ immunogenicities and protective efficacies have been weaker
than that of the analogous O1 component. We have derived panels of O139
variant strains with the aim of identifying one with improved immunogenicity,
with respect to the induction of potentially-protective antibodies to
O139 LPS. We are also attempting to develop a new cholera model, which
would allow the direct evaluation of the protective efficacies of novel
PhD Michael Lebens is
leader is leader of a research group working on the project ”Recombinant
fusion proteins based on cholera toxin B subunit for the prevention and
treatment of autoimmune disease”. Other members of the
group include Prof. Jan Holmgren, and the PhD candidate Johan
Wiman. In 2003 Sida/SAREC gave SEK
1.05 Million to the project as a three-years grant. More
information Sida/SAREC grants 2003. Project desription: Inflammatory autoimmune
responses directed against human 60 kDa heat shock protein (HSP60) have
been implicated in a number of important autoimmune diseases. For some
of these, intervention therapy aimed at tolerance induction or immune
deviation from a Th1 to a Th2 dominated response has had positive effects
on the progression of the disease. Notably in type 1 diabetes a single
HSP60-derived peptide (p277) has been used to immunize patients with
early symptoms . A second disease in which a specific HSP60 peptide has
been identified as having a role in pathology is Behcet’s syndrome. In
this multisystem inflammatory disorder the major manifestation is uveitis.
Disease activity is correlated with T cell proliferative responses to
the HSP60 peptide p336-351. The same peptide, chemically coupled to cholera
toxin B subunit (CTB), could suppress development of experimentally induced
disease in Lewis rats and in a limited clinical trial, significantly
reduce symptoms in Behcet’s patients. The aim of our work is therefore
to develop CTB fusion proteins for the treatment of autoimmune diseases
as we have previously done in schistosomiasis liver inflammation. A number
of proteins have been constructed and purified carrying epitopes from
proteins implicated in different inflammatory diseases. Among these are
HSP60-derived peptides (including p336-351) and two fusion proteins derived
from low density lipoprotein (LDL), a protein implicated in development
of atherosclerosis . One of these LDL fusion proteins has been shown
to be active in reduction of aortic plaque size in ApoE null mice and
the proteins serve as good examples of the advantages and disadvantages
of this technology. Further work is aimed at developing novel methods
for identification of active T cell epitopes from proteins implicated
in the development of different autoimmune diseases.
Sjöling has worked on a yet another similar project titled ”Expression
of virulence factors in enterotoxigenic Escherichia coli (ETEC) during
infection (in vivo)”, together with Prof. Ann-Mari
Svennerholm and Dr. Matilda
Nicklasson. Abstract: The
gastrointestinal pathogen enterotoxigenic Escherichia coli (ETEC) colonises
the human intestine and causes severe diarrhoea by the secretion of
toxins. This project aims at identification of the environmental factors
that regulate virulence during infection. We are identifying conditions
that promote toxin production and secretion by analysis of gene expression
and protein production. The obtained results are compared to the expression
in ETEC derived directly from patient stool samples. The ultimate goals
are to identify the molecular mechanisms that regulate virulence in
ETEC and to identify potential vaccine candidate antigens expressed
on the surface of ETEC during infection of the human intestine.
In 2005, Åsa Sjöling received a stipend to pay for
two years of continued postdoctoral medical research, by the Swedish
Association for Medical Research (Svenska Sällskapet för
Medicinsk Forskning), for this project. Read
about her research (in Swedish only).
In June 2005 Dr. Sjöling also received SEK 675 000 as a two-years
grant from the Swedish research council FORMAS for a project dealing
of pathogenic viable but non-culturable bacteria (VBNC) in water, to
identify transmission of infection in different types of water sources
in Bangladesh”. More
information about the project (only in Swedish).
Earlier the same year, in June 2007, she received SEK 918 000 as another grant from Formas, for an application to the Joint Formas – Sida/SAREC grants for research
on sustainable development in developing countries. The title of the project was ”Detection and charaterisation of pathogenic bacteria in water samples in Bangladesh in order to identify tools to improve household water procedures and avoid infection”. More information.