“At first, I was very afraid”—a qualitative description of participants’ views and experiences in the first Human Infection Study in Malawi

Background: Human infection studies (HIS) involve deliberately infecting healthy volunteers with a pathogen in a controlled environment to understand infection and support the development of effective vaccines or treatments. HIS research is expanding to many low and middle-income settings to accelerate vaccine development. Given the implementation of the first HIS research to establish the experimental human pneumococcal carriage model’s feasibility, we sought to understand the participant’s opinions and experiences. Methods: We used a qualitative, descriptive approach to understand participants perceptions and experiences on HIS participation. Sixteen healthy adult participants were invited to participate in in-depth exit interviews to discuss their experiences, motivations and concerns. Results: Our findings showed that the likelihood of participation in HIS research rests on three essential conditions: motivation to participate, compensation and advocacy. The motivation and decision to participate was based on reasons including altruism, patriotism, monetary and material incentives, and while compensation was deemed appropriate, concerns about unanticipated research-related risks were raised. Participant advocate groups were recommended for increasing awareness and educating others in the broader community about HIS research. Conclusions: Participants’ experiences of HIS in Malawi provide the basis of what can be acceptable in HIS research in lower-income countries and areas where study procedures could be adjusted.

Download Full-text

Stakeholder views on the acceptability of Human Infection Studies in Malawi

10.21203/rs.2.11346/v3 ◽

2019 ◽

Author(s):

Blessings M. Kapumba ◽

Kondwani Jambo ◽

Jamie Rylance ◽

Markus Gmeiner ◽

Rodrick Sambakunsi ◽

...

Keyword(s):

Vaccine Development ◽

Human Infection ◽

Stakeholder Perceptions ◽

Ethical Challenges ◽

Inclusion Criteria ◽

Government Officials ◽

District Health ◽

Middle Income ◽

Rural And Urban ◽

Ongoing Assessment

Abstract Background: Human infection studies (HIS) are valuable in vaccine development. Deliberate infection, however, creates challenging questions, particularly in low and middle-income countries (LMIC) where HIS are new and ethical challenges may be heightened. Consultation with stakeholders is needed to support contextually appropriate and acceptable study design. We examined stakeholder perceptions about the acceptability and ethics of HIS in Malawi, to inform decisions about planned pneumococcal challenge research and wider understanding of HIS ethics in LMIC. Methods: We conducted 6 deliberative focus groups and 15 follow-up interviews with research staff, medical students, and community representatives from rural and urban Blantyre. We also conducted 5 key informant interviews with clinicians, ethics committee members and district health government officials. Findings: Stakeholders perceived HIS research to have potential population health benefits, but they also had concerns, particularly related to safety of volunteers and negative community reactions. Acceptability depended on a range of conditions related to procedures for voluntary and informed consent, inclusion criteria, medical care or support, compensation, regulation, and robust community engagement. These conditions largely mirror those in existing guidelines for HIS and biomedical research in LMICs. Stakeholder perceptions pointed to potential tensions, for example balancing equity, safety and relevance in inclusion criteria. Conclusions: Our findings suggest HIS research could be acceptable in Malawi, provided certain conditions are in place. Ongoing assessment of participant experiences and stakeholder perceptions will be required to strengthen HIS research during development and roll-out. Key words: Human Infection Studies, pneumococcal, Malawi, acceptability, ethics

Download Full-text

Contribution of noncanonical antigens to virulence and adaptive immunity in human infection with enterotoxigenic E. coli

10.1101/2020.10.20.348110 ◽

2020 ◽

Author(s):

FM Kuhlmann ◽

RO Laine ◽

S Afrin ◽

R Nakajima ◽

M Akhtar ◽

...

Keyword(s):

Immune Responses ◽

Vaccine Development ◽

Human Infection ◽

Middle Income ◽

Symptomatic Disease ◽

E Coli ◽

Middle Income Countries ◽

Colonization Factor ◽

Specific Antigens ◽

Colonization Factors

AbstractEnterotoxigenic E. coli (ETEC) contribute significantly to the substantial burden of infectious diarrhea among children living in low and middle income countries. In the absence of a vaccine for ETEC, children succumb to acute dehydration as well as non-diarrheal sequelae related to these infections including malnutrition. The considerable diversity of ETEC genomes has complicated canonical vaccine development approaches focused on a subset of antigens known as colonization factors (CFs). To identify additional conserved immunogens, we mined genomic sequences of 89 ETEC isolates, bioinformatically selected potential surface-exposed pathovar-specific antigens conserved in more than 40% of the genomes (n=118), and assembled the representative proteins onto microarrays, complemented with known or putative colonization factor subunit molecules (n=52), and toxin subunits to interrogate samples from individuals with acute symptomatic ETEC infections. Surprisingly, in this open-aperture approach, we found that immune responses were largely constrained to a small number of antigens including individual colonization factor antigens and EtpA, an extracellular adhesin. In a Bangladeshi cohort of naturally infected children < 2 years of age, both EtpA and a second noncanonical antigen, EatA, elicited significant serologic responses that were associated with protection from symptomatic illness. In addition, children infected with ETEC isolates bearing either etpA or eatA genes were significantly more likely to develop symptomatic disease. These studies support a role for more recently discovered noncanonical antigens in virulence and the development of adaptive immune responses during ETEC infections, findings that may inform vaccine design efforts to complement existing approaches.

Download Full-text

Stakeholder views on the acceptability of Human Infection Studies in Malawi

10.21203/rs.2.11346/v4 ◽

2020 ◽

Cited By ~ 2

Author(s):

Blessings M. Kapumba ◽

Kondwani Jambo ◽

Jamie Rylance ◽

Markus Gmeiner ◽

Rodrick Sambakunsi ◽

...

Keyword(s):

Vaccine Development ◽

Human Infection ◽

Stakeholder Perceptions ◽

Ethical Challenges ◽

Inclusion Criteria ◽

Government Officials ◽

District Health ◽

Middle Income ◽

Rural And Urban ◽

Ongoing Assessment

Abstract Background: Human infection studies (HIS) are valuable in vaccine development. Deliberate infection, however, creates challenging questions, particularly in low and middle-income countries (LMICs) where HIS are new and ethical challenges may be heightened. Consultation with stakeholders is needed to support contextually appropriate and acceptable study design. We examined stakeholder perceptions about the acceptability and ethics of HIS in Malawi, to inform decisions about planned pneumococcal challenge research and wider understanding of HIS ethics in LMICs. Methods: We conducted 6 deliberative focus groups and 15 follow-up interviews with research staff, medical students, and community representatives from rural and urban Blantyre. We also conducted 5 key informant interviews with clinicians, ethics committee members, and district health government officials. Results: Stakeholders perceived HIS research to have potential population health benefits, but they also had concerns, particularly related to the safety of volunteers and negative community reactions. Acceptability depended on a range of conditions related to procedures for voluntary and informed consent, inclusion criteria, medical care or support, compensation, regulation, and robust community engagement. These conditions largely mirror those in existing guidelines for HIS and biomedical research in LMICs. Stakeholder perceptions pointed to potential tensions, for example, balancing equity, safety, and relevance in inclusion criteria. Conclusions: Our findings suggest HIS research could be acceptable in Malawi, provided certain conditions are in place. Ongoing assessment of participant experiences and stakeholder perceptions will be required to strengthen HIS research during development and roll-out.

Download Full-text

Stakeholder views on the acceptability of Human Infection Studies in Malawi

10.21203/rs.2.11346/v2 ◽

2019 ◽

Author(s):

Blessings M. Kapumba ◽

Kondwani Jambo ◽

Jamie Rylance ◽

Markus Gmeiner ◽

Rodrick Sambakunsi ◽

...

Keyword(s):

Vaccine Development ◽

Human Infection ◽

Stakeholder Perceptions ◽

Ethical Challenges ◽

Inclusion Criteria ◽

Government Officials ◽

District Health ◽

Middle Income ◽

Rural And Urban ◽

Ongoing Assessment

Abstract Background: Human infection studies (HIS) are valuable in vaccine development. Deliberate infection, however, creates challenging questions, particularly in low and middle-income countries (LMIC) where HIS are new and ethical challenges may be heightened. Consultation with stakeholders is needed to support contextually appropriate and acceptable study design. We examined stakeholder perceptions about the acceptability and ethics of HIS in Malawi, to inform decisions about planned pneumococcal challenge research and wider understanding of HIS ethics in LMIC. Methods: We conducted 6 deliberative focus groups and 15 follow-up interviews with research staff, medical students, and community representatives from rural and urban Blantyre. We also conducted 5 key informant interviews with clinicians, ethics committee members and district health government officials. Findings: Stakeholders perceived HIS research to have potential population health benefits, but they also had concerns, particularly related to safety of volunteers and negative community reactions. Acceptability depended on a range of conditions related to procedures for voluntary and informed consent, inclusion criteria, medical care or support, compensation, regulation, and robust community engagement. These conditions largely mirror those in existing guidelines for HIS and biomedical research in LMICs. Stakeholder perceptions pointed to potential tensions, for example balancing equity, safety and relevance in inclusion criteria. Conclusions: Our findings suggest HIS research could be acceptable in Malawi, provided certain conditions are in place. Ongoing assessment of participant experiences and stakeholder perceptions will be required to strengthen HIS research during development and roll-out. Key words: Human Infection Studies, pneumococcal, Malawi, acceptability, ethics

Download Full-text

A framework for Controlled Human Infection Model (CHIM) studies in Malawi: Report of a Wellcome Trust workshop on CHIM in Low Income Countries held in Blantyre, Malawi

Wellcome Open Research ◽

10.12688/wellcomeopenres.12256.1 ◽

2017 ◽

Vol 2 ◽

pp. 70 ◽

Cited By ~ 22

Author(s):

Stephen B Gordon ◽

Jamie Rylance ◽

Amy Luck ◽

Kondwani Jambo ◽

Daniela M Ferreira ◽

...

Keyword(s):

Low Income ◽

Vaccine Development ◽

Clinical Laboratory ◽

Human Infection ◽

Low Income Countries ◽

Infection Model ◽

Proof Of Concept ◽

Middle Income ◽

Regulatory Issues ◽

Middle Income Countries

Controlled human infection model (CHIM) studies have pivotal importance in vaccine development, being useful for proof of concept, pathogenesis, down-selection and immunogenicity studies. To date, however, they have seldom been carried out in low and middle income countries (LMIC), which is where the greatest burden of vaccine preventable illness is found. This workshop discussed the benefits and barriers to CHIM studies in Malawi. Benefits include improved vaccine effectiveness and host country capacity development in clinical, laboratory and governance domains. Barriers include acceptability, safety and regulatory issues. The report suggests a framework by which ethical, laboratory, scientific and governance issues may be addressed by investigators considering or planning CHIM in LMIC.

Download Full-text

Stakeholder views on the acceptability of Human Infection Studies in Malawi

10.21203/rs.2.11346/v1 ◽

2019 ◽

Author(s):

Blessings Kapumba ◽

Kondwani Jambo ◽

Jamie Rylance ◽

Markus Gmeiner ◽

Rodrick Sambakunsi ◽

...

Keyword(s):

Vaccine Development ◽

Human Infection ◽

Stakeholder Perceptions ◽

Ethical Challenges ◽

Inclusion Criteria ◽

Government Officials ◽

District Health ◽

Middle Income ◽

Rural And Urban ◽

Ongoing Assessment

Abstract Background Human infection studies (HIS) are essential in vaccine development. Deliberate infection, however, creates challenging questions, particularly in low and middle-income countries (LMIC) where CHIM are new and ethical challenges may be heightened. Consultation with stakeholders is needed to support contextually appropriate and acceptable study design. We examined stakeholder perceptions about the acceptability and ethics of HIS in Malawi, to inform decisions about planned pneumococcal challenge research and wider understanding of HIS ethics in LMIC. Methods We conducted 6 deliberative focus groups and 15 follow-up interviews with research staff, medical students, and community representatives from rural and urban Blantyre. We also conducted 5 key informant interviews with clinicians, ethics committee members and district health government officials. Findings Stakeholders perceived HIS research to have potential population health benefits, but they also had concerns, particularly related to safety of volunteers and negative community reactions. Acceptability depended on a range of conditions related to procedures for voluntary and informed consent, inclusion criteria, medical support, compensation, regulation, and robust community engagement. These conditions largely mirror those in existing guidelines for HIS and biomedical research in LMICs. Stakeholder perceptions pointed to potential tensions, for example balancing equity, safety and relevance in inclusion criteria. Conclusions Our findings suggest HIS research can be acceptable in Malawi, provided certain conditions are in place. Ongoing assessment of participant experiences and stakeholder perceptions will be required as HIS are implemented.

Download Full-text

Stakeholder views on the acceptability of Human Infection Studies in Malawi

10.21203/rs.2.11346/v5 ◽

2020 ◽

Author(s):

Blessings M. Kapumba ◽

Kondwani Jambo ◽

Jamie Rylance ◽

Markus Gmeiner ◽

Rodrick Sambakunsi ◽

...

Keyword(s):

Vaccine Development ◽

Human Infection ◽

Stakeholder Perceptions ◽

Ethical Challenges ◽

Inclusion Criteria ◽

Government Officials ◽

District Health ◽

Middle Income ◽

Rural And Urban ◽

Ongoing Assessment

Abstract Background: Human infection studies (HIS) are valuable in vaccine development. Deliberate infection, however, creates challenging questions, particularly in low and middle-income countries (LMICs) where HIS are new and ethical challenges may be heightened. Consultation with stakeholders is needed to support contextually appropriate and acceptable study design. We examined stakeholder perceptions about the acceptability and ethics of HIS in Malawi, to inform decisions about planned pneumococcal challenge research and wider understanding of HIS ethics in LMICs. Methods: We conducted 6 deliberative focus groups and 15 follow-up interviews with research staff, medical students, and community representatives from rural and urban Blantyre. We also conducted 5 key informant interviews with clinicians, ethics committee members, and district health government officials. Results: Stakeholders perceived HIS research to have potential population health benefits, but they also had concerns, particularly related to the safety of volunteers and negative community reactions. Acceptability depended on a range of conditions related to procedures for voluntary and informed consent, inclusion criteria, medical care or support, compensation, regulation, and robust community engagement. These conditions largely mirror those in existing guidelines for HIS and biomedical research in LMICs. Stakeholder perceptions pointed to potential tensions, for example, balancing equity, safety, and relevance in inclusion criteria. Conclusions: Our findings suggest HIS research could be acceptable in Malawi, provided certain conditions are in place. Ongoing assessment of participant experiences and stakeholder perceptions will be required to strengthen HIS research during development and roll-out.

Download Full-text

Consensus Report on Shigella Controlled Human Infection Model: Immunological Assays

Clinical Infectious Diseases ◽

10.1093/cid/ciz909 ◽

2019 ◽

Vol 69 (Supplement_8) ◽

pp. S596-S601 ◽

Cited By ~ 2

Author(s):

Robert W Kaminski ◽

Marcela F Pasetti ◽

Ana Older Aguilar ◽

Kristen A Clarkson ◽

Sjoerd Rijpkema ◽

...

Keyword(s):

Vaccine Development ◽

Human Infection ◽

Health Concern ◽

Substantial Contribution ◽

Enzyme Linked Immunosorbent Assay ◽

Infection Model ◽

Middle Income ◽

Severe Diarrhea ◽

Vaccine Type ◽

Immunological Assays

Abstract Moderate to severe diarrhea caused by Shigella is a global health concern due to its substantial contribution to morbidity and mortality in children aged <5 years in low- and middle-income countries. Although antibiotic treatment can be effective, emerging antimicrobial resistance, limited access, and cost affirm the role of vaccines as the most attractive countermeasure. Controlled human infection models (CHIMs) represent a valuable tool for assessing vaccine efficacy and potentially accelerating licensure. Currently, immunological analysis during CHIM studies is customized based on vaccine type, regimen, and administration route. Additionally, differences in type of immunoassays and procedures used limit comparisons across studies. In November 2017, an expert working group reviewed Shigella CHIM studies performed to date and developed consensus guidelines on prioritization of immunoassays, specimens, and collection time points. Immunoassays were ranked into 3 tiers, with antibodies to Shigella lipopolysaccharide (LPS) being the highest priority. To facilitate comparisons across clinical studies, a second workshop was conducted in December 2017, which focused on the pathway toward a recognized enzyme-linked immunosorbent assay (ELISA) to determine serum immunoglobulin G titers against Shigella LPS. The consensus of the meeting was to establish a consortium of international institutions with expertise in Shigella immunology that would work with the National Institute for Biological Standards and Control to establish a harmonized ELISA, produce a reference sera, and identify a reliable source of Shigella LPS for global utilization. Herein we describe efforts toward establishing common procedures to advance Shigella vaccine development, support licensure, and ultimately facilitate vaccine deployment and uptake.

Download Full-text

Contribution of noncanonical antigens to virulence and adaptive immunity in human infection with enterotoxigenic E. coli

Infection and Immunity ◽

10.1128/iai.00041-21 ◽

2021 ◽

Author(s):

F. M. Kuhlmann ◽

R. O. Laine ◽

S Afrin ◽

R Nakajima ◽

M Akhtar ◽

...

Keyword(s):

Immune Responses ◽

Vaccine Development ◽

Human Infection ◽

Middle Income ◽

Symptomatic Disease ◽

E Coli ◽

Middle Income Countries ◽

Colonization Factor ◽

Specific Antigens ◽

Colonization Factors

Enterotoxigenic E. coli (ETEC) contribute significantly to the substantial burden of infectious diarrhea among children living in low and middle income countries. In the absence of a vaccine for ETEC, children succumb to acute dehydration as well as non-diarrheal sequelae related to these infections including malnutrition. The considerable diversity of ETEC genomes has complicated canonical vaccine development approaches defined by a subset of ETEC pathovar-specific antigens known as colonization factors (CFs). To identify additional conserved immunogens unique to this pathovar we employed an “open-aperture” approach to capture all potential conserved ETEC surface antigens in which we mined genomic sequences of 89 ETEC isolates, bioinformatically selected potential surface-exposed pathovar-specific antigens conserved in more than 40% of the genomes (n=118), and assembled the representative proteins onto microarrays, complemented with known or putative colonization factor subunit molecules (n=52), and toxin subunits. These arrays were then used to interrogate samples from individuals with acute symptomatic ETEC infections. Surprisingly, in this approach, we found that immune responses were largely constrained to a small number of antigens including individual colonization factor antigens and EtpA, an extracellular adhesin. In a Bangladeshi cohort of naturally infected children < 2 years of age, both EtpA and a second antigen, EatA, elicited significant serologic responses that were associated with protection from symptomatic illness. In addition, children infected with ETEC isolates bearing either etpA or eatA genes were significantly more likely to develop symptomatic disease. These studies support a role for antigens not presently targeted by vaccines (non-canonical) in virulence and the development of adaptive immune responses during ETEC infections. These findings that may inform vaccine design efforts to complement existing approaches.

Download Full-text