Campylobacter spp. Transmission Dynamics in Low- and Middle-Income Countries

Campylobacter infections have been associated with diarrheal disease as well as growth faltering in children. The fraction of severe diarrheal cases in infants attributed to Campylobacter jejuni or Campylobacter coli ranged from 6% in Kenya to 12% in Bangladesh in the Global Enteric Multicenter Study (Liu et al. 2016). Campylobacter is also increasingly implicated in growth faltering among children <2y of age. In the MAL-ED (Etiology, Risk Factors, and Interactions of Enteric Infections and Malnutrition and the Consequences for Child Health and Development Project) study, 85% of children were found to have had at least one Campylobacter infection by 1 year of age, and a high burden of infection was associated with lower length-for-age Z-score (Amour et al. 2016).

The environment in which a child lives is implicated in linear growth faltering, and the relationship may be mediated by environmental enteric dysfunction (EED). Poor nutrition availability and fecal contamination are key aspects of the environment, and may interact to result in EED and stunting (Schnee and Petri, 2017). Campylobacter jejuni is a commensal in birds and in ruminants, and interaction of children with chicken feces, unpasteurized milk, and contaminated water are hypothesized to be possible sources of exposure to the bacterium especially in areas where co-housing of humans and domestic animals is common.

Recently concluded randomized controlled trials that tested the efficacy of improvements in drinking water, sanitation, and handwashing (WSH) in Low and Middle-Income Countries (LMICs) found no significant effects on gut markers of EED, growth at 18mo age, or diarrhea incidence in two out of three sites (Humphrey et al. 2017). Whereas the impact of WSH interventions in these trials on transmission of Campylobacter and other specific pathogens is as yet unknown, it is possible that they targeted only one or a few routes of exposure, and didn’t reduce transmission to below a threshold required to observe a health impact (Briscoe 1984). The MAL-ED study suggests that household crowding and chickens in the house were both associated with an increased risk ratio of asymptomatic infection with Campylobacter, whereas treatment of drinking water and improved sanitation reduced risk, suggesting that multiple routes of transmission may exist (Amour et al. 2016). Thus, understanding the possible routes of transmission in LMIC communities of interest is a priority.

In spite of mounting evidence regarding the burden of Campylobacter-attributed diarrhea as well as growth-faltering, we know little about from what, how, and where children contract infection. What role do domestic animals, which are known reservoirs of Campylobacter, play in transmission? Does infection result from fecal contamination in the environment and how long does Campylobacter survive in the environment? Are undernourished children at greater risk of contracting or transmitting infection? Do older siblings or adults in the household transmit infection to neonates and younger children? In particular, half of the children below 6 months of age—who are not yet mobile—were infected in the MAL-ED study (Amour et al. 2016), leading us to ask if human-to-human transmission is more prevalent in these settings compared to high-income settings.

Objectives of this call

In this new grand challenge, we solicit proposals to examine the transmission of Campylobacter spp. in communities.

Proposals responsive to this call will generate data to understand the sources of Campylobacter infection in children in LMICs, and the dynamics of transmission in LMIC communities of interest. Analyses of these data are expected to address the question of whether a human vaccine for Campylobacter is a necessary and appropriate strategy in spite of the complexities associated with auto-immune responses to Campylobacter antigens. Alternatively, are an avian Campylobacter vaccine, sanitation and hygiene measures, or behavioral interventions that promote the segregation of young children from domestic birds and animals—alone or in combination—effective in preventing Campylobacter infections in children?

Alternative routes for Campylobacter infection in humans include exposure to domestic or wild animals carrying the bacterium, exposure to raw meat or raw milk, exposure to contaminated soil or water, and direct human-to-human transmission (Blaser 1997). These routes are not mutually exclusive, and understanding their relative importance in Campylobacter transmission is important so that we can intervene effectively to stop transmission, especially to the youngest, most vulnerable children.

The role of domestic animals in Campylobacter transmission

Campylobacter infects poultry, wild birds, and dairy animals, but we do not know to what extent human infection is caused by exposure to these animals in LMIC. Source attribution studies in Europe have uncovered an important role for poultry in transmitting infection in some countries but a larger role for wild birds in others (Mughini-Gras et al. 2016). There is a need to acquire more comprehensive sequence typing data from multiple sources sampled in different geographic locations in LMICs. Ideally, studies will factor in seasonality of infections and transmission routes, taking into account infections caused by other enteric pathogens. Coupled with computational models of transmission, such data can help assess the impact of alternative interventions in reducing the burden of infection and disease.

Undernourishment and transmissibility

Campylobacter infections have been associated with under-nutrition in children below 2 years of age (Platts-Mills et al. 2017; Amour et al. 2016). Yet, few data are available on the age-specific incidence and clinical importance of Campylobacter jejuni, Campylobacter coli, and non-jejuni/coli Campylobacter infection in many LMICs. The non-jejuni/coli Campylobacter species may be responsible for a larger proportion of the diarrhea burden than previously believed (François et al. 2018). It is not known if species or strains vary in their ability to infect undernourished individuals. We also do not know if host nutrition status affects whether infection is clinical or sub-clinical, or if shedding and transmissibility vary depending on nutrition status. Finally, how co-infections with other enteric pathogens might impact transmissibility is unknown.

The role of the environment in Campylobacter survival and transmission

We know very little about the impact of environmental factors (temperature fluctuations, changes in osmolarity, nutrient deprivation, and natural ultraviolet radiation) and the presence of environmental protozoans on the survival and transmissibility of Campylobacter in LMICs (Snelling et al. 2005). These data will help determine how Campylobacter populations are structured in space and time, and the potential biases in prioritized interventions introduced by not sampling reservoirs contemporaneously with cases in the same geographic location.

Successful proposals responding to this call will move the community closer to understanding the source of infections, so that we can begin to define a strategy to mitigate Campylobacter infection in LMIC communities.

Examples of what we are looking for:

1. Understanding whether strains that infect domestic and wild animals, and humans vary in a given location, and source attribution of strains causing human infection to contaminated food or water, or domestic or wild animals.
2. Studies on transmission dynamics of Campylobacter within households and in communities. Such studies should include environmental assessments to determine relevant fomites. Studies might possibly (but need not necessarily) include data-informed computational models of transmission to assess intervention impact. Technical input and modeling expertise will be available to aid transmission modeling based on the data generated in studies funded under this call.
3. How host (human and animal) under-nutrition affects pathogenicity and transmissibility of Campylobacter, including whether strains that cause clinical or sub-clinical infection are different.
4. Geographic distribution of Campylobacter strains affecting children in LMICs and overlap therein. This may include concurrently assessing infection with other pathogens such as Cryptosporidium.

What we will not support:

1. Vaccine development
2. Studies in high-income countries
3. Development of clinical diagnostic tools without application to transmission studies
4. Studies of transmission based only on culture-based methods.
5. Studies seeking to interrupt transmission.

To apply, please submit a concept note in the required format of up to 4 pages, including references and the budget, using the LOI template.

FAQs

Who can participate? This is an open solicitation. We welcome submissions from organizations in all sectors (private, NGO, government, academic, and UN). Submissions cannot come from individuals without organizational affiliation.

When are responses due? Responses are due by May 2, 2018.

When will selected applicants be invited to submit a full proposal? Finalists will be invited to submit a full proposal in June 2018.

Will I receive any compensation for submitting? You will not receive any compensation for your submission even if it is used by the foundation or third parties in any way.

What are the focus countries for this RFP? While we are not defining a set of countries, countries in South Asia and Sub-Saharan Africa with high rates of childhood under-nutrition are of specific interest.

What is the length of a grant that will be considered? We will consider research studies that propose a rational timeline from inception to research completion that do not exceed 2 years.

What is the budget that will be considered? We will consider research studies that propose appropriate costs for the study length, outcomes, and methods, and that propose strong value for money.

References

Amour, Caroline, Jean Gratz, Estomih Mduma, Erling Svensen, Elizabeth T. Rogawski, Monica McGrath, Jessica C. Seidman, et al. 2016. "Epidemiology and Impact of Campylobacter Infection in Children in 8 Low-Resource Settings: Results From the MAL-ED Study." Clinical Infectious Diseases 63 (9). Oxford University Press: ciw542. https://doi.org/10.1093/cid/ciw542.

Blaser, Martin J. 1997. "Epidemiologic and Clinical Features of Campylobacter Jejuni Infections." The Journal of Infectious Diseases 176 (s2). Oxford University Press: S103–5. https://doi.org/10.1086/513780.

Briscoe, John. 1984. "Intervention Studies and the Definition of Dominant Transmission Routes." American Journal of Epidemiology 120 (3). Oxford University Press: 449–56. https://doi.org/10.1093/oxfordjournals.aje.a113909.

François, Ruthly, Pablo Peñataro Yori, Saba Rouhani, Mery Siguas Salas, Maribel Paredes Olortegui, Dixner Rengifo Trigoso, Nora Pisanic, et al. 2018. "The Other Campylobacters: Not Innocent Bystanders in Endemic Diarrhea and Dysentery in Children in Low-Income Settings." Edited by Joseph M. Vinetz. PLOS Neglected Tropical Diseases 12 (2). Public Library of Science: e0006200. https://doi.org/10.1371/journal.pntd.0006200.

Humphrey, J, A Prendergast, R Ntozini, and M Gladstone. 2017. "Sanitation Hygiene Infant Nutrition Efficacy (SHINE) Trial in Zimbabwe: Rationale, Design, Methods, Intervention Uptake." In Proceedings of the Annual Meeting of the American Society of Tropical Medicine & Hygiene.

Liu, Jie, James A Platts-Mills, Jane Juma, Furqan Kabir, Joseph Nkeze, Catherine Okoi, Darwin J Operario, et al. 2016. "Use of Quantitative Molecular Diagnostic Methods to Identify Causes of Diarrhoea in Children: A Reanalysis of the GEMS Case-Control Study." The Lancet 388 (10051). Elsevier: 1291–1301. https://doi.org/10.1016/S0140-6736(16)31529-X.

Mughini-Gras, Lapo, Christian Penny, Catherine Ragimbeau, Franciska M. Schets, Hetty Blaak, Birgitta Duim, Jaap A. Wagenaar, et al. 2016. "Quantifying Potential Sources of Surface Water Contamination with Campylobacter Jejuni and Campylobacter Coli." Water Research 101 (September). Pergamon: 36–45. https://doi.org/10.1016/J.WATRES.2016.05.069.

Platts-Mills, James A, Mami Taniuchi, Md Jashim Uddin, Shihab Uddin Sobuz, Mustafa Mahfuz, Sm Abdul Gaffar, Dinesh Mondal, et al. 2017. "Association between Enteropathogens and Malnutrition in Children Aged 6-23 Mo in Bangladesh: A Case-Control Study." The American Journal of Clinical Nutrition 105 (5). American Society for Nutrition: 1132–38. https://doi.org/10.3945/ajcn.116.138800

Schnee, Amanda E, William A, Petri, and Jr. 2017. "Campylobacter Jejuni and Associated Immune Mechanisms: Short-Term Effects and Long-Term Implications for Infants in Low-Income Countries." Current Opinion in Infectious Diseases 30 (3). NIH Public Access: 322–28. https://doi.org/10.1097/QCO.0000000000000364.

Snelling, W J, J P McKenna, D M Lecky, and J S G Dooley. 2005. "Survival of Campylobacter Jejuni in Waterborne Protozoa." Applied and Environmental Microbiology 71 (9). American Society for Microbiology (ASM): 5560–71. https://doi.org/10.1128/AEM.71.9.5560-5571.2005.