Assessment of the Duration of Protection in Campylobacter jejuni Experimental Infection in Humans

Abstract

A human Campylobacter jejuni infection model provided controlled exposure to assess vaccine efficacy and investigate protective immunity for this important diarrheal pathogen. A well-characterized outbreak strain, C. jejuni 81-176, was investigated using a volunteer experimental infection model to evaluate the dose range and duration of protection. Healthy Campylobacter-seronegative adults received C. jejuni strain 81-176 via oral inoculation of 10 5 , 10 7 , or 10 9 CFU (5 adults/dose), which was followed by clinical and immunological monitoring. Based on dose range clinical outcomes, the 10 9 -CFU dose (n ‫؍‬ 31) was used to assess homologous protection at 28 to 49 days (short-term veterans [STV]; n ‫؍‬ 8) or 1 year (long-term veterans [LTV]; n ‫؍‬ 7) after primary infection. An illness dose effect was observed for naïve subjects (with lower doses, 40 to 60% of the subjects were ill; with the 10 9 -CFU dose, 92% of the subjects were ill) along with complete protection for the STV group and attenuated illness for the LTV group (57%). Partial resistance to colonization was seen in STV (25% of the subjects were not infected; 3-log-lower maximum excretion level). Systemic and mucosal immune responses were robust in naïve subjects irrespective of the dose or the severity of illness. In contrast, in STV there was a lack of circulating antibody-secreting cells (ASC), reflecting the local mucosal effector responses. LTV exhibited comparable ASC responses to primary infection, and anamnestic fecal IgA responses likely contributed to self-resolving illness prior to antibiotic treatment. Campylobacter antigen-dependent production of gamma interferon by peripheral blood mononuclear cells was strongly associated with protection from illness, supporting the hypothesis that TH1 polarization has a primary role in acquired immunity to C. jejuni. This study revealed a C. jejuni dose-related increase in campylobacteriosis rates, evidence of complete short-term protection that waned with time, and immune response patterns associated with protection.Campylobacter species, the most common of which is Campylobacter jejuni, are zoonotic food-and waterborne bacterial enteropathogens (1, 2, 52). The gastrointestinal tracts of animals used for food, such as chickens, are the reservoirs for these common organisms (1). Worldwide, C. jejuni is among the most frequent causes of diarrhea, including traveler's diarrhea, and the spectrum of illness ranges from mild watery diarrhea to febrile dysentery (6,14,16,21). Evidence for acquired immunity against C. jejuni has been obtained from epidemiologic studies performed in developing countries that documented that there is a decline in the incidence of disease with increasing age that is accompanied by a shift in the illness-to-infection ratio for children between 2 and 5 years old, development of resistance to colonization, and a shorter excretion period during convalescence (12,44,45). Age-related increases in C. jejuni-specific serology coincide with acquisition of resistance to infection and ...

Characterization of Mucosal Immune Responses to Enterotoxigenic Escherichia coli Vaccine Antigens in a Human Challenge Model: Response Profiles after Primary Infection and Homologous Rechallenge with Strain H10407

“…Our findings are similar to those of previously published studies showing that an oral booster dose given at a time of active mucosal immunity results in lower or similar levels of antibody-secreting cells (ASC) and serum IgA responses to CTB (cholera toxin B) (15,(24)(25)(26). Similar blunting of responses has also been seen with Campylobacter (27) and Shigella (28) volunteer challenge models.…”

“…Since there was only one subject who was not protected from diarrhea when rechallenged, our data were not able to identify such a marker for protection in the present study. Given the high level of interest in ETEC vaccine development, the field could benefit from a longer follow-up after initial infection similar to the challenge-rechallenge studies performed with Campylobacter (27) which may give more insights into correlates of long-term immunity.…”

Global Epidemiology of Campylobacter Infection

“…In contrast, an association between dose and occurrence of disease was observed in humans experimentally infected with C. jejuni strain 81-176. In addition, exposure to C. jejuni strain 81-176 offered only short-term protection (7). This can be reconciled by the fact that the severity of disease, dose-response relationship, and illness/infection ratio are dependent, at least in part, on the strain used.…”

A systematic review of experimental infections with enterotoxigenic Escherichia coli (ETEC)

“…Based on the relatively high inoculum required to elicit diarrhea in a sufficient number of subjects and the inverse association between diarrhea risk and baseline LT IgG titers, one may hypothesize that inclusion of serologic screening, as has been utilized for Campylobacter jejuni challenge model development [59,60], may decrease the required inoculum. None of the studies reviewed here reported serologic screening of potential study participants.…”