Gut Microbiota and Response to Immunotherapeutic Drugs in Oncology: More Questions Than Answers.

Immuno-oncology drugs (IODs) have revolutionized the treatment of some cancers. Although IODs are enabling some patients with cancer to become long-time survivors, only 30% to 40% respond to these drugs. There is experimental and clinical evidence that the gut microbiome may play a role in IOD response, leading to speculation that manipulation of the gut microenvironment might improve the response rate to IODs. We review the evidence relating to how gut microorganisms may affect response to IODs and discuss the implications of targeting the microbiome to improve IOD response, including the challenges to refine and translate the findings to practical clinical use.

Comparison of the urine Leukocyte Esterase Test to a Nucleic Acid Amplification Test for screening non-health care-seeking male soldiers for Chlamydia trachomatis and Neisseria gonorrhoeae infections.

We evaluated the Leukocyte Esterase Test (LET) as a screening tool by testing urine from 1,438 non-health care-seeking male Army basic trainees with LET and a Nucleic Acid Amplification Test. Compared to Nucleic Acid Amplification Test results, LET sensitivity and specificity for detection of chlamydia and gonorrhea were 45.8% and 97.4%, and 60.0% and 96.2%, respectively. The prevalence of chlamydia and gonorrhea was 3.3% and 0.3%, respectively. In this population, the prevalence of gonorrhea was too low to produce reliable estimates of performance characteristics of the LET for gonorrhea. The LET is not warranted for use in screening non-health care-seeking male Army trainees.

An assessment of health status among medical research volunteers who served in the Project Whitecoat program at Fort Detrick, Maryland.

Between 1954 and 1973, more than 2000 men entering military service as conscientious objectors participated in Project Whitecoat as medical research volunteers for the Army's biological warfare defense program. An assessment of self-reported, current health status among 358 "exposed" individuals and 164 unexposed control subjects found no conclusive evidence that receipt of investigational agents was related to adverse health outcomes. No differences in current overall health, current exercise levels, self-reported symptoms, and self-reported medical conditions were seen between the study groups. Possible associations were seen between exposure to antibiotics or other biological agents and self-reported asthma (13.0% vs. 2.4%, relative risk [RR] = 6.00, 95% confidence interval [CI] = 1.03-34.90, p = 0.050), as well as between receipt of tularemia vaccine(s) and self-reported asthma (13.3% vs. 2.4%, RR = 6.15, 95% CI = 1.03-36.70, p = 0.049) and increased frequency/severity of headaches (35.6% vs. 18.3%, RR = 2.46, 95% CI = 0.99-6.15, p = 0.074). However, the size of the population under study was insufficient to assert with confidence that these statistical associations are real.

Phase I study of safety and immunogenicity of an Escherichia coli-derived recombinant protective antigen (rPA) vaccine to prevent anthrax in adults.

BACKGROUND: The fatal disease caused by Bacillus anthracis is preventable with a prophylactic vaccine. The currently available anthrax vaccine requires a lengthy immunization schedule, and simpler and more immunogenic options for protection against anthrax are a priority for development. In this report we describe a phase I clinical trial testing the safety and immunogenicity of an anthrax vaccine using recombinant Escherichia coli-derived, B. anthracis protective antigen (rPA). METHODOLOGY/PRINCIPAL FINDINGS: A total of 73 healthy adults ages 18-40 were enrolled and 67 received 2 injections separated by 4 weeks of either buffered saline placebo, or rPA formulated with or without 704 µg/ml Alhydrogel® adjuvant in increasing doses (5, 25, 50, 100 µg) of rPA. Participants were followed for one year and safety and immunologic data were assessed. Tenderness and warmth were the most common post-injection site reactions. No serious adverse events related to the vaccine were observed. The most robust humoral immune responses were observed in subjects receiving 50 µg of rPA formulated with Alhydrogel® with a geometric mean concentration of anti-rPA IgG antibodies of 283 µg/ml and a toxin neutralizing geometric 50% reciprocal geometric mean titer of 1061. The highest lymphoproliferative peak cellular response (median Lymphocyte Stimulation Index of 29) was observed in the group receiving 25 µg Alhydrogel®-formulated rPA. CONCLUSIONS/SIGNIFICANCE: The vaccine was safe, well tolerated and stimulated a robust humoral and cellular response after two doses. TRIAL REGISTRATION: ClinicalTrials.gov NCT00057525.

Patterns of antibody response in humans to the anthrax vaccine adsorbed (AVA) primary (six-dose) series.

The antibody profile during and after the six-dose primary vaccination series with anthrax vaccine adsorbed (AVA, Biothrax) was characterized in 86 human volunteers. Ninety-three percent of recipients developed IgG antibodies to Bacillus anthracis protective antigen (PA) after two doses, and 100% were seropositive after dose #3. Geometric mean concentrations (GMC) of IgG to PA measured before and after each dose were significantly lower after injection #3 (peak GMC=146.65 microg/mL, trough GMC=15.16 microg/mL) than after injections #4 (peak GMC=430.46 microg/mL, trough GMC=94.57 microg/mL), #5 (peak GMC=415.05 microg/mL, trough GMC=81.94 microg/mL), or #6 (peak GMC=401.16 microg/mL, trough GMC=96.19 microg/mL) (por=0.7923 for each). Decay rates for IgG to PA were significantly faster after injection #3 (half life [T1/2]=39.21 days) than after injections #4 (T1/2=72.03 days), #5 (T1/2=70.14 days), and #6 (T1/2=74.59 days) (p

Protective antigen and toxin neutralization antibody patterns in anthrax vaccinees undergoing serial plasmapheresis.

Recipients of licensed anthrax vaccine (AVA; Biothrax) could serve as a source of hyperimmune plasma and immunoglobulin for therapy and prophylaxis. We measured serum antibodies during serial weekly to biweekly plasmapheresis in 38 individuals previously vaccinated with 4 to 27 doses of AVA. Immunoglobulin G (IgG) to protective antigen (PA) and toxin neutralization assay (TNA) antibody levels were highly correlated (r = 0.86930 and P < 0.0001 for anti-PA concentration versus TNA concentration). Significant decreases in antibody titer and concentration were observed over time when compared for the number of days from the last AVA injection (P < 0.0001 for both anti-PA and TNA concentration) and for the number of days from the first plasmapheresis (P = 0.0007 for anti-PA concentration and P = 0.0025 for TNA concentration). The rate of the decrease in total IgG concentration (half-life [t(1/2)] = 198.90 days after first plasmapheresis) was significantly less than the decrease in anti-PA IgG (t(1/2) = 63.53 days) (P < 0.0001), indicating that the reduction in anti-PA IgG was more likely due to natural decay than plasmapheresis. The time since the last injection and the time after initial plasmapheresis are important elements in considering an optimal schedule for collecting anthrax hyperimmune plasma. Good correlation between IgG to PA and TNA antibodies suggests that the anti-PA enzyme-linked immunosorbent assay can be used as a high-throughput screen for functional immune reactivity in donor plasma units.

First case of bioterrorism-related inhalational anthrax, Florida, 2001: North Carolina investigation.

The index case of inhalational anthrax in October 2001 was in a man who lived and worked in Florida. However, during the 3 days before illness onset, the patient had traveled through North Carolina, raising the possibility that exposure to Bacillus anthracis spores could have occurred there. The rapid response in North Carolina included surveillance among hospital intensive-care units, microbiology laboratories, medical examiners, and veterinarians, and site investigations at locations visited by the index patient to identify the naturally occurring or bioterrorism-related source of his exposure.

Long-term health effects of repeated exposure to multiple vaccines.

The health of 155 former workers in a US military research program who had received multiple vaccines and 265 matched community controls was assessed. The study population was mostly male (83%) and elderly (median age, 69 years). Multiply immunized (MIP) subjects received vaccines and/or skin tests (median = 154) over a median of 17.3 years; interval from start of immunizations to survey completion was 15-55 years (mean = 43.1 years). MIP subjects characterized themselves as slightly less healthy than controls (P = 0.057). Fatigue (but no other symptom) was reported more frequently in the MIP group (P = 0.011), but was not associated with number of injections, number of vaccines, or time in program. No differences between MIP and control groups were seen for numerous self-reported medical conditions. Several statistically significant abnormalities were seen in clinical laboratory tests among MIP subjects, but none appeared to be clinically significant. A significant difference in frequency of monoclonal spikes and/or paraprotein peaks between MIP (12.5%) and control (4.5%) groups (RR = 2.7, P < 0.003) was observed; no associations with lifestyle, vaccine exposure, or medical conditions were found.

Feasibility and short-term impact of linked education and urine screening interventions for Chlamydia and gonorrhea in male army recruits.

OBJECTIVE: The objective of this study was to assess the feasibility of an intervention for sexually transmitted diseases (STDs) and a screening program for Chlamydia trachomatis and Neisseria gonorrhoeae infections in male Army recruits. GOALS: The goals of this study were to identify and treat chlamydia and gonorrhea infections in recruits, assess their perceptions of risk, and increase their STD knowledge and behavioral intentions. STUDY DESIGN: Volunteers (n = 3911) entering basic training (July 1999-June 2000) at Fort Jackson, South Carolina, attended an educational intervention, completed pre- and post-questionnaires, and provided a urine specimen for chlamydia and gonorrhea screening by nucleic acid amplification testing. RESULTS: Chlamydia and gonorrhea prevalences were 4.7% and 0.4%, respectively. The mean STD knowledge score, intent to use condoms, and confidence in using condoms correctly increased (P <0.001). Participants reported increased risk perception and considered the educational program valuable (96.9%) and a learning experience (94.6%). CONCLUSIONS: A linked educational and screening program is feasible and acceptable in male Army recruits.

Sustained high prevalence of Chlamydia trachomatis infections in female army recruits.

BACKGROUND: Chlamydia trachomatis infections are prevalent among young sexually active females, have serious sequelae, and are mostly asymptomatic. Screening and treatment of infected females has been demonstrated to prevent sequelae such as pelvic inflammatory disease. GOAL: To assess prevalence and risk factors for chlamydia infection in US Army female recruits, whether these changed over time, and to examine variables contributing to any observed patterns. STUDY DESIGN: Prevalence study of 23,010 non-healthcare-seeking female Army recruits enrolled in a chlamydia screening program at Fort Jackson, SC, from January 1996 through June 1999. Each of the 4-year cohorts was examined separately for prevalence and risk factors. MAIN OUTCOME MEASURES: Urine-based testing for C trachomatis by ligase chain reaction was used to determine prevalence, and questionnaires were used to collect demographic and risk information. State home of record for each recruit was transformed into Public Health reporting region: West, Midwest, South, Northeast, and Territories. RESULTS: Prevalence for all years was 9.51%, but a progressive increase from 8.51% to 9.92% occurred over the course of study (P=0.018). The proportion of individuals reporting specific risk factors during the 90 days preceding the study generally decreased over time. In a regression model, significant risk factors for infection included black race, age 25 years or younger, home-of-record from the South, being screened during years 3 and 4 of the study, more than one sex partner, a new sex partner, and history of any sexually transmitted disease. Condom use was protective. In another model controlling for age and home-of-record from the South, being screened in years 2, 3, and 4 of the study were significantly predictive for being chlamydia positive. CONCLUSION: A high and slightly increasing prevalence of C trachomatis infection was observed among young females entering the military over 4 consecutive years. Young age, black race, home-of-record from the South, more than one sex partner, a new sex partner, condom use, and a history of having a sexually transmitted disease were correlates of chlamydia infection. Sustained high rates of C trachomatis infection in this population provide clear justification for a chlamydia control program for young women entering the Army consisting of screening at entry on the basis of age and possibly home-of-record together with continued periodic rescreening. SUMMARY: A study of 23,010 female Army recruits demonstrated that a high prevalence of C trachomatis was sustained during 4 years of observation. Year of study, young age, and being from the South were significant predictors of infection.

Antibody response to a delayed booster dose of anthrax vaccine and botulinum toxoid.

We evaluated the prevalence and concentration of serum antibodies 18-24 months after primary inoculation with anthrax and botulinum vaccines, and assessed the reactogenicity and immunogenicity of a significantly delayed booster dose of these vaccines. Five hundred and eight male active-duty military personnel received one, two or three inoculations with anthrax vaccine and/or botulinum toxoid in 1990/1991 in preparation for Operations Desert Shield/Desert Storm. Subjects were vaccinated with the licensed anthrax vaccine, adsorbed (AVA) and pentavalent (ABCDE) botulinum toxoid (PBT) BB-IND 3723. Anthrax protective antigen (PA) IgG antibody was measured in serum using an immunocapture enzyme-linked immunosorbent assay (ELISA). A mouse neutralization test was used to determine the titer of Clostridium botulinum type A antitoxin in serum samples. The prevalence of anti-PA IgG was 30% in individuals 18-24 months after priming with one, two or three doses of AVA. After boosting, 99% of volunteers had detectable anti-PA IgG; only two individuals failed to respond. The prevalence of antibodies against botulinum toxin type A was 28% 18-24 months after initial priming. Following boosting, 99% of volunteers had serum titers >0.02IU/ml, and 97% responded with titers > or =0.25IU/ml. Systemic reactions to booster vaccinations could not be specifically ascribed to one or the other vaccine, but were generally mild and of brief duration. Forty-five percent of volunteers reported one or more systemic reactions over the course of 7 days. Injection site reactions of any kind occurred in 25% of AVA recipients and in 16% of PBT recipients; persistence of local reactions beyond 7 days was infrequent. While the kinetics and durability of immune responses must be studied, these findings suggest that booster doses of anthrax vaccine and botulinum toxoid sufficient to stimulate a robust anamnestic response may be given at times distant from receipt of the primary inoculations.

Hospitalization rates in female US Army recruits associated with a screening program for Chlamydia trachomatis.

BACKGROUND: A volunteer program to test non-healthcare-seeking women for genital Chlamydia trachomatis infection was instituted at the US Army's largest basic training center and evaluated for its effectiveness in reducing sequelae. GOAL: To compare hospitalization rates between women with positive test results for C trachomatis and those with negative results, and between women tested and those not tested for C trachomatis. STUDY DESIGN: For this study, 28,074 women who entered the Army in 1996 and 1997 were followed for hospitalizations through December 1998. Of these women, 7053 were tested for C trachomatis, and 21,021 were not screened. Hospital admissions were calculated per person-year, and adjusted relative risks were determined. RESULTS: The overall prevalence of C trachomatis in the screened group was 9.1%. The relative risk of hospitalization for pelvic inflammatory disease in the screened cohort was 0.94 (95% CI, 0.69-1.29), as compared with those not screened. The relative risk of hospitalization for any reason was 0.94 (95% CI, 0.90-0.99). Among women screened, no difference was found in pelvic inflammatory disease hospitalizations between women with positive test results who were being treated for C trachomatis and those with negative test results. CONCLUSIONS: The investigated C trachomatis intervention program for female Army recruits was associated with a lower overall hospitalization rate in screened volunteers, as compared with unscreened women. The pelvic inflammatory disease hospitalization rate in women with C trachomatis who were screened and treated was similar to that observed in uninfected women.

Evaluation of dry and wet transported intravaginal swabs in detection of Chlamydia trachomatis and Neisseria gonorrhoeae infections in female soldiers by PCR.

Screening women for sexually transmitted diseases (STD) in nonclinic settings is highly desirable because many infections are asymptomatic. This is especially true for military women, for whom logistical, social, and other job-related obstacles present barriers to accessing medical care. We assessed the accuracy of intravaginal swabs transported by mail in a wet versus a dry state for PCR (Amplicor CT/NG test) detection of chlamydia and gonorrhea infections in a cross-sectional study of 793 active-duty military women attending an STD clinic. PCR tests of vaginal swabs (wet and dry) were compared to local clinical methods used on cervical swabs. Standard wet vaginal swab PCR testing detected more chlamydia (11.6%) than cervical enzyme immunoassay (9.3%). For detection of chlamydia using wet swabs, the sensitivity and specificity compared with adjudicated true positives were 94.6% (87 of 92) and 99.3% (696 of 701), respectively. Comparing dry swabs to true-positives for chlamydia, the sensitivity was 91.3% (84 of 92) and the specificity was 99.3% (696 of 701). Standard wet vaginal swab PCR detected more gonorrhea (3.3%) than routine cervical culture (2.1%). The sensitivity and specificity of PCR testing of wet swabs compared to true-positives (infected patients) were 96.3% (26 of 27) and 98.2% (752 of 766) for gonorrhea, respectively. For gonorrhea, the sensitivity and specificity of dry swabs compared to true-positives (infected patients) were 88.9% (24 of 27) and 98.3% (753 of 766), respectively. PCR testing of wet and dry transported intravaginal swabs to detect chlamydia and gonorrhea infections was an accurate diagnostic method for military women.

Toward a vaccine against Argentine hemorrhagic fever

A vaccine against Argentine hemorrhagic fever, the "mal de los rastrojos" of the pampas, has been a dream of physicians and scientists involved with the disease since its regognition in the 1950s. Several killed and live immunogens have been produced and tested in pursuit of this goal, none of which has proved suitable for widespread human use. Recently, a new live-attenuated Junin virus vaccine. Candid #1, was developed through a cooperative international effort. Testing conducted to date indicates that this vaccine holds considerable promise

Toward a vaccine against Argentine hemorrhagic fever

A vaccine against Argentine hemorrhagic fever, the "mal de los rastrojos" of the pampas, has been a dream of physicians and scientists involved with the disease since its regognition in the 1950s. Several killed and live immunogens have been produced and tested in pursuit of this goal, none of which has proved suitable for widespread human use. Recently, a new live-attenuated Junin virus vaccine. Candid #1, was developed through a cooperative international effort. Testing conducted to date indicates that this vaccine holds considerable promise