Humoral immune responses associated with control of SARS-CoV-2 breakthrough infections in a vaccinated US military population.

BACKGROUND: COVID-19 vaccines have been critical for protection against severe disease following infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) but gaps remain in our understanding of the immune responses that contribute to controlling subclinical and mild infections. METHODS: Vaccinated, active-duty US military service members were enrolled in a non-interventional, minimal-risk, observational study starting in May, 2021. Clinical data, serum, and saliva samples were collected from study participants and were used to characterise the humoral immune responses to vaccination and to assess its impact on clinical and subclinical infections, as well as virologic outcomes of breakthrough infections (BTI) including viral load and infection duration. FINDINGS: The majority of VIRAMP participants had received the Pfizer COVID-19 vaccine and by January, 2022, N = 149 had a BTI. The median BTI duration (PCR+ days) was 4 days and the interquartile range was 1-8 days. Participants that were nucleocapsid seropositive prior to their BTI had significantly higher levels of binding and functional antibodies to the spike protein, shorter median duration of infections, and lower median peak viral loads compared to seronegative participants. Furthermore, levels of neutralising antibody, ACE2 blocking activity, and spike-specific IgA measured prior to BTI also correlated with the duration of infection. INTERPRETATION: We extended previous findings and demonstrate that a subset of vaccine-induced humoral immune responses, along with nucleocapsid serostatus are associated with control of SARS-CoV-2 breakthrough infections in the upper airways. FUNDING: This work was funded by the DoD Joint Program Executive Office for Chemical, Biological, Radiological and Nuclear Defense (JPEO-CBRND) in collaboration with the Defense Health Agency (DHA) COVID-19 funding initiative for the VIRAMP study.

Integrating Somatic and Germline Next-Generation Sequencing Into Routine Clinical Oncology Practice.

Next-generation sequencing (NGS) is rapidly expanding into routine oncology practice. Genetic variations in both the cancer and inherited genomes are informative for hereditary cancer risk, prognosis, and treatment strategies. Herein, we focus on the clinical perspective of integrating NGS results into patient care to assist with therapeutic decision making. Five key considerations are addressed for operationalization of NGS testing and application of results to patient care as follows: (1) NGS test ordering and workflow design; (2) result reporting, curation, and storage; (3) clinical consultation services that provide test interpretations and identify opportunities for molecularly guided therapy; (4) presentation of genetic information within the electronic health record; and (5) education of providers and patients. Several of these key considerations center on informatics tools that support NGS test ordering and referencing back to the results for therapeutic purposes. Clinical decision support tools embedded within the electronic health record can assist with NGS test utilization and identifying opportunities for targeted therapy including clinical trial eligibility. Challenges for project and change management in operationalizing NGS-supported, evidence-based patient care in the context of current information technology systems with appropriate clinical data standards are discussed, and solutions for overcoming barriers are provided.

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.

Clinical trials recruitment planning: A proposed framework from the Clinical Trials Transformation Initiative.

Patient recruitment is widely recognized as a key determinant of success for clinical trials. Yet a substantial number of trials fail to reach recruitment goals-a situation that has important scientific, financial, ethical, and policy implications. Further, there are important effects on stakeholders who directly contribute to the trial including investigators, sponsors, and study participants. Despite efforts over multiple decades to identify and address barriers, recruitment challenges persist. To advance a more comprehensive approach to trial recruitment, the Clinical Trials Transformation Initiative (CTTI) convened a project team to examine the challenges and to issue actionable, evidence-based recommendations for improving recruitment planning that extend beyond common study-specific strategies. We describe our multi-stakeholder effort to develop a framework that delineates three areas essential to strategic recruitment planning efforts: (1) trial design and protocol development, (2) trial feasibility and site selection, and (3) communication. Our recommendations propose an upstream approach to recruitment planning that has the potential to produce greater impact and reduce downstream barriers. Additionally, we offer tools to help facilitate adoption of the recommendations. We hope that our framework and recommendations will serve as a guide for initial efforts in clinical trial recruitment planning irrespective of disease or intervention focus, provide a common basis for discussions in this area and generate targets for further analysis and continual improvement.

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.

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.

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.

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.

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.

Musculoskeletal injuries in an Army airborne population.

To maintain operational readiness, military personnel engage in vigorous physical and training activities that carry risk for injury. A 1-year prospective cohort study, starting April 1996, was conducted at Fort Bragg, North Carolina among 1,965 members of the 82nd Airborne Division to quantify musculoskeletal injuries. Information collected included type of injury, site, circumstances, and resultant limited duty days. These soldiers suffered 508 overuse injuries (including 38 stress fractures), 1,415 traumatic injuries (including 100 fractures), and 101 unclassified injuries. Injury rates were 6.8% per soldier per month for traumatic injury and 2.4% for overuse injury (totaling 1.2 injuries per soldier per year). Injuries resulted in 22,041 limited duty days, averaging 11 days per injury and 13 days per soldier (4.5% of total workdays). Fractures and stress fractures/reactions produced the most days lost per case. Most of these injuries resulted from military-specific activities.

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.

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.