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Background The epidemiology of antibiotic-resistant pathogens guides antimicrobial therapy for bacterial bloodstream infections (BSI). We describe changes in antimicrobial-resistant BSI pathogens over time within the US Military Health System (MHS), which prospectively captures clinical and microbiological data from both retired and active-duty US Uniformed service members and their beneficiaries. Methods The study population included MHS beneficiaries with blood cultures positive for any bacterial pathogens (Jan 2010 – Dec 2019). Microbiological data were obtained from the Navy and Marine Corps Public Health Center and antibiotic resistance was interpreted using CLSI breakpoints corresponding to collection year. Blood contaminants were excluded. Difficult to treat resistance (DTR) was defined in Gram-negative bacteria (GNB) as isolates with in vitro resistance to three classes of antibiotics: carbapenems, extended-spectrum cephalosporins, and fluoroquinolones. Results The 15 most frequent bacterial pathogens, representing 15,358 BSI episodes from 12,749 individuals, were subcategorized in four groups based on shared BSI clinical features. Lactose-fermenting GNB (LFGNB) were most common, accounting for 42% of BSI pathogens, following by Streptococcus/Enterococcus spp. (33%), Staphylococcus aureus (20%), and non-lactose fermenting GNB (NLGNB, 5.5%). The rate of LFGNB BSI increased from 7.57 per 100,000 beneficiaries in 2010 to 8.42 in 2019 (peak of 8.83 in 2016), resulting in an increase of 11.3% during the study period (Figure). Rates of BSI attributed to Streptococcus/Enterococcus spp., S. aureus, and NLGNB decreased 26%, 29%, and 45%, respectively, over the study period. The average annual rates of methicillin-resistant S. aureus, vancomycin-resistant Enterococcus spp., and DTR GNB BSI were 1.30, 0.25, and 0.05 per 100,000 beneficiaries, respectively. Over the study period, these rates decreased 58.3%, 72.4% and 24.2%, respectively. Conclusion LFGNB BSI numerically increased over time while NLGNB BSI (e.g., Pseudomonas aeruginosa and Acinetobacter spp.) decreased. The burden of DTR GNB BSI also decreased, indicating that first-line antibiotics remain clinically available for most patients with BSI. Disclosures John H. Powers, III, MD, Arrevus: Advisor/Consultant|Eicos: Advisor/Consultant|Evofem: Advisor/Consultant|Eyecheck: Advisor/Consultant|Gilead: Advisor/Consultant|GlaxoSmithKline: Advisor/Consultant|OPKO: Advisor/Consultant|Resolve: Advisor/Consultant|Romark: Advisor/Consultant|SpineBioPharma: Advisor/Consultant|UTIlity: Advisor/Consultant|Vir: Advisor/Consultant.

Background The epidemiology of recurrent bacterial bloodstream infections (rBSI) has not been fully characterized. Evaluating rBSI represents opportunities to inform morbidity risk factors and prevention strategies. We describe the clinical and microbiological features of rBSI in the US Military Health System (MHS) in a prospective cohort study, including retired and active-duty US uniformed service members and their beneficiaries. Methods We collected data for rBSI episodes from MHS beneficiaries (Jan 2010 – Dec 2019). A rBSI is defined as growth of the same bacterial pathogen in blood culture >14 days after the index or previous episode. Demographics and comorbidities were collected prior to the index BSI. Microbiological data were obtained from the Navy and Marine Corps Public Health Center. Descriptive statistics are presented. Results A total of 12,749 beneficiaries were diagnosed with a BSI attributed to 1 of the 15 most common bacterial pathogens associated with BSI in the MHS, with 646 (5.1%) experiencing a rBSI. Escherichia coli had the largest proportion among all patients with rBSI (31% of 646); however, Enterococcus spp. accounted for the highest proportion of rBSI within a given pathogen subgroup (7.4% of 1,154 Enterococcus BSI; Table). Pseudomonas aeruginosa BSI had the shortest average time to recurrence (119 days), and Acinetobacter spp. had the highest frequency of BSI recurrences per patient (mean of 3). Male sex (59.9%) and age ≥65 years (52.9%) were most common among the rBSI patients. The updated Charlson Comorbidity index score preceding the index BSI was a median of 5.0, and chronic pulmonary disease (57.3%) and diabetes (56.6%) contributed the largest proportion of common comorbidities. A total of 88 (13%) rBSI patients had their index BSI while hospitalized following trauma where S. aureus was the most common (37.5%) bacterial pathogen. Conclusion Overall, the proportion of rBSI (5.1%) in our cohort of MHS beneficiaries was generally lower than that previously reported in the literature. Individuals with rBSI had a substantial burden of comorbid disease with 13% having trauma precede the index BSI. Identifying risk factors for recurrence may improve management strategies of primary BSI and may reduce morbidity of subsequent BSI. Disclosures John H. Powers, III, MD, Arrevus: Advisor/Consultant|Eicos: Advisor/Consultant|Evofem: Advisor/Consultant|Eyecheck: Advisor/Consultant|Gilead: Advisor/Consultant|GlaxoSmithKline: Advisor/Consultant|OPKO: Advisor/Consultant|Resolve: Advisor/Consultant|Romark: Advisor/Consultant|SpineBioPharma: Advisor/Consultant|UTIlity: Advisor/Consultant|Vir: Advisor/Consultant.

Background We sought to determine the frequency of asymptomatic SARS-CoV-2 infections, the BNT162b2 mRNA COVID 19 vaccine-related symptoms, and the correlates of immunity in post-vaccination breakthrough infections in a prospective cohort of healthcare workers. Methods We have been conducting a single-center, observational cohort study of healthcare workers. 271 participants were enrolled since August 25, 2020. Testing for SARS-CoV-2 spike (S)-specific IgG antibodies is conducted using a microsphere-based multiplex immunoassay interpolated against an internal standard curve for binding antibody (bAb) units (BAU) and has been performed on serum samples collected at monthly visits between September 2020 to August of 2021, and quarterly since then. Neutralizing antibody titers against wild-type (WT) virus are determined by microneutralization assays and against Delta and Omicron variants by lentiviral pseudovirus neutralization assays. For the first 6 months, participants completed a symptoms questionnaire every day they had any symptoms. Results 12 participants were diagnosed with SARS-CoV-2, with at least mild symptoms. Of 206 participants evaluated for adverse effects after 1st and 2nd vaccine doses, no relationship was observed between vaccine-associated symptom scores and antibody titers 1 month after the 2nd dose. Longitudinal studies demonstrate that anti-S IgG bAbs decrease from a geometric mean (GM) of 1929 BAU/mL at 1 month post-vaccination to a GM of 442 BAU/mL at 6 months post-vaccination (P< 0.001, n=187), and that boosting increases S-specific IgG BAU. While only 5 of 39 participants had detectable anti-Omicron neutralizing activity 1 month after 2 vaccinations, booster vaccination resulted in detectable neutralizing activity for all participants. Conclusion Asymptomatic infection is likely rare, that there is no relationship between vaccine-associated symptom severity and antibody titers 1 month after the 2nd vaccination, and that booster results in better protection against the Omicron variant. Ongoing studies are evaluating serological and cellular immune responses immediately prior to 38 breakthrough infections in an attempt to identify immune correlates of protection and will be reported at the conference. Disclosures John H. Powers, III, MD, Arrevus: Advisor/Consultant|Eicos: Advisor/Consultant|Evofem: Advisor/Consultant|Eyecheck: Advisor/Consultant|Gilead: Advisor/Consultant|GlaxoSmithKline: Advisor/Consultant|OPKO: Advisor/Consultant|Resolve: Advisor/Consultant|Romark: Advisor/Consultant|SpineBioPharma: Advisor/Consultant|UTIlity: Advisor/Consultant|Vir: Advisor/Consultant David Tribble, MD, DrPH, Astra Zeneca: The HJF, in support of the USU IDCRP, was funded to conduct or augment unrelated Phase III Mab and vaccine trials as part of US Govt. COVID19 response Simon Pollett, MBBS, Astra Zeneca: The HJF, in support of the USU IDCRP, was funded to conduct or augment unrelated Phase III Mab and vaccine trials as part of US Govt. COVID19 response Timothy Burgess, MD, MPH, AstraZeneca: The HJF, in support of the USU IDCRP, was funded to conduct or augment unrelated Phase III Mab and vaccine trials as part of US Govt. COVID19 response.

Background The frequency of asymptomatic severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections is unclear and may be influenced by how symptoms are evaluated. In this study, we sought to determine the frequency of asymptomatic SARS-CoV-2 infections in a prospective cohort of health care workers (HCWs). Methods A prospective cohort of HCWs, confirmed negative for SARS-CoV-2 exposure upon enrollment, were evaluated for SARS-CoV-2 infection by monthly analysis of SARS-CoV-2 antibodies as well as referral for polymerase chain reaction testing whenever they exhibited symptoms of coronavirus disease 2019 (COVID-19). Participants completed the standardized and validated FLU-PRO Plus symptom questionnaire scoring viral respiratory disease symptom intensity and frequency at least twice monthly during baseline periods of health and each day they had any symptoms that were different from their baseline. Results Two hundred sixty-three participants were enrolled between August 25 and December 31, 2020. Through February 28, 2021, 12 participants were diagnosed with SARS-CoV-2 infection. Symptom analysis demonstrated that all 12 had at least mild symptoms of COVID-19, compared with baseline health, near or at time of infection. Conclusions These results suggest that asymptomatic SARS-CoV-2 infection in unvaccinated, immunocompetent adults is less common than previously reported. While infectious inoculum doses and patient factors may have played a role in the clinical manifestations of SARS-CoV-2 infections in this cohort, we suspect that the high rate of symptomatic disease was due primarily to participant attentiveness to symptoms and collection of symptoms in a standardized, prospective fashion. These results have implications for studies that estimate SARS-CoV-2 infection prevalence and for public health measures to control the spread of this virus.

Background We evaluated clinical outcomes, functional burden, and complications 1 month after coronavirus disease 2019 (COVID-19) infection in a prospective US Military Health System (MHS) cohort of active duty, retiree, and dependent populations using serial patient-reported outcome surveys and electronic medical record (EMR) review. Methods MHS beneficiaries presenting at 9 sites across the United States with a positive severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) test, a COVID-19-like illness, or a high-risk SARS-CoV-2 exposure were eligible for enrollment. Medical history and clinical outcomes were collected through structured interviews and International Classification of Diseases–based EMR review. Risk factors associated with hospitalization were determined by multivariate logistic regression. Results A total of 1202 participants were enrolled. There were 1070 laboratory-confirmed SARS-CoV-2 cases and 132 SARS-CoV-2-negative participants. In the first month post–symptom onset among the SARS-CoV-2-positive cases, there were 212 hospitalizations, 80% requiring oxygen, 20 ICU admissions, and 10 deaths. Risk factors for COVID-19-associated hospitalization included race (increased for Asian, Black, and Hispanic compared with non-Hispanic White), age (age 45–64 and 65+ compared with Conclusions Older age, reporting Asian, Black, or Hispanic race/ethnicity, and obesity are associated with SARS-CoV-2 hospitalization. A proportion of acute SARS-CoV-2 infections require long-term oxygen therapy; the impact of SARS-CoV-2 infection on short-term functional status was substantial. A significant number of MHS beneficiaries had not yet returned to normal activities by 1 month.

Antibodies against SARS-CoV-2 decay but persist six months post-vaccination, with lower levels of neutralizing titers against Delta than wild-type. Only 2 of 227 vaccinated healthcare workers experienced outpatient symptomatic breakthrough infections despite 59 of 227 exhibiting serological evidence of exposure to SARS-CoV-2 as defined by development of anti-nucleocapsid protein antibodies.

Background The relationship between postvaccination symptoms and strength of antibody responses is unclear. The goal of this study was to determine whether adverse effects caused by vaccination with the Pfizer/BioNTech BNT162b2 vaccine are associated with the magnitude of vaccine-induced antibody levels. Methods We conducted a single-center, observational cohort study consisting of generally healthy adult participants that were not severely immunocompromised, had no history of coronavirus disease 2019, and were seronegative for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein before vaccination. Severity of vaccine-associated symptoms was obtained through participant-completed questionnaires. Testing for immunoglobulin G antibodies against SARS-CoV-2 spike protein and receptor-binding domain was conducted using microsphere-based multiplex immunoassays performed on serum samples collected at monthly visits. Neutralizing antibody titers were determined by microneutralization assays. Results Two hundred six participants were evaluated (69.4% female, median age 41.5 years old). We found no correlation between vaccine-associated symptom severity scores and vaccine-induced antibody titers 1 month after vaccination. We also observed that (1) postvaccination symptoms were inversely correlated with age and weight and more common in women, (2) systemic symptoms were more frequent after the second vaccination, (3) high symptom scores after first vaccination were predictive of high symptom scores after second vaccination, and (4) older age was associated with lower titers. Conclusions Lack of postvaccination symptoms after receipt of the BNT162b2 vaccine does not equate to lack of vaccine-induced antibodies 1 month after vaccination., We found no correlation between BNT162b2-associated symptom severity and vaccine-induced antibody titers 1 month after vaccination. Adverse effects inversely correlated with age and weight, whereas symptom severity after first vaccination was predictive of that after second vaccination.

Background SARS-CoV-2 is a recently emerged pandemic coronavirus (CoV) capable of causing severe respiratory illness. However, a significant number of infected people present as asymptomatic or pauci-symptomatic. In this prospective assessment of at-risk healthcare workers (HCWs) we seek to determine whether pre-existing antibody or T cell responses to previous seasonal human coronavirus (HCoV) infections affect immunological or clinical responses to SARS-CoV-2 infection or vaccination. Methods A cohort of 300 healthcare workers, confirmed negative for SARS-CoV-2 exposure upon study entry, will be followed for up to 1 year with monthly serology analysis of IgM and IgG antibodies against the spike proteins of SARS-CoV-2 and the four major seasonal human coronavirus - HCoV-OC43, HCoV-HKU1, HCoV-229E, and HCoV-NL63. Participants will complete monthly questionnaires that ask about Coronavirus Disease 2019 (COVID-19) exposure risks, and a standardized, validated symptom questionnaire (scoring viral respiratory disease symptoms, intensity and severity) at least twice monthly and any day when any symptoms manifest. SARS-CoV-2 PCR testing will be performed any time participants develop symptoms consistent with COVID-19. For those individuals that seroconvert and/or test positive by SARS-CoV-2 PCR, or receive the SARS-CoV-2 vaccine, additional studies of T cell activation and cytokine production in response to SARS-CoV-2 peptide pools and analysis of Natural Killer cell numbers and function will be conducted on that participant’s cryopreserved baseline peripheral blood mononuclear cells (PBMCs). Following the first year of this study we will further analyze those participants having tested positive for COVID-19, and/or having received an authorized/licensed SARS-CoV-2 vaccine, quarterly (year 2) and semi-annually (years 3 and 4) to investigate immune response longevity. Discussion This study will determine the frequency of asymptomatic and pauci-symptomatic SARS-CoV-2 infection in a cohort of at-risk healthcare workers. Baseline and longitudinal assays will determine the frequency and magnitude of anti-spike glycoprotein antibodies to the seasonal HCoV-OC43, HCoV-HKU1, HCoV-229E, and HCoV-NL63, and may inform whether pre-existing antibodies to these human coronaviruses are associated with altered COVID-19 disease course. Finally, this study will evaluate whether pre-existing immune responses to seasonal HCoVs affect the magnitude and duration of antibody and T cell responses to SARS-CoV-2 vaccination, adjusting for demographic covariates.

Background Bloodstream infections (BSI) are associated with inpatient morbidity in the United States. We sought to characterize the epidemiology of common bacterial BSIs in individuals receiving care within the US Military Health System (MHS), which actively prospectively captures clinical and microbiological data from both retired and active-duty US Uniformed Service members and their beneficiaries. Methods We performed a retrospective cohort study analyzing MHS patients with blood cultures positive for all bacterial pathogens, between January 2010 and December 2019. Microbiological data captured by the Navy and Marine Corpse Public Health Center, excluding cultures isolating contaminants, were retrospectively collated with clinical and demographic data from the MHS Data Repository. Results The most frequent nine bacterial pathogens, as well as Acinetobacter spp. represented 17,206 episodes of BSI from 14,531 individuals. The cohort was predominantly male (59.4%) and ≥65 years old (48.7%). Most individuals were retired (N=5,249) or active duty (N=1,418) service members and their dependents (N=5,236). Median Updated Charlson Comorbidity Index Score was 2. Chronic pulmonary disease was the most frequent comorbid condition. Hospital admission was associated with 13,733 (79.8%) BSI episodes, including 5,870 admissions to the ICU. Overall, inpatient mortality was 8.3%. E. coli (29.7%, N= 5,114) was isolated with the highest frequency, followed by S. aureus (22.4%, N=3,853). Further, 9.5% of E. coli and 36.9% of S. aureus isolates were resistant to ceftriaxone and oxacillin, respectively. Beta-hemolytic streptococci represented the highest percentage (6.3%) of recurrent BSI episodes occurring at least 14 days post-initial BSI. Males or Native American race were most commonly infected with S. aureus. E. coli BSI was most common in all other demographic categories. Frequency of Bacterial Blood Stream Infections in the US Military Health System The most frequent nine bacterial pathogens, as well as Acinetobacter spp. in the US Military Health System. Conclusion We assessed the epidemiologic features of all individuals with BSI receiving care in the MHS over a 10-year period. We noted demographic differences in the occurrence of microbiological causes of BSI including S. aureus. Further assessments are underway into BSI-related risk factors for occurrence, antimicrobial resistance and mortality, after controlling for comorbidities and disease severity. Disclosures All Authors: No reported disclosures

Background The Prospective Assessment of SARS-CoV-2 Seroconversion (PASS) study is following over 200 healthcare workers who have received the Pfizer-BioNTech BNT162b2 COVID-19 mRNA vaccine. A major aim of the study is to determine whether baseline antibody titers against the seasonal human coronaviruses are associated with altered levels of vaccine-induced antibody responses to SARS-CoV-2. Methods Serial serum samples obtained pre-vaccination and 1 month after the second dose were tested for IgG antibodies against the full pre-fusion spike protein and the receptor binding domain (RBD) of SARS-CoV-2, as well as the full pre-fusion spike proteins of OC43, HKU1, 229E, and NL63. Antibodies were measured using highly sensitive and specific multiplex assays based on Luminex-xMAP technology. Results Preliminary analyses of the first 103 subjects in whom we have 1 month post-vaccination serum demonstrate development of high IgG geometric mean titers (GMT) to both the full spike protein (GMT: 13,685, 12,014-15,589, 95% CI) and the RBD (GMT: 19,448, 17,264-21,908, 95% CI) of SARS-CoV-2 after the 2nd vaccine dose. Preliminary analysis demonstrates no association between baseline antibody titers against spike protein of OC43 and antibody titers against SARS-CoV-2 spike protein (Pearson’s r-value= 0.13, P-value= 0.21) or RBD (Pearson’s r-value= 0.09, P-value= 0.36) one month after vaccination. Future analyses will evaluate whether there is an association with baseline seasonal coronavirus antibody titers and either SARS-CoV-2 neutralization titers or anti-SARS-CoV-2 spike protein titers at 6 months after vaccination. Conclusion These preliminary results suggest that baseline antibody responses to seasonal coronaviruses neither boost nor impede SARS-CoV-2 vaccine-induced antibody responses. Longitudinal sampling will enable assessment of vaccine durability and determination of whether baseline seasonal coronavirus antibody levels are associated with altered duration of detectable COVID-19 vaccine-induced antibody responses. Disclosures Simon Pollett, MBBS, Astra Zeneca (Other Financial or Material Support, HJF, in support of USU IDCRP, funded under a CRADA to augment the conduct of an unrelated Phase III COVID-19 vaccine trial sponsored by AstraZeneca as part of USG response (unrelated work)) David Tribble, M.D., DrPH, Astra Zeneca (Other Financial or Material Support, HJF, in support of USU IDCRP, funded under a CRADA to augment the conduct of an unrelated Phase III COVID-19 vaccine trial sponsored by AstraZeneca as part of USG response (unrelated work))

Background Bloodstream infections (BSI) are associated with both inpatient mortality and substantial morbidity in the United States. We sought to characterize the epidemiology of BSIs with ESKAPE pathogens on patients served by the United States Military Healthcare System (MHS), which actively prospectively captures clinical and microbiological data from US service members and their beneficiaries. Methods We performed a retrospective analysis of MHS patients with blood cultures positive for ESKAPE pathogens (E. faecium, S. aureus, K. pneumoniae, A. baumannii, P. aeruginosa, and Enterobacter spp.), as well as Neisseria gonorrhoeae and Raoultella spp. between January 2010 and December 2015. Microbiological data from the Navy and Marine Core Public Health Center was retrospectively collated with clinical and demographic data from the MHS Data Repository. Results We identified 7,404 patients who experienced 8,791 episodes of ESKAPE (including N. gonorrhoeae and Raoultella spp.) BSI. The patients were predominately active duty (N=688) or retired (N=2,517) Armed Forces service members and their dependents (N=2,361). Further, 59.4% were male and 47.5% were >65 years old. A total of 5,594 (75.5%) of BSI episodes were associated with hospital admission, with an average length of stay of 14.9 days (SD of 27.5 days) and 47.4% (N=2,650) of those admissions were associated with an ICU stay averaging 8.6 days (SD of 18.0 days). The most common pathogens detected were E. coli (34.6%, N= 3,042) followed by S. aureus (28.0%,N=2,464), with 7.6% and 40.7% of isolates resistant to ceftriaxone and methicillin, respectively. We found a larger proportion of E. coli BSI in females (47.4% versus 26.2%) and S. aureus BSI in males (32% versus 21.9%). The frequency of A. baumannii BSI in younger patients, ages 18-30, was an average 4.5 fold higher than in older age groups (30-50, 50-65 and >65). Conclusion We noted epidemiological differences in the burden of ESKAPE pathogen BSIs, in various populations including sex and age specific risk factors in a population served by the MHS. Further work is underway to evaluate risk factors for infection and outcomes with pathogens with in vitro resistance controlling for factors such as age, gender, co-morbid diseases and severity of illness. Disclosures All Authors: No reported disclosures