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Background In previous influenza challenge studies we observed that the incidence of influenza symptoms was higher in women than in men, and that women experience more symptoms overall. Women also demonstrated lower neuraminidase (NA) inhibition (NAI) antibody titers than men after challenge and regression analysis suggested that NAI titers predict clinical outcomes. We sought to evaluate this using data from a more recent challenge study with more immunologically varied volunteers, while also assessing mucosal immunity. Methods We obtained mucosal and serum samples from healthy adults. Half underwent intramuscular quadrivalent influenza vaccination followed by influenza A (H1N1) intranasal challenge while others just challenge alone. Antibody titers and clinical outcomes between sexes were compared. Results No significant differences in shedding or symptom outcomes were observed between sexes. Similarly, no differences in systemic titers against NA or hemagglutinin (HA) were seen. Serum total IgG and IgA were also similar between sexes. Prior to vaccination, mucosal IgA titers were significantly lower against HA stalk and NA in women, but these differences disappeared after vaccination. In the unvaccinated group, lower nasal IgA titers were also seen in women pre-challenge. At 7 days post-challenge, differences in mucosal titers between sexes disappeared. However, at 56 days post-challenge, mucosal IgA titers against HA, HA stalk, and NA were all significantly lower in women. Conclusion In contrast to our previous findings, no differences in clinical outcomes or systemic NAI titers were observed between men and women, possibly due to differences in underlying immunity between study populations or the lower sample size in this study. However, mucosal differences were noted with women having lower mucosal titers than men against HA stalk and NA at baseline. While influenza vaccination and challenge eliminated differences in the short term, they reappeared 8 weeks after challenge, with all nasal IgA antibody titers (HA, HA stalk, and NA) lower in women. Further studies are necessary to understand the differences in influenza disease and immunity between sexes. Disclosures All Authors: No reported disclosures.

Background Preclinical animal studies and retrospective human studies suggest that adult females have worse outcomes from influenza than males. Prospective studies in humans are missing. Methods Data from 164 healthy volunteers who underwent influenza A/California/04/2009/H1N1 challenge were compiled to compare differences between sexes. Baseline characteristics, including hormone levels, hemagglutination inhibition (HAI) titers, neuraminidase inhibition (NAI) titers, and outcomes after challenge were compared. Linear and logistic regression models were built to determine significant predictor variables with respect to outcomes of interest. Results HAI titers were similar between the sexes, but NAI titers were higher in males than females at 4 weeks and 8 weeks postchallenge. Females were more likely to have symptoms (mean, 0.96 vs 0.80; P = .003) and to have a higher number of symptoms (median, 3 vs 4; P = .011) than males. Linear and logistic regression models showed that prechallenge NAI titers, but not HAI titers or sex hormone levels, were predictive of all shedding and symptom outcomes of interest. Conclusions Females in our cohorts were more likely to be symptomatic and to have a higher number of symptoms than males. NAI titers predicted all outcomes of interest and may explain differential outcomes between the sexes.

Asymptomatic SARS-CoV-2 infection and delayed implementation of diagnostics have led to poorly defined viral prevalence rates. To address this, we analyzed seropositivity in US adults who have not previously been diagnosed with COVID-19. Individuals with characteristics that reflect the US population (n = 11,382) and who had not previously been diagnosed with COVID-19 were selected by quota sampling from 241,424 volunteers (ClinicalTrials.gov NCT04334954). Enrolled participants provided medical, geographic, demographic, and socioeconomic information and 9,028 blood samples. The majority (88.7%) of samples were collected between May 10(th) and July 31(st), 2020. Samples were analyzed via ELISA for anti-Spike and anti-RBD antibodies. Estimation of seroprevalence was performed by using a weighted analysis to reflect the US population. We detected an undiagnosed seropositivity rate of 4.6% (95% CI: 2.6 – 6.5%). There was distinct regional variability, with heightened seropositivity in locations of early outbreaks. Subgroup analysis demonstrated that the highest estimated undiagnosed seropositivity within groups was detected in younger participants (ages 18-45, 5.9%), females (5.5%), Black/African American (14.2%), Hispanic (6.1%), and Urban residents (5.3%), and lower undiagnosed seropositivity in those with chronic diseases. During the first wave of infection over the spring/summer of 2020 an estimate of 4.6% of adults had a prior undiagnosed SARS-CoV-2 infection. These data indicate that there were 4.8 (95% CI: 2.8-6.8) undiagnosed cases for every diagnosed case of COVID-19 during this same time period in the United States, and an estimated 16.8 million undiagnosed cases by mid-July 2020.

16.8 million SARS-CoV-2 infections in the US went undiagnosed in the first 6 months of the pandemic compared to 3.5 million diagnosed infections., Elucidating seroprevalence in COVID-19 Symptoms of SARS-CoV-2 infection range from completely asymptomatic, to those of a common cold, to a drop in oxygen saturation and lung function, and death in some patients. To evaluate the proportion of the U.S. population who had an undiagnosed infection during the first wave of the COVID-19 pandemic, we measured antibody prevalence in study participants who had not previously been diagnosed with a SARS-CoV-2 infection. By mid-July of 2020, 16.8 million people had an undiagnosed SARS-CoV-2 infection, almost five times the rate of diagnosed infections., Asymptomatic SARS-CoV-2 infection and delayed implementation of diagnostics have led to poorly defined viral prevalence rates in the United States and elsewhere. To address this, we analyzed seropositivity in 9089 adults in the United States who had not been diagnosed previously with COVID-19. Individuals with characteristics that reflected the U.S. population (n = 27,716) were selected by quota sampling from 462,949 volunteers. Enrolled participants (n = 11,382) provided medical, geographic, demographic, and socioeconomic information and dried blood samples. Survey questions coincident with the Behavioral Risk Factor Surveillance System survey, a large probability-based national survey, were used to adjust for selection bias. Most blood samples (88.7%) were collected between 10 May and 31 July 2020 and were processed using ELISA to measure seropositivity (IgG and IgM antibodies against SARS-CoV-2 spike protein and the spike protein receptor binding domain). The overall weighted undiagnosed seropositivity estimate was 4.6% (95% CI, 2.6 to 6.5%), with race, age, sex, ethnicity, and urban/rural subgroup estimates ranging from 1.1% to 14.2%. The highest seropositivity estimates were in African American participants; younger, female, and Hispanic participants; and residents of urban centers. These data indicate that there were 4.8 undiagnosed SARS-CoV-2 infections for every diagnosed case of COVID-19, and an estimated 16.8 million infections were undiagnosed by mid-July 2020 in the United States.

The continued explosive spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) despite aggressive public health measures has triggered an unprecedented international vaccine effort. However, correlates of protection, which can help guide intelligent vaccine design, are not known for SARS-CoV-2. Research on influenza immunity and vaccine development may provide valuable lessons for coronavirus efforts, especially considering similarities in rapid evolutionary potential. The apparent inevitability of future novel coronavirus outbreaks must prompt work on a universal coronavirus vaccine.

Vaccines against Coronavirus Disease 2019 Originated-19) have been developed with unprecedented rapidity, many utilizing novel strategies. As of November 2020, a series of publications have outlined the results of phase 1/2 studies of nine different vaccines planned to move forward to phase 3 trials. The results are encouraging, demonstrating a paucity of severe or serious adverse events and robust induction of antibody titers. Determination of the vaccine candidates with the highest protective efficacy and best adverse event profiles will be essential in refining public health strategies. However, differences in study design and reporting of data make comparisons of existing phase 1/2 studies difficult. With respect to safety, studies have variable follow-up times and may use different definitions for adverse events. Immunogenicity outcomes are even more inconsistent, with variations in timepoints and critical differences in the types of antibodies studied as well as methodological differences in assays. Furthermore, the correlates of protection in COVID-19 are not known. Harmonization of phase 3 trial designs and use of objective and meaningful clinical outcomes will be crucial in streamlining future global responses to the pandemic.

Background Our understanding of the impact of biological sex on influenza-associated disease and the mechanisms that underpin it is still incomplete. Further investigation of sex-linked effects on influenza pathogenesis and clinical outcomes may help tailor vaccine strategies. Animal studies have shown female mice experience more symptoms than male mice during influenza infection. Similarly, human females of reproductive age have higher rates of influenza and influenza-related hospitalizations. However, data is sometimes conflicting and may be confounded by other important differences in baseline characteristics. Human challenge studies have demonstrated the importance of NAI titers as a correlate of protection and may also provide an ideal opportunity to study sex differences in a homogenous group of participants controlled for confounders. Methods Data from 168 volunteers who underwent Influenza A/California/04/2009/H1N1 challenge studies affiliated with NIAID’s LID Clinical Studies Unit were compiled to compare differences between sexes. Participants were included in the analysis if they received a challenge dose of virus of 107 TCID50 and were excluded if they had received any vaccines or experimental therapy during the study period. Results Baseline differences between male and female participants were observed in NAI titers but not HAI titers or age. Outcomes of interest included presence of viral shedding/duration which were similar among sexes. However, symptom number and duration were higher among female participants (p=0.008 and p=0.045 respectively). Ongoing data analysis also shows females have lower post-challenge NAI titers than males. Conclusion Female participants in our H1N1 challenge studies had more symptoms and a longer duration of symptoms compared to their male counterparts. Differences in NAI titers may potentially explain the observed relationship between sex and symptoms associated with influenza. Disclosures All Authors: No reported disclosures

Neuraminidase (NA) is an influenza surface protein that helps to free viruses from mucin-associated decoy receptors and to facilitate budding from infected cells. Experiments have demonstrated that anti-NA antibodies protect animals against lethal influenza challenge by numerous strains, while decreasing pulmonary viral titers, symptoms, and lung lesions. Studies in humans during the influenza A/H3N2 pandemic and in healthy volunteers challenged with influenza A/H1N1 showed that anti-NA immunity reduced symptoms, nasopharyngeal viral shedding, and infection rates. Despite the benefits of anti-NA immunity, current vaccines focus on immunity against hemagglutinin and are not standardized to NA content leading to limited and variable NA immunogenicity. Purified NA has been shown to be safe and immunogenic in humans. Supplementing current vaccines with NA may be a simple strategy to improve suboptimal effectiveness. Immunity against NA is likely to be an important component of future universal influenza vaccines.

Background The Streptococcus anginosus group (SAG) causes a variety of infections in adults. To better understand the burden of SAG infections and their associated morbidity and mortality, we conducted a retrospective analysis of these infections in adults at a tertiary care center. Methods A retrospective review of all cultures positive for SAG in adults and a corresponding review of their medical records were conducted at a tertiary care facility in Central New York. Patients with these cultures during the period of January 2007-December 2011 were included. Demographic data, area of residence, clinical features and underlying illnesses, site of infection, length of hospital stay, antibiotic susceptibility and antibiotic therapy were recorded and analyzed. Results There were 332 SAG cases; most patients were males (59%), mean age of 47 years and 84% lived in urban areas. Overall mortality was 3% with underlying conditions common such as diabetes (25%), hypertension (31%) and immunodeficiency (22%). Most of the infections were related to skin and soft tissue (72%) and polymicrobial (70%) with gram-negative anaerobes and Enterobacteriaceae commonly isolated with SAG. Conclusions We present the largest study, thus far, reviewing the clinical presentation, management and outcome of infections due to the SAG of organisms. Notable findings from our study are the low mortality associated with SAG infection, and the propensity to present as a skin, soft tissue and polymicrobial infection. Our findings will assist clinicians in managing patients with SAG infections and recognizing that Streptococcus anginosus may be one of several organisms responsible for infection.

Background Seasonal influenza causes significant annual morbidity and mortality. The effects of yearly exposures on immunity are not clear and recent observations have demonstrated that long lasting protection against a matched strain may not naturally occur. The 2018–2019 influenza season consisted of an initial peak of H1N1 infections followed by a wave of H3N2 infections. These consecutive waves raise questions about how influenza immunity is affected by sequential exposure to different influenza strains. Challenge studies provide a unique opportunity to study this phenomenon. Here we describe a subset of participants who were sequentially infected in two separate challenge studies with wild-type H1N1 and H3N2 viruses. Methods Healthy volunteers completed two sequential influenza challenge studies at the NIH Clinical Center. Participants were inoculated with reverse genetics, cell-based, GMP wild-type influenza viruses, A(H1N1)pdm09 and A(H3N2) strains. Participants remained isolated in the hospital for a minimum of 9 days and were monitored daily for viral shedding and clinical symptoms. After discharge, participants were followed for 2 months. Results Between 2014 and 2017, 14 healthy volunteers were exposed to Influenza A(H1N1) and Influenza A(H3N2). Time between infections ranged from 2 months to 2 years. Thirteen (93%) participants developed confirmed influenza infection after H1N1 challenge and 9 (64%) after H3N2 challenge. Eight (57%) participants developed confirmed infections after both exposures. Variable degrees of symptoms, shedding, and disease severity were observed. Systemic antibody responses to the HA and NA of both H1N1 and H3N2 varied over time during these sequential infections. Conclusion More than half of all participants who completed 2 sequential H1N1 and H3N2 challenge studies demonstrated confirmed infection to both viruses. These sequential infections had varying effects on the disease experienced and the immunity that developed after infection. These observations are important in understanding the impact of sequential exposures on influenza immunity. Disclosures All authors: No reported disclosures.

Mycobacterium goodii has only rarely been reported to cause invasive disease in humans. Previously reported cases of M. goodii infection have included prosthetic joint infections, pacemaker pocket infections, and pneumonia. We present a case of M. goodii bacteremia with concomitant pulmonary septic emboli that developed in a 32-year-old woman with an indwelling central venous catheter (CVC). The CVC had been placed one year previously for intermittent treatment with intravenous, broadspectrum antibiotics, administered by an outside physician for the treatment of symptoms attributed to chronic Lyme disease. Despite our recommendations, the patient declined follow-up in our Infectious Diseases clinic, opting to continue care under her chronic Lyme disease physician. This case clearly demonstrates the potential for serious medical complications that can arise from the inappropriate use of longterm intravenous antibiotics using a CVC to treat non-specific symptoms attributed to Lyme disease and patients should be counseled regarding these risks.

Haemophilus parainfluenzae, which uncommonly causes endocarditis, has never been documented to cause mural involvement. A 62-year-old immunocompetent female without predisposing risk factors for endocarditis except for poor dentition presented with fever, emesis, and dysmetria. Echocardiography found a mass attached to the left ventricular wall with finger-like projections. Computed tomography showed evidence of embolic phenomena to the brain, kidneys, spleen, and colon. Cardiac MRI revealed involvement of the chordae tendineae of the anterior papillary muscles. Blood cultures grewHaemophilus parainfluenzae. The patient was treated successfully with ceftriaxone with resolution of symptoms, including neurologic deficits. After eleven days of antibiotics a worsening holosystolic murmur was discovered. Worsening mitral regurgitation on echocardiography was only found three weeks later. Nine weeks after presentation, intraoperative evaluation revealed chord rupture but no residual vegetation and mitral repair was performed. Four weeks after surgery, the patient was back to her baseline. This case illustrates the ability ofHaemophilus parainfluenzaeto form large mural vegetations with high propensity of embolization in otherwise normal cardiac tissue among patients with dental risk factors. It also underscores the importance of physical examination in establishing a diagnosis of endocarditis and monitoring for progression of disease.