Prototype Pathogen Approach for Vaccine and Monoclonal Antibody Development: A Critical Component of the NIAID Plan for Pandemic Preparedness.

Severe acute respiratory syndrome coronavirus 1 (SARS-CoV-1) emerged 20 years ago, presaging a series of subsequent infectious disease epidemics of international concern. The recent emergence of SARS-CoV-2 has underscored the importance of targeted preparedness research to enable rapid countermeasure development during a crisis. In December 2021 the National Institute of Allergy and Infectious Diseases (NIAID), building upon the successful strategies developed during the SARS-CoV-2 response and to prepare for future pandemics, published a pandemic preparedness plan that outlined a research strategy focused on priority pathogens, technology platforms, and prototype pathogens. To accelerate the discovery, development, and evaluation of medical countermeasures against new or previously unknown pathogens of pandemic potential, we present here a strategy of research directed at select prototype pathogens. In this manner, leveraging a prototype pathogen approach may serve as a powerful cornerstone in biomedical research preparedness to protect public health from newly emerging and reemerging infectious diseases.

Toward Understanding COVID-19 Recovery: National Institutes of Health Workshop on Postacute COVID-19.

Over the past year, the SARS-CoV-2 pandemic has swept the globe, resulting in an enormous worldwide burden of infection and mortality. However, the additional toll resulting from long-term consequences of the pandemic has yet to be tallied. Heterogeneous disease manifestations and syndromes are now recognized among some persons after their initial recovery from SARS-CoV-2 infection, representing in the broadest sense a failure to return to a baseline state of health after acute SARS-CoV-2 infection. On 3 to 4 December 2020, the National Institute of Allergy and Infectious Diseases, in collaboration with other Institutes and Centers of the National Institutes of Health, convened a virtual workshop to summarize existing knowledge on postacute COVID-19 and to identify key knowledge gaps regarding this condition.

A Universal Influenza Vaccine: The Strategic Plan for the National Institute of Allergy and Infectious Diseases.

A priority for the National Institute of Allergy and Infectious Diseases is development of a universal influenza vaccine providing durable protection against multiple influenza strains. NIAID will use this strategic plan as a foundation for future investments in influenza research.

Alcohol use, anal sex, and other risky sexual behaviors among HIV-infected women and men.

Effective sexual risk reduction strategies for HIV-infected individuals require an understanding of alcohol's influence on specific sexual behaviors. We conducted audio-computer-assisted-self-interviews on 910 patients from two HIV primary care programs. The association between alcohol use and risky sexual behaviors was examined using multivariable logistic regression adjusting for age, education, race/ethnicity and drug use. Frequent/binge drinking was associated with engaging in anal sex and having multiple sex partners among women, engaging in insertive anal sex among gay/bisexual men, and was unrelated to risky sexual behaviors among heterosexual men. Infrequent drinkers did not differ in sexual risk behaviors from abstainers among women or men. Finally, there was no interaction effect between race/ethnicity and alcohol use on the association with sexual risk behaviors. The study has yielded important new findings in several key areas with high relevance to HIV care. Results underscore the importance of routinely screening for alcohol use and risky sexual behaviors in HIV primary care.

Changes in fluoroquinolone use for gonorrhea following publication of revised treatment guidelines.

OBJECTIVES: We evaluated the impact of revised national treatment recommendations on fluoroquinolone use for gonorrhea in selected states. METHODS: We evaluated gonorrhea cases reported through the Sexually Transmitted Disease Surveillance Network as treated between July 1, 2006 and May 31, 2008, using interrupted time series analysis. Outcomes were fluoroquinolone treatment overall, by area, and by practice setting. RESULTS: Of 16,126 cases with treatment dates in this period, 15,669 noted the medication used. After revised recommendations were released, fluoroquinolone use decreased abruptly overall (21.5%; 95% confidence interval [CI] = 15.9%, 27.2%), in most geographic areas evaluated, and in sexually transmitted disease clinics (28.5%; 95% CI = 19.0%, 37.9%). More gradual decreases were seen in primary care (8.6%; 95% CI = 2.6%, 14.6%), and in emergency departments, urgent care, and hospitals (2.7%; 95% CI = 1.7%, 3.7%). CONCLUSIONS: Fluoroquinolone use decreased after the publication of revised national guidelines, particularly in sexually transmitted disease clinics. Additional mechanisms are needed to increase the speed and magnitude of changes in prescribing in primary care, emergency departments, urgent care, and hospitals.

Treatment of syphilis in HIV-infected subjects: a systematic review of the literature.

BACKGROUND: The optimal antimicrobial regimen to treat syphilis in HIV-infected subjects remains controversial. OBJECTIVE: To systematically assess the literature for studies evaluating syphilis treatment regimens in this population. METHODS: Two reviewers independently assessed studies published between 1980 and June 2008 in electronic databases, trial registries and bibliographies (with no language restrictions) for content and quality. Studies that included 10 or more people, with documented HIV status, type and duration of syphilis treatment and at least 6 months of follow-up were included. The primary outcome was syphilis serological or clinical failure stratified by syphilis stage. RESULTS: Of 1380 unique citations, 23 studies (22 published papers and 1 conference abstract) were included in the systematic review. Owing to the significant heterogeneity among studies, pooled summary statistics could not be generated. The range of probabilities for serological failure with 2.4 million units (MU) of intramuscular benzathine penicillin G (BPG) was 6.9% (95% CI 2.6% to 14.4%) to 22.4% (11.7% to 36.6%); that of 7.2 MU of BPG in late latent syphilis was 19.4% (11.9% to 28.9%) to 31.1% (22.3% to 40.9%) and failure estimates with 18-24 MU of aqueous penicillin for the treatment of neurosyphilis were 27.3% (6.0% to 61.0%) to 27.8% (14.2% to 45.2%). CONCLUSIONS: The optimal antimicrobial regimen to treat syphilis in HIV-infected subjects is unknown; guideline recommendations in this population are based on little objective data.

Sexually transmitted infections and adverse pregnancy outcomes among women attending inner city public sexually transmitted diseases clinics.

BACKGROUND: Studies in antenatal care clinics suggest that lower genital tract infections (LGTI) may be associated with adverse pregnancy outcomes (APO). We sought to characterize antenatal care patterns and determine whether LGTI are independently associated with preterm birth and/or low-birth weight among a high-risk public sexually transmitted diseases (STD) clinic population. METHODS: Electronic STD clinic medical records and state birth records were matched for 730 pregnant women age 13 to 49 tested for 5 treatable LGTI (bacterial vaginosis, chlamydia, gonorrhea, early syphilis, and trichomoniasis) in a case-control analysis. Cases were women with preterm and/or low-birth weight newborns; controls were women without APO. The association between LGTI and APO was assessed using logistic regression. RESULTS: Although pregnant women attending STD clinics reported high risk behaviors and were found to have high rates of LGTI (55%), most of these women were engaged in antenatal care (85%). Of the pregnant women, 22% experienced an APO (7% preterm birth, 4% low birth weight, and 12% preterm birth and low birth weight). In multivariate analyses, chlamydia was associated with low-birth weight (adjusted odds ratio [aOR]: 2.07, 95% confidence interval [CI]: 1.01-4.24), and gonorrhea was associated with preterm birth (aOR: 2.01, 95% CI: 1.02-3.97), particularly when diagnosed during the first trimester (aOR: 2.95, 95% CI: 1.30-6.70). CONCLUSIONS: Our findings confirm the association of some LGTI with APO and suggest that timing of LGTI screening may affect outcomes. STD clinic visits represent a critical opportunity to target interventions aimed at improving pregnancy outcomes.

Sexually transmitted infection prevalence and behavioral risk factors among Latino and non-Latino patients attending the Baltimore City STD clinics.

BACKGROUND: Many studies have evaluated factors influencing sexually transmitted diseases (STD)/HIV disparities between black and white populations, but fewer have explicitly included Latinos for comparison. METHODS: We analyzed demographic and behavioral data captured in electronic medical records of patients first seen by a clinician in 1 of 2 Baltimore City public STD clinics between 2004 and 2007. Records from white, black, and Latino patients were included in the analysis. RESULTS: There were significant differences between Latinos and other racial/ethnic groups for several behavioral risk factors studied, with Latino patients reporting fewer behavioral risk factors than other patients. Latinos were more likely to have syphilis, but less likely to have gonorrhea than other racial/ethnic groups. English-proficient Latina (female) patients reported higher rates of infection and behavioral risk factors than Spanish-speaking Latina patients. After adjustment for gender and behavioral risk factors, Spanish-speaking Latinas also had significantly less risk of sexually transmitted infections than did English-speaking Latinas. CONCLUSIONS: These results are consistent with other studies showing that acculturation (as measured by language proficiency) is associated with increases in reported sexual risk behaviors among Latinos. Future studies on sexual risk behavior among specific Latino populations, characterized by country of origin, level of acculturation, and years in the United States, may identify further risk factors and protective factors to guide development of culturally appropriate STD/HIV interventions.

Digital divide: variation in internet and cellular phone use among women attending an urban sexually transmitted infections clinic.

We sought to describe: (1) the prevalence of internet, cellular phone, and text message use among women attending an urban sexually transmitted infections (STI) clinic, (2) the acceptability of health advice by each mode of information and communication technology (ICT), and (3) demographic characteristics associated with ICT use. This study is a cross-sectional survey of 200 English-speaking women presenting to a Baltimore City STI clinic with STI complaints. Participants completed a self-administered survey querying ICT use and demographic characteristics. Three separate questions asked about interest in receiving health advice delivered by the three modalities: internet, cellular phone, and text message. We performed logistic regression to examine how demographic factors (age, race, and education) are associated with likelihood of using each modality. The median age of respondents was 27 years; 87% were African American, and 71% had a high school diploma. The rate of any internet use was 80%; 31% reported daily use; 16% reported weekly use; and 32% reported less frequent use. Almost all respondents (93%) reported cellular phone use, and 79% used text messaging. Acceptability of health advice by each of the three modalities was about 60%. In multivariate analysis, higher education and younger age were associated with internet use, text messaging, and cellular phone use. Overall rate of internet use was high, but there was an educational disparity in internet use. Cellular phone use was almost universal in this sample. All three modalities were equally acceptable forms of health communication. Describing baseline ICT access and the acceptability of health advice via ICT, as we have done, is one step toward determining the feasibility of ICT-delivered health interventions in urban populations.

Lumbar puncture in HIV-infected patients with syphilis and no neurologic symptoms.

BACKGROUND: The decision to perform lumbar puncture in patients with asymptomatic human immunodeficiency virus (HIV) infection and syphilis is controversial. The Centers for Disease Control and Prevention recommend certain criteria that warrant lumbar puncture. Here, we assess the performance of these criteria for detecting asymptomatic neurosyphilis (ANS). METHODS: Eligible subjects consisted of all patients with concurrent HIV infection and syphilis in a prospective clinical cohort who had no neurologic symptoms at the time of lumbar puncture. We retrospectively applied different stratification criteria to calculate the performance of lumbar puncture in detecting ANS: (1) lumbar puncture in patients with late latent syphilis or syphilis of an unknown duration, regardless of the CD4 cell count or rapid plasma reagin titer; (2) lumbar puncture if the CD4 cell count was 350 cells/mL and/or the rapid plasma reagin titer was 1:32, regardless of the syphilis stage; and (3) lumbar puncture in the context of serologic nonresponse to syphilis therapy. RESULTS: Two hundred two of 231 patients with syphilis did not have neurologic symptoms. Immediate lumbar puncture was performed for 46 patients, and 10 cases (22%) of ANS were detected. With use of the first criterion, 2 (14%) of 10 cases of ANS in patients with early-stage syphilis would have been missed (sensitivity, 80% [95% confidence interval [CI], 44%-97%]; specificity, 23% (95% confidence interval [CI], 11.4%-40.2%) [corrected] Criterion 2 would not have missed any cases of ANS (sensitivity, 100% [95% CI, 70%-100%]; specificity, 13.2% (95% CI, 4.4%-29.1%) [corrected] but would have required that a lumbar puncture be performed for 88% of patients. Performance of lumbar puncture performed in 13 cases based on serologic nonresponse to syphilis therapy yielded 4 cases (31%) of ANS. CONCLUSIONS: In patients with concurrent HIV infection and syphilis, the use of criteria based on rapid plasma reagin titer and CD4 cell count, instead of stage-based criteria, improved the ability to identify ANS.

Antiretroviral therapy is associated with reduced serologic failure rates for syphilis among HIV-infected patients.

BACKGROUND: Syphilis and human immunodeficiency virus (HIV) frequently coexist in patients, but the effects of immunosuppression on the course of syphilis are unknown. Our goal was to determine whether the degree of HIV-mediated immunosuppression and the use of highly active antiretroviral therapy impact syphilis serologic responses. METHODS: We assessed all cases of syphilis with positive serologic test results from 1990 through 2006 in a prospective, observational clinical cohort of HIV-infected patients. We defined seroreversion as the loss of reactivity in a patient who previously had a serologic test result positive for syphilis. We defined serologic failure as the lack of a 4-fold decrease in rapid plasma reagin titers 270-365 days after therapy or a 4-fold increase in titers > or =30 days after therapy. We used Cox proportional hazards models with statistical adjustments for multiple failure instances. RESULTS: One hundred eighty subjects experienced 231 cases of syphilis. The median follow-up time was 5.3 years. A total of 71 episodes of serologic failure were documented. A CD4 cell count of <200 cells/mL at the time of syphilis diagnosis was associated with an increased risk of serologic failure (adjusted hazard ratio, 2.48; 95% confidence interval, 1.26-4.88). The receipt of highly active antiretroviral therapy was associated with a 60% reduction in the rate of serologic failure (adjusted hazard ratio, 0.40; 95% confidence interval, 0.21-0.75), independent of concomitant CD4 cell response. Rapid plasma reagin seroreversion was infrequent (16.1%) and inconsistent, and it was more likely to occur among patients who received macrolides. CONCLUSION: The use of highly active antiretroviral therapy to reverse immunosuppression and the routine use of macrolides for the prevention of opportunistic infections may reduce syphilis serologic failure rates among HIV-infected patients who have syphilis.

The relationship between recent alcohol use and sexual behaviors: gender differences among sexually transmitted disease clinic patients.

BACKGROUND: Binge drinking is associated with risky sexual behaviors and sexually transmitted diseases (STDs). Few studies have investigated this by gender or in an STD clinic. This cross-sectional study examined the association between binge drinking and risky sexual behaviors/STDs among patients attending an urban STD clinic. METHOD: A total of 671 STD clinic patients were tested for STDs, and queried about recent alcohol/drug use and risky sexual behaviors using audio computer-assisted-self-interview. The association between binge drinking and sexual behaviors/STDs was analyzed using logistic regression adjusting for age, employment, and drug use. RESULTS: Binge drinking was reported by 30% of women and 42% of men. Gender differences were found in rates of receptive anal sex which increased linearly with increased alcohol use among women but did not differ among men. Within gender analyses showed that women binge drinkers engaged in anal sex at more than twice the rate of women who drank alcohol without binges (33.3% vs. 15.9%; p < 0.05) and 3 times the rate of women who abstained from alcohol (11.1%; p < 0.05). Having multiple sex partners was more than twice as common among women binge drinkers than women abstainers (40.5% vs. 16.8%; p < 0.05). Gonorrhea was nearly 5 times higher among women binge drinkers compared to women abstainers (10.6% vs. 2.2%; p < 0.05). The association between binge drinking and sexual behaviors/gonorrhea remained after controlling for drug use. Among men, rates of risky sexual behaviors/STDs were high, but did not differ by alcohol use. CONCLUSION: Rates of binge drinking among STD clinic patients were high. Among women, binge drinking was uniquely associated with risky sexual behaviors and an STD diagnosis. Our findings support the need to routinely screen for binge drinking as part of clinical care in STD clinics. Women binge drinkers, in particular, may benefit from interventions that jointly address binge drinking and risky sexual behaviors. Developing gender-specific interventions could improve overall health outcomes in this population.

Findings associated with recurrence of bacterial vaginosis among adolescents attending sexually transmitted diseases clinics.

STUDY OBJECTIVE: Bacterial vaginosis (BV) is a common infection and has been associated with adverse health outcomes, including preterm birth, pelvic inflammatory disease (PID), and acquisition of HIV. There are limited data on recurrent BV in adolescents. A relationship between the frequency of BV recurrence and specific risk factors might shed light on the pathophysiology of BV and lead to targeted interventions. DESIGN: Record-based historical clinic study. SETTING: Adolescent visits to two sexually transmitted disease (STD) clinics between 1990 and 2002. PARTICIPANTS: 254 girls who had >/= 2 episodes of BV and at least 3 clinical visits, matched on clinic attendance frequency to 254 girls with only 1 documented BV episode and 254 girls with no history of BV. MAIN OUTCOME MEASURE: Risk factor differences between groups. ANALYSIS: Multinomial logistic regression with robust estimator of the standard errors, accounting for repeated measures. RESULTS: 5,977 adolescent girls visited the clinics. 1509 (25%) had at least one episode of BV; of those, 303 (19.9%) had 2 or more BV episodes. Girls with a history of 1 BV episode and girls with a history of 2 or more BV episodes were more likely to be infected with Trichomonas vaginalis [OR 1.77, 95% CI: 1.17-2.67, OR 1.56, 95% CI: 1.05-2.34] and be diagnosed with PID [OR 1.50, 95% CI: 1.02-2.22, OR 2.05, 95% CI: 1.41-2.98] compared to girls with no BV history, respectively. Girls with a history of BV were also more likely to report active oral sex and lack of contraceptive use. CONCLUSION: Adolescent girls who attend STD clinics have a high prevalence of BV. Although the association between BV and PID is not clearly causal, when one condition is diagnosed, evaluation and counseling for the other may reduce recurrence and sequelae.

Doxycycline compared with benzathine penicillin for the treatment of early syphilis.

BACKGROUND: Doxycycline is the preferred recommended second-line agent for the treatment of syphilis, although efficacy data from controlled trials are lacking. We compared the serological responses of patients with early syphilis treated with doxycycline with the responses of patients treated with benzathine penicillin G (BPG). METHODS: All patients who received a diagnosis of early syphilis attending 2 public sexually transmitted disease clinics in Baltimore, Maryland, who were treated with doxycycline (100 mg orally, twice daily for 14 days) between October 1993 and June 2000 were eligible. Patients treated with BPG (a single dose of 2.4 million units intramuscularly) were selected as the control group. Inclusion criteria included a clinician-recorded diagnosis of primary, secondary, or early latent syphilis with reactive serological test results at the time of diagnosis and at least 1 follow-up serological test titer. Serological failure was defined as lack of a 4-fold drop in rapid plasma reagin titer 270-400 days after treatment, or a 4-fold increase in titer 30-400 days after therapy. RESULTS: During the study period, 1558 patients were treated for early syphilis, and 87 received doxycycline. Of those treated with doxycycline, 34 met the inclusion criteria. Seventy-three patients from a randomly selected group of 200 age-matched individuals treated with BPG met the inclusion criteria. There were 4 patients with serological failure in the BPG group (5.5%; 95% confidence interval [CI], 1.6%-13.8%) and 0 patients with serological failure in the doxycycline group (0%; 95% CI, 0%-10.3%; P=.2). The median times to successful serological responses for patients in the doxycycline and BPG groups were 106 days (95% CI, 75-149 days) and 137 days (95% CI, 111-172 days), respectively (P=.6). CONCLUSION: Doxycycline appears to be an effective agent for the treatment of early syphilis.

Cost-effectiveness of screening strategies for Gonorrhea among females in private sector care.

OBJECTIVE: To identify the optimal screening algorithm for gonorrhea infection among females in private sector care, using cost-effectiveness analysis. METHODS: We compared 6 strategies using decision analysis for urine nucleic acid amplification testing for gonorrhea testing in a theoretical cohort of 10,000 females aged 15-35 years: 1) screen women aged younger than 25 years; 2) screen women aged younger than 30 years; 3) screen women aged younger than 25 years who report any risk (pregnant, drug use, new sexual partner < 30 days); 4) screen women aged younger than 30 years who report any risk; 5) screen women aged younger than 25 years or those who report any risk; and 6) screen women aged younger than 30 years or those who report any risk. Infection prevalence and sensitivity and specificity were by direct observation from a retrospective cohort of females attending the Baltimore City Sexually Transmitted Disease Clinics between 1999 and 2002. The main outcome measures were untreated gonorrhea cases and their sequelae in women, transmission to a male partner, congenital outcomes, and cost to prevent a case. RESULTS: Prevalence of gonorrhea was 3.0%. Not screening would result in 300 untreated cases. Not screening was cost-saving over all screening strategies. Strategy 6 resulted in the fewest cases of untreated infection (82), although Strategy 3 was the most cost-effective of the screening strategies. Univariate sensitivity analysis identified a threshold of 4.75% gonorrhea prevalence, more than which Strategy 3 became cost-saving over not screening. CONCLUSION: Screening is recommended for females aged younger than 25 years with specific risks in populations with a gonorrhea prevalence of 4.75% or greater. LEVEL OF EVIDENCE: II-2.

Concurrent sexually transmitted infections (STIs) in sex partners of patients with selected STIs: implications for patient-delivered partner therapy.

BACKGROUND: Patient-delivered partner therapy (PDPT) is the practice of providing disease-specific antimicrobial agents to patients for delivery to their sex partners. Some partners who receive PDPT may forgo clinical evaluation, resulting in missed opportunities for the diagnosis and treatment of comorbid conditions. METHODS: We conducted a review of electronic charts for 8623 individuals attending 4 sexually transmitted disease clinics who were sex partners of patients with selected sexually transmitted infections (STIs). We evaluated the concordance between STIs diagnosed in partners and their reported exposures for which they might have received PDPT. RESULTS: Among 3503 female and 4647 heterosexual male partners, 19 (0.4%) of 4716 individuals tested were newly diagnosed with human immunodeficiency virus (HIV) infection, and 61 individuals (0.7%) had syphilis. Pelvic inflammatory disease was diagnosed in 133 women (3.8%). Seventy-two (3.2%) of 2226 female and heterosexual male partners reporting exposure to patients with chlamydial infection had gonorrhea diagnosed. Chlamydial infection or gonorrhea was diagnosed in 81 heterosexual male partners (10.3%) who reported contact with women with trichomoniasis. Among 473 men who have sex with men (MSM; including bisexual men), 13 (6.3%) of 207 tested were newly diagnosed with HIV infection, and 8 (1.7%) had syphilis. Six (6.1%) of 98 MSM reporting exposure to patients with chlamydial infection had gonorrhea diagnosed. CONCLUSIONS: Infrequent coinfections in female and heterosexual male partners exposed to patients with chlamydial infection or gonorrhea would not preclude use of PDPT. However, PDPT for male partners of women with trichomoniasis and for MSM requires further study.

Trichomonas vaginalis polymerase chain reaction compared with standard diagnostic and therapeutic protocols for detection and treatment of vaginal trichomoniasis.

Wet preparation has limited sensitivity for diagnosis of Trichomonas vaginalis (TV) infection. An observational study of 337 women was conducted to evaluate a new polymerase chain reaction (PCR) test for TV. The sensitivities of wet preparation and TV culture were 52% (95% confidence interval [CI], 41-62) and 78% (95% CI, 69-86), respectively. TV PCR had a sensitivity of 84% (95% CI, 75-90) and a specificity of 94% (95% CI, 90-97). Metronidazole was provided to 67 (69%) of 97 women with TV because of TV on wet preparation, exposure to TV, or a diagnosis of bacterial vaginosis or pelvic inflammatory disease; however, if TV PCR had been used for diagnosis, 81 (84%) of 97 women with TV would have been treated (P=.02). TV is significantly undertreated using standard algorithms for metronidazole therapy. Given the association of trichomoniasis with perinatal morbidity and HIV transmission, women in high-risk groups may benefit from TV PCR.

Depression and HIV risk behaviors among patients in a sexually transmitted disease clinic.

OBJECTIVE: The authors' goal was to investigate the relationship between depression and HIV risk behaviors or sexually transmitted disease (STD) diagnosis at an urban STD clinic. METHOD: Using audio computer-assisted self-interview, 671 STD clinic patients answered questions about HIV risk behaviors and depression in a large-scale, cross-sectional study. A subset of the patients (N=201) was evaluated for current major depressive disorder by interviewers using the nonpatient edition of the Structured Clinical Interview for DSM-IV. RESULTS: Depressed patients were more likely to have sex for money or drugs, to have had sex with an intravenous drug user, to have sex when "high" on alcohol or drugs, to have a greater number of lifetime sex partners, and to abuse alcohol or drugs than were nondepressed patients. Associations of HIV risk behaviors with depression persisted after adjustment for substance abuse. CONCLUSIONS: Depression in STD clinic patients is associated with HIV risk behaviors but not STD diagnosis. Identifying depression and developing strategies to intervene effectively may reduce HIV risk behaviors and improve health outcomes.