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.

Integrating behavioral and biomedical research in HIV interventions: challenges and opportunities.

Recent clinical trials have demonstrated overwhelming success of biomedical tools to prevent the spread of HIV infection. However, the complex and somewhat disparate results of some of these trials have highlighted the need for effective integration of biomedical and behavioral sciences in the design and implementation of any future intervention trial. Integrating behavioral and biomedical sciences will require appropriate behavioral theories that can be used in the context of biomedical clinical trials and multidisciplinary teams working together from the earliest stages of trial design through to completion. It is also clear that integration of behavioral science will be necessary to implement prevention at the population level and reverse the HIV epidemic.

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.

Hormonal contraception and risk of bacterial vaginosis diagnosis in an observational study of women attending STD clinics in Baltimore, MD.

BACKGROUND: The protective effect of hormonal contraception may offer a potential intervention against bacterial vaginosis (BV). STUDY DESIGN: Three hundred thirty reproductive-age women enrolled in a contraceptive program from April 2005 to October 2006 at two sexually transmitted diseases clinics in Baltimore, MD. Participants were supplied with hormonal contraceptives of their choice and followed prospectively. BV was diagnosed by Amsel's criteria. Results from population-level analysis were compared to a case-crossover analysis. RESULTS: BV was diagnosed in 189 (13.0%) of the visits among 133 (40.3%) women. In the population-level analysis, the use of progestin-only and combined contraception was associated with a decreased risk of BV compared to intervals of no hormonal contraceptive use [adjusted odds ratio (AOR): 0.42 (95% CI: 0.20-0.88) and AOR: 0.66 (95% CI: 0.39-1.10), respectively]. The case-crossover analysis demonstrated a similar trend in findings. CONCLUSION: Hormonal contraception was associated with a decreased risk of BV in an STD clinic cohort.

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.

Male circumcision and risk of HIV infection among heterosexual African American men attending Baltimore sexually transmitted disease clinics.

BACKGROUND: Male circumcision has received international attention as an intervention for reducing HIV infection among high-risk heterosexual men; however, few US studies have evaluated its association with the risk of HIV infection. METHODS: We analyzed visit records for heterosexual African American men who underwent HIV testing while attending sexually transmitted disease (STD) clinics in Baltimore, Maryland, from 1993 to 2000. We used multivariable binomial regression to evaluate associations between circumcision and the risk of HIV infection among visits by patients with known and unknown HIV exposure. RESULTS: Overall, 1096 (2.7%) of 40,571 clinic visits yielded positive HIV test results. Among 394 visits by patients with known HIV exposure, circumcision was significantly associated with lower HIV prevalence (10.2% vs. 22.0%; adjusted prevalence rate ratio [PRR], 0.49 [95% confidence interval [CI], 0.26-0.93]). Conversely, among 40,177 visits by patients with unknown HIV exposure, circumcision was not associated with reduced HIV prevalence (2.5% vs. 3.3%; adjusted PRR, 1.00 [95% CI, 0.86-1.15]), and age >or=25 years old and diagnosis of ulcerative STD were associated with increased prevalence. CONCLUSIONS: Circumcision was associated with substantially reduced HIV risk in patients with known HIV exposure, suggesting that results of other studies demonstrating reduced HIV risk for circumcision among heterosexual men likely can be generalized to the US context.

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.

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.

Neurosyphilis in a clinical cohort of HIV-1-infected patients.

OBJECTIVES: To describe the risk factors, clinical presentation, and long-term follow up of patients enrolled in a clinical cohort of HIV-infected patients who were diagnosed and treated for neurosyphilis. METHODS: Comprehensive demographic, clinical, and therapeutic data were collected prospectively on all patients between 1990 and 2006. Patients were diagnosed with neurosyphilis if they had positive syphilis serologies and any of the following: (a) one or more cerebrospinal fluid abnormalities on lumbar puncture [white blood cells >10/microl; protein >50 mg/dl; reactive venereal diseases research laboratory], (b) an otherwise unexplained neurological finding. RESULTS: Of 231 newly diagnosed syphilis cases, 41 neurosyphilis cases met entry criteria (median age 38.6 years, 79.1% male). Risk factors for neurosyphilis included a CD4 cell count of less than 350 cells/ml at the time of syphilis diagnosis (odds ratio: 2.87; 95% confidence interval: 1.18-7.02), a rapid plasma regain titer >1: 128 (2.83; 1.11-7.26), and male sex (2.46; 1.06-5.70). Use of any highly active antiretroviral therapy before syphilis infection reduced the odds of neurosyphilis by 65% (0.35; 0.14-0.91). Sixty-three percent of cases presented with early neurosyphilis and the median time to neurosyphilis diagnosis was 9 months. Symptomatic patients had more cerebrospinal fluid abnormalities on initial lumbar puncture than asymptomatic patients (P = 0.01). Follow-up lumbar puncture within 12 months revealed that only 38% had resolution of all cerebrospinal fluid abnormalities. At 1 year, 38% had persistence of their major symptom despite adequate treatment for neurosyphilis. Twelve of 41 (29%) patients were retreated for syphilis. CONCLUSION: Early neurosyphilis was common in this cohort. Highly active antiretroviral therapy to reverse immunosuppression may help mitigate neurological complications of syphilis.

Increases in oral and anal sexual exposure among youth attending sexually transmitted diseases clinics in Baltimore, Maryland.

We examined reports of receptive oral or anal sex among clinic patients aged 12-25 years over time. Odds of reporting oral sex were approximately three times higher in 2004 than in 1994; odds of anal sex were twice as high. Providers should be aware of increased risk behavior among young people.

Sexually transmitted diseases and risk behaviors among pregnant women attending inner city public sexually transmitted diseases clinics in Baltimore, MD, 1996-2002.

OBJECTIVE: To determine the prevalence of sexually transmitted diseases (STDs) and characterize behavioral correlates among pregnant women attending inner city public STD clinics. STUDY DESIGN: A retrospective study of 2303 pregnant women frequency matched by clinic and year of visit to 2303 nonpregnant women seeking services during years 1996 to 2002 at public STD clinics in Baltimore, MD. RESULTS: On average, 329 pregnant women attended Baltimore City STD clinics each year during 1996 to 2002. Forty-six and a half percent of pregnant women knew they were pregnant when they presented to the STD clinic. Although pregnant women were younger (23.3 vs. 28.3 years of age, P <0.01) and more likely to have sought STD clinical services in the past (55.4% vs. 51.5%, P <0.01), they were less likely to report high-risk sexual behaviors such as new (4.6% vs. 7.0%, P <0.01) or multiple sex partners (11.6% vs. 13.9%, P <0.01) than nonpregnant women. However, prevalence of gonorrhea (4.8% pregnant vs. 4.2%), chlamydia (9.9% vs. 7.7%), trichomoniasis (12.4% vs. 12.0%), and early syphilis (1.5% vs. 1.2%) was high, and both groups were equally as likely to have any STD. CONCLUSION: The prevalence of STDs was similar for pregnant and nonpregnant women attending the inner city public STD clinics, despite differences in risk factors for STDs. Understanding the impact of STDs on perinatal outcomes among this population and developing targeted interventions to reduce STD-related maternal and infant morbidity are critical public health issues.

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.