SARS-CoV-2 seroprevalence in vaccine-naïve participants from the Democratic Republic of Congo, Guinea, Liberia, and Mali.

OBJECTIVES: The InVITE study, starting in August 2021, was designed to examine the immunogenicity of different vaccine regimens in several countries including the Democratic Republic of Congo, Guinea, Liberia, and Mali. Prevaccination baseline samples were used to obtain estimates of previous SARS-CoV-2 infection in the study population. METHODS: Adult participants were enrolled upon receipt of their initial COVID-19 vaccine from August 2021 to June 2022. Demographic and comorbidity data were collected at the time of baseline sample collection. SARS-CoV-2 serum anti-Spike and anti-Nucleocapsid antibody levels were measured. RESULTS: Samples tested included 1016, 375, 663, and 776, from DRC, Guinea, Liberia, and Mali, respectively. Only 0.8% of participants reported a prior positive SARS-CoV-2 test, while 83% and 68% had anti-Spike and anti-Nucleocapsid antibodies, respectively. CONCLUSIONS: Overall SARS-CoV-2 seroprevalence was 86% over the accrual period, suggesting a high prevalence of SARS-CoV-2 infection. Low rates of prior positive test results may be explained by asymptomatic infections, limited access to SARS-CoV-2 test kits and health care, and inadequate surveillance. These seroprevalence rates are from a convenience sample and may not be representative of the population in general, underscoring the need for timely, well-conducted surveillance as part of global pandemic preparedness.

Sudden death after a bite by a lowland swamp viper (Proatheris superciliaris) in Malawi: Dying of fright?

Proatheris superciliaris, the lowland swamp viper, has a limited distribution along lakeshores and rivers in Malawi, Southern Tanzania, and central Mozambique. Its venom is known to be procoagulant. Only five P. superciliaris bites have been reported, all inflicted by captive snakes, and none was fatal. Here we present a case of sudden death following a bite by Proatheris superciliaris in rural Malawi that cannot be attributed to envenoming. A healthy 32-year-old woman was planting rice in a flooded rice paddy field when she suddenly told her sister in a quiet voice that she had been bitten by a snake. She then collapsed face-upwards into the ankle-deep water. She remained motionless while her sister and uncle carried her out of the rice paddy onto dry land a few meters away. The victim did not regain consciousness. Her uncle heard one exhalation but no further breathing. The snake responsible was killed by a friend. Although the venom of this species can cause life-threatening coagulopathy, this woman's death occurred too rapidly to be attributable to envenoming. Only two explanations seem plausible: anaphylaxis, or vasovagal shock triggered by fear. In the present case, the victim died within minutes of the bite, closely observed by her anxious relatives, but showed no features of anaphylaxis. In Malawi, as in much of sub-Saharan Africa, many people are reportedly terrified of snakes, believing that bites by almost any species can cause rapid death. In this case, death occurred less than 2 min after a bite from Proatheris superciliaris. We believe that the cause of death was most likely a severe vasovagal attack, in response to the fear and pain of the snakebite that triggered vasodilatation, bradycardia, and hypotension leading to cardiac arrest.

Randomized controlled phase IIa clinical trial of safety, pharmacokinetics and pharmacodynamics of tenofovir and tenofovir plus levonorgestrel releasing intravaginal rings used by women in Kenya.

Introduction: Globally, many young women face the overlapping burden of HIV infection and unintended pregnancy. Protection against both may benefit from safe and effective multipurpose prevention technologies. Methods: Healthy women ages 18-34 years, not pregnant, seronegative for HIV and hepatitis B surface antigen, not using hormonal contraception, and at low risk for HIV were randomized 2:2:1 to continuous use of a tenofovir/levonorgestrel (TFV/LNG), TFV, or placebo intravaginal ring (IVR). In addition to assessing genital and systemic safety, we determined TFV concentrations in plasma and cervicovaginal fluid (CVF) and LNG levels in serum using tandem liquid chromatography-mass spectrometry. We further evaluated TFV pharmacodynamics (PD) through ex vivo CVF activity against both human immunodeficiency virus (HIV)-1 and herpes simplex virus (HSV)-2, and LNG PD using cervical mucus quality markers and serum progesterone for ovulation inhibition. Results: Among 312 women screened, 27 were randomized to use one of the following IVRs: TFV/LNG (n = 11); TFV-only (n = 11); or placebo (n = 5). Most screening failures were due to vaginal infections. The median days of IVR use was 68 [interquartile range (IQR), 36-90]. Adverse events (AEs) were distributed similarly among the three arms. There were two non-product related AEs graded >2. No visible genital lesions were observed. Steady state geometric mean amount (ssGMA) of vaginal TFV was comparable in the TFV/LNG and TFV IVR groups, 43,988 ng/swab (95% CI, 31,232, 61,954) and 30337 ng/swab (95% CI, 18,152, 50,702), respectively. Plasma TFV steady state geometric mean concentration (ssGMC) was <10 ng/ml for both TFV IVRs. In vitro, CVF anti-HIV-1 activity showed increased HIV inhibition over baseline following TFV-eluting IVR use, from a median of 7.1% to 84.4% in TFV/LNG, 15.0% to 89.5% in TFV-only, and -27.1% to -20.1% in placebo participants. Similarly, anti-HSV-2 activity in CVF increased >50 fold after use of TFV-containing IVRs. LNG serum ssGMC was 241 pg/ml (95% CI 185, 314) with rapid rise after TFV/LNG IVR insertion and decline 24-hours post-removal (586 pg/ml [95% CI 473, 726] and 87 pg/ml [95% CI 64, 119], respectively). Conclusion: TFV/LNG and TFV-only IVRs were safe and well tolerated among Kenyan women. Pharmacokinetics and markers of protection against HIV-1, HSV-2, and unintended pregnancy suggest the potential for clinical efficacy of the multipurpose TFV/LNG IVR. Clinical Trial Registration: NCT03762382 [https://clinicaltrials.gov/ct2/show/NCT03762382].

Challenges of conducting an international observational study to assess immunogenicity of multiple COVID-19 vaccines.

The International Study on COVID-19 Vaccines to Assess Immunogenicity, Reactogenicity, and Efficacy is an observational study to assess the immunogenicity of COVID-19 vaccines used in Democratic Republic of Congo, Guinea, Indonesia, Liberia, Mali, Mexico, and Mongolia. The study, which has enrolled 5,401 adults, is prospectively following participants for approximately two years. This study is important as it has enrolled participants from resource-limited settings that have largely been excluded from COVID-19 research studies during the pandemic. There are significant challenges to mounting a study during an international health emergency, especially in resource-limited settings. Here we focus on challenges and hurdles encountered during the planning and implementation of the study with regard to study logistics, national vaccine policies, pandemic-induced and supply chain constraints, and cultural beliefs. We also highlight the successful mitigation of these challenges through the team's proactive thinking, collaborative approach, and innovative solutions. This study serves as an example of how established programs in resource-limited settings can be leveraged to contribute to biomedical research during a pandemic response. Lessons learned from this study can be applied to other studies mounted to respond rapidly during a global health crisis and will contribute to capacity for stronger pandemic preparedness in the future when there is a crucial need for urgent response and data collection.

Traditional Medicine Beliefs and Practices among Caregivers of Children under Five Years-The Child Health and Mortality Prevention Surveillance (CHAMPS), Western Kenya: A qualitative study.

BACKGROUND: Approximately 80% of the population residing in sub-Saharan Africa relies on Traditional Medicine (TM). However, literature on factors motivating the use of TM for children under the age of five in these settings is limited. Such information can guide policy formulation for integration of TM into mainstream health care services. This study aimed to describe the motivation on use of TM among caregivers of children residing in rural and urban communities in western Kenya. METHODS: The socio-behavioral sciences (SBS) arm of the Child Health and Mortality Prevention Surveillance (CHAMPS) program in western Kenya, conducted a cross-sectional qualitative study in Manyatta-an urban informal settlement located in Kisumu town and Karemo-a rural setting in Siaya County. We performed 29 in-depth interviews, 5 focus group discussions and 11 semi-structured interviews with community representatives (n = 53), health workers (n = 17), and community leaders (n = 18). All the participants were purposively sampled. We performed thematic analysis using both inductive and deductive approaches. Data management was completed on Nvivo 11.0 software (QSR International, Melbourne, Australia). RESULTS: Our findings reveal that some caregivers prefer TM to treat some childhood diseases. Use of TM was informed by illness beliefs about etiology of disease. We observed an appreciation from the study participants that malaria can effectively be treated by Conventional Medicine (CM) while TM was preferred to treat measles and diseases believed to be associated with supernatural etiology such as witchcraft, evil spirit or breaching cultural taboos. TM was also used in instances where CM failed to provide a diagnosis or when CM was 'slow'. TM in such cases was used as a last resort. CONCLUSION: We observed varied beliefs that motivate caregivers' choice of TM use among children in western Kenya. It is therefore crucial to consider perceptions and socio-cultural beliefs about illnesses when formulating interventions that are geared towards child health.

Consolidated Overview of Notifiable Adverse Events in the U.S. President's Emergency Plan for AIDS Relief's Voluntary Medical Male Circumcision Program Through 2020.

PURPOSE OF REVIEW: Through December 2020, the U.S. President's Emergency Plan for AIDS Relief (PEPFAR) supported more than 25 million voluntary medical male circumcisions (VMMC) as part of the combined HIV prevention strategy in 15 African countries. PEPFAR monitors defined adverse events (AEs) occurring within 30 days of VMMC through its notifiable adverse event reporting system (NAERS). All NAERS reports through December 2020 were reviewed to quantify AE type, severity, and relation to the VMMC procedure. Interventions to improve client safety based on NAERS findings are described. RECENT FINDINGS: Fourteen countries reported 446 clients with notifiable adverse events (NAEs); 394/446 (88%) were determined VMMC-related, representing approximately 18 NAE reports per million circumcisions. Fatalities comprised 56/446 (13%) with 24/56 (43%) of fatalities determined VMMC-related, representing 0.96 VMMC-related fatalities per million circumcisions. The remaining 390 NAEs were non-fatal with 370/390 (95%) VMMC-related. Multiple programmatic changes have been made based on NAERS data to improve client safety. Client safety is paramount in this surgical program designed for individual and population-level benefit. Surveillance of rare but severe complications following circumcision has identified pre-existing or new safety concerns and guided continuous programmatic improvement.

Genital microbiota of women using a 90 day tenofovir or tenofovir and levonorgestrel intravaginal ring in a placebo controlled randomized safety trial in Kenya.

In a phase-IIa trial, we investigated the influence of 90 days continuous-delivery tenofovir (TFV) intravaginal rings (IVRs) with/without levonorgestrel (LNG) on the genital microbiota of Kenyan women. Eligible women (n = 27; 18-34 years; negative for HIV, sexually transmitted infections, and Amsel-bacterial vaginosis) were randomized 2:2:1 to use of IVRs containing TFV, TFV/LNG, or placebo. Using vaginal wall and IVR swabs at IVR insertion and removal, the genital microbial composition was determined using 16S rRNA gene sequencing. The presence of Candida spp. was determined using qPCR. The vaginal total bacterial burden appeared to decrease with TFV and TFV/LNG IVR use (log100.57 and log100.27 decrease respectively; p > 0.05). The TFV/LNG IVR was more 'stabilizing': 50% of the participants' microbiota community state types remained unchanged and 50% shifted towards higher Lactobacillus abundance. Specifically, TFV/LNG IVR use was accompanied by increased abundances of Lactobacillus gasseri/hominis/johnsonii/taiwanensis (16.3-fold) and L. fermentum/reuteri/vaginalis (7.0-fold; all p < 0.01). A significant shift in the overall microbial α-diversity or ß-diversity was not observed for either IVR, and IVR use did not influence Candida spp. prevalence. TFV/LNG and TFV IVRs did not adversely affect the genital microbiota and are safe to use. Our findings support further studies assessing their efficacy in preventing HIV/HSV-2 and unintended pregnancies.

Causes of death in HIV-infected and HIV-uninfected children aged under-five years in western Kenya.

OBJECTIVES: Describe the causes of death among infants and children less than 5 years stratified by HIV status. DESIGN: Cross-sectional analysis of causes of death ascertained through minimally invasive tissue sampling (MITS) in the Kenya Child Health and Mortality Prevention Surveillance site. METHODS: We included decedents aged 28 days to less than 5 years, whose death was reported within 36 h, underwent MITS, and had HIV test results and causes of death determined. MITS specimens were tested using Taqman Array Cards, culture, cytology, histopathology and immunohistochemistry and HIV PCR. A panel evaluated epidemiologic, clinical, verbal autopsy and laboratory data to assign causes of death using ICD-10 guidelines. Causes of death and etiological agents were stratified by HIV status. RESULTS: Of 176 included decedents, 14% (n = 25) were HIV-infected, median viral load was 112 205 copies/ml [interquartile range (IQR) = 9349-2 670 143). HIV-disease (96%; n = 24) and malnutrition (23%; n = 34) were the leading underlying causes of death in HIV-infected and HIV-uninfected decedents, respectively. Malnutrition was more frequent in the causal chain of HIV-infected (56%; n = 14) than HIV-uninfected decedents (31%; n = 49) (P value = 0.03). Viral pneumonia was twice as common in HIV-infected (50%; n = 9) than HIV-uninfected decedents (22%; n = 7) (P value = 0.04). CONCLUSION: Nearly all HIV-infected decedents' underlying cause of death was HIV disease, which was associated with malnutrition. Our findings underscore the need for strengthening early identification and management of HIV-infected children. Prevention, early diagnosis and treatment of malnutrition could be instrumental in improving the survival of HIV-infected and HIV-uninfected children.

Progress in voluntary medical male circumcision for HIV prevention supported by the US President's Emergency Plan for AIDS Relief through 2017: longitudinal and recent cross-sectional programme data.

OBJECTIVE: This article provides an overview and interpretation of the performance of the US President's Emergency Plan for AIDS Relief's (PEPFAR's) male circumcision programme which has supported the majority of voluntary medical male circumcisions (VMMCs) performed for HIV prevention, from its 2007 inception to 2017, and client characteristics in 2017. DESIGN: Longitudinal collection of routine programme data and disaggregations. SETTING: 14 countries in sub-Saharan Africa with low baseline male circumcision coverage, high HIV prevalence and PEPFAR-supported VMMC programmes. PARTICIPANTS: Clients of PEPFAR-supported VMMC programmes directed at males aged 10 years and above. MAIN OUTCOME MEASURES: Numbers of circumcisions performed and disaggregations by age band, result of HIV test offer, procedure technique and follow-up visit attendance. RESULTS: PEPFAR supported a total of 15 269 720 circumcisions in 14 countries in Southern and Eastern Africa. In 2017, 45% of clients were under 15 years of age, 8% had unknown HIV status, 1% of those tested were HIV+ and 84% returned for a follow-up visit within 14 days of circumcision. CONCLUSIONS: Over 15 million VMMCs have been supported by PEPFAR since 2007. VMMC continues to attract primarily young clients. The non-trivial proportion of clients not testing for HIV is expected, and may be reassuring that testing is not being presented as mandatory for access to circumcision, or in some cases reflect test kit stockouts or recent testing elsewhere. While VMMC is extremely safe, achieving the highest possible follow-up rates for early diagnosis and intervention on complications is crucial, and programmes continue to work to raise follow-up rates. The VMMC programme has achieved rapid scale-up but continues to face challenges, and new approaches may be needed to achieve the new Joint United Nations Programme on HIV/AIDS goal of 27 million additional circumcisions through 2020.

Bleeding and Blood Disorders in Clients of Voluntary Medical Male Circumcision for HIV Prevention - Eastern and Southern Africa, 2015-2016.

Male circumcision reduces the risk for female-to-male human immunodeficiency virus (HIV) transmission by approximately 60% (1) and has become a key component of global HIV prevention programs in countries in Eastern and Southern Africa where HIV prevalence is high and circumcision coverage is low. Through September 2017, the President's Emergency Plan for AIDS Relief (PEPFAR) had supported 15.2 million voluntary medical male circumcisions (VMMCs) in 14 priority countries in Eastern and Southern Africa (2). Like any surgical intervention, VMMC carries a risk for complications or adverse events. Adverse events during circumcision of males aged ≥10 years occur in 0.5% to 8% of procedures, though the majority of adverse events are mild (3,4). To monitor safety and service quality, PEPFAR tracks and reports qualifying notifiable adverse events. Data reported from eight country VMMC programs during 2015-2016 revealed that bleeding resulting in hospitalization for ≥3 days was the most commonly reported qualifying adverse event. In several cases, the bleeding adverse event revealed a previously undiagnosed or undisclosed bleeding disorder. Bleeding adverse events in men with potential bleeding disorders are serious and can be fatal. Strategies to improve precircumcision screening and performance of circumcisions on clients at risk in settings where blood products are available are recommended to reduce the occurrence of these adverse events or mitigate their effects (5).

Systematic review of the effect of economic compensation and incentives on uptake of voluntary medical male circumcision among men in sub-Saharan Africa.

Voluntary medical male circumcision (VMMC) prevalence in priority countries in sub-Saharan Africa, particularly among men aged ≥20 years, has not yet reached the goal of 80% coverage recommended by the World Health Organization. Determining novel strategies to increase VMMC uptake among men ≥20 years is critical to reach HIV epidemic control. We conducted a systematic review to analyze the effectiveness of economic compensation and incentives to increase VMMC uptake among older men in order to inform VMMC demand creation programs. The review included five qualitative, quantitative, and mixed methods studies published in peer reviewed journals. Data was extracted into a study summary table, and tables synthesizing study characteristics and results. Results indicate that cash reimbursements for transportation and food vouchers of small nominal amounts to partially compensate for wage loss were effective, while enrollment into lotteries offering prizes were not. Economic compensation provided a final push toward VMMC uptake for men who had already been considering undergoing circumcision. This was in settings with high circumcision prevalence brought by various VMMC demand creation strategies. Lottery prizes offered in the studies did not appear to help overcome barriers to access VMMC and qualitative evidence suggests this may partially explain why they were not effective. Economic compensation may help to increase VMMC uptake in priority countries with high circumcision prevalence when it addresses barriers to uptake. Ethical considerations, sustainability, and possible externalities should be carefully analyzed in countries considering economic compensation as an additional strategy to increase VMMC uptake.

Innovative Methods of Male Circumcision for HIV Prevention-Getting the Right Evidence.

World Health Organization recommends that countries with hyperendemic and generalized HIV epidemics implement voluntary medical male circumcision programs for HIV prevention. Innovative methods of male circumcision including devices have the potential to simplify the procedure, reduce time and cost, increase client acceptability, enhance safety, and expand the numbers of providers who may perform circumcision. We describe work led by World Health Organization and supported by global partners to define a pathway for the evaluation of efficacy and safety of male circumcision devices, to set priority criteria, and to establish a process to guide the use of devices in publicly funded voluntary medical male circumcision programs for HIV prevention. A device classification scheme, an expert Technical Advisory Group on Innovations in Male Circumcision, and a formal prequalification program have also guided considerations on safe use of devices. A rigorous approach was deemed appropriate given the intervention is for use among healthy men for public health purposes. The pathway and processes led to coordinated research, better standardization in research outcomes, and guidance that informed the research, introduction and implementation phases. The lessons learnt from this case study can inform evaluation and use of future public health innovations.

Employing Demand-Based Volumetric Forecasting to Identify Potential for and Roles of Devices in Scale-Up of Medical Male Circumcision in Zambia and Zimbabwe.

INTRODUCTION: Devices for male circumcision (MC) are becoming available in 14 priority countries where MC is being implemented for HIV prevention. Understanding potential impact on demand for services is one important programmatic consideration because countries determine whether to scale up devices within MC programs. METHODS: A population-based survey measuring willingness to undergo MC, assuming availability of surgical MC and 3 devices, was conducted among 1250 uncircumcised men, ages 10-49 years in Zambia and 1000 uncircumcised men, ages 13-49 years in Zimbabwe. Simulated Test Market methodology was used to estimate incremental MC demand and the extent to which devices might be preferred over surgery, assuming availability of: surgical MC in both countries; the devices PrePex, ShangRing, and Unicirc in Zambia; and PrePex in Zimbabwe. RESULTS: Modeled estimates indicate PrePex has the potential to provide an overall increase in MC demand ranging from an estimated 13%-50%, depending on country and WHO prequalification ages, replacing 11%-41% of surgical procedures. In Zambia, ShangRing could provide 8% overall increase, replacing 45% of surgical procedures, and Unicirc could provide 30% overall increase, replacing 85% of surgical procedures. CONCLUSIONS: In both countries, devices have potential to increase overall demand for MC, assuming wide scale awareness and availability of circumcision by the devices. With consideration for age and country, PrePex may provide the greatest potential increase in demand, followed by Unicirc (measured in Zambia only) and ShangRing (also Zambia only). These results inform one program dimension for decision making on potential device introduction strategies; however, they must be considered within the broader programmatic context.

Notes from the Field: Tetanus Cases After Voluntary Medical Male Circumcision for HIV Prevention--Eastern and Southern Africa, 2012-2015.

Voluntary medical male circumcision (VMMC) decreases the risk for female-to-male HIV transmission by approximately 60%, and the President's Emergency Plan for AIDS Relief (PEPFAR) is supporting the scale-up of VMMC for adolescent and adult males in countries with high prevalence of human immunodeficiency virus (HIV) and low coverage of male circumcision. As of September 2015, PEPFAR has supported approximately 8.9 million VMMCs.

Voluntary medical male circumcision: an HIV prevention priority for PEPFAR.

As the science demonstrating strong evidence for voluntary medical male circumcision (VMMC) for HIV prevention has evolved, the President's Emergency Plan for AIDS Relief (PEPFAR) has collaborated with international agencies, donors, and partner country governments supporting VMMC programming. Mathematical models forecast that quickly reaching a large number of uncircumcised men with VMMC in strategically chosen populations may dramatically reduce community-level HIV incidence and save billions of dollars in HIV care and treatment costs. Because VMMC is a 1-time procedure that confers life-long partial protection against HIV, programs for adult men are vital short-term investments with long-term benefits. VMMC also provides a unique opportunity to reach boys and men with HIV testing and counseling services and referrals for other HIV services, including treatment. After formal recommendations by WHO in 2007, priority countries have pursued expansion of VMMC. More than 1 million males have received VMMC thus far, with the most notable successes coming from Kenya's Nyanza Province. However, a myriad of necessary cultural, political, and ethical considerations have moderated the pace of overall success. Because many millions more uncircumcised men would benefit from VMMC services now, US President Barack Obama committed PEPFAR to provide 4.7 million males with VMMC by 2014. Innovative circumcision methods-such as medical devices that remove the foreskin without injected anesthesia and/or sutures-are being rigorously evaluated. Incorporation of safe innovations into surgical VMMC programs may provide the opportunity to reach more men more quickly with services and dramatically reduce HIV incidence for all.

Epidemic Intelligence Service investigations of respiratory illness, 1946-2005.

Infectious respiratory pathogens were the suspected cause of 480 outbreaks investigated by the Centers for Disease Control and Prevention's Epidemic Intelligence Service officers during 1946-2005. All epidemic-assistance investigation reports and associated articles from scientific journals were reviewed. Investigations identified 25 different infectious respiratory pathogens including, most frequently, tuberculosis, influenza, and legionellosis. Other bacterial-, viral-, and fungal-related pathogens also were identified. Epidemic-assistance investigations were notable for first identifying Legionnaires disease and Pontiac fever, hantavirus pulmonary syndrome, and new strains of human and avian influenza, as well as emerging challenges (e.g., multidrug-resistant tuberculosis and pneumococcus). The investigations provided clinical insights into such diseases as pulmonary anthrax and identified high risks of serious respiratory illnesses for persons infected with human immunodeficiency virus, other immunocompromised persons, and persons with diabetes. They identified settings placing persons at high risk of acquiring disease, including nursing homes, prisons, homeless shelters, and hospitals. Travel also placed persons at risk. Key environmental factors related to spread of diseases and occupational risks for brucellosis and psittacosis were identified. The outbreak investigations constitute a wealth of prevention experience and provide the basis for recommendations to mitigate outbreaks and reduce future risks.