Gay, bisexual, and other men who have sex with men (MSM), particularly Black or African American MSM (BMSM) and Hispanic or Latino MSM (HLMSM), continue to be disproportionately affected by the HIV epidemic in the United States. Previous HIV self-testing programs have yielded high testing rates, although these studies predominantly enrolled White, non-Hispanic MSM. Mobile health tools can support HIV prevention, testing, and treatment. This protocol details an implementation study of mailing free HIV self-tests (HIVSTs) nested within a randomized controlled trial designed to assess the benefit of a mobile phone app for increasing the uptake of HIV prevention and other social services.This study was a comparative effectiveness trial of innovative recruitment and testing promotion strategies intended to effectively reach cisgender BMSM and HLMSM. We evaluated the use of a mobile app for increasing access to care.Study development began with individual and group consultations that elicited feedback from 3 core groups: HIV care practitioners and researchers, HIV service organization leaders from study states, and BMSM and HLMSM living in the study states. Upon completion of the formative qualitative work, participants from 11 states, based on the observed areas of highest rate of new HIV diagnoses among Black and Hispanic MSM, were recruited through social networking websites and smartphone apps. After eligibility was verified, participants consented and were randomized to the intervention arm (access to the Know@Home mobile app) or the control arm . We provided all participants with HIVSTs. The evaluation of the efficacy of a mobile phone app to support linkage to posttest prevention services that included sexually transmitted infection testing, pre-exposure prophylaxis initiation, antiretroviral treatment, and acquisition of condoms and compatible lubricants has been planned. Data on these outcomes were obtained from several sources, including HIVST-reporting surveys, the 4-month follow-up survey, laboratory analyses of dried blood spot cards returned by the participant, and data obtained from the state health department surveillance systems. Where possible, relevant subgroup analyses were performed.During the formative development phase, 9 consultations were conducted: 6 in-depth individual discussions and 3 group consultations. From February 2020 through February 2021, we enrolled 2093 MSM in the randomized controlled trial from 11 states, 1149 BMSM and 944 HLMSM.This study was designed and implemented to evaluate the effectiveness of recruitment strategies to reach BMSM and HMSM and of a mobile app with regard to linkage to HIV prevention or treatment services. Data were also obtained to allow for the analyses of cost and cost-effectiveness related to study enrollment, HIV testing uptake, identification of previously undiagnosed HIV, sexually transmitted infection testing and treatment, and linkage to HIV prevention or treatment services.ClinicalTrials.gov (NCT04219878); https://clinicaltrials.gov/ct2/show/NCT04219878DERR1-10.2196/43414 HIV testing is the cornerstone of HIV prevention and care and is the starting point for parallel HIV prevention and care continua -3. The CConsidering the HIV prevention cascade, MSM who obtain a negative HIV test result also have indications for important follow-up prevention services, including sexually transmitted infection (STI) testing , provisiTo address this gap, we developed a protocol for the Implementation of the Rapid HIV Self-testing Among MSM Project (iSTAMP), with the goal of demonstrating the costs and best practices for reaching BMSM and HLMSM on the internet and providing all participants with free HIVSTs. To ensure prompt linkage to additional HIV testing and care for those with a preliminary positive result and promote linkage to appropriate posttest sexual health care, we provided the intervention arm with a mobile phone app to facilitate linkage to services. We developed methods to enroll BMSM and HLMSM, provide them with HIVSTs, and evaluate the efficacy of a mobile phone app to support linkage to posttest prevention services, including STI testing, PrEP initiation, and acquisition of condoms and compatible lubricants. This paper describes the protocol and enrollment numbers for providing HIVSTs to BMSM and HLMSM enrolled in 11 select US states.The purpose of this paper is to describe our study procedures and provide recommendations for reaching and distributing HIVSTs to MSM most disproportionately affected by HIV in the United States. In addition, although an HIVST is not designed to link the user to HIV testing and prevention services, we will evaluate the efficacy of a mobile app to increase the linkage to HIV and STI prevention services.This study was a comparative effectiveness trial of 2093 cisgender MSM living across 11 states in the United States, including 1149 BMSM and 944 HLMSM. We selected these states based on race- and state-specific estimates of the MSM population size previously developed collaboratively by the CDC and Emory University . We seleThe study was conducted in 2 phases: phase 1 involved formative discussions with stakeholders to inform the implementation of phase 2. Phase 2  was a raThis study was approved by the Emory Institutional Review Board (IRB00099710).To inform the implementation trial recruitment strategy, study procedures, and linkage-to-care protocol, we conducted individual and group consultations to elicit feedback during the Know@Home study planning and app development phase. This formative work solicited feedback from three core groups: (1) HIV care practitioners and researchers, (2) HIV service organization leaders from study implementation states, and (3) BMSM and HLMSM who live within the implementation study states.To gain insight into the nuances of HIV screening among BMSM and HLMSM, 6 HIV care physicians and researchers specializing in working with these populations were invited to participate in one-on-one discussions over video calls. Discussions centered around understanding their experiences of engaging BMSM and HLMSM in HIV research, what advertising venues they found effective for recruiting each population, recommendations for advertising imagery and written content, and approaches to garner trust and foster retention within the project. The notes taken during each discussion were compiled, reviewed by the study team, and assembled into overarching themes. These consultants primarily had experience working with BMSM and had less advice pertaining to HLMSM. There was consensus that dating and hookup apps were the most successful in recruiting BMSM and HLMSM and that images should reflect age, body type, and diversity of skin tone within these populations. Providers working in southern states noted that HIV stigma and distrust of health care and academic institutions were barriers to engaging BMSM in HIV research and prevention and care services. To build confidence, consultants recommended creating relationships with trusted community-based organizations (CBOs) and clinics embedded within these communities. Consultants recommended obtaining support from respected local and state CBOs and clinics to provide study credibility, help keep participants engaged in the duration of the project, and boost linkage-to-care efforts.In an effort to help establish relationships with CBOs and ensure practical research deliverables, 5 directors of HIV service organizations were invited to participate in a consultation over a video call. These CBO directors specialized in providing HIV screening and linkage services for BMSM and HLMSM in Alabama, Florida, Mississippi, New York, and North Carolina. The discussions focused on the types of data that would support the creation and implementation of a web-based HIV self-testing program, strategies for reaching BMSM and HMSM, and considerations for scaling such a program to a local organizational level. The notes taken during the consultation were reviewed by the study team, sorted thematically, and assembled into overarching themes. To help create an HIV self-testing program, the CBO directors highlighted their desire for metrics surrounding overall kit distribution, how many results were returned, and how many participants were successfully linked to care. In addition, all directors described the utility of a cost-effectiveness analysis to understand the expenses associated with such a self-testing program in relation to being able to link people who obtained a preliminary positive test result to HIV care. As many of the CBOs had existing laboratory partnerships, the consultants felt that if this program were brought to scale, they would be able to accommodate the processing of returned biospecimens for HIV testing  and triple-site bacterial STI testing . All directors communicated that their implementation concerns were around staffing and funding, tracking HIVST kits, following up with clients who had a positive test result, and preventing some clients from acquiring more kits than necessary. Finally, CBO directors discussed how having a fully developed protocol for implementing an HIV self-testing program would help them bring a program to scale in their local service provision area.The last element of the consultations sought to receive developmental input from BMSM and HLMSM regarding our recruitment materials, plans, and study procedures. To enlist BMSM and HLMSM, we asked our consultants  in implementation study states to nominate community members who they felt were engaged with HIV and STI issues. Among the nominations offered, 3 HLMSM from California, Florida, and New York and 3 BMSM from California, Florida, and South Carolina participated. Two separate consultations were conducted via video calls—one with HLMSM and another with BMSM. During each consultation, a PowerPoint (Microsoft Corp) presentation was screen shared to elicit feedback on advertising imagery and content, possible recruitment venues, and strategies for disbursing incentives. The discussions also covered participant retention and study implementation design. Notes taken during each consultation were reviewed by the study team and assembled into a set of themes. Across both groups, community members advised using different dating or hookup apps for advertising in each state, based on their varying popularity, in addition to mainstream social media platforms. Retention issues that were cited included participants moving out of eligible study states during the follow-up period and the low monetary incentive for DBS sample collection. Their recommendations for implementation highlighted the importance of discreet shipment packaging, confidentiality of the result-reporting mechanism, linking those with a positive test result to locally trusted CBOs, and privacy of any study app notifications. Finally, the HLMSM group cautioned about the variability of Spanish dialects across the United States when attempting to offer Spanish-translated resources and materials.During the 2 consultations with BMSM and HLMSM, feedback was obtained on draft advertisement images and taglines to be used for recruitment purposes. Consultants preferred joyous, light-hearted stock images of men to photos that conveyed solemnness. Consultants rated advertisements higher if they showcased everyday situations and “relatable” models that they felt were recognizable within their communities. Images that felt staged, unnatural, generic, or too commercial were ranked lower. Advertisements that portrayed physical affection and intimacy between men were also favored. Men who were shown hugging, kissing, or cuddling portrayed why HIV self-testing may be relevant to the target audience and related to healthy relationships or partner seeking. However, some images where men appeared too serious with their partners were thought to potentially depict intimate partner violence situations. In terms of race and ethnicity, participants gravitated to photos that included Black or African American and Hispanic or Latino men together and represented diverse skin tones. Finally, consultants endorsed tagline text that incorporated puns or turn of phrases such as “It Pays to Know” to more generic messaging such as “Find out your HIV status.”After the study states were selected, we contacted each state health department, beginning with HIV surveillance programs, and had multiple group webinars to share the proposed methods for the study and individual calls with some states to discuss the possibility of matching study participants to HIV surveillance records to ascertain the outcomes of testing.Study eligibility and exclusion criteria are listed in Eligibility criteria:Black or African American race, or Hispanic or Latino ethnicityMale sex at birthCurrently identifies as maleReported anal sex with at least one man in the past 12 monthsAged ≥18 yearsHas an Android or iOS smartphoneCurrently resides in a study state Willing to download the study mobile appWilling to provide valid contact informationSuccessful completion of baseline surveyExclusionary criteria:Currently participating in another HIV prevention research study or programHad a bleeding disorderHad previously participated in an HIV vaccine studyCurrently taking pre-exposure prophylaxis for HIV preventionReported living with HIVHas plans to move out of a study state during the 4-month study periodrecruitment sources: (1) general, non–lesbian, gay, bisexual, transgender, and queer (LGBTQ)–oriented social networking websites that were not geared toward sex-seeking ; (2) LGBTQ-oriented websites ; (3) LGBTQ-oriented mobile social networking apps or dating websites geared toward sex-seeking ; and (4) other . Advertisements were placed in these web-based venues and directed users to a web page containing basic study information. Interested individuals were required to complete the web-based consent form and screener, and those who were eligible were required to provide contact information. Those who were determined to be ineligible were asked if they could be contacted for future research. We did not indicate why participants were ineligible to prevent unintentional disclosure of the eligibility criteria or repeated attempts to enroll. All participants who completed the screener were directed to web-based resources for HIV prevention and sexual health. After verification and deduplication by study staff, eligible participants were electronically sent links to the main study informed consent form and the baseline survey. The baseline survey was estimated to be completed in approximately 20 minutes.Potential participants were reached through several web-based avenues, hereafter referred to as Completed baseline responses and participant information were reviewed and checked for duplication by the study team. Web-based screener and baseline survey responses were compared to ensure consistency , and contact information and IP addresses were compared for duplication, as described elsewhere . ParticiAfter completing verification, participants were enrolled and assigned in a 1:1 ratio to the intervention or control arms using stratified randomization by race or ethnicity, state of residence, and recruitment source , totaling 88 strata. Within the strata, participants were randomly assigned to the next treatment allocation from a randomly permuted block sequence (block sizes were 2 and 4).guests) were advised to have the guest report their result and upload a photograph of their device via a web-based survey that did not collect any identifiable information. Guests were directed to a landing page with a consent form indicating that they were aged ≥18 years before completing an anonymous survey. At any point in the study, the participants and guests were allowed to stop participating.Participants in both the intervention and control arms were mailed 2 HIVSTs after completing the baseline survey. Participants were encouraged to use the second HIVST to either (1) test again if the first test did not work  or (2) provide the HIVST to someone they thought may benefit from HIV testing . After completing the 4-month follow-up survey, participants were mailed 1 additional HIVST along with the DBS self-collection kit. Participants were encouraged to use the HIVST because the results from laboratory tests conducted on the DBS card could not be returned to participants. When participants used one or more of the study-provided HIVSTs, they were instructed to report each of their HIVST results and upload a photograph of each HIVST device via a secure web-based survey. Participants who gave HIVSTs to someone not enrolled in the study  preliminary positive, (2) invalid, or (3) discrepant, meaning the result reported did not match the result image uploaded. When a preliminary positive result was provided, a staff member attempted to contact the participant to assess their emotional state, elicit existing systems of support, locate nearby HIV testing sites, and create a plan for the next steps. When the staff member identified an invalid result, they attempted to contact the participant about either receiving a replacement HIVST in the mail or providing HIV testing site referrals in their local area. After additional testing had been sought, the study staff member followed up with participants to document their corrected test result. If a discrepant result was identified, the study staff member attempted to contact the participant to verify the result entered in the test result survey, describe the source of the discrepancy, and review the test procedures, if needed. State guidelines for reporting an HIV test result to health departments were followed by study staff. As the guest test result survey  did not collect identifiable information, the study staff member was unable to contact guests about their reported test results. Study contact information was listed on the guest test result survey, and guests had the option to schedule video counseling with trained study staff.The study staff member attempted to contact all participants who reported a preliminary positive HIVST result, up to 10 times, by phone call, encrypted email, and SMS text message. Any unencrypted form of communication  made no reference to HIV testing or their preliminary positive test result. If not successfully contacted by the third attempt, the study staff member sent a list of free or low-cost local HIV testing sites and care providers through an encrypted email. When the study staff member was able to speak to the participant over the phone, they confirmed that the participant was in a private location where they could talk about their result. If the participant was unable to discuss the results at that time, the study staff member asked for another time to call again. Once privacy had been established, the study staff member started by outlining the purpose of the interaction and then transitioned into inquiring about the participant’s emotional state after receiving the preliminary positive result. The study staff member discussed the importance of having support from someone and addressed HIV disclosure strategies. The study staff member then discussed additional local HIV testing and care options in the context of the participant’s insurance status. Additional referrals offered were case management services, mental health support, HIV support groups, housing programs, food assistance, and transportation services. Agreed-upon referrals were sent via encrypted email that included information about the provider’s website, their hours of operation, and a Google Maps link to the location. After successfully sending additional HIV testing referrals, subsequent contact attempts inquired if an appointment was made or attended, if the preliminary positive result was confirmed, and if the participant was able to initiate treatment. Additional care and support referrals were assessed at each follow-up contact attempt. Participants with a positive additional HIV test result and those who received an HIV diagnosis, had seen an HIV care provider, and received HIV medication were asked if they would like any additional follow-up from the study staff members. Participants were able to opt out of study linkage-to-care support contacts at any time.Participants in the intervention arm also had the option of ordering STI self-collection kits that included instructions and materials for collecting and returning samples for gonorrhea, chlamydia, and syphilis testing. For any positive bacterial STI test results, the study staff member attempted to contact the participant up to 10 times, following the same procedures as the HIV test results. If after 3 attempts, the participant was not reachable, the participant was sent an encrypted email with a PDF document detailing the laboratory test results and information on several local free or low-cost STI treatment providers. Participants who had specific samples rejected by the laboratory owing to quality or sample collection issues were offered a replacement STI self-collection kit and a list of local STI testing services. Additional contact attempts by the study staff member assessed whether an appointment concerning the STI results had been made or attended and if any additional referrals were needed. Participants who had seen a care provider and received antibiotic treatment had no further contact from the study staff member.Remotely conducted video counseling services were made available to all iSTAMP participants and guests throughout the study. Staff members who provided video counseling were trained in the state health department HIV testing and counseling and were certified following their state guidelines. In addition, staff members were trained in motivational interviewing techniques for HIV risk behavioral change. Sessions were conducted using HIPAA-compliant Zoom Health with meeting passcodes, waiting room requirements, and end-to-end encryption.Participants were able to schedule a video counseling session for any reason, but session types were advertised as (1) a pretest session where counselors explained how to collect samples and interpret the HIVST result, and for participants in the intervention arm, the STI collection procedures; (2) a facilitated HIV test session where the participant conducted the HIVST during the video call, discussed current HIV or STI prevention behaviors, interpreted results with the assistance of the video counselor, and then discussed next steps; and (3) a posttest session where participants, who have already completed their HIV self-testing or STI self-collection, discussed their results and received appropriate referrals for treatment or prevention services. Because participants were able to schedule a session at any time during the study without describing their needs beforehand, video counselors were trained to respond to any of these standard scenarios and had a detailed knowledge of study procedures to answer participation-related questions.After their baseline HIVSTs had been shipped, participants received an email describing the video counseling service and a list of available appointment times for that week. A similar video counseling email was sent 4 months later when another HIVST and DBS card had been shipped to participants. Throughout the project, automated email reminders regarding study activities continued to advertise video counseling services. Participants were able to respond to any study-related communication  to request a video counseling session. Guaranteed video counselor availability was established during standard business hours, Monday through Friday from 9 AM to 6 PM in the eastern time zone. Participants were also able to schedule during evenings and weekends upon request. The study staff member followed telehealth procedures for client setup, provider setup, troubleshooting, and long-distance referrals described elsewhere . To helpA comprehensive cost analysis has been initiated to assess the cost of implementing recruitment strategies and the intervention. A microcosting approach was implemented, along with the standard literature practice of itemizing and assigning a dollar value to each component. Three cost-effectiveness analyses have been initiated from the health care payer perspective (the cost to the party implementing the program), which will include the different cost categories.First, we obtained the costs incurred for the 3 web-based recruitment venue categories on the outcome of study enrollment (defined as the completion of the baseline survey and downloading of the study app). We collected data on the following cost categories: web-based banner advertisement placement and study staff time to (1) manage enrollment, (2) validate participant eligibility, and (3) monitor and evaluate enrollment data.Second, we obtained cost data for the 3 venue categories on the outcome of HIVST results returned during the study period and the number of participants with a reactive result. We collected data on the costs of enrollment along with HIVST procurement and shipping, staff or personnel time to manage mailing or return of test kits, study staff time to manage monitoring and evaluation of HIV test result data, and study staff time to provide phone counseling to those who reported a preliminary positive HIV test result.Finally, we obtained costs data for the intervention on linkage to 3 sexual health services . We collected data on the costs incurred after the participants are provided with HIVSTs and randomly assigned them to 1 of the 2 study arms.These analyses have included the cost of study staff time for processing orders, contacting participants, and app management or participant registration and are independent of the prerandomization cost-effectiveness analyses; no cost related to recruitment strategies were included.Cost data were collected by extraction from accounting and budget records, external contracts, and study or personnel time required to manage the outlined tasks. Data were estimated using Clockify (COING Inc), a free software (both web- and mobile based) that allows personnel to track the time spent on daily tasks. To calculate personnel costs, we multiplied these hours by wage rates plus fringe. Only implementation costs (defined as the ongoing costs of delivering the intervention) were considered, and no costs associated with survey or app development, incentives, or research were included.A web-based screening survey collected information to determine eligibility, including demographics, sexual behaviors, state of residence, HIV status, and contact information. Participants, if eligible, then completed a web-based baseline survey that collected information on additional demographic characteristics, sexual behaviors, HIV testing history, future preferences for PrEP use, HIV testing intentions, other health service history, internet and mobile app use, medical mistrust, and health literacy. Participants were prompted by email, SMS text message, or phone to take a web-based follow-up survey after 4 months, which covered the same domains as the baseline survey, with reporting limited to the postbaseline period. Additional topics in the follow-up survey included PrEP use, HIV treatment and care, and time and costs. Participants in the intervention arm answered additional questions in the follow-up survey regarding their experiences using the Know@Home mobile app, and individuals who used the video prevention counseling option were asked about their experiences using this service.Separate test result–reporting surveys were distributed to participants after the baseline and 4-month follow-up surveys, referred to as the baseline test result–reporting survey and 4-month follow-up test result–reporting survey, respectively. The participant and guest surveys asked about their experience regarding (1) receiving HIVSTs, (2) experience using the rapid test, (3) the result of each HIVST, and (4) distributing HIVSTs.As participants interacted with the Know@Home app, data about the features used, pages visited, functions used, and time spent were captured by the app and stored in the administrative portal.Participants who consented to provide DBS samples for laboratory-based research were provided DBS self-collection kits after completing the 4-month survey. Using the instructions provided, participants prepared and mailed the DBS card for HIV diagnostic testing. Testing included an algorithm with antigen and antibody combination and HIV-1 and HIV-2 differentiation supplemental testing. The DBS samples served both as secondary testing that is more sensitive than the baseline rapid tests and to corroborate or identify new positive HIV results. As a supplemental assessment, participants who returned the DBS card and reported taking HIV medications  were sent a microtainer self-collection kit to mail the blood sample to the CDC. The purpose of the microtainer collection activity was to evaluate the feasibility and specimen integrity of self-collected microtainer samples from untrained participants in the United States. The samples were tested for HIV viral load and HIV medications .The state departments of public health receive all reports of reactive HIV diagnostic tests, CD4 counts, and viral load tests performed on patients residing in their jurisdictions through systems such as the electronic HIV and AIDS Reporting System. The study staff member requested HIV surveillance data from state departments of public health following the end of a person’s participation in the study. We requested that names and dates of birth of all participants be verified. The goal of this request was to identify participants who received a confirmed reactive HIV test result or entered HIV care for both participants who did or did not report a positive HIV test result during the study.Electronic case report forms (CRFs) were used to capture data for validation and enrollment, HIVST result follow-up communications, STI test result follow-up communications, referrals, and video counseling. For those who engaged in video counseling, data on the length and content of sessions were captured and stored in CRFs, excluding identifiable information.In the first part of the study, we characterized the cultural appropriateness, possible web-based recruitment venues, barriers to engaging BMSM and HLMSM in HIV prevention including HIV testing promotion strategies, and additional considerations for the implementation and potential scale-up of mail-out HIVSTs, following conversations with key stakeholders.In the second part of the study, we initiated several cost-effectiveness analyses and a comparative effectiveness evaluation of the intervention (Know@Home mobile app) on the linkage of participants to appropriate services .In primary analyses, we have initiated an evaluation of the cost and cost-effectiveness of the 2 LGBTQ-oriented recruitment platforms and the general, non–LGBTQ-oriented social networking websites for the following outcomes: (1) enrollment in the study defined as completion of the baseline survey, (2) HIVST results returned within 1 month of enrollment, and (3) identification of established HIV infections . The secondary analyses consisted of the cost-effectiveness of the 2 randomized study arms for outcomes of linkage to HIV prevention or HIV care services: (1) HIV counseling and treatment for MSM with HIV, (2) PrEP counseling and uptake for MSM who obtained a negative HIV test result, and (3) STI testing and treatment for MSM. The time horizon used was the time from baseline to follow-up, and both costs and effects will be discounted at an annual rate of 3%. Analyses included the overall study population and were performed separately for the 2 MSM populations (BMSM and HLMSM) enrolled.sex-seeking apps – Costreference)] / [(Enrollmentsex-seeking apps – Enrollmentreference)]. This value yields the incremental cost per participant enrolled. Where no observed differences in the outcomes of interest by recruitment strategy (primary aim) or study arm (secondary aim) exist, then a cost minimization analysis is planned. One-way sensitivity analyses were planned for all input variables to determine the inputs for which the net costs and ICERs were the most sensitive. We explored the effects of realistic implementation scenarios, including health departments with or without the ability to outsource HIV testing, robust eHealth systems, and tech-savvy staff.Standard methods ,24 for eData on use of HIVSTs were collected in multiple surveys. Information on the use of HIVSTs was provided in test result–reporting surveys during the study, and all participants were also asked about their use of study-provided HIVSTs during the 4-month follow-up survey. The date and result of the most recent HIV test before enrollment in iSTAMP were collected at baseline. Participants were asked to report any additional HIV testing and result that occurred outside the study on their 4-month follow-up survey. For the outcome of HIVST use, we report descriptive statistics about the number of HIVSTs distributed or used during the study period, overall and stratified by race or ethnicity, HIV testing history at enrollment, and recruitment source.We used data collected on CRFs to calculate the number and proportion of people who used the telehealth counseling provided through the study. We used data from counseling CRFs to describe the main reasons for seeking counseling and the types of services used.Linkage to care is critical for people diagnosed with HIV. We documented the proportion of participants who tested positive for HIV that were linked to care and described the distribution of time from receiving a positive test result to linkage to care, as previously described . We usedHIV testing is the entry point for multiple care continua; for those who received a positive test result in this study, their linkage to care was assessed. We assessed the receipt of HIV and STI services during the follow-up period for those who received a negative result or who do not report HIV testing. We also determined whether randomization to the intervention arm  was Key themes in formative work among HIV providers and researchers (N=6) indicated that dating and hookup mobile apps have previously been successful in recruiting BMSM and HLMSM for research studies. In addition, HIV stigma and distrust of health care and academic institutions may act as barriers to engaging with these populations. Among HIV organization directors (n=5), primary themes included their desire for cost-effectiveness data for possible implementation of HIV self-testing services and concerns about staffing, funding, and linkage to care for clients who use an HIVST. Among the BMSM (n=3) and HLMSM (n=3) community members, the central findings consisted of their advertising preferences for noncommercial images, diverse skin tones, and joyous and everyday scenes, accompanied by text that incorporated puns.iSTAMP began enrollment in February 2020 and concluded in February 2021, with participant follow-up data completed in September 2021. Of the individuals assessed for eligibility with screening questions, 9.08%  were considered eligible to join . Of the To examine enrollment proportions relative to state demographic data, we compared participant enrollment numbers with the 2018 Census , which eFormative research synthesized concrete guidance from stakeholders and community members who informed the methods used to recruit and retain participants in this study. We were able to effectively engage BMSM and HLMSM in this project and share best practices related to recruiting this key population. BMSM and HLMSM are disproportionately affected by HIV , and to Barriers to HIV testing have been described for decades throughout the HIV epidemic in the United States. These include a lack of perception of risk, stigma associated with seeking testing, lack of convenient options for HIV testing, and fear of obtaining a positive test result. Stigma-related concerns may be heightened for BMSM and HLMSM who face intersectional stigmas around race and ethnicity, sexual or gender minority status, and HIV. It is crucial to develop a robust slate of option for HIV testing that will allow MSM at elevated risk for HIV to test as frequently as recommended by the CDC. One approach is by supplementing provider-based testing with HIV self-testing.Working closely with the states in which the study was conducted was an important aspect of our study. We conducted this study in states with large populations of BMSM, HLMSM, or both . InvolviThe cost-effectiveness analyses outlined in this protocol will provide necessary information for providers wishing to implement similar recruitment and testing promotion strategies to reach BMSM and HLMSM, among others. Data on both the cost and impact of such strategies can guide decision-making regarding the efficient allocation of limited resources to increase HIV testing among these populations. Although cost-effectiveness analyses are recognized as an important component of implementation science research, limited data on the cost-effectiveness of varied recruitment, HIV testing, and linkage strategies currently exist. Thus, iSTAMP will make an important contribution to HIV testing and prevention services.Our study had some limitations, including standard biases for randomized controlled trials. The study may be affected by selection bias in that the men who agreed to participate were not representative of all BMSM and HLMSM in the implementation states. Another potential limitation is the differential loss to follow-up between the intervention and control arms. This was mitigated through comprehensive efforts to retain participants in both arms by using multiple modes of contact , compensating participants for their time to complete study activities, and by allowing all survey and study activities to be completed remotely. There is risk for misclassification bias because we rely, to a large extent, on participant-reported outcomes for the use of tests and linkage to follow-up services. We have taken steps to reduce this bias by allowing participants to complete surveys remotely, using survey tools that have been validated , and by The distribution of HIVSTs is already moving into public health programs. It is critical that we identify and disseminate effective methods to reach BMSM and HLMSM through programs that strive toward health equity for these priority populations. A pilot project in which a community organization partnered with state and local health departments to fulfill orders for free HIVSTs showed that providing HIVST in a “direct-to-consumer” model is feasible and can reach populations with substantial HIV risk and those who have not recently tested for HIV . In 2021


In November, 2022, WHO published updated recommendations for antenatal corticosteroids and tocolytic therapyThe benefits and possible harms of antenatal corticosteroids were questioned after the publication of the Antenatal Corticosteroids Trial (ACT) in 2015.In the 2022 updated recommendations, the guideline panel considered evidence from 27 efficacy trials, including the WHO ACTION-I trial, which was done in 29 adequately equipped hospitals in five low-resource countries between 2017 and 2019 and incorporated the criteria previously recommended.The gestational age threshold for antenatal corticosteroid use remains clinically important. At less than 34 weeks of gestation, there is compelling evidence of reduced perinatal and neonatal mortality and respiratory-related morbidity.vs no further courses) of antenatal corticosteroids for individuals at ongoing risk of preterm birth more than 7 days after their first course was associated with reduced adverse neonate outcomes, respiratory morbidity, oxygen supplementation, and surfactant use, which could reduce costs. Although there was a small reduction in mean birthweight and an increased risk of being small for gestational age, the guideline panel considered these effects to be clinically less significant than the benefits, and therefore retained the 2015 recommendation of one repeat course of antenatal corticosteroids for eligible women.Animal and human studies indicate that there is a relationship between time from antenatal corticosteroid administration to birth and preterm neonate outcomes, although which interval offers the best perinatal outcomes is not clear.In 2015, WHO recommended against the use of tocolytic treatments for spontaneous preterm labour on the basis of no substantive benefit of tocolysis for reducing adverse perinatal or neonatal outcomes.We declare no competing interests. The WHO guideline development panel that formulated the antenatal corticosteroids and tocolytics recommendations was an independent, international panel of experts convened by WHO. The panel was co-chaired by GLD and ZPQ. JPV was project manager, and RB and OTO were project coordinators for WHO ACTION-I trial. JPV, RB, and OTO did not take part in the formulation of the recommendations.


Effective preventive strategies are urgently needed to address the rising burden of non-communicable diseases such as cardiovascular disease and cancer. To date, most prevention efforts to reduce disease incidence have primarily targeted populations using “one size fits all” public health recommendations and strategies. However, the risk for complex heterogeneous diseases is based on a multitude of clinical, genetic, and environmental factors, which translate into individual sets of component causes for every person. Recent advances in genetics and multi-omics enable the use of new technologies to stratify disease risks at an individual level fostering personalized prevention. In this article, we review the main components of personalized prevention, provide examples, and discuss both emerging opportunities and remaining challenges for its implementation. We encourage physicians, health policy makers, and public health professionals to consider and apply the key elements and examples of personalized prevention laid out in this article while overcoming challenges and potential barriers to their implementation. The global burden of complex heterogeneous diseases with multiple etiologies, such as cancer, diabetes mellitus type 2 (DM2), and cardiovascular diseases (CVD), is rising globally. At the same time, adverse lifestyle changes at a population level also add to risk. These trends represent a serious public health concern, and indicate a need for more effective prevention strategies. To date, most preventive strategies to reduce disease burden have targeted the general public by providing “one-size-fits-all” recommendations . These iannual physical check-ups, which include a standardized battery of examinations and tests including weight, blood pressure, body temperature, vaccinations, screening tests, and disease (risk) biomarkers .Personalized preventive behavioral interventions may be more effective than general preventive recommendations in achieving long term behavior change that might affect risk of complex diseases like DM2 and CVD . In thisWith respect to dietary changes, a personalized 6-month lifestyle intervention for moderate CVD risk resulted in significant reductions in snack and fruit intake . AnotherA 12-month-intervention found significant improvement in smoking reduction only at 6 months with no effects of personalized prevention observed for physical activity .In some studies personalized lifestyle-based interventions led to significantly greater reductions in body weight , 11, 16,In two studies the interventions had a significant effect on increasing high-density lipoprotein (HDL) cholesterol , 11. A svia validated disease risk score using a comprehensive online questionnaire (step 1), followed by additional risk profiling through laboratory tests, visiting general practitioners in case of high-risk individuals (step 2), and providing web-based individualized lifestyle advice (step 3)  , 14. A l(step 3)  (15).The findings suggest that the provision of lifestyle-based risk advice might be a more useful tool for behavioral lifestyle changes compared to the use of general recommendations , 16–19. Preventive approaches targeting clinical biomarker measurements are also an important pillar of personalization that already have been partly realized. Cardiometabolic biomarkers  from laboratory testing in several combinations may provide a primary risk profile and indicate preliminary stages of CMD and their phenotypes, particularly when additional information like anthropometrics, sociodemographics, and/or familial history  is consiImproving clinical biomarkers can be achieved by various means including weight loss, physical activity, and nutritional adjustments. Nowadays, a steady expansion of the product range and marketing of nutritional supplements means that more and more consumers are taking supplements, regardless of whether or not they actually exhibit a deficient or insufficient supply of minerals, vitamins and micronutrients. A targeted supplementation of food supplements tailored to the individual deficiency should occur only when based on laboratory diagnostics.Moreover, there is increasing evidence that the human gut microbiome plays a crucial role in immune function, human health, and disease. There is evidence to suggest that stratification of individuals according to two microbial enterotypes (either Prevotella or Bacteroides dominance) may be valuable in predicting responses to diets for obesity management . FurtherPersonalized nutrition guidance that involves biomarkers identified by various omics technologies, self-reported questionnaire-based dietary assessment tools, and useful tools to improve real-time assessment of dietary intake and feedback provision , may have the potential for more effective glycemic control and prevention of DM2. A machine-learning algorithm that integrates particular dietary habits (using a smartphone-adjusted website), blood parameters, gut microbiota and continuous glucose monitoring was effective to predict postprandial glycemic responses to real-life meals more accurately than general dietary advice .In addition, metabotyping is a new concept in which individuals are clustered into metabolic phenotypes based on clinical and biochemical parameters, anthropometric measures, metabolomics and metagenomics data. This concept, which aims to tailor diets that fit each metabotype specifically, has been suggested as a nutritional strategy, for example in the context of CMD prevention. However, health economics studies are still lacking .As part of ongoing technological progress including molecular diagnostics, more and more biomarkers are likely to be discovered. The combination of biomarkers with sociodemographic, anthropometric, clinical and behavioral factors, and omics data can help with the identification of individuals at high risk and the detection of even pre-symptomatic chronic diseases.Interest in identifying individual genetic biomarkers as a strategy to help achieve a high degree of personalization in prevention is currently increasing. One approach is the analysis of monogenetic genes to identify increased risks for developing specific diseases. An examination of genes for coding variations likely to make individuals susceptible to breast cancer revealed an association between breast cancer risk and protein-shortening variants of these genes in ATM, BRCA1, BRCA2, Check2, and PALB2 .Genome-wide association studies (GWAS) assess genetic variants across the genomes of a large number of individuals to identify genotype–phenotype associations using the technologies of whole genome sequencing and the determination of single-nucleotide polymorphisms (SNPs). Furthermore, GWAS enable the calculation of polygenic risk scores (PRS) as a measurement of risk summed over multiple risk alleles . In one GWAS studies investigating genetic variants associated with obesity and weight loss resistance have identified several potentially relevant variants. These include the obesity predisposing FTO (fat mass and obesity associated gene)  and MC4RHowever, a limitation of GWAS is the missing impact of the environment and identifying gene-environment interactions, which are both assumed to have a high influence on the individual disease risk , 31.The DNA cannot be changed directly, but the function of individual genes can be influenced by epigenetic mechanisms. Epigenetics is one section of genetics which describes the variations in gene expression without a change in the DNA sequence itself . One maiGenetic and genomic testing seems promising for people having a family history of genetic conditions. The implementation of epigenetics has an even bigger potential for personalization due to its modifiability and the possibility of adaptations through environmental interactions.Gene and environment interactions (GxE) determine the responses of individuals to environmental variation based on their (epi)genetic profile . Those vObesity represents a major risk factor for CMD like CVD and DM2, all of which exhibit complex interplay mechanisms of genetic and environmental risk factors . GxE stuNutrigenetics studies how genes affect nutrient metabolism . Large pTo date, the Food4me study  is the lFurther RCTs exhibited significant reductions in sodium intake , and totvia accelerometer) compared to the use of general guidelines  did not reveal significant effects of communicating DNA based risk estimates on diet, physical activity, smoking cessation, alcohol use, or behavioral support programs . A cohorThe evidence regarding the effectiveness of personalized prevention in the long-term (≥6 months) during the intervention phase is not clear. While in some RCTs only one follow-up time point was recorded and analyzed [ ≤ 3 , 45, 49 The motivational effect of personalized prevention can be directly measured by lifestyle changes and improvements in biomarkers. However, few RCTs have investigated the motivational effect of genetic- or genotype-based communication interventions on personal motivation for lifestyle changes , 48, 49 With respect to possible adverse effects, two RCTs have reported that communication of genetic risk does not seem to increase anxiety , 50. Neivia face-to-face or web-based human-delivered counseling seem to be essential. The presented findings also suggest that the provision of a genetic-based risk advice may motivate healthy behavior changes, and that communication of genetic risk does not arise to predict adverse effects like anxiety.In summary, the largest study to date  revealedPersonalized prevention offers promising opportunities as summarized in The aim of the German National Cohort is to investigate the causes of diseases through long-term monitoring, to discover and validate new biomarkers, and to develop preventive measures. Progress in biomarker research will enable continuous improvement in the early detection of chronic diseases and their precursors .The incorporation of personalized prevention into health practice remains limited. Healthcare systems face a variety of challenges that stand in the way of a successful realization of the full potential of this approach. One of the greatest long-term challenges is the implementation of policies. In their 2021 review, Trein and Wagner give an overview of the four most relevant policy challenges found in the literature for implementing precision health  in practice: (1) creating, maintaining and harmonizing an infrastructure for research, (2) building and fostering trust in precision health amongst citizens in general and patients in particular, (3) establishing regulatory frameworks to ensure cooperation and to avoid discrimination, and (4) integrating precision health into existing health systems .In order to incorporate more genetic testing into medical procedures in the future, the acceptance of these technologies by the general public will be an important factor . PreviouFor a successful implementation of personalized prevention in health care practice, a better understanding of personalized concepts and technologies among healthcare providers is crucial. The demand for appropriately trained health professionals is currently growing. Therefore, the continued development of educational programs and training in omics sciences, personalized communication skills and personalized prevention concepts in general will be of key importance. It will be both necessary to define core competencies that can be integrated into the curricula of health care professional training programs and to develop national policies and regulatory frameworks that ensure the integration of adequate personalized preventive practice .Health literacy and an understanding of the benefits and limits of personalized preventive technologies like omics-testing is needed for citizen empowerment and engagement in both contributing to research and adopting new behaviors in everyday life , 57, 67.Guaranteed access to healthcare for all is a crucial goal that will require focused and sustained effort. The elimination of health disparities will require system changes that promote health equities and access to high quality care for all . Social,A lack of ethnic diversity in the data creates a disturbing potential for the exacerbation of already existing health disparities. For future research, it is therefore essential that study samples include diverse patient populations  to ensure that scientific advances benefit all populations , 68, 69.Few reviews have summarized strategies and recommendations for the implementation of personalized medicine into preventative care. The recommendations most mentioned in the literature include: (1) develop education programs for personalized prevention and the building of community awareness, (2) empower and engage patients, (3) develop infrastructure and information management systems, (4) value recognition for precision health, and (5) ensure access to care , 70. TabCurrent prevention strategies and recommendations are largely based on the results from large population-based studies and target shifts in the entire population. Public health prevention is often viewed as an altruistic principle which values the benefit of the population above that of the individual . Such population-strategies of prevention are in contrast with a personalized prevention approach. Thus, the implementation of personalized prevention strategies dependent at least in part upon the public health infrastructure .Personalized prevention demonstrates great potential to increase the effectiveness of preventive interventions. However, achieving the successful integration of personalized prevention into everyday health care will require changes in health care systems. The pursuit of this goal will require all stakeholders to work to enable the implementation of personalized prevention. Along with improving the training of health practitioners, policies, regulations, and companies will also have to adapt. Some of the required changes will require long term implementation. These include structural changes in the healthcare system and the development of policies and legal foundations to address issues like health disparities and genetic discrimination. In terms of changes that may be achieved in the short term, we see great potential in advancing the education of health professions in omics sciences and enhancing citizen awareness and engagement. For the clinical setting, we recommend further development of personalized prevention techniques using predictive biomarkers as well as telemedical approaches in primary care institutions. Personalized prevention offers a variety of promising opportunities. Therefore, we encourage physicians, health policy makers, and public health professionals to consider and apply the key elements of personalized prevention into practice.KM obtained funding and critically reviewed the manuscript. SJ, CN, and KM conceptualized the review, contributed to manuscript revision, and have responsibility for final content. SJ and CN wrote the manuscript and did the literature research, study selection, and interpretation. SJ created the figures. All authors read and approved the final manuscript.


Streptococcus, a pathogen with an underrecognized global burden, and give specific examples pertinent to 8 clinical endpoints. This dynamic framework can be adapted for any disease with a vaccine in development and can be updated as vaccine candidates progress through clinical trials. This framework will also help with research and innovation priority setting of the Immunization Agenda 2030 (IA2030) and accelerate development of future vaccines.Vaccine development and implementation decisions need to be guided by accurate and robust burden of disease data. We developed an innovative systematic framework outlining the properties of such data that are needed to advance vaccine development and evaluation, and prioritize research and surveillance activities. We focus on 4 objectives—advocacy, regulatory oversight and licensure, policy and post-licensure evaluation, and post-licensure financing—and identify key stakeholders and specific requirements for burden of disease data aligned with each objective. We apply this framework to group A  Streptococcus to aid efforts to accelerate vaccine development.We introduce an innovative systematic framework prioritizing burden of disease data requirements for vaccines through advocacy, regulatory and licensing, policy and post-introduction evaluation, and financing. We apply this framework to group A  Vaccines are an important public health tool to prevent infectious diseases and improve population health and well-being , 2. MultBeyond incorporating traditional disease burden measures, a systematic framework for prioritizing burden of disease should also include estimates of social and economic impact, community acceptability, and recognition of the need for adding vaccines to existing prevention and control measures. The global effort to rapidly develop, evaluate, and implement coronavirus disease 2019 (COVID-19) vaccines in the face of the largest global pandemic in modern history exemplifies how high rates of disease burden, widespread economic disruption, and the scientific, political, and community demand for vaccination can drive vaccine development . This caStreptococcus , which is recognized as a WHO vaccination priority, is 1 example [www.savac.ivi.int).Despite the global success of some vaccines, vaccine development for other pathogens with an established high burden have faced impediments. Group A  example , 8. Vacc example . Despite example , the burWe describe the properties of burden of disease data that are needed to progress vaccine development, evaluation, and policy making and a framework to prioritize studies and surveillance activities that would yield robust data addressing different vaccine objectives. Using this framework, we aimed to provide specific examples for Strep A and identify future research priorities.SAVAC established an expert Burden of Disease Working Group (BoDWG) comprising 13 members from 7 geographically diverse countries, with wide-ranging expertise in Strep A and other vaccine-preventable diseases (VPDs), disease surveillance, and vaccine implementation. The BoDWG identified and reached consensus on 4 overarching vaccine objectives  through iterative discussion to build a framework . We descCreating partnerships with private- and public-sector stakeholders, communicating the evidence-based value of an intervention, and seeking political commitment are key advocacy objectives for successful implementation of immunization and other public health prevention programs , 11, 12.An effective advocacy tool enables comparisons between the burden of the targeted disease and other diseases already prioritized for vaccine introduction or diseases with high public awareness. Communicating burden of disease data within the context of global public health goals  and theVaccine licensure requires well-designed vaccine efficacy studies (or studies of accepted correlates of protection such as immunogenicity) that measure the impact of the vaccine candidate on prevention of well-defined, pathogen-specific disease endpoints of clinically significant severity, as well as a careful assessment of vaccine-associated adverse events. Contemporary local disease data are needed to identify clinical trial sites for conducting such efficacy studies. Age-specific incidence estimates of the clinical disease endpoint that the vaccine is targeting are needed to design adequately powered trials. These disease endpoints, key clinical indications, and target populations are often defined in WHO Preferred Product Characteristics. Background rates of disease-related conditions using standard burden of disease measures from populations where vaccine trials are being conducted can provide context for evaluations of potential of vaccine-associated disease . Data deBurden of disease estimates are among the key considerations for policy decisions on vaccine introduction. These estimates, along with cost-effectiveness data, enable comparison with other public health priorities and facilitate prioritization of a vaccine for inclusion in national programs. Population-level socioeconomic indicators  and environmental factors that influence disease burden are also important considerations in making equity-based vaccination policies and maximizing their impact .In addition, high-quality surveillance is essential to fill data gaps, enhance the credibility of the burden estimates, and provide epidemiological data needed to optimize the use of preventive strategies. The establishment of surveillance systems using standardized methods is essential for measurements of “real world” vaccine effectiveness and impact, and for monitoring epidemiological trends  post-implementation. These assessments may be useful for justifying the continued use of the vaccine and informing vaccination policies and schedules. For certain vaccines , WHO recommends at least 2 years of pre-vaccine data and 3–5 years of post-vaccine data to appropriately make such decisions .In addition to measuring the performance of a vaccine, vaccine efficacy trials can be used to estimate vaccine-preventable disease burden by measuring the proportion of non-specific clinical syndromes prevented by the vaccine . Such clThe key stakeholders for the policy objective are the immunization technical advisory groups at global, regional, and national levels and global bodies, like WHO, which many resource-poor countries look to for advice and guidance.The financing objective refers to the post-licensure financing of vaccine introduction and scale-up, as opposed to financing pre-licensure vaccine research. A key global stakeholder is Gavi, the Vaccine Alliance, which supports the introduction of new vaccines in the poorest countries. Its vaccine investment strategy analyses provide ranking criteria for the evaluation of vaccines that includes the economic impact (direct and indirect costs averted) and health impact (cases and deaths averted) . HoweverThe clinical spectrum of Strep A is broad . The lacTo address this challenge and highlight the need for a Strep A vaccine, we used our framework to provide a roadmap and identify priority data requirements specific to key Strep A clinical endpoints, grouped into acute diseases  and immuemm types of Strep A causing disease vary across geographical settings and over time [In application of this framework to Strep A, we have considered the target population, established by the WHO Preferred Product Characteristics , to be iver time . While sver time  and seroPrioritization of disease burden estimates of acute Strep A clinical syndromes varies by vaccine objective. For advocacy, it is important to focus on clinical endpoints that are most likely to influence decision making, such as invasive Strep A, which is the highest driver of overall Strep A deaths in most HICs. The incidence of invasive Strep A has remained high or is increasing in multiple countries  will be necessary to generate burden of disease data for this objective. Sites with established active surveillance for pharyngitis or impetigo can transition to become phase II or III vaccine trial sites.Policy review often assesses the impact of vaccination on all-cause disease syndromes . Due to the mild–moderate symptomatology of Strep A pharyngitis, estimates of disease incidence should include community surveillance data and data from primary care, healthcare clinics, and emergency departments to enable policy decisions within the health sector. While impetigo is generally seen as an issue requiring primary care and also requires community surveillance, a high hospitalization burden in First Nations populations  has beeCost-of-illness data are essential for financing decisions. However, the drivers of costs differ across acute Strep A endpoints and different socioeconomic settings. For pharyngitis, the associated consequences of increasing AMR and parental productivity losses are likely key drivers for the value of vaccination; the importance of population AMR trends is recognized by WHO’s vaccine roadmap . It was Rheumatic heart disease has been a major focus of Strep A burden of disease research , 36 and For policy evaluation, longitudinal data describing the changes in incidence and prevalence will be needed pre- and post-vaccine introduction to assist in understanding population vaccine impact. Knowledge of background ARF and RHD rates in jurisdictions of high incidence is important, especially in light of concerns of enhanced disease following vaccination—one of the prior impediments to a Strep A vaccine development . AdditioGuided by this framework, we have identified 4 research priorities for Strep A burden of disease.Establish sentinel surveillance sites for pharyngitis (and impetigo) measuring age-specific disease burden. To address the regulatory and licensure objective, surveillance sites need to be established to facilitate future vaccine trials. Such activities are underway through the Australian Strep A Vaccine Initiative  and surveillance activities in remote Australia [ustralia , but surustralia , 41.Collate data to describe the incidence of invasive Strep A in LMICs. There is currently a dearth of published age-specific data in LMICs, which is critical for advocacy, policy evaluation, and financing vaccine objectives. Leveraging Strep A data from existing surveillance networks, focusing on LMICs, presents an option to fill this data gap.Assess the attributable fraction of Strep A to cellulitis. Cellulitis has been demonstrated as a major contributor to Strep A burden, cost, and therefore value of a vaccine in Australia [ustralia  and New ustralia . The burustralia .Develop Strep A burden of disease estimates through the Global Burden of Disease (GBD) Project. There are few Strep A–specific burden estimates. These will become increasingly important, especially for advocacy, to compare its disease burden with that of other diseases within and across countries.Other research priorities identified include the following: (1) the need to better understand the drivers of country, regional, and international vaccine decision making with increased connections through the relevant immunization technical advisory groups; (2) multi-country epidemiological record linkage studies using administrative health data across all Strep A endpoints; and (3) quantifying antibiotic use for pharyngitis.We developed a framework that describes the different requirements and components of burden of disease data to address 4 interrelated but distinct vaccine objectives—advocacy, regulatory oversight and licensure, policy, and financing. By using these 4 different lenses, we described the data needs across the spectrum of Strep A clinical outcomes and identified research priorities that map to and will facilitate achieving each of these critical vaccine objectives. This framework is meant to be dynamic, being both updated as Strep A vaccine candidates progress through clinical trials and development, as well as adapted for other diseases with defined vaccine needs. Importantly, its use is envisaged in coordinating the vaccine research and development efforts among international stakeholders and setting the IA2030 research and innovation agenda for Strep A and other important diseases on the vaccine development horizon.ciac291_Supplementary_DataClick here for additional data file.


Public health practitioners often design interventions prioritizing potential impact over sustainability. To assess the potential for impact and institutionalization, we applied systems thinking to postpartum family planning approaches for first-time mothers in Bangladesh. Donor-funded multilevel approaches to address barriers for young first-time mothers in using modern postpartum family planning methods have largely focused on integrated service delivery—an approach that has proven challenging to institu-tionalize within government health systems.To achieve lasting impact, an approach must be both effective (able to produce the desired impact) and able to be institutionalized. Yet, considerations for whether and how approaches can be institutionalized within existing health systems are often underrepresented in program design.To increase the use of postpartum family planning by first-time mothers in Bangladesh, we adapted the Viable System Model to the context of the Bangladeshi health system and developed a tool and process for assessing the potential for institutionalization alongside potential for impact during a program design process. Integrated service delivery approaches have shown promise to increase use of services including postpartum family planning (PPFP) by young, first-time mothers (FTMs) but have proven challenging to scale and institutionalize. Integration adds complexity, requiring careful assessment of effects on a range of key system functions from demand creation and service delivery to oversight and governance. Through an innovative design process, we selected approaches to increase FTMs’ PPFP use through existing health systems. We generated programmatic options and then sought to select approaches based on (1) potential impact on FTMs’ PPFP uptake and (2) potential to institutionalize in the health system. The latter represented an innovation in addressing management systems’ drivers of scalability and sustainability; to accomplish it, we developed a participatory design process to assess the potential of an approach to be institutionalized in a specific context.We adapted a management systems theory, the Viable System Model (VSM), which presents 5 essential organizational functions and the relations required between them to improve the viability  of organizational systems. Drawing from the VSM, we developed a process for reviewing the effects of proposed approaches on provider workload, client flow, infrastructure, revisions to guidelines and job descriptions, coordination and management, and information systems. The VSM provided a structure to identify potential displacement of capacity in the health system and mitigate often neglected organizational challenges that compromise institutionalization. The process informed the elimination of approaches with potential for impact but that had deal-breakers to institutionalization, such as increased workload or shifted job descriptions, in the Bangladeshi context. For the selected approaches, consideration of systems elements fostered discussion of expected risks to institutionalization, highlighting needed mitigation efforts and monitoring during implementation. In many low- and middle-income countries (LMICs), family-, community-, and health system–level factors shape FTMs’ PPFP use.,Despite the promise of effectiveness, complex, multilevel FTM initiatives have proven challenging to fully scale and institutionalize.Most efforts targeting FTMs’ PPFP use have entailed complex, multilevel approaches coupling integrated service delivery with community-level interpersonal communication efforts.–The field of systems thinking has increasingly gained recognition among researchers and practitioners as offering frameworks through which to understand and manage organizational complexity, such as that of a health system.,Despite growing recognition of the need to consider the complexity of health systems beyond static elements, or building blocks,Led by Save the Children with funding from the Bill & Melinda Gates Foundation, the Connect project (2019–2024) aims to develop sustainable PPFP approaches for FTMs in Bangladesh and Tanzania through existing large-scale, donor-funded projects already supporting primary health care platforms. Having worked on the project, we chose to focus on Bangladesh to provide an in-depth exploration of the experience there. In 2020, the project design team, comprising project technical and management colleagues, national health system stakeholders, and researchers, and led by global and country experts, formulated effective, scalable PPFP integration approaches. Approaches were required to show (1) potential for impact with the target population, based on global evidence and formative research; and (2) potential for institutionalization, based on organizational management conditions of the health system. In this article, we detail a practical method for designing integration approaches with potential for both impact and institutionalization, applied to the design of approaches to increase PPFP use among FTMs in Bangladesh.We detail a practical method for designing integration approaches with potential for both impact and institutionalization.In Bangladesh, while median birth intervals are relatively long at 55.7 months, mothers aged 15–19 years have significantly shorter intervals compared to mothers aged 20–29 years (25.3 months vs. 49.4 months).Within the Ministry of Health and Family Welfare, the Directorate General of Health Services and the Directorate General of Family Planning oversee separate facility- and community-level health facilities and provider cadres. The Government of Bangladesh had made strong commitments to PPFP, as demonstrated in its FP2020 commitments.Our process for designing sustainable FTM approaches entailed conducting formative research, ideating approaches for integrated PPFP service provision targeting FTMs, and assessing potential for institutionalization. We outline each step, detailing the assessment of potential for institutionalization as an innovation, which is underrepresented in many design processes. With the start of the coronavirus disease (COVID-19) pandemic coinciding with the design onset, our process had to avoid travel and large gatherings. We conducted formative research and reviewed demographic evidence to identify key barriers to FTMs’ PPFP use.,We led a formative barrier and facilitator analysisUsing context experience and expertise, Bangladeshi Connect project staff compiled basic information about the health system organization and delivery of RMNCH services. Using a simple checklist probing each of the VSM functions, they documented the number and type of health facilities, facility- and community-based providers by cadre, client flows for each RMNCH service, supervisory roles and mechanisms, community health worker tasks and client loads, and community groups involved in health promotion.The design phase encompassed 8 sequential modules , with 1 BOX 1The core design team included 6 Connect project staff:Bangladesh (3)Project lead with expertise in adolescent health (1)Technical experts:Maternal and newborn health (1)Monitoring and evaluation (1)Global (3)Project director with expertise in adolescent health (1)Technical experts:Health systems strengthening and systems thinking (1)Maternal and newborn health (1)At key decision points, the expanded design team, which included 20 national stakeholders outside of the core team and 3 U.S.-based program evaluators, provided input into the conceptualization and selection of the approaches.Ministry of Health and Family Welfare (8)Directorate General of Family Planning (7)Directorate General of Health Services (1)Nongovernmental organizations (7)Private sector service delivery organizations (4)Professional association (1)Global evaluation and research experts (3)Develop Selection Criteria A Priori. In the opening modules, a member of the core design team with expertise in systems thinking provided an orientation to systems thinking and to the VSM for the expanded design team.Supplement 1).Drawing from the VSM and considering ExpandNetBrainstorm Ideas With Potential for Impact. The core and expanded design teams reviewed barrier and facilitator analysis findings, focusing on key barriers to FTMs’ PPFP use. Drawing from collective expertise, we brainstormed 54 approaches that had the potential to increase PPFP uptake among FTMs in Bangladesh by addressing barriers identified in the formative stage.Group and Narrow Ideas. The core design team subsequently narrowed the list significantly by grouping duplicative ideas (18 ideas) and removing those that may have contributed to improving PPFP uptake as part of a comprehensive approach but did not address barriers on their own , or did not address a clear barrier to FTMs’ service use  and thus presented limited impact potential (16 ideas removed). We clustered the remaining 20 ideas by the entry point at which FTMs would be reached for the first time . The core design team then prioritized 1 idea from each entry point for further discussion. The team based these decisions on consideration of potential for impact and feasibility of implementation, as informed by existing evidence, and technical and context experience and expertise. By the conclusion of this short-listing exercise, 5 approaches remained for further examination and consideration.Develop Client Journey Maps. For each of the 5 remaining ideas, through a collaborative asynchronous approach, the core design team developed a visual client journey map depicting the entry point where facility- or community-based providers would interact with FTMs to provide information and/or services, referral point(s) where providers may send FTMs for information, services, and/or follow-up, and needed coordination between service delivery points. These journey maps depicted a future state in which all needed functions would be established and operational . Supplement 2 details the VSM and its application to health systems.We adapted the VSM to the health system context to assess the potential for institutionalization of approaches . This inWe adapted the VSM to the health system context to assess the potential for institutionalization of approaches.Complete Viability Assessment Tool. To operationalize the VSM to the questions faced by the primary health care systems in Bangladesh in integrating PPFP into existing services, the core global project design team developed the Viability Assessment Tool (VAT) through an iterative process over Modules 4–7. The VAT probed organizational functions including service delivery interactions; coordination; supervision, management, oversight, and control; and systems for higher-level planning, policy and governance, support, and information. We considered information systems as a support system, alongside the supply chain support system; the VAT explored these as support systems to the delivery of client services. Under VSM principles, the performance and sustainability of these support systems must also meet conditions of viability.Supplement 3.The VAT used a client-centered approach following an FTM’s journey through the Bangladesh primary health care system, beginning from a facility or community entry point and encompassing needed referrals within and between service delivery points. Open-ended and closed questions guided Bangladesh-based members of the core design team to define intervention packages  and consider the implications of each of the 5 short-listed approaches, guided by the VSM functions . The VATReview Potential for Institutionalization. Based on information recorded in the VAT, the core design team discussed the potential of each approach to be institutionalized. We chose not to use the VAT as a scoring or ranking tool but rather as a thinking tool to systematically identify strengths and weaknesses of the 5 final approaches  and discussed collaboratively. While we calculated mean scores for each approach, we did not simply select the highest-scoring approach. Rather, scores informed further discussion about whether low-scoring items constituted deal-breakers compromising viability, and how low-scoring items could be mitigated in implementation.Develop Risk Mitigation Strategies. After selecting the final approaches, the core design team identified implementation strategies to proactively mitigate identified risks.Our formative assessment identified service use patterns, key barriers to FTMs’ PPFP use, and opportunities to reach FTMs with PPFP.Our formative work identified service use patterns, key barriers to FTMs’ PPFP use, and opportunities to reach FTMs with PPFP.Secondary analyses of Demographic and Health Surveys identified opportunities to reach FTMs by integrating PPFP into highly used services. Among mothers aged 15–24 years at the national level, used as a proxy for FTMs, ANC and immunization were the most utilized services; 86% made at least 1 ANC visit, often late in pregnancy, and 84% of babies born to mothers aged 15–24 years received 8 basic immunizations by age 2 years.The barrier and facilitator analysis pinpointed the following key factors influencing FTMs’ use and nonuse of RMNCH services. Mothers-in-law and male partners determined whether and where FTMs accessed RMNCH services; FTMs had limited negotiation power within family structures. Many PPFP adopters discontinued method use within 12 months due to side effects and pressure to become pregnant again. Mothers of all ages had increased responsibilities and restrictions on movement outside the home for 40 days postpartum due to religious and social prohibitions, which limited facility visits.The core design team determined that the selected approach(es) must address the above barriers by: reaching FTMs regardless of place of delivery; accounting for postpartum restrictions on movement; engaging family; addressing factors encouraging discontinuation; and integrating PPFP into other RMNCH touchpoints.Strengthening immediate PPFP uptake through FTM-targeted FP counseling in ANC, early stages of labor, and immediately following delivery. Reaching FTMs with an integrated care package, leveraging higher ANC coverage, could provide multiple touchpoints for family involvement and offers the possibility of immediate PPFP.Strengthening predischarge counseling for FTMs in public and/or private facilities. This counseling, inclusive of PPFP, would reach FTMs delivering in health facilities, supporting early PPFP initiation and encouraging continuity of care.Supporting targeted home visits (HVs) to FTMs. HVs to pregnant and postnatal FTMs could reach FTMs regardless of place of delivery, engage family, and refer FTMs for facility-based PPFP.Strengthening PPFP counseling for FTMs with babies in kangaroo mother care units and special care newborn units. Adolescent FTMs are more likely to have preterm or low-birthweight babies.Strengthening PPFP/immunization integration targeting FTMs. Integrating PPFP into the Expanded Programme on Immunization could leverage the service with the highest reach, engage FTMs regardless of place of delivery, and engage family. The potential of FP/immunization integration is well documented as a promising practice.As described above, the expanded design team brainstormed 54 initial ideas with potential for impact (improved PPFP use among FTMs). The core design team subsequently narrowed a short list of 5 approaches for deeper discussion, developing 1 journey map for each to guide discussions. Approaches identified for deeper assessment, and the rationale from the perspective of impact, included:We completed 1 VAT for each of these 5 approaches and discussed them among the core design team. The key findings from the assessment against the organizational functions that informed final decisions are presented in detail here and in We completed 1 VAT for each of the 5 approaches on the short list and discussed them among the core design team.The core design team excluded 2 approaches from further consideration following the initial VAT completion, which identified the following deal-breakers . After rBOX 2Strengthening PPFP Counseling for FTMs Through Kangaroo Mother Care and Special Care Newborn UnitsFacilities with kangaroo mother care units and special care newborn units did not include family planning (FP) services. The management and coordination burden of shifting provider job descriptions to provide FP counseling and methods in these units would be beyond the project’s scope. Further, some lower-level facilities served less than 10 mothers of all ages annually. We determined that the low potential to reach significant numbers of FTMs would not justify the needed management and coordination adjustments and risk of displacement.Strengthening PPFP/Immunization Integration Targeting FTMsIn the Bangladeshi health system, 2 distinct directorates of the Ministry of Health and Family Welfare, the Directorate General of Health Services (DGHS) and the Directorate General of Family Planning (DGFP), deliver Expanded Programme on Immunization (EPI) and FP services, respectively. These directorates oversee separate service delivery points and provider cadres, with known coordination gaps. To integrate FP into EPI, the DGHS would need to revise job descriptions of health assistants, who provide immunization services, to allow FP service provision. Alternatively, the DGFP, would need to revise job descriptions of community-based family welfare assistants who provide FP services to encompass support to EPI sessions. These shifts would create displacement, including an expanded mandate with additional training and supervisory needs, commodity provision, increased provider workload, and possibly longer client wait times. Additionally, while about one-third of facilities had infrastructure allowing privacy during immunization visits, most facilities used public areas with few opportunities for private FP counseling or service provision. The Government of Bangladesh and Obstetrical and Gynecological Society of Bangladesh had both prioritized postpartum intrauterine devices. Many existing providers were trained in PPFP and provided integrated services, requiring minimal training and revisions to coordination mechanisms or existing job aids. Existing tools and processes would facilitate immediate PPFP delivery; PPFP counseling began in ANC, with preferences written in government-provided ANC cards reviewed during facility delivery. However, documentation of PPFP preferences was inconsistent. Counseling would require careful coordination and documentation to confirm FTMs’ PPFP intentions during intrapartum care. Lower facility delivery rates would limit immediate PPFP uptake.Many providers were trained in PPFP and provided integrated services, requiring minimal additional training or shifts to supervision and coordination processes. However, adding a tool to strengthen the predischarge counseling process risked expanding provider workload and client wait time due to additional tasks. Existing referral coordination  was poor and a source of confusion for providers and clients. Lack of existing mechanisms documenting the condition of mother and baby at discharge complicated coordination.A community-level system for registering all pregnant women provided a platform for timely identification of FTMs beginning from pregnancy, although no existing mechanism would inform a family welfare assistant (FWA) of a facility or home delivery to prompt a postnatal HV. FWA job descriptions include HVs to all mothers. However, Bangladesh had not realized full HV coverage due to high FWA vacancy rates and infeasible targets, with each FWA assigned to visit approximately 600 households monthly, among other responsibilities. FWAs rarely received supportive supervision, and HVs were rarely observed.In total, 18 members of the expanded design team completed the Google survey, scoring the 3 remaining approaches using the criteria determined in Module 1. On a synchronous call during Module 8, the core and expanded design teams discussed the highest- and lowest-scoring criteria for each approach assessed. The team discussed whether high-scoring items outweighed low-scoring items and identified strategies to mitigate risk reflected in lower-scoring items. Informed by these discussions and guided by the quantitative approaches , the core design team determined which approach(es) to move forward and identified mitigation strategies.The core design team selected the 3 remaining approaches  to be combined into a final approach, and developed mitigation strategies addressing identified risks. This approach aims to increase uptake of PPFP through strengthening the quality and responsiveness of facility-based antenatal and postnatal counseling and care (including predischarge counseling and care) to FTMs. At the community level, FWAs are supported to provide targeted postnatal HVs, prioritizing mother-baby dyads who are identified to have risk factors, including clinical and nonclinical .The final approach aims to increase PPFP uptake through strengthening the quality and responsiveness of facility-based counseling and care.Combined, the selected approaches align with existing job descriptions and supervision processes, with mitigation measures to address identified gaps in workload, information, documentation, and supervision. The facility components entail minor adaptations to existing government approaches, tools, and processes. The introduction of the predischarge counseling approach will be carefully monitored to understand implications for workload and client flow. Introduction of a predischarge counseling approach also provides the opportunity to establish processes for documenting the status of mother-baby dyads at the time of discharge. The targeted approach to HVs is essential to mitigating challenges with HV coverages, to reaching FTMs regardless of place of delivery, and to engaging family.Many public health practitioners are most familiar with selecting approaches based on assessment of potential for impact. Yet any intervention is implemented within and inherently disrupts dynamic, complex health systems,The application of the VSM provided structure to guide stakeholders to identify the strengths and limitations of the platforms under consideration. Given that this was the first application of the VAT, we chose a qualitative approach to interpreting findings and to drawing actionable decisions. Ultimately, the design team made final decisions based on discussion and reflection on the facts gathered through the process, with decisions heavily influenced by identified deal-breakers that could not be mitigated. This underscores the importance of having the right stakeholders involved in the process so that their country experience, technical expertise, and knowledge of existing tools and platforms can help to distinguish a mitigatable risk from a deal-breaker. Close engagement with national stakeholders, as system experts and owners of institutionalization and scale, is key.The application of the VSM provided structure to guide stakeholders to identify strengths and limitations of platforms under consideration.The consideration of systems in general, or organizational functions more specifically, is not a panacea but provides useful tools to understand, analyze, and guide interventions for complex problems.what can be done, while the VSM-derived functions emphasize how it can be managed with minimal disruption to and adaptation of the existing systems. As elucidated through client journey maps, each service delivery point, including facilities and their service delivery units, is a micro-system in itself. Thus, strengthening a platform requires not only strengthening the core health system building blocks from the community to the highest levels of the health system, but also strengthening organizational functions at all levels. Visualizing a client’s journey illustrated the complexity of health systems. Beyond individual components, effective coordination and information sharing are required to work harmoniously.The established system inputs (expanded building blocks)We found that certain functions, namely service delivery interactions and coordination, elicited more robust discussion, and informed identification of viability deal-breakers and risk of displacement. In particular, we found necessitating formal shifts to job descriptions of underresourced cadres to be a key decision point, with such shifts beyond the scope and time frame of a donor-funded initiative and a deal-breaker overriding potential for impact. As in many LMICs, interventions relying on underresourced community health worker cadres in Bangladesh face threats to sustainability,,Our experience highlights the importance of contextual factors, including health system structure and capacity, in developing and adapting interventions and planning for sustainability.Our experience highlights the importance of contextual factors, including health system structure and capacity, in planning for sustainability.Our process deepened insights into scalable approaches for increasing FTMs’ PPFP use that enhance existing government platforms, rather than unsustainable project-driven FTM outreach. While we designed approaches to address barriers to PPFP identified by FTMs, many barriers were not unique to FTMs , and instead may reflect barriers experienced by all Bangladeshi mothers that may be aggravated by factors such as age, social norms, and lack of financial means.Further efforts are needed to better understand the inputs needed to strengthen the underlying system functions along each step of a client’s journey, the associated measurement implications, and how most effectively to support health system actors to manage complexity. Further exploration of a systems thinking–informed means to identify and articulate displacement risks beyond the intervention design phase is warranted.The adaptation to a virtual format due to COVID-19 eliminated the possibility of face-to-face workshops that may have enriched our discussions. However, the format of spacing design modules over a longer period of time offered unintended benefits, allowing for reflection and information gathering between synchronous discussions that would have been infeasible in a time-bound live workshop setting.Health systems are by nature dynamic. While our application of the VSM proved valuable in understanding, analyzing, and guiding the design of the intervention, its use at an initial design phase does not (and we suggest should not) obviate the need for continued monitoring of unintended effects, including displacement to other services or demographic segments. Additionally, findings related to the potential to institutionalize each approach are specific to the unique contexts of the health systems in 1 country and are not intended to be generalizable.Our use of the VSM at an initial design phase does not obviate the need for continued monitoring of unintended effects within a health system.The VSM posits a fractal nature of organizations, with each level requiring viable functions similar to the whole system. While our tools probed on information and supply chain support systems, they remained cursory in the examination. We aimed to be as systematic as possible to build replicability in the design process, but it also included a substantial amount of iterative discussions, back-and-forth questioning, and even well-informed gut-checks, which all factored into decisions. While this critical collective engagement will always be necessary, our process could benefit from streamlining in subsequent applications.In the context of a first implementation, we relied on a core team and an expanded design team of national stakeholders. We hope to see more expanded team members as central to the core team in future applications. Finally, the test of the viability of our efforts will be implementation, monitoring, evaluation, learning, and adaptive management.Our design process informed the selection of community- and facility-based approaches that had potential for both impact and institutionalization in context, guided us to move beyond approaches with limited institutionalization potential , and informed proactive risk mitigation. Considerations of the feasibility of institutionalizing impactful approaches are underemphasized and require deeper attention in global health efforts, to the same level as the focus on the potential for an approach to produce desired impacts. Any approach has risks to sustainability; considering organizational functions in the design process can inform proactive mitigation approaches and ongoing monitoring efforts.