The coronavirus disease 2019 (COVID-19) pandemic rendered congregate shelter settings high risk, creating vulnerability for people experiencing homelessness (PEH). This study employed participant observation and interviews over 16 months in two Veteran encampments, one located on the grounds of the West Los Angeles Veteran Affairs Medical Center (WLAVA) serving as an emergency COVID-19 mitigation measure, and the other outside the WLAVA gates protesting the lack of onsite VA housing. Study participants included Veterans and VA personnel. Data were analyzed using grounded theory, accompanied by social theories of syndemics, purity, danger, and home. The study reveals that Veterans conceptualized home not merely as physical shelter but as encompassing a sense of inclusion and belonging. They sought a Veteran-run collective with a harm reduction approach to substance use, onsite healthcare, and inclusive terms . The twin encampments created distinct forms of community and care that protected Veterans from COVID-19 infection and bolstered collective survival. The study concludes that PEH constitute and belong to communities that provide substantial benefits even while amplifying certain harms. Housing interventions must consider how unhoused individuals become, or fail to become, integrate into various communities, and foster therapeutic community connections. The coronavirus disease 2019 (COVID-19) pandemic rendered congregate shelter settings high risk, creating vulnerability for people experiencing homelessness . ResidinThis article addresses interacting biological and social pathogens. While the SARS-CoV-2 virus is the biological pathogen causing the COVID-19 pandemic, homelessness can be conceptualized as a social pathogen. This notion of “social pathogen” is influenced by anthropologist Mary Douglas’ classic work on pollution and taboo entitled Purity and Danger, where she defines “dirt” as “matter out of place” . Dirt, aDue to their multiple and intersecting socioenvironmental vulnerabilities, PEH have higher rates of mortality, physical illness, mental illness, and substance use disorder (SUD) and are more likely to utilize emergency departments, be admitted to the hospital at a younger age, and have longer lengths of stay at a greater cost as compared to the housed population ,12. PEH Scholars have proposed the term “syndemic” to describe the intersecting risk factors for COVID-19 and homelessness, rejecting as reductive the biomedical-risk-factor and lifestyle models routinely applied to the analysis of chronic illness and infectious disease . A syndeThis article examines twin encampments. The first, an emergency COVID-19 mitigation intervention for unhoused Veterans called the “Care, Treatment, and Rehabilitation Service” (CTRS), was a “sanctioned encampment” on the grounds of the WLAVA. Beginning as 25 tents in a VA parking lot in April 2020, CTRS infrastructure continuously improved, increasing capacity to 100 tents by September 2020 (further described below). Though CTRS staffing varied, full-time staff included two social workers and two Veteran peer specialists. Supplemental/occasional staff included additional social workers, a preventative medicine physician, an occupational therapist, and primary care clinicians providing bimonthly onsite urgent care. Veterans had access to regular healthcare via virtual or in-person appointments within the campus medical center . The second encampment consisted of as many as 50 Veterans camping in a row on the sidewalk abutting the WLAVA fence. They leveraged the social anxiety around the pandemic to render visible the plight of the homeless Veterans. Simultaneously displaying their “patriotism,” “ingenuity,” and “vulnerability” through their encampment, these Veterans argued they deserved the home on the VA campus that had been promised in the original land grant of 1888. This “unsanctioned” encampment became known as “Veterans Row.” Veterans on Veterans Row instigated a debate within the VA and in the media about what constituted a home for Veterans amid a global pandemic and in a local context of stark inequities in Brentwood, one of the most affluent neighborhoods in the country. Through this public debate, Veterans challenged the VA to collaborate with them in providing better housing options for Veterans on the VA campus in response to the crises of COVID-19 and Veteran homelessness.Veterans argued that what they needed to mitigate their vulnerability to COVID-19 infection was neither solely social distancing, masks, and vaccines nor a motel or apartment voucher, but rather, a home for Veterans on the VA campus. This ethnographic research reveals that Veterans conceptualized “home” not merely as physical shelter but as constituted by “feelings, practices, and relationships [with others in] familiar spaces” that produce “a powerful sense of belonging” . UnderstWhile “home” can have a material and physical designation, it can also be understood as an ongoing process of negotiation and as a set of practices that draw from experience and work towards an ideal future  (p. 9) . Home caThe question of home, and not simply shelter, has been at the forefront of Veteran activism at WLAVA. The WLAVA stands on 388 acres, surrounded by West LA, Westwood, and Brentwood, neighborhoods with median home values of $1.5 million, $1.4 million, and $2.7 million, respectively . The lanData collection was part of a quality improvement (QI) project to iteratively improve care experiences for Veterans residing in CTRS . BetweenEthnographic methods served as the foundation for developing QI recommendations and interventions that rapidly responded to Veteran and staff concerns. Two PhD-level medical anthropologists conducted ethnographic fieldwork in the encampments . EthnogrTo disseminate field reports quickly, the QI team facilitated a real-time feedback loop among multiple stakeholders, including Veterans, CTRS management and staff (hereafter referred to collectively as “CTRS personnel”), VA leadership, VA primary and mental healthcare providers, VA homelessness and health services researchers, and LAC street medicine experts. Updates and recommendations were presented during weekly QI meetings with CTRS personnel, monthly meetings with researchers, and meetings with street medicine experts. Preliminary results were iteratively discussed with participants to ensure accurate interpretations and conclusions were being drawn. Veteran participants in digitally recorded semistructured interviews were recruited via purposive sampling with attention paid to diversity in race, ethnicity, age, and gender as well as in diagnostic and health profiles, thus including participants with and without serious mental illness (SMI), substance abuse, physical disability, and chronic health needs. All CTRS personnel were invited for interviews. The demographics and diagnoses of CTRS participants were characterized using data from the VA’s Corporate Data Warehouse and homeless registry. Using physical distancing and masks, 65+ onsite participant-observation visits were made at least weekly from 1 September 2020, to 1 October 2021, with episodic visits into December 2021, yielding 450+ pages of fieldnotes. These data were integrated with semistructured interviews (60–90 min each) with 21 unique Veterans who resided in CTRS and/or Veterans Row and follow-up interviews with 7 Veterans for a total of 28 Veteran interviews. Semistructured interviews were also conducted with 11 CTRS personnel with 6 additional follow-up interviews for a total of 17 CTRS personnel interviews (60 min each). Rapid ad hoc targeted interviews were conducted to answer specific questions posed by the larger QI team. Targeted interviews were transcribed in our fieldnotes verbatim in real-time and/or from memory as quickly as possible. After two months of fieldwork, the QI team drafted interview questions that explored participant issues and concerns. Veteran interview guide domains included: (1) background and homeless history; (2) previous experiences with VA clinical and housing services; (3) experiences of integration and/or exclusion in CTRS and/or Veterans Row; (4) satisfaction with facilities, care, and services at CTRS, Veterans Row, VA, and outside the VA; (5) expectations for care and housing. While interviews ideally followed a semistructured format, they deviated from this structure at times for reasons including intoxication and psychosis. An open-ended, person-centered approach was used to explore these experiences as they contributed to our understanding of what it meant to be an unhoused Veteran at this place and time . The CTRGrounded theory informed data collection and analysis throughout the project . As a thRecorded interviews were professionally transcribed. Fieldnotes and interview transcripts were summarized and integrated using rapid turn-around analysis. Feedback and cross-checking with the QI team, Veterans, and CTRS staff during regular presentations of data contributed to developing a codebook derived from the interview guides . InterviSince at least 2018, unhoused Veterans had been sleeping on the street just outside the western gates of the WLAVA, the site that would become Veterans Row. A former resident from Veterans Row described discovering the site two years before the pandemic. He had traveled to the WLAVA for residential treatment services. When the program would not accommodate his service dog, he spent the night on Veterans Row:I see all these people lined up and tents and people sleeping on the sidewalk. And so, I just walk over to see what this is and its Veterans! They say, “What’s up, man, what happened to you?” And they’re laughing about it. They ask, “They’re not letting you in?’” And I say, “No, they told me to come back tomorrow.” They say, “Well, we got you, this happens all the time.” I mean it was common knowledge and I was blown away. I thought, “What’s going on?”…They gave me blankets, they gave me something to eat. They told me where everything was at.What became known as “Veterans Row” during the pandemic had been a place for Veterans to sleep and care for one another for years. Veterans Row became an informal safety net for those seeking VA services or who had been discharged from the ED, hospital, or residential programs. Veterans on Veterans Row felt abandoned by the VA, but Veterans Row itself was not a space of abandonment. It was a place for Veterans to find a modicum of care and community.Veterans Row was a site of intergenerational kinship and camaraderie. One Veteran discovered his aunt living there while he was enrolled as a service user in a residential treatment program on campus. He recalled, “When I was in the [The Domiciliary Care for Homeless Veterans Program] in 2018, nine tents were there. I found my auntie out there.” She was dealing with bipolar disorder and alcoholism and had just left her husband. Veterans on Veterans Row helped her enter a VA program. Veterans Row reminded him that Veterans like him are chronically precarious, “one bad day away from a tent.” Prior to the pandemic, Veterans Row was periodically forcibly removed by the LAC Sherriff’s Department with bulldozers, often prompted by complaints from the local community. In response to a December 2019 sweep, these Veterans returned to the courtroom, and in February 2020, they delivered a sworn declaration regarding the mistreatment of unhoused Veterans. They had been asking for permission to camp on the VA property in 2019. Sympathetic VA administrators explored the possibility of temporary encampments or mobile housing on campus with wrap-around supportive services, but it took the sudden emergence of the COVID-19 pandemic to prompt implementation of such a plan. Simultaneously, the LAC moratorium on encampment sweeps provided Veterans Row with a beachhead to organize, network, and ultimately expand as both a protest of the VA denying onsite housing and an informal demonstration project for a Veteran-driven model of care.Tentative explorations for Veteran encampments became a blueprint for action as the WLAVA received emergency authorization to allow Veterans to camp on campus, with the justification that outdoor congregate living did not present the same COVID-19 transmission risks as indoor living and that a temporary outdoor tent shelter did not count as housing. A small parking lot area, unused thanks to the rapid transition to telecommuting by VA employees, was designated as a space where up to 25 Veterans could camp in their own tents. The emergency initiative was conceptualized as a medical intervention and paid for by health systems funding. Therefore, all nonmedical services, such as food, had to be provided by outside entities. Community groups, VA Voluntary Services, a local private school, and the WLAVA’s academic affiliate offered support, and the encampment soon provided 3 daily meals, tents, sleeping bags, and clothing. The VA provided limited healthcare, case management services, and contracted security. CTRS began as a “low barrier” to entry initiative, with no curfew or sobriety requirements in particular, a novelty amongst local transitional housing and shelter programs that often discharge residents for repeated episodes of behavioral disturbance, intoxication, or alcohol or drug possession. CTRS personnel understood that while implementing pandemic safety precautions was paramount , another critical purpose of CTRS was to repair relationships with Veterans as a prerequisite to connecting them to healthcare and housing services. One staff member explained: “Develop relationships, have the care that people need, whether it’s substance abuse, mental health, primary care. Help people navigate and get connected to those [services] they have a right to. Let’s repair your relationship with the VA…It’s the foundation of good healthcare.” The process of developing trusting relationships entailed, in the words of another staff member: “[Giving Veterans] the time and the space and the support to figure out what it is that they want.” In the early days of the pandemic, CTRS became an attractive destination because of its low-barrier approach, which included regular access to necessities. Some of CTRS’ growth was due to word-of-mouth and Veteran self-referral. VA programs also referred unhoused Veterans to CTRS. Relatedly, pandemic conditions impacted the capacity at other VA and LAC shelters and housing programs, options that often shut down or had limited capacity. While VA staff outreached to Veterans Row daily, inviting residents to the inside encampment and offering them other housing options, most Veterans did not accept these invitations. As the CTRS census grew, the Veterans Row census grew as well. Some Veterans chafed against the rules at CTRS, such as the mandatory security search upon each entry to the encampment, a prohibition on guests, limited accumulation of personal belongings, and weekly COVID tests. Others complained that tents on a concrete parking lot were too small, uncomfortable, and undignified, requiring elderly and disabled Veterans to bend over to enter them. One Veteran dismissed CTRS as “tiny little shit pup tents.” Veterans Row accepted donations of larger 10’x14’ tents. The tents were spacious and looked tidy, uniform, and organized next to each other, with an American flag affixed to the front of each tent. Photographs circulated in media reports of what some characterized as defiant Veterans fighting a righteous cause, and this imagery staved off rumors that disparaged those sleeping on the street. A Veteran explained why the appearance of large, orderly tents with the American flags was important:We put flags on them to show that these were Veterans because there was…a lot of this public ignorance being built [by local residents] And they’re posting on social media…[that] they’re not Veterans, they don’t have benefits, they’re criminals. And we’re like, okay, we got the flags on them. No, these are Veterans.The larger tents took on multiple purposes in the early days of the VA. They provided Veterans a comfortable place to reside to help foster a better community and home. The tents also countered perceptions that these Veterans were “dishonorable” or “criminals.” They projected a sense of organization, industriousness, and tidiness from a community of Veterans deserving of the home owed to them due to their service, combating dominant narratives about homeless encampments rooted in individual blame, criminalization, and reinforcement of substance use and mental health-related stigma. Veterans Row attempted to demonstrate how to provide a home and cultivate a community while, at the same time, offering the same, or better, provisions and services as compared to CTRS.While many deplored the sight of the encampment in the affluent neighborhood and repeatedly sought its removal, a few local residents responded with concern. Veterans on Veterans Row outreached to the Brentwood residents who pulled over their cars and asked about the situation. A Veteran explained, “You need to stop and talk to people. So we do that [with] people in the community.” Interactions with residents raised awareness that Veterans Row residents wanted the VA to provide homeless Veterans with a home on campus. Veterans also solicited volunteers, donations, and further networking opportunities. Donations of a 40-foot-long dumpster, portable toilets, and handwashing stations with regular service and maintenance helped keep the sidewalk and street clean. Veterans Row did not want their “dirty” status used as a reason to ask the LAC Sheriff to bulldoze their encampment despite the moratorium. A Veteran said:If I leave [garbage] in the street, they’re gonna come through and plow this shit out. That’s what they’re gonna say because this is always their excuse, “It looks like shit, get rid of it. There’s feces. There’s this, there’s that.” So I’m trying to stop that from happening, okay?Veterans Row was continually improving through the involvement of the Veteran residents as well as outside benefactors. Veterans Row had recognized leaders and a loose leadership council. These leaders facilitated partnerships with local restaurants, bakeries, and caterers to deliver daily meals. They also put on a successful fundraiser that raised $4000—an exhibit of photographs of Veterans Row residents and art made by residents. Veterans Row leaders created a census and tracking sheet of Veterans and their partners/family members residing in the 45+ tents. They developed intake and orientation procedures for newly arrived Veterans. Non-Veterans were not welcome unless they were Veteran partners or family members. A list of duties and tasks were assigned to the residents: fire watch, dumpster detail, street clean-up, flag detail, and visitor and donation assistance. They created their own incident report forms. A military sensibility was palpable in these designations, roles, and hierarchies, especially in an expressed vigilance for the infiltration of “insurgents” intent on sabotaging Veterans Row. One resident shared that he had experience working undercover, and he expected VA spies had already infiltrated Veterans Row. Order and community were actively monitored and enforced. Veteran advocacy organizations supported Veterans Row, as did a few former residents who had obtained permanent housing. One former resident explained how they developed relationships with a range of agencies within and outside of the VA, connecting residents and often recruiting them to services related to housing, substance use, medical, and mental health needs. They facilitated housing placements for Veterans but also found that many of these Veterans returned because “people want to be by the VA.” Volunteers also spearheaded collective recycling efforts for income generation. Veterans on Veterans Row pointed out that their community worked because they had ownership of it. In the words of one Veteran, “we take care of each other and ourselves,” while in many programs, including CTRS, they were treated “like children.” While Veterans in Veterans Row worked to maintain a tidy, hygienic area, they emphasized that it was still a homeless encampment unsuitable for human habitation. They leveraged a dense web of meanings through their bodies and residence. They made visible their unimpeachable status as Veterans, in many cases medal-awarded combat Veterans, embodying American ideals of patriotism, by welcoming media coverage from all political slants, from local news affiliates to the far-right Epoch Times and Fox News, to NPR, to “citizen-journalists” posting images and commentary on social media. They also made visible the dirt and wounds on their bodies. A notable example was a male Veteran, wearing a tank top, displaying a 5-inch self-inflicted gash in his upper arm, a deep wound in need of sutures, visibly infected. Despite clearly experiencing pain, he lifted heavy items, swept, and cleaned outside the tents in view of all – outreach workers, reporters, VA employees, and cars that sped by. Shaking off offers of care, he simultaneously displayed his vulnerability and his industriousness. seeing this, right?” Veterans were aware of the paradox of creating an organized encampment while also rendering visible to the public how residing on the sidewalk is unsafe, unsanitary, and, ultimately, an injustice worthy of protest. They posted signs reading “no pee zone” and chastised a resident who dumped his urine into the gutter outside his tent, creating smelly, unsightly streams. The Veteran protested that he did this because his physical disability rendered him unable to walk to the portable toilets at the end of the row. Bathing was a challenge for residents, as another explained: “I’m bathing in a bucket in a tent.” Washing his body, he told us, was a way to wash away negative thoughts: “personal hygiene does a lot for mental health and a lot for keeping up the drive. Any drive I have to be productive…just gets washed away because I can’t wash away. You know?” The dirt accruing on his body impacted him deeply. The difficulty accessing shower facilities structured the very existential possibilities he felt his life had. A clean body helped him “keep up the drive” to live. This drive to live was implicated in a suicide attempt prior to his arrival on Veterans Row: “if my mental health isn’t there because of something simple like I can’t wash, how much more am I going to do for myself if I can’t even do that?” He emphasized the impact of not having access to basic hygiene resources as it eroded his sense of self and his desire to “be productive” to participate in mainstream American society as a worker and a consumer. Veterans Row residents wanted observers from local communities and the media to understand the daily challenges they faced and to help them advocate and amplify the narrative that the very dirt and wounds on their skin, the explosion of substance use, which many told us was a way to calm their nerves from chronic stress or to delay sleep to avoid nightmares and the vulnerability of sleeping on the street, and the many dangers they were exposed to were the result of not having the safe home they were entitled to. As one Veteran put it, “What do you want me to do?…But this situation, you guys are Even though Veterans Row created a community through advocacy, political action, and networking, residents were still supportive of CTRS. One Veterans Row leader declared the creation of CTRS a momentous achievement: “I think that CTRS is awesome—it was like taking the Beaches of Normandy, getting the guys back on the property.” He encouraged Veterans to use CTRS: “I’m always trying to sell Veterans on going inside.” The hope for those residing at CTRS was that the VA would eventually upgrade them to a better home. In this way, Veterans on Veterans Row were also waiting to be welcomed home and hoped to be able to one day abandon their encampment, but on their terms. They were not simply antagonists but optimists that they could push the VA to do the right thing and make Veterans Row obsolete by providing an on-campus community—a home—for unhoused Veterans.In response to positive early experiences, growing demands from Veterans to improve the CTRS environment, and the increasing impacts of an ever-growing pandemic, the VA moved the encampment to “The Great Lawn,” a large field near a shaded rose garden with tables and benches. There was more space in this setting, and for staff, the move gave the initiative a sense of permanence. Large tents similar in size to those on Veterans Rows replaced the small tents, and they were placed on raised wooden platforms to keep them off the wet grass. Each tent had a cot, bedding, storage locker, clothes, and a range of personal items available by request through VA Voluntary Services. Gravel pathways laid down between rows of tents allowed for easier movement. Floodlights and security cameras were installed, and a 24/7 contracted security detail was positioned at the entrance and around the field. Additional tents were erected in a paved parking lot at the entrance to CTRS for Veterans with limited mobility. A laundry service was provided for several months. Veterans were transported daily to showers at either the VA Welcome Center or YMCA by CTRS staff until an onsite shower trailer began service in January 2021. Veterans could receive mail, a vital service that facilitated the completion of the extensive paperwork applying for housing and other services entailed. Onsite urgent care services were provided every other week, and staff attempted to facilitate Veterans making their healthcare appointments. An onsite physician provided COVID tests to new admissions. Encampment capacity expanded to 100, though its largest census as a tent encampment was ~60.The provider area—several tables on a raised platform under an open-air canopy—was initially in the center of the encampment, along with a coffee and snack station and a phone charging area. While CTRS personnel reported some difficulty working in an open-air environment during hot summers and blustery winters, this area became a place for Veterans and personnel to socialize. One staff proudly pointed out that the lack of doors and walls facilitated a spirit of transparency, access, and collaboration with Veterans. Veterans gathered near the open-air provider tent in the morning to make coffee and linger in conversation. Many Veterans ate together and started their day in this communal area. Personnel reminded them about upcoming appointments regarding healthcare or housing. One Veteran regularly shared anecdotes about riding motorcycles. Another insisted on receiving his “morning hug” from a Veteran peer specialist. Veterans also placed locally scavenged couches and tables at the front of the encampment under the shade of tall pine trees. This “lounge” area facilitated Veteran socializing.A local spike in COVID cases in December 2020 led to fear of an outbreak, a period of limiting new admissions, increased enforcement of masks and social distancing, and testing within CTRS. Most of the original staff had turned over by this time, the 10th month of operation, and the early enthusiasm and idealism about the potential for CTRS were fading. Personnel expressed that there was a lack of consensus around the mission of CTRS from VA leadership and felt unsupported and understaffed . There wBy January 2021, Veterans were discouraged from socializing at the provider tent. Instead, Veteran discussions with the staff needed to focus on individualized “housing plans.” The “lounge” was removed over concerns that socializing encouraged illicit drug use. This left Veterans few places to socialize in CTRS. A Veteran said that it was “dead” and lacked the community spirit that once existed. Another Veteran told us how focusing on the “other stuff” such as housing plans rather than Veteran morale was a “waste of time”:You can look at their faces—our faces…and you don’t see a lot of smiling faces. So that’s one thing that could really use some help and improvement is building morale and trying to figure out why there’s not many smiling faces…because all the other stuff would be probably a waste of time if everybody’s still angry and upset.CTRS personnel worried that “getting too comfortable is a problem here. [This Veteran] has all this stuff in [his tent]. When he leaves, we’ll have to clean up all that stuff…We are cleaning urine and feces and we are tired of it. It’s a problem.” Personnel shifted the initiative’s focus to quickly transitioning Veterans to alternative housing . They were concerned that if too many services were provided, Veterans would feel encouraged to permanently reside within the encampment. They said, “I’m sympathetic to Veterans…and the traumas they face [but] we’re only 50% of it. They’ve got to meet us halfway…” Another bluntly said: “You’re never supposed to work harder than the Veteran trying to get his recovery. The Veteran has to put some blood into it.” For some personnel, comfort and community were associated with substance use, as indicated by concerns that “none of these people will seek services on their own if they are just allowed to be here, getting high” and “a lot of these guys aren’t going to go nowhere until they’re forced.” They advocated brief CTRS stays as a transition to more permanent housing programs. Discharges for rule violations were described as incentives for Veterans to practice more self-control and responsibility in order to transition into better housing.Many Veterans left CTRS for Veterans Row by January 2021, either voluntarily or through involuntary discharge. Some Veterans “double tented”: kept a tent in each encampment to access the benefits of each site. CTRS began forcing residents to choose one encampment or the other around December 2020. A discharged CTRS resident residing on Veterans Row situated the failure to care for unhoused Veterans like him within systemic societal failures: The problem is that we fail time and time again just as being derelict in our own duty to the person in front of us, derelict to the idea that every person that is sitting in a bed that is a Veteran that needs help, receive help and who has a voice should be heard. And rather than being heard are being muted, are being left out, are being discarded, are being cast away, are being sent in the opposite direction, are being sent in a worse system of existence. Many Veterans felt CTRS had become too restrictive and that it no longer practiced the low-barrier, harm-reduction approach it originally aspired to. Veterans Row welcomed all Veterans, but the community had its own rules. One resident was asked to leave after he was caught stealing from other residents. Another was kicked out for leaving too many of his collected recyclables strewn around the encampment. Already on thin ice because he refused to join in collective recycling efforts, his untidiness seemed to be the last straw. Veterans Row was potentially combustible: a community of combat-trained Veterans with high rates of substance use, trauma, chronic distress, and poverty, living in close quarters under the scrutiny of the VA, the sheriff’s office, the media, and the local community. Conflicts were usually settled without resorting to blows or calls to the authorities. VA staff hoped to convince all the Veterans Row residents to move into CTRS. They assumed that those who refused to move inside preferred the easier access to illicit substances they had outside the gates. Substance use was a part of the social ecology on Veterans Row. However, Veterans expressed that what they valued most was both the camaraderie and their autonomy, including involvement in various economies . One Veteran’s tent was full of computers and electronics, and another was a musician. Many Veterans felt safer with weapons hidden in their tents, which would have been a felony on the VA campus. One Veteran whose disability impacted his ability to walk and led to his discharge from CTRS repeatedly returned to Veterans Row after stints in the hospital and skilled nursing facilities (SNF), which was against the advice of some of his fellow Veterans. He explained that he returned because he felt controlled and disrespected in institutional settings. He felt his presence was valued on Veterans Row, where he had been since prior to the pandemic and where he was proud to be referred to as “one of the founders.” Several Veterans found it difficult to leave the communities of their respective encampments. Despite obtaining a permanent apartment, one Veteran explained that he stayed in CTRS because he had a series of procedures and appointments upcoming at the VA, and it was more convenient to stay on campus. However, he also had developed relationships with other Veterans at CTRS and appeared to seek out their company. One Veterans Row resident suffered a panic attack on his way to tour a potential apartment for rent and demanded he be returned to his tent as he was not ready to leave. Another compared the solidarity he experienced in Veterans Row and the duty he felt towards his fellow unhoused Veterans to the solidarity he felt during deployment in Iraq. Two members of his unit went missing, and despite exhaustive searches, their bodies, buried in unmarked graves, were not recovered until a year after he had returned home. He explained he carried that experience to Veterans Row: “I didn’t like the idea of leaving like that. And then with this situation…I don’t like the idea of leaving anyone behind.” He continued to advocate for the residents on Veterans Row and to be an active part of the community, even after obtaining housing. He did not want to leave any Veteran behind on the street. st year of the pandemic, not due to COVID but to fentanyl overdoses  but I cannot get into the apartment because the housing authority is saying [the VA doesn’t] have the people to process the paperwork!” She contextualized her own predicament by emphasizing the structural difficulties individuals face in navigating the housing process in LAC. An administrator referred her to a staff member who was present and offered to contact the housing authority. Within a week, she moved into her apartment. This underscored both the VA’s strengths and blind spots. They could respond rapidly to individual-level service issues on a case-by-case basis but were not able to systematically address the broader obstacles individuals faced when confronting the maze of different agencies, institutions, and gatekeepers that needed to be navigated to provide Veterans housing in Los Angeles. This resulted in a bracketing out or even disregard of structural issues. Veterans at town hall meetings consistently brought up the contradiction that VA land was being leased to non-Veteran entities for purposes not connected to Veteran housing or health. At times, these protests were visceral and angry: “We served our country. Why doesn’t our country serve us?”; “I just want to know when the fuck I can get my land back!” and “I feel like they are stealing land that Veterans actually own.” One Veteran read the history of Veteran housing at the GLAVA from the Draft Master Plan, adding:We’ve got 50 years of this land being neglected and it’s been used for tax write-offs, for grantee donations, and everything that’s been used has been milking the cow, taking our federal grant money. And we don’t see no housing. We need housing. This land is…to be used for housing for our Veterans and medical services, which the VA is responsible for…This is not your land. It is our land.The administrator’s response articulated the legal constraints on the process by which the VA could provide housing, acknowledging the slow pace and the many obstacles. A Veteran interrupted, reminding everyone of the precarity of living on the street, shouting: “And a Veteran dies! A Veteran on a street dies!” This interaction reflected the slow pace of change at the VA that so frustrated Veterans and their advocates. After one town hall meeting, a VA representative remarked, “I think part of the problem is that they don’t focus on their recovery.” The representative questioned the preoccupation with land use, adding, “let’s get some treatment…then when you’re better, then you can [protest]…They are aggressively homeless… [and] want to stay homeless as part of this protest.” This representative felt the protest and demands around land use were distractions and that the Veterans should be focusing on their own recovery, which was an individual process involving treatment for biomedical disorders. For this representative, “aggressively homeless” meant that Veteran activism was misguided and lacked a sense of self-responsibility that impeded the process of recovery. “Aggressively homeless,” however, could also be seen as an apt description of the advocacy tactics Veterans Row deployed. They highlighted the negative aspects of their existence that were all too public and visible—the abject filth, poverty, vulnerability, substance use, and violence—as evidence of broader society’s neglect. In contrast to the VA representative, they saw political mobilization around creating a home for Veterans as critical to their recovery efforts. The Veterans often pushed against the biomedicalization of their unhoused status. One Veteran pointed out that while their homelessness was often attributed to substance use, mental illness, and individual failings, the high-paying union jobs veterans used to receive had been replaced by less secure, low-wage labor: “We can’t support our families, we get left [by our families], we have PTSD, we lose it, then start drinking and doing drugs.” Despite these discordant perspectives, the town hall meetings identified common ground, and Veterans and VA personnel alike expressed gratitude for the forum. Eventually, the Veterans Row encampment was demolished by the LAC Sheriff’s Department. However, the VA was able to accommodate nearly 50% of the residents in a new tiny shelter village, replacing the original CTRS tent encampment. These Veterans were granted their request to keep their community intact, as they were all housed together with indefinite lengths of stay in what was termed Veterans Row 2.0. During this time, the QI team helped improve meal quality and delivery services by leveraging a pre-existing partnership with UCLA dining services. A partnership with VA Whole Health offered community-building activities such as a healthy teaching kitchen, storytelling, gardening, and battlefield acupuncture. An “encampment medicine team” was mobilized for onsite medical, mental health, and harm reduction services . Following Veteran requests, an open-ended length of stay with no barriers to entering or remaining was instituted. Tents were replaced by tiny shelters . A Veteran-run Veteran engagement committee was created for residents to provide feedback to management. Purity and Danger, Mary Douglas famously noted that dirt is “matter out of place” [Infectious disease epidemics are social processes with complex structural and environmental factors that manifest in locally specific ways ,43,44,45f place” . During The Veterans’ perspective of their vulnerability resonates with the syndemics framework that goes beyond risk groups and behaviors to encompass “environments of risk and agents promoting risk”  (p. 157)The anthropology of infectious disease has highlighted how narrow biomedical and individualized responses to syndemic problems can exacerbate the existing social inequities that create vulnerability to epidemic infectious disease in the first place ,47. In tTheir encampment was not just a site of pathology and risk but a source of vitality, care, and support. PEH can and do constitute and belong to communities that provide substantial benefits even while amplifying certain harms. As Bourgois and Schonberg demonstrate in their ethnography of homeless encampments, obtaining and using drugs requires developing relationships and occurs within the context of “a community of addicted bodies that is held together by a moral economy of sharing”  (p. 6). In his ethnographic study of an informal “asylum” in Southern Brazil, anthropologist João Biehl introduced the term “zone of social abandonment” to refer to a space of “social death” where “in the face of increasing economic and biomedical inequality and the breakdown of the family, human bodies are routinely separated from their normal political status and abandoned to the most extreme misfortune, death-in-life"  (p. 38).Veterans Row protected against the harms of isolation, despair, and solitary drug use. However, it exposed residents to relational forms of violence, reflecting tension around space, resources, and power in the encampment. The most visible tragedies of Veterans Row were two murders perpetrated in the context of relationships and disagreements. This points to a vulnerability that would benefit from intervention but does not invalidate the beneficial aspects of the community. Initially, CTRS staff attempted to build a sense of community, acknowledging the power and potential of Veteran camaraderie. As CTRS developed, staff faced challenges with understaffing, turnover, and burnout, exacerbated by the difficulties caring for medically complex Veterans. CTRS personnel worried about Veterans becoming “too comfortable” and began transitioning away from the initiative’s initial low-barrier model. During these times, many Veterans left CTRS, preferring the communal encampment outside the gates. However, with the LAC Sheriff’s Department signaling their intent to demolish Veterans Row during the summer of 2021, VA administrators and CTRS management diligently and empathically worked together to re-envision CTRS as a hospitable place for these Veterans to stay. CTRS personnel and the QI team collaborated with Veterans to create a renewed sense of community. VA administrators acted on Veteran feedback through the ethnographic research of this QI project. The result was not a perfect, conflict-free encampment but an ongoing effort by the VA and Veterans to preserve a space of dialogue, discussion, and experimentation, attentive to safety, risk, relationship, and community. While the dialectic of the dual encampments ended with the encampments ultimately being collapsed into one, the process of debate and negotiation between Veterans and the VA continues. Encampments can provide residents benefits, including safety, autonomy, and stability, as well as an opportunity for health and housing services to engage with vulnerable communities ,54. It iWhile CTRS is a bold attempt to respond to the ongoing crisis of Veteran homelessness during a pandemic, it also is a reminder of the ongoing lack of adequate housing for Veterans. The Veterans’ frustration with the slow pace of housing construction has resulted in a new lawsuit against the VA . CTRS isUnhoused Veterans were pathologized, often treated as pathogens themselves. The Veterans simultaneously fought against and instrumentalized their identity as pathogens to make demands for care. They contested the notion that they were pathogens when they evoked their status as Veterans, patriots who sacrificed themselves to defend the “American way of life” but were abandoned by their country. They demanded that the VA fulfill its promise of giving them a home. Moreover, they also leveraged their reputation as pathogens, feared and despised in one of the most affluent zip codes in the US, as a means of foregrounding the injustice they suffered. These Veterans are not just patients in a healthcare system but political actors in ways that resonate with other social movements for recognition, care, and social justice, such as the activism around HIV/AIDS treatment and the Occupy Wall Street Movement ,57,58. T


We explored priorities and perspectives on health policy and payer strategies for improving HPV vaccination rates in safety-net settings in the United States.We conducted qualitative interviews with policy and payer representatives in the greater Los Angeles region and state of New Jersey between December 2020 and January 2022. Practice Change Model domains guided data collection, thematic analysis, and interpretation.Five themes emerged from interviews with 11 policy and 8 payer participants, including: (1) payer representatives not prioritizing HPV vaccination specifically in incentive-driven clinic metrics; (2) policy representatives noting region-specific HPV vaccine policy options; (3) inconsistent motivation across policy/payer groups to improve HPV vaccination; (4) targeting of HPV vaccination in quality improvement initiatives suggested across policy/payer groups; and (5) COVID-19 pandemic viewed as both barrier and opportunity for HPV vaccination improvement across policy/payer groups.Our findings indicate opportunities for incorporating policy and payer perspectives into HPV vaccine improvement processes. We identified a need to translate effective policy and payer strategies, such as pay-for-performance programs, to improve HPV vaccination within safety-net settings. COVID-19 vaccination strategies and community efforts create potential policy windows for expanding HPV vaccine awareness and access. Human papillomavirus (HPV) vaccination rates are lower than target levels for adolescents in the United States (US) despite a safe, effective HPV vaccine and national guidelines from the Advisory Committee on Immunization Practices recommending adolescents get fully vaccinated by age 11 or 12, and starting as early as age 9 . Urgent Addressing inequities in low HPV vaccine uptake communities where HPV-associated cancer burden is high continues to be paramount , especiaSeveral factors at the community and policy levels influence HPV vaccination . PreviouIncreasing health system focus on population health and prevention metrics, as well as innovations in community vaccination programs due to the COVID-19 pandemic, indicate that there are other potentially important opportunities for policy and payer strategies  that can contribute to HPV vaccine improvement, which are largely underexplored. Prior research on payer strategies has focused on increasing access to HPV vaccines through the Vaccines for Children (VFC) program   as well Data for this analysis were drawn from a larger study that seeks to identify feasible evidence-based strategies (EBS) to increase HPV vaccination rates within safety-net settings through implementation of EBS in two US regions: the greater Los Angeles region and the state of New Jersey . The larThis analysis focuses on data from in-depth interviews with 11 policy and 8 payer representatives across the two target regions. Principles of saturation and sufficiency were used to determine the sample size and the process was iterative in which we assessed for thematic saturation by group throughout data collection , 32. AllInterviews were conducted virtually and digitally recorded via Zoom between December 2020 and January 2022, which were transcribed verbatim and de-identified by the study team . Interviews with payer and policy representatives lasted ~30 min. Participants were asked for their perspectives on existing priorities and strategies related to HPV vaccination and opportunities for improvement within safety-net settings. Interview guides were theoretically informed by the PCM domains of “Motivation,” “Resources for Change,” “Outside Motivators,” and “Opportunities for Change,” guiding the interviews with policy and payer participants to explore both internal and external factors that impact implementation of EBS and their interrelationships . In guidOur multidisciplinary research team  conducted analysis of all transcripts. Team members had varying levels of training in health policy and reflected on their positionality throughout data interpretation. PCM domains guided the thematic analysis and interpretation, which was further informed by study team members . Given the complex, multilevel factors that impact promotion and delivery of HPV vaccination , safety-Several rounds of analysis occurred using an immersion/crystallization approach, thoroughly described elsewhere . All traResults informed by the perspectives of policy and payer representatives indicate strategies that are external to clinic settings can influence internal settings for better or worse. Five themes resulting from interview data include: (1) lack of prioritization of HPV vaccination by payer representatives in incentive-driven clinic metrics, (2) region-specific policy options for HPV vaccination improvement identified by policy representatives, (3) inconsistent motivation across policy and payer representatives to improve HPV vaccination, (4) opportunities to target HPV vaccination specifically in clinic quality improvement (QI) initiatives, and (5) acknowledging the COVID-19 pandemic as a disruption to but also an opportunity for HPV vaccination improvement see . OverallOverall, payer representatives we interviewed in both regions spoke broadly about adolescent immunizations and did not prioritize HPV vaccination specifically in QI initiatives, including P4P and value-based programs. As one participant from a health plan in LA County shared:I don't believe that HPV or adolescent immunizations today are a part of our pay-for-performance [P4P] piece…The specificity for HPV and the VIP [value improvement plan]…I don't think it's one of the yet stated targets by itself. We look at those every year and decide what we're [going to] add and delete from the pay-for-performance [P4P]…” “Based on interviews with payers in LA, the HPV vaccine was not included in P4P programs nor were combined metrics for adolescent immunizations . One NJ payer discussed how the HPV vaccine was previously a separate quality metric, but was later merged with the two other adolescent immunizations ; however, HPV vaccination rates continue to trail behind the other adolescent immunizations rates:HPV is the rate-limiting, not the other immunizations…It's the HPV that's the problem…” “According to this NJ payer, combining HPV together with the two other adolescent vaccinations in this plan's value-based program limited specific focus on improving HPV vaccination rates within safety-net settings.Policy representatives discussed different policy options for HPV specific to their region (greater LA region or state of NJ), beyond school entry mandates, which have not been passed in either NJ or California. Most frequently, policy representatives in California referenced minor consent laws in which adolescents do not need parental consent for HPV vaccination  . LA poliAnother policy representative discussed limiting religious exemptions in NJ, especially given momentum of the anti-vaccine/vaccine choice movement over the last decade, which could also complement a future school entry mandate if passed.And I think that part of that [anti-vaccine/vaccine choice] movement, like, it started to really get ginned up because of the flu vaccine getting passed and because of the meningitis vaccine [MCV4]. And then there was a fear that pushing the HPV vaccine would then even give them more ammunition. And so, we changed our focus to try to eliminate the religious exemption…right now, a mandate is pretty fruitless because of the religious exemption that exists in New Jersey and how it's enforced.” “In LA, suggestions for policy changes focused more on HPV vaccine coverage and reimbursement by Family PACT, a state-wide program offering family planning services to low-income residents, in which sexually transmitted infection screening/treatment and cervical cancer screening are already covered services, but HPV vaccination is not . Two LA Motivation regarding the need for change to improve HPV vaccination rates varied across policy and payer representatives who occupied diverse roles in health plans and organizations focused on population health policy. While some served as HPV champions within their organizations, such as policy representatives who actively advocated for mandated vaccination among adolescents in school-based settings, others did not perceive HPV vaccination to be of higher importance than other types of preventive care. As one LA payer shared:…if you were to look at all the priorities that healthcare providers have to address, I mean, HPV? Important priority. So is cervical cancer screening…So is breast cancer screening…So is postpartum depression…” “Payers we interviewed, particularly those who were health plan executives and physicians, stressed the importance of HPV vaccination and vaccinations generally, and some payers were aware of the need to increase HPV vaccination in clinics in order to improve quality metrics  for adolescent immunizations.However, few payers appeared to be both motivated and interested in leading efforts for HPV vaccination improvement in their current roles. No policy or payer representatives opposed HPV vaccination, most recognized as the “right thing” as one NJ payer representative (Participant 17) put it, but many did not view their current role as critical for HPV vaccination improvement within safety-net settings. Payers pointed to competing priorities for providers or viewed the role of health plans as strictly related to vaccine reimbursement. One NJ payer stated:Well, we actually have a completely open policy with regards to reimbursement. And we really don't have any barriers to that…I don't know what else would be possible since there are no barriers at the moment.” “Overall, while policy and payer representatives we interviewed supported HPV vaccination, few representatives emerged as clear champions for HPV vaccination improvement in safety-net settings.Policy and payer representatives in both regions described current or potential targeting of HPV vaccination in QI initiatives, including using provider or member incentives. Payers discussed using provider incentives through P4P programs, as well as vaccine administration fees. For example, one payer commented how their LA County health plan paid a higher administration fee for its contracts than other health plans to incentivize providers to deliver HPV vaccinations:If they get the vaccine free from the Vaccine for Children Program, of course, they can't be compensated for something they didn't pay for, but the administration fee varies… we pay the vaccine administration fee on top of the capitated payment amount. So, it further incentivizes. We don't want practices not to vaccinate people because it takes time and they don't get paid.” “An NJ policy representative suggested pressing payer organizations to improve engagement and outreach efforts for HPV vaccination to providers and members in order to increase rates:…how do we get them to help us engage their members more? So, Medicaid, MCOs [Managed Care Organizations]…how can they engage? So, can they send out the reminders? Can they do the electronic reminders to a physician when they're doing the well visit?… ‘You got to talk about HPV.' How can we incentivize them to get people to get the shot?” “Additionally, some payer representatives in both regions expressed a desire to use data monitoring and sharing of HPV vaccination rates at the provider or practice levels to improve rates and bring a specific focus to HPV within their organizations.Policy and payer representatives in both regions cited the COVID-19 pandemic as a barrier, noting missed doses as adolescents were not going to in-person appointments, especially early in the pandemic. Some policy and payer representatives also described the politicization of vaccines, as well as an active anti-vaccination/vaccine choice movement especially in NJ, as a barrier:…the whole vaccinations landscape is fairly volatile right now…hopefully, it doesn't continue to be politicized which I see has happened with COVID…” “Simultaneously, some policy and payer representatives saw potential opportunities of how COVID-19 vaccination strategies could be translated to HPV vaccination. Strategies included bringing vaccination to communities through vaccine events, mobile vaccination, and bundling with delivery of COVID-19 vaccines, in addition to adolescent engagement using social media, youth-designed campaigns, and directly reaching parents and adolescents in schools. Policy representatives, specifically those who were government officials, also expressed new opportunities to improve HPV vaccination in their role since the pandemic began:I see a very active role for people in my position, for my boss [LA County Supervisor], and vaccination efforts…right now, the public health also is just raising awareness for any number of issues, HPV being one of them.” “Additionally, there were payer representatives in both regions who expressed opportunities for HPV vaccination due to health plans shifting toward using P4P and value-based programs that could be utilized as resources to increase HPV vaccination rates, especially given a drop in rates due to pandemic disruption. Payer representatives we interviewed also indicated opportunities for HPV vaccination due to health plans bringing increased focus to health equity, highlighted by the pandemic due to health inequities by race, ethnicity, and socioeconomic status that became more apparent and further emphasized the importance of increasing utilization of preventive health care services like vaccination.Public health policy and payer strategies clearly have important influences on HPV vaccination rates in safety-net settings, and our findings illustrate how these perspectives can and should be taken into account for HPV vaccination improvement in the US. Policy and payer strategies have influence that can be positive or negative in terms motivating clinics and providing available resources for change within clinic settings. Two kinds of policy strategies were offered by policy and payer representatives in our study as important for improving HPV vaccination in safety-net clinics. These included region-specific policies, or “big P” policies, such as minor consent laws and limiting religious exemptions. Both groups of participants also saw potential in “little p” policies involving financial incentives, including P4P programs, that are targeted to HPV vaccination. Finally, while our interviews with payer representatives mainly focused on how payers influence HPV vaccination in safety-net clinics, some payers also mentioned the potential strategy of their health plans improving awareness within the safety-net population of the need for HPV vaccination as part of community outreach and engagement missions. Thus, engaged representatives of policy and payer perspectives are important for informing HPV vaccination improvement within safety-net settings, as few champions currently exist within these broader levels of influence. Our findings also align with international efforts which emphasize taking a value-based approach to prevention of cervical cancer through optimal vaccination uptake –36.Recent literature points to success in using P4P programs to improve vaccination rates for routine pediatric and childhood immunizations  in addition to adolescent immunizations  , as wellOur findings indicated there was limited mention in interviews of health plans that serve safety-net populations specifically targeting adolescent vaccination as part of their P4P programs. Payers who did mention HPV vaccination as part of P4P programs elaborated that HPV vaccination was only part of the existing HEDIS metric, which combines HPV and two other adolescent immunizations together, thereby limiting focus on specific HPV vaccination improvement benchmarks. Thus, our findings suggest existing payer and policy metrics are not enough to bring attention to HPV vaccination to improve rates within safety-net settings.Based on our interviews with payer representatives, we found that combining three adolescent vaccines into one quality metric is ineffective. Payers described how rates for the two other adolescent immunizations  already exceed HPV vaccination rates, and policy representatives noted how both Meningococcal and Tdap are already mandated for school entry in the two states in this study (as well as throughout the US) while HPV is not. Considering school entry mandates for HPV vaccines were described as not politically feasible by our policy interview participants, and especially in light of the COVID-19 pandemic and increased anti-vaccine sentiment discussed by both payer and policy representatives, there is a need for HPV vaccination to be targeted separately from other adolescent vaccinations. The lack of a stand-alone HPV vaccination quality metric limits the ability of health plans to monitor rates of HPV vaccination specifically and track improvements in rates over time or identify potential opportunities for intervention that could improve rates. Without specific focus on the HPV vaccine, rates of HPV vaccination will likely continue to remain lower than target levels despite a safe, available HPV vaccine already shown to effectively prevent cancer.Future system-based work in this area should focus on engagement with broader health plan representatives and the potential for targeted programs to incentivize HPV vaccination improvements in adolescent populations. Additionally, future research should examine the dynamic of interactions between providers, payers, and policy representatives and how providers can partner with payers and policy representatives to increase HPV vaccine uptake among safety-net populations. Lastly, given parental hesitancy and concern about HPV vaccination promoting sexual activity among adolescents remains a barrier , 44, futOur study has limitations. Although we purposively recruited participants from these two groups (policy and payer representatives), the purpose of the larger parent study was to discuss change to improve HPV vaccination in safety-net settings. Policy representatives could have been focused on broader community settings rather than safety-net clinic settings, and payer representatives may have been thinking of non-safety-net and privately insured populations in addition to safety-net populations. Another limitation is that our study focused on two states/regions (New Jersey and greater Los Angeles) in the US, and findings may be difficult to generalize to other states. However, this qualitative study used purposive sampling that allowed for in-depth analysis of two regions with varying policy landscapes and payer compositions, thereby offering valuable perspective on similarities and differences across the regions. Lastly, our findings are hypothesis generating but not confirming and should be viewed as such.Our study finds that representatives of policy and healthcare payer perspectives bring important insights about the external setting of safety-net clinics that influence the priorities and actions of internal clinic members . Currently, many representatives of policy and payer perspectives do not view HPV vaccination as high priority  which in turn can make providers and clinic leaders less inclined to prioritize HPV vaccination within clinic settings. The views of policy and payer representatives on strategies to improve HPV vaccination have largely been overlooked, but are clearly important for identifying broader population and system level changes that are necessary for HPV vaccination rates to meaningfully improve in the US. We identified opportunities for change and a need to translate effective policies and payer strategies, such as P4P programs (little “p” policies) that have been used to increase utilization of other preventive health care services (other specific childhood immunizations and types of cancer screening), to HPV vaccination, as well as big “P” policies such as minor consent for vaccination, in order to increase HPV vaccine uptake within safety-net settings.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.This study involving human participants was reviewed and approved by the University of Southern California Institutional Review Board and the Rutgers University Institutional Review Board. Written informed consent for participation was not required for this study in accordance with the national legislation and the institutional requirements.JT, JC, BC, SH, and LP contributed to the conception and design of the study. KS analyzed the data and wrote the first draft. MS and JT contributed to the analysis and interpretation of interview data. All authors contributed to the interpretation of data analysis, manuscript revision, read, and approved the final manuscript.


Firstly, the imaging signals of theranostic nanomaterials are lack of sufficient specificity, penetrating depth, and resolution. As a result, it is challenge to detect small lesions at the early stage of diseases. It is necessary to optimize the specificity and sensitivity of disease diagnosis, especially for occult and early lesions. Secondly, the therapeutic activity of theranostic nanomaterials is expected to be adjusted according to the diagnosis results, so as to achieve personalized treatment. However, the majority of the current theranostic nanomaterials lack flexible means to adjust the therapeutic activity post their administration. Thirdly, traditional small molecule drugs are prone to cause drug resistance in target tissues. Nanomedicines with high efficacy and low risk of drug resistance are highly desirable for the disease treatments. In addition, the exact mechanism of theranostic nanomaterials in body is still poorly understood. Although possible mechanisms can be inferred through a series of in vitro studies, the biological environment in vivo is much more complex than that in vitro. More endevours are required to disclose the acting mechanism of theranostic nanomaterials, which will be helpful for their future design and optimization.The effective treatment of diseases requires the combination of diagnosis and therapy, which has become one of the important directions in the field of biomedicine. Theranostic nanomaterials can achieve this goal by loading both drug molecules and diagnostic reagents. Theranostic nanomaterials can also improve the targeting and precision of diagnosis and therapy through surface modifications. The commonly used theranostic nanomaterials include liposomes, polymer nanoparticles, inorganic nanoparticles and organic/inorganic hybrid nanomaterials. Various diagnostic methods have been developed with theranostic nanomaterials, such as ultrasound imaging, radiography, fluorescence imaging and photoacoustic imaging. However, the clinical applications of theranostic nanomaterials faces some challenges due to the complexity of the physiological environment Kakaei et al. reviewed the recent progress and challenges in perfluorocarbon nanomaterials for theranostic applications. The oxygen dissolving ability of perfluorocarbons allows them to act as oxygen carriers and enable ultrasound imaging. Moreover, with incorporation of magnetic resonance contrast agents and photothermal agents, perfluorocarbons can also achieve magnetic resonance imaging and photoacoustic imaging in vivo. The oxygen delivered by perfluorocarbons can alleviate the hypoxia in the lesions of diseases such as tumors, thrombosis, arthritis, and muscle atrophy.Based on the above challenges, this Research Topic covers the latest research progress in theranostic nanomedicine. In terms of diagnostics, Nie et al. reported the use of selenium-based agents for radiosensitization of lung cancer. Selenium compounds and nanoselenium induced lung cancer cell apoptosis by blocking G2/M cell cycle arrest, thus enhancing the efficacy of radiotherapy. Wu et al. reported perfluorane-loaded liposomal microbubbles for antitumor immunotherapy under low intensity pulsed ultrasound. The cavitation effect induced by ultrasound microbubbles disrupted tumor blood vessels and facilitated the infiltration of immune cells into the tumor, triggering a sustained antitumor immune response. Besides tumor therapy, theranostic nanomedicines have also been applied in other diseases. Zhang et al. prepared poly (lactic-co-glycolic acid) (PLGA) nanoparticles loaded with sulfasalazine to inhibit neointimal hyperplasia by inducing autophagy. The inhibition of neointimal hyperplasia by sulfasalazine loading PLGA nanoparticles was through NF-kB/mTOR-mediated autophagy. Yan et al. used PLGA nanoparticles as carriers to deliver growth factors and controlled their release process by low-intensity pulsed ultrasound. Due to the controlled release of growth factors and physical stimulation by ultrasound, PLGA nanoparticles loaded with growth factors significantly promoted periodontal bone regeneration.In terms of disease therapy with theranostics nanomaterials, In summary, theranostic nanomaterials can combine imaging agents and therapeutic drugs into one nanoplatform to achieve disease theranostics. Moreover, the therapeutic process of theranostic nanomedicines can be tunned with the assistance of external stimulus such as ultrasound. The bioimaging functions of theranostic nanomaterials are helpful to understand their therapeutic activity in biological environment. All these two aspects endow theranostic nanomaterials with great potential in the treatment of various diseases, such as cancer, cardiovascular diseases and bone diseases. Many challenges remain to be overcome prior to their clinical translation, such as biocompatibility, biodistribution, bioavailability and biosafety. Therefore, more efforts are needed to develop novel nanomaterials and strategies for theranostics in the future. We hope that this project will stimulate the interest of researchers in chemistry, materials, biomedicine and other disciplines, aiming to promote the development of theranostic nanomaterials.


Recent advances in immunotherapeutic approaches have spanned different tumor types including head and neck cancer. HPV-related head and Neck Cancers are virally driven tumors with notable immune characteristics and recent advances in immune targeting that desrve a closer examination. We aimed in this comprehensive review to offer a description of recent advances in immunotherapeutic applications in this disease. Head and neck cancer (HNC) is the seventh most common malignancy, with oropharyngeal squamous cell carcinoma (OPSCC) accounting for a majority of cases in the western world. While HNC accounts for only 5% of all cancers in the United States, the incidence of a subset of OPSCC caused by human papillomavirus (HPV) is increasing rapidly. The treatment for OPSCC is multifaceted, with a recently emerging focus on immunotherapeutic approaches. With the increased incidence of HPV-related OPSCC and the approval of immunotherapy in the management of recurrent and metastatic HNC, there has been rising interest in exploring the role of immunotherapy in the treatment of HPV-related OPSCC specifically. The immune microenvironment in HPV-related disease is distinct from that in HPV-negative OPSCC, which has prompted further research into various immunotherapeutics. This review focuses on HPV-related OPSCC, its immune characteristics, and current challenges and future opportunities for immunotherapeutic applications in this virus-driven cancer. Head and neck cancer (HNC) remains a highly prevalent disease and is now ranked the seventh most common malignancy globally. In the United States, there are almost 66,000 new cases yearly . OropharHPV is well-known to be a predominant factor in the development of cervical cancer and has also been implicated in anal, penile, vaginal, and oropharyngeal carcinomas, as it can affect the squamous epithelium in these sites. HPV is relatively common within the general population, and most individuals are able to clear the virus or remain largely asymptomatic . Howeverp < 0.001) [Although primarily thought to be associated with middle-aged, white men, more recent data suggest increasing rates of HPV-positive OPSCC among elderly (65 and above) patients in the United States ,9,10. HP< 0.001) . The stu< 0.001) . Several< 0.001) ,15,16,17Studies with a higher prevalence of HPV-positive OPSCC patients are showing even higher rates of disease-specific and overall survival. In a phase II clinical trial of intensity-modulated chemoradiotherapy to reduce dysphagia in advanced-stage OPSCC, 90% of patients were HPV-positive, and 3-year disease-specific survival was 88% . TransorThe reasons behind the survival benefit demonstrated in HPV-related diseases are not entirely clear at present. One theory suggests the improved locoregional control may be due to increased radiosensitivity . AdditioDespite phenotypic similarities between HPV-related and unrelated OPSCC, it is vital to understand their underlying differences as this can shed light on their respective biology and potentially impact treatment strategies. This review will outline the management principles for HPV-related disease, discuss immunological differences when compared to HPV-unrelated OPSCC, and consider current and future targets for immunotherapy. Additionally, integrating further primary prevention strategies with these novel therapeutic strategies will enable us to move toward the eradication of HPV-related OPSCC. The aims of this review include detailing HPV-related OPSCC, its immune characteristics, and current challenges and future opportunities for immunotherapeutic applications in this virus-driven cancer.In order to understand the particulars of immune evasion by HPV-related OPSCC, the general immune microenvironment of HNC must first be delineated. The interplay between the tumor and the immune system is complex; various mechanisms allow for cancer immunity . DestrucHPV-related OPSCC has demonstrated a distinct immune microenvironment. One difference is that, although the expressed viral oncoproteins are foreign and thus exquisite immunological targets, the viral oncoproteins E6 and E7 can inhibit the presentation of tumor antigens on tumor cells through the downregulation of major histocompatibility complex (MHC) class I and class II molecules ,29. ThisHPV-related OPSCC also exhibits increased activation of immune infiltrates compared to HPV-unrelated disease. Multiple studies have indicated increased activation of T cells in HPV-related disease as evidenced by increased levels of perforin and granzymes, which are integral to the induction of apoptosis through cytotoxic T cells ,33. OtheThe increased tumor infiltration by a variety of lymphocytes is particularly important as this has been correlated with improved prognosis ,39. WhenAnother explanation for the difference in prognosis has been attributed to the increased expression of PD-L1 in HPV-positive OPSCC ,50. Appr2) every three weeks with concurrent radiation. A large meta-analysis demonstrated the benefit of CRT compared to induction chemotherapy and cemented single-agent, platinum-based therapy as the preferred chemotherapeutic option [Treatment modalities for locally advanced (LA) and recurrent/metastatic (RM) HNC have drastically changed over the past several decades. Traditionally, the treatment of LA HNC, regardless of HPV status, entails a combined modality approach involving surgical resection, radiotherapy, and/or chemoradiotherapy (CRT) . The curc option . Howeverc option . A retroc option . Additioc option ,59.In addition to cytotoxics, the inhibition of epidermal growth factor receptor (EGFR) through targeted monoclonal antibodies such as cetuximab significantly altered the treatment landscape in the definitive management of LA and RM HNC. Two landmark trials led to the approval of cetuximab in conjunction with radiation therapy as first-line treatment in LA in addition to platinum-based chemotherapy in RM HNC ,61. SeveImmune checkpoint inhibitors (ICIs) have shown unprecedented promise in the treatment of RM HNC, including HPV-related OPSCC, primarily through their impact on immune escape. One mechanism for tumor immune evasion is through the PD-1/PD-L1 axis . Tumor cThe anti-PD-1 antibody pembrolizumab initially demonstrated success in KEYNOTE-012, a phase Ib trial assessing safety and efficacy in an expansion cohort with a reported overall response rate (ORR) of 18%, 6-month progression-free survival (PFS) and OS of 23% and 59%, respectively. However, when assessing HPV-related and unrelated diseases, the ORR was 32% vs. 14%, 6-month PFS was 37% vs. 20%, and 6-month OS was 70% vs. 56%, respectively . This suNivolumab, a human IgG4 anti-PD-1 monoclonal antibody, demonstrated success in the treatment of RM HNC in the CheckMate-141 study. CheckMate-141 was the first phase III randomized trial showing superior survival of an immunotherapeutic agent over cytotoxic chemotherapy in patients with RM HNC, including HPV-related OPSCC. CheckMate-141 assessed 361 patients who failed platinum-based therapy in the recurrent setting or progressed within six months of platinum-based definitive chemotherapy. The patients were randomized to nivolumab every two weeks or SOC and received either methotrexate, docetaxel, or cetuximab. The study met its primary endpoint with significantly improved median OS in the nivolumab arm (7.5 vs. 5.1 months). Patients receiving nivolumab also maintained their quality-of-life scores, whereas the SOC arm had worse outcomes with treatment . The impDurvalumab is another well-studied PD-L1 monoclonal antibody in the treatment of RM HNC. The HAWK trial was a multi-institutional, single-arm, phase II study assessing durvalumab in platinum-refractory RM disease. The study included 112 immunotherapy naive patients with high PD-L1 expression and demonstrated an ORR of 16.2%, PFS of 2.1 months, and median OS of 7.1 months. A secondary analysis performed on all HPV-positive tumor sites demonstrated an ORR of 29.4% (10/34) in HPV-positive versus 10.8% (10/65) in HPV-negative tumors. Additionally, HPV-positive tumors had a numerically higher PFS and median OS compared to HPV-negative tumors. However, it should be noted that this population included solely patients with high PD-L1 expression, which may be a contributing factor to improved survival rates . The CONIt is clear, based on the aforementioned, that ICIs provide an improved OS with minimal toxicity in HPV-related and unrelated HNC, allowing patients to preserve both quantity and quality of life. Given the improved survival in patients with OPSCC compared to other head and neck tumor sites, there was reason to believe immunotherapy would enhance this survival benefit. However, as discussed above, there are conflicting data regarding if immunotherapy favorably impacts HPV-positive tumors. A meta-analysis that assessed nine studies with PD-1/PD-L1 inhibition provided further answers. The study performed a subgroup analysis for pooled ORR and demonstrated an ORR of 18.8% in HPV-positive patients versus 12.2% in HPV-negative patients. The study also suggested a 56% higher chance of achieving ORR in HPV-positive patients than in HPV-negative patients. However, these results did not meet statistical significance . FurtherOf note is the potential of other immunomodulatory approaches in the realm of immunostimulatory options and novel combinatorial approaches in treating recurrent and metastatic head and neck squamous cell carcinomas. These may, in the future, alter the therapeutic landscape of HPV-related OPSCC. Examples include targeting IDO1 , TLR8 agT cells are an integral part of the immune system, working to detect foreign agents and facilitate adaptive immune responses. Thus, they play a crucial role in mounting the body’s antitumor response. There are several ongoing studies focusing on formulating T cells that target specific antigens to provide therapeutic benefits.A specific form of T cell engineering known as adoptive cell-based therapy is currently being investigated. This therapy isolates target T cells from the patient, transduces them in vivo to specifically target various antigens, and then transplants them back into the host after being genetically modified. Adoptive cell-based therapy has been previously administered in patients with B cell malignancies and metastatic melanoma ,79. A phMHC molecules serve as an intermediary between tumor antigens and T cell receptors on antigen-specific T cells. Some particular tumor antigens for HPV include E6 and E7, which are oncoproteins inside HPV-positive cancer cells and whose peptides can be presented on MHCs. Researchers are now focusing on these proteins as optimal targets, as they are absent from healthy human tissues. Therapy targeting E7 oncoprotein has been validated in a preclinical study in mice, which revealed that genetically modified T cells inhibited tumor growth, prolonged survival, and promoted immunological memory in HPV-related cervical and oropharyngeal cancer . A phaseAlthough initial efforts are promising, multiple impediments have been established that need to be further elucidated. One concern is the risk of T cell receptor mispairing, which involves the formation of a hybrid T cell receptor by pairing the endogenous with the genetically engineered T cell receptor chains. This mispairing has been shown to cause graft vs. host disease in previous animal studies . AnotherImmuno-STATs (Selective Targeting and Alteration of T cells) are the most recent development utilizing T cells for cancer-targeted therapy. The Immuno-STAT is a modular fusion protein consisting of a tumor-associated human leukocyte antigen (HLA) peptide complex that delivers interleukin-2 to induce the proliferation of tumor-antigen-specific T cells. Selective targeting and delivery of the tumor antigen-specific T cells reduce systemic activation of the immune system, thereby avoiding toxicity .A recent phase I trial (NCT03978689) studied CUE-101, an Immuno-STAT composed of an HLA presenting an HPV-16 E7 peptide and four molecules of IL-2, which binds to HPV-specific CD8 T cells and induces their activation and proliferation. The study assessed escalating doses of CUE-101 monotherapy or in combination with pembrolizumab based on previous PD-L1 treatment in patients with HPV-16+ recurrent or metastatic HNC. Therapy was provided every 3 weeks until disease progression or toxicity. CUE-101 demonstrated safety and tolerability with sustained increases in NK cells and Treg cells. Of the 14 evaluable patients in the monotherapy cohort, there was 1 partial response (7%) and 6 stable disease (43%). Of the 7 evaluable patients in the combination arm, there were 2 partial responses (29%) and 2 stable disease (29%) for >12 weeks. Given its target of E7, this modular fusion protein can be utilized across several different cancer types, including HPV-positive HNC. The FDA has now provided provisional approval for the use of CUE-101 at this time . Novel tDespite significant strides in understanding T cell action within the TME, there is still much to learn regarding antitumor immunity provided by B cells. The humoral immune response has several functions, including antigen presentation, cytokine release, and evoking antibody-dependent cellular cytotoxicity through antibody secretion. More importantly, B cells have been shown to exhibit several surface receptors, such as PD-1, PD-L1, and CTLA-4, which will be affected by current immunotherapeutic agents and might thus also contribute to their clinical activity .The presence of increased B cell infiltration within HPV-related tumors has also been associated with a more favorable prognosis ,93. StudAnother way to induce T cell responses in recognizing and destroying malignant cells is through personalized cancer vaccination therapy . There aMultiple phase I studies have demonstrated success in this endeavor. A phase I study (NCT00257738) evaluated the immunologic response of a peptide immunomodulator GL-0810 and MAGE-A3. A limited number of patients completed the dose-escalated vaccination course, of which 80% (4/5 patients) in the GL-8010 cohort and 67% (4/6 patients) in the MAGE-A3 cohort had an objective T cell and antibody response measured through IFN-γ ELISPOT and ELISA, respectively. Apart from mild reactions at injection sites such as erythema, pain, or pruritis, the treatment was overall well tolerated. Despite the clinically documented progression in all patients, these results suggested that the peptide vaccine was safe and could induce an immunologic response .Another phase I study investigated the DNA vaccine AMV002 in patients with previously treated HPV-associated OPSCC. In total, 12 patients were assigned to four different groups and received varying dosages of the AMV002 vaccine. The vaccine was tolerated at all dosage levels, and 83.3% of patients demonstrated vaccine-induced cell-mediated response as measured by IFN-γ ELISPOT and ELISA. One subject was noted to have a greater than four-fold increase in antibody response to HPV16 E6 and E7 post-vaccine administration .A phase Ib/IIa trial (NCT02163057) studied the MED10457 DNA vaccine administration in 21 patients with locally advanced HPV16+ HNC. MED10457 expresses HPV 16/18 E6/E7 proteins as well as IL-12. Two separate cohorts were studied, one with administration prior to surgery and another with administration two months post-chemoradiation therapy. Results showed that 18 out of 21 patients generated a durable HPV16 antigen-specific immune response post-MED10457 administration . A folloThe benefits of combining ICI and therapeutic vaccines are an enticing prospect. Another phase Ib/II trial (NCT03260023) investigated TG4001, a modified Ankara vector-based vaccine, in addition to avelumab therapy in patients with HPV-16-positive cancers. Nine patients were included, of which five were patients with HPV-related oropharyngeal cancer. Interim results revealed no serious adverse events, and 33% had a confirmed partial response. Three patients exhibited an increased peripheral T cell response against E6/E7, as assessed by ELISPOT. Subsequent analyses are planned to compare TG4001 with avelumab versus avelumab therapy alone .An additional therapeutic vaccine that has been more extensively studied is the peptide vaccine ISA-101. ISA-101 incorporates long peptide chains derived from E6 and E7. Previous studies in HPV-related cervical cancer have shown that monotherapy with ISA-101 caused an increased T cell response but did not lead to regression or prevention of tumor progression ,105. A sA phase I/II trial (NCT0523851) is investigating the PDS0101 liposomal peptide vaccine as monotherapy and combined with pembrolizumab in patients with HPV-related OPSCC . AdditioWhile several therapeutic vaccines show encouraging results, some trials have shown less promising results. A phase I study (NCT01493154) investigated the use of the pNGVL4a-CRT/E7 DNA vaccine in conjunction with cyclophosphamide in HPV-16-associated HNC patients and was terminated early due to serious adverse reactions . AnotherOverall the therapeutic vaccination efforts in HPV-related OPSCC are promising and multifaceted. Progress in vaccine development and translation to clinical applications may alter the therapeutic landscape of managing advanced or localized HPV-related OPSCC within the next decade.Despite the many advancements described above, primary prevention through prophylactic vaccine administration should be a primary effort toward reducing the burden of this disease. There are currently three clinically developed vaccines for human papillomavirus, including the quadrivalent vaccine (Gardasil), the 9-valent vaccine (Gardasil-9), and the bivalent vaccine (Cervarix). In the United States, Gardasil-9 is primarily available, which targets HPV types 6, 11, 16, 18, 31, 33, 45, 52, and 58 ,117. As Currently, no established randomized controlled trials or epidemiological studies have evaluated how prophylactic vaccines impact the incidence or progression of OPSCC related to HPV. Despite this, the potential benefits are assumed, given the effectiveness that has been demonstrated for anogenital and other HPV-associated disease states ,120,121.The efficacy of prophylactic HPV vaccination in impeding HPV-related HNC is limited to various studies analyzing its effects on the reduction of oral HPV disease. A randomized control trial conducted in the United States and Brazil, published in 2018, demonstrated that the quadrivalent HPV vaccine was approximately 88% effective in preventing persistent oral HPV infection amongst HIV-infected adults when compared to a placebo group . These rOther retrospective studies have demonstrated that introducing the HPV vaccine into the general populations of the United States and the United Kingdom has decreased the prevalence of HPV-16 infections in unvaccinated individuals, suggesting that there is a herd community component and advantage of prophylactic vaccination for reducing disease burden ,128. AmoResearchers have worked for decades to find new therapies to treat cancer, and immunotherapy now represents a beacon of hope for many types of malignancy. Recent advancements have further supported that metaphor, with PD-1/PD-L1-based immunotherapies positively impacting outcomes in HNC specifically. Studies so far have indicated this benefit to be limited to a small subset of patients, making further research into novel immunotherapeutics even more vital. Such benefits are much needed in HNC as it remains a challenging disease with an overall poor prognosis and limited treatment options.There are multiple modalities in which immunotherapy is being investigated based on therapeutic targets and emerging biomarkers. HPV-related HNC represents both a unique potential and challenge in that its distinct immune microenvironment may affect how the disease responds to immunotherapy; these differences have and will direct how therapeutic approaches are devised and administered. Future research into this area is exciting as previous studies have demonstrated that HPV-associated disease has increased expression of PD-L1 and immune infiltration.Understanding these differences further will be essential for developing personalized immunotherapies for HPV-related HNC. Considering how experimental and pioneering the current advancements are, evidence is still limited in terms of how this may impact HPV-related HNC. However, the ongoing development of HPV-specific immune modulators is revolutionary, including therapeutic vaccines and T cell-associated therapeutics targeting HPV. Whether these immunotherapeutics will be sufficient in their own merit or whether combinatorial approaches with ICIs and other anti-cancer agents will be needed are areas that require future exploration.