Rachael Zimlich, RN, BSN

Seasonal flu vaccine efficacy has hovered around 60 percent, varying by age and health status, but researchers are now working to investigate whether certain adjuvants can boost immune responses and improve overall protection.

The National Institute of Allergy and Infectious Diseases (NIAID) is in the early stages of a clinical trial to determine the safety and efficacy of two adjuvants that could induce stronger immune responses on existing influenza vaccines.

 is currently enrolling adults to test the adjuvants at eight clinical sites across the country. With the efficacy of existing influenza vaccines varying from year to year, the goal of the trial is to determine whether adjuvants can boost the immune responses generated by these vaccines to result in better overall protection.

“Adjuvants as immune boosting molecules may have the potential to increase the level, quality and duration of the immune response to a given vaccine, providing broader protection against circulating strains of influenza virus,” according to a spokesperson for the NIAID.

Currently, both of the vaccines being tested are only licensed and approved as non-adjuvanted vaccines, according to NIAIS.

Trial researchers expect to enroll 240 adult volunteers between the ages of 18 and 45, and the trial will run for 18 months. Volunteers enrolled in the trial will receive one dose of either Fluzone Quadrivalent or Flublock Quadrivalent influenza vaccines. The vaccines will either be administered alone or in combination with either the 

These adjuvants have shown promise in animal studies, according to NIAID. The AF03 adjuvant was developed by Sanofi Pasteur and has been shown to be particularly effective in improving immune responses with avian influenza vaccines, while the Advax-CpG55.2 adjuvant from Australia’s Vaxine Pty Ltd has already been linked to improved human immune responses in influenza vaccines in other studies.

While these adjuvants have already been linked to improved immune responses in certain situations, the clinical trial will assess specific uses and safety.

“The primary goals of this study are to evaluate the safety, reactogenicity and immunogenicity of these vaccines when combined with these novel adjuvants,” according to the NIAID spokesperson. “By combining licensed seasonal vaccines with immune boosting adjuvants, it is envisioned that more cross-protective and durable immune responses will be elicited that may improve patient outcomes by providing more robust protection against influenza virus infection and development of severe disease.”

Patients who receive the vaccines with and without adjuvants will be assessed through clinical visits for at least 57 days, during which time adverse effects and blood samples to track immune responses will be monitored. Patients will then be given a dose of seasonal vaccine without adjuvants 90 days after administration of the first vaccine and observed again.

Final assessments will occur a year after the initial vaccination, according to NIAID. The first phase of the trial is expected to conclude in August 2020.

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Researchers are examining whether two adjuvants could help boost the power of flu vaccines.

Clinical trials underway to test adjuvants for flu vaccines

Physicians and patients feel the consequences of clinician burnout, but it’s not a battle they can fight alone.

Christine A. Sinsky, MD, a board-certified internist, vice president of professional satisfaction at the American Medical Association (AMA), director of the American Board of Internal Medicine (ABIM) and chair of the Board of Trustees for ABIM, said the AMA began working earnestly on the issue of physician burnout in 2012, convening a group of chief executive officers from some of the largest healthcare systems in 2016 to raise awareness of the issue as a public health crisis.

The goal, she said, is to advance the understanding that burnout is primarily a systems problem, not an individual problem, so the focus should be on fixing the workplace rather than fixing the worker.

“The fact that the burnout rate among U.S. physicians dropped modestly in 2017 from a peak in 2014 may indicate that growing national efforts to address physician burnout are on the right track, but more work is needed to achieve meaningful change,” Sinsky said. “Addressing the crisis requires continued investment from hospitals and health system in a comprehensive strategy that targets barriers to efficiently providing patients with high-quality care as the primary driver of physician burnout.”

An energized, engaged and resilient physician workforce is essential to reaching national health goals and is well worth an investment from the health system, Sinsky said. The cost of clinician burnout is significant, she said, and there is a considerable return on investment for systems that invest in programs to address burnout. The AMA offers a cost of burnout calculator based on existing research data, she said.

Recognizing the importance of addressing burnout is a hurdle of its own, but creating a roadmap for change is sometimes an even greater challenge.

Jay Bhatt, DO, chief medical officer and president and chief executive office of the health research and executive trust at the American Hospital Association (AHA), said it’s critical to create an infrastructure for wellbeing that takes into account existing attitudes, beliefs, and gaps in the system. Wellbeing must be measures in a continuous manner, with interventions designed in a way that addresses those gaps while keeping in mind a health system’s current capabilities.

Team-based care is one intervention that has been successful in streamlining the administrative burden that contributes to burnout, but it takes support at the system level and cultural changes to achieve success.

“Team-based care isn’t intuitive. It requires intentionality and systems and mindset for that to happen,” Bhatt said. “We want well-intentioned clinicians that want to take care of patients and families.”

Physicians need better training on management and delegation, and having a sense of community among clinicians can help in this regard. Having a space for physicians to support each other and offer camaraderie is a thing of the past in many institutions, Bhatt said. Clinicians have lamented having a space to share thoughts and debate cases with out clinicians, he said.

“Those places create community and space for team-based care,” Bhatt said.

There also needs to be work at the national level to support policy changes that can aid in reducing burnout, Bhatt said.

“There has to be a balance between the information that needs to be documented so that care can be provided and a clinician’s time,” Bhatt said. “There are opportunities to reduce burden and put patients above paperwork.”

Bhatt said there is some headway being made in conversations with CMS in terms of documentation requirements and allowing team members to contribute to that process.

While there is still a long way to go, Bhatt said these discussions are a sign that physician burnout is on the radar at the national level and changes are on the horizon.

“We are also seeing that the flexibility in the way some organizations are getting systems to tackle documentation redesign,” he said. “Some of what we’re seeing from a policy perspective is aligned with reducing regulatory burden.”

While there are some changes physicians can make at the personal and practice level, it requires system-wide transformation to alleviate burnout.

Solving physician burnout solution requires system-wide changes

	Early infection with a seemingly innocuous virus may trigger an autoimmune response that could lead to later development of celiac disease, according to a new study that suggests the discovery could result in the creation of a vaccine against the increasingly common disease.

“Reovirus infection triggers inflammatory responses to dietary antigens and development of celiac disease,”

 suggests that the relatively common reovirus may be in part to blame for celiac virus, but researchers believe a prophylactic vaccine could possibly be developed for at-risk individuals.

	According to the study, celiac disease results from a specific autoimmune reaction certain individuals have to the peptides in dietary gluten. Increased incidence over the years has suggested that there may be an environmental link in some cases, and infection by several virus types-particularly the reovirus-have been associated with a sort of scarring in the immune system that may lead to later development of celiac disease.

	The reovirus typically doesn’t cause significant illness on its own, but researchers found that the individuals they studied with celiac disease had significantly higher antireovirus antibody titers that those without celiac disease, as well as elevated levels of interferon regulatory factor 1-a protein that induces an adaptive immune response and is associated with an increased risk of celiac disease.

	Reovirus, and possibly others, were therefore found to elicit proinflammatory responses that could affect immune system homestasis and oral tolerance of food antigens including gluten, according to the report.

	Terence S. Dermody, MD, Vira I. Heinz Professor and Chair of Pediatrics and professor of Microbiology and Molecular Genetics and the University of Pittsburgh School of Medicine, and one of the authors of the study, says the antibodies against reovirus in celiac patients signal early viral damage that may contribute to later celiac development.

	 “It’s the first demonstration that a virus can induce loss of tolerance to a dietary antigen, and in particular, we provide evidence that reovirus can trigger loss of oral tolerance and inflammatory immune responses to gluten,” Dermody, who is also physician-in-chief and scientific director at Children’s Hospital of Pittsburgh of UPMC, told 

. “We show that a virus that is apparently innocuous and cleared from the body can alter in the background in absence of overt disease the way the intestinal immune system sees a dietary antigen.”

	The study also provides evidence that a subset of celiac patients have abnormally high antibody titers to reovirus and that those high titers are associated with the transcriptional signature that has been found in mice with reovirus-induced loss of oral tolerance.

	If researchers are able to show that reovirus is indeed the cause of celiac disease, this means that a vaccine could be created that may prevent celiac disease in genetically at-risk individuals, Dermody said.

	“This study enhances our basic understanding of how the immune system distinguishes between food antigens and intestinal invaders and points a way forward to preventing autoimmune diseases by vaccination,” he said.

	Other enteric viruses have been found to affect different pathways, as well, according to the report, such as norovirus being associated with later development of colitis. Recent studies have also identified opportunistic bacterial pathogens that colonize in the small intestine of celiac and alter gluten metabolism.

 accompanying the study suggests that the discoveries outlined by the research team may not only lead to the development of a vaccine, but could have implications for treatment beyond celiac disease.

	“The implications of the Bouziat et al., study expand beyond food sensitivities and celiac disease to possibly other autoimmune disorders where the triggering agent is still un- known,” the editorial states. “In the future, new strategies could be implemented to prevent autoimmunity and food sensitivities, through the monitoring and prophylactic intervention of common viral infections, some of which are currently considered clinically irrelevant.”

Researchers believe a vaccine could be developed to prevent the formation of celiac disease and possibly other autoimmune disorders.

Early viral infection may contribute to celiac development

	The flu vaccine has been shown to prevent, or at least lessen symptoms, of influenza, yet less than half of American adults receive the vaccine annually, according to the 

Centers for Disease Control and Prevention (CDC). 

	The key to improved vaccination rates can be as simple as a programming change that reminds physicians to have the conversation about the flu vaccine with their patients.

 "Using Active Choice Within the Electronic Health Record to Increase Influenza Vaccination Rates," 

conducted by researchers at the Perelman School of Medicine at the University of Pennsylvania and published in the 

 researchers found that a simple prompt programmed into an electronic health record (EHR) at an internal medicine outpatient office resulted in a nearly 40% relative increase in flu vaccinations among adult patients over the prior year and a 6% increase in comparison to two other internal medicine clinics in the same health system used as controls.

	Mitesh S. Patel, MD, MBA, MS, an assistant professor of medicine and healthcare management in Penn’s Perelman School of Medicine and the Wharton School and lead author of the report told 

 well-designed "nudges" can be helpful across many areas of practice, especially when used to increase uptake of evidence-based practices like influenza vaccination.

	"Medical decision-making is often sub-optimal," Patel says. "Active choice is a method used to prompt one's attention, provide information on the risks and benefits of options, and make it easy to submit a decision."

	Previous support has supported the benefits of active choice, particularly in increasing the use of certain diagnostic tests. In this case, Patel and his team took that a step further, programming a "best practices alert" into the clinic's EHR that would display any time an adult patient was eligible to receive the flu vaccine. To move on within the EHR, providers would have to select "accept" or "cancel" on the prompt, cashing in on what may previously have been a missed opportunity for the physician to offer to and discuss a flu vaccine with the patient. The prompt also resulted in the generation of an order, allowing the vaccine to be administered quickly at the time of the visit, removing steps that previously required providers to manually search a patient's eligibility and then place an order.

	The intervention was programmed into the EHR system in February 2012, and by the end of the 2012-2013 flu season, orders for flu vaccines in that clinic rose by 37% in comparison to the prior flu season. As a result of the success of the intervention, the prompt was programmed into the EHRs of all of the internal medicine outpatient clinics across Penn Medicine.

	While prompts like this can be beneficial to both practice operations and patient outcomes, Patel warned that there can also be too much of a good thing.

	"Alerts in the electronic health record should be balanced to prevent overload and alert fatigue," he said. "The way choices are offered and information is framed in the electronic health record can have significant impact on how clinicians behave. Our study indicates that better testing can help to optimize the design of choices to improve the delivery of high-value healthcare."

A simple prompt reminding patients of their flu shot was found to be highly effective in a trial run at the University of Pennsylvania.

Author | Rachael Zimlich, RN, BSN

Articles

Clinical trials underway to test adjuvants for flu vaccines

Solving physician burnout solution requires system-wide changes

Early viral infection may contribute to celiac development

Patient prompts can increase flu shot rates nearly 40%