Body

Thermal imaging has been available for decades to detect temperature differences on the skin that could signal breast cancer without exposing patients to radiation, although the method is not as reliable as mammography.

New research performed at The University of Texas at Dallas and published June 22 in Nature Research's Scientific Reports takes a critical step toward making digital infrared thermal imaging more useful for monitoring breast cancer.

Engineers in the Erik Jonsson School of Engineering and Computer Science, working with radiologists at UT Southwestern Medical Center, recruited 11 female patients who volunteered for the study through UT Southwestern and Parkland Health & Hospital System in Dallas. The team used a high-resolution infrared camera, clinical data from patient volunteers, 3D scanning and computer-aided design to build a proof-of-concept computer model of the thermal properties of breast cancer.

Dr. Fatemeh Hassanipour, corresponding author of the study and associate professor of mechanical engineering in the Jonsson School, said their goal is to improve digital thermal imaging as a tool for monitoring cancer and its treatment, rather than replacing cancer screening by mammograms.

"Infrared imaging could potentially provide useful information in a diagnostic setting to radiologists," Hassanipour said. "We want it to be used like a second device for monitoring tumors."

The research utilized thermal imaging, with the infrared camera taking images of the skin, to identify temperature changes generated by breast cancer as it induces changes to the local vasculature and cellular metabolism. The technique only shows patterns of heat and blood flow on or near the surface of breasts, however, leaving unknown information about tumor activity deeper in the breast tissue.

The UT Dallas researchers worked to address this issue by applying engineering tools to imaging data to develop a model that quantifies the thermal characteristics of breast cancer throughout one patient's breast. The results showed a detectable temperature difference in metabolic heat generation between the patient's normal and cancerous breasts. They also noted increased perfusion rates, which is the rate of blood flow through a given volume, in the affected breast.

The researchers cautioned that the model cannot be applied to all types of breast cancer. In addition, not all breast cancers generate sufficient heat to be detected via thermography. Now that UT Dallas researchers have demonstrated their computational model, they plan to develop models for the other breast cancer patients enrolled in the study.

"Our team has many great ideas moving forward," Hassanipour said. "We'd like to add more dedicated graduate students to this project. The subject case that we reported in the manuscript was a proof of concept. A lot of lessons were learned that will facilitate modeling other cancers."

Recent UT Dallas graduate Adolfo Lozano PhD'20, who works for Raytheon Technologies Corp., was lead author of the paper; in addition to Hassanipour, Jamasp Azarnoosh PhD'20 was a co-author. The UT Dallas researchers teamed up with UT Southwestern assistant professors of radiology Dr. Jody C. Hayes and Dr. Lindsay M. Compton.

Lozano said he was eager to join Hassanipour's breast-cancer research project because his mother was diagnosed with breast cancer in 2009.

"I still recall hearing the news and how shocked and saddened we were as a family," said Lozano, whose mom's cancer is in remission. "When I had the opportunity to join Dr. Hassanipour's research group and establish this new project in the area of breast cancer, I was immensely grateful and saw it as a gift from above."

Hassanipour's work is supported by a National Science Foundation CAREER award, which she received in 2015 to study the biomechanics of breastfeeding. She said she became interested in the thermal imaging project after discovering that little work had been done to create a thermal model of the breast based on real clinical data.

Researchers at Tel Aviv University, led by Prof. Ronit Satchi-Fainaro of TAU's Department of Physiology and Pharmacology at the Sackler School of Medicine, have developed an innovative nanotechnological drug delivery system that significantly enhances the effectiveness of treatment for the aggressive skin cancer melanoma.

The nanocarrier is a biocompatible and biodegradable polymer, which comprises repeating units of glutamic acids. It packages together two drugs belonging to different families with proven efficacy for the treatment of melanoma: BRAF inhibitors (Dabrafenib) and MEK inhibitors (Selumetinib, approved for use in children with neurofibromatosis type I).

The research group included PhD students Evgeni Pisarevsky, Dr. Rachel Blau, and Yana Epshtein from Prof. Satchi-Fainaro's research laboratory at the Sackler School. The paper was published on August 10, 2020, in Advanced Therapeutics.

"One of the major obstacles of the biological treatments is that, after a while, the cancer cells develop resistance to the drugs," Prof. Satchi-Fainaro says. "We assume that by precise delivery of two or more targeted drugs that will attack the cancer cells forcefully and simultaneously from different directions, we can delay or even prevent the acquisition of this drug resistance.

"In this project, we looked for a solution to a problem often associated with drug cocktails," Prof. Satchi-Fainaro continues. "Most oncological treatments today are administered in the form of cocktails of several medications. But even though the drugs are administered simultaneously, they do not reach the tumor at the same time, due to differences in basic parameters, like how long they survive in the bloodstream and the time it takes each drug to reach the tumor tissue. Thus, in most cases, the medications do not work concurrently, which prevents them from attaining optimal synergistic activity."

Responding to these challenges, the researchers developed an innovative, efficient, and biodegradable drug delivery system. Two drugs known to be effective for the treatment of melanoma, Dabrafenib and Selumetinib, were chosen, with the intention of delivering them jointly to the tumor using a nanocarrier. The drug nanocarrier chosen for the task was PGA, a polymer of glutamic acid, one of nature's most common amino acids. Developed in Prof. Satchi-Fainaro's lab several years ago, the nanocarrier has already been tested successfully for treating pancreatic, breast, and ovarian cancer in animal models.

The researchers first determined the optimal ratio between the two medications based on levels and types of toxicity, as well as the resistance mechanism developed by cancer cells for each medication. This would ultimately ensure maximum effectiveness, minimal toxicity, and optimal synergistic activity. Another important advantage of joint delivery is reduced dosage: a much lower dose is required compared to each drug when administered independently.

The next step was using chemical modifications to enable bonding between the polymeric carrier and the chosen drugs. This combined system can travel through the body with total safety, inflicting no damage to healthy tissues. Upon reaching the cancer cells, the nanocarrier encounters proteins of the cathepsins enzyme family, which are highly activated in malignant tumors. The proteins degrade the polymer, releasing the drugs which become active and join forces to attack the tumor. "It's like several passengers riding in one cab and getting off together at the same address," Prof. Satchi-Fainaro explains. "They all arrive at the same destination, right at the same time."

Tested on a mouse model of melanoma, the new treatment showed promising results. The nanocarrier delivered the two drugs to the tumor and released them there simultaneously in quantities about 20 times greater than those that reach the tumor when similar doses of the same medications are administered independently. In addition, the therapeutic effect achieved by the drugs delivered by the nanocarrier lasted twice to three times longer compared to a control group and a group treated with free medications.

According to the researchers, this means that the new platform enables much lower dosages -- about one-third of the dose required in regular drug cocktails. The treatment as a whole is also both safer and more effective. If necessary, the new approach allows for dosages that are much higher than the maximum dosage permissible in current methods, thereby enhancing the effectiveness of the treatment even further.

"In this project, we developed an innovative drug delivery system for treating melanoma, delivering two proven medications and releasing them simultaneously at the tumor site," Prof. Satchi-Fainaro summarizes. "The treatment proved both safer and more effective than the same medications administered as a cocktail. Moreover, our new platform is highly modular and can be used for delivering a vast range of medications. We believe that its potential for enhancing therapeutics for different diseases is practically endless."

BOSTON - A targeted therapy called capmatinib can provide significant benefits to patients who have advanced lung cancer with specific gene mutations, according to recently published results from a phase two clinical trial. The trial, which is published in the New England Journal of Medicine, was conducted by an international team led by investigators at Massachusetts General Hospital (MGH).

A protein called MET affects a wide range of processes within cells, and alterations that activate the MET gene, which codes for this protein, have been implicated in many cancers. MET can be activated by a variety of mechanisms. Multiples copies of the MET gene, called MET amplification, occurs in one-to-six percent of patients with non-small-cell lung cancer (NSCLC). MET exon 14 skipping mutations, which cause deletion of a region called exon 14 in the expressed protein, occur in approximately three-to-four percent of patients with NSCLC and are associated with a poor prognosis.

The drug capmatinib is a highly potent and selective inhibitor of MET. Now researchers report results from the phase 2 GEOMETRY mono-1 study, which investigated the activity of capmatinib in 364 patients with advanced NSCLC with MET exon 14 skipping mutations or MET amplification. Results from this study were the basis for the US Food and Drug Administration's May 2020 approval of capmatinib for the treatment of NSCLC patients with MET exon 14 skipping.

In patients with MET exon 14 skipping mutations, capmatinib had a very high response rate (68 percent) when used as the first line of treatment, and an excellent response rate (41 percent) when used after patients had been treated with other therapies such as chemotherapy and immunotherapy. Among patients with MET amplification with at least 10 copies of the gene, capmatinib had a response rate of 40 percent when used as a first-line treatment and a response rate of 29 percent when used after other treatments. The drug had limited effectiveness in patients with a lower level of MET amplification.

The results indicate that capmatinib may be an especially effective treatment for patients who have NSCLC with MET exon 14 skipping mutations and who have not been treated previously.

"There are many advances in NSCLC treatment that are helping people live longer and better with their disease, and it is really important that all newly diagnosed patients with NSCLC get broad molecular profiling to determine what their optimal first-line therapy should be," said senior author Rebecca Suk Heist, MD, investigator in the MGH Cancer Center and assocoiate professor of Medicne at Harvard Medical School. "If we don't test, we don't know." Heist noted that MET exon 14 skipping and amplification join a number of other drivers of NSCLC for which researchers have developed targeted therapies. "It is critically important that all patients have their lung cancers tested for these to know whether there is a targeted treatment option or not," she said.

BOSTON - A new software program effectively brings the expertise of Massachusetts General Hospital (MGH) specialists to many more patients with Down syndrome (DS), according to a study published today in Genetics in Medicine. Down Syndrome Clinic to You (DSC2U) is a first-of-its kind online health tool aimed at improving adherence to US national Down syndrome guidelines. This study finds the tool effective. Most caregivers and primary care physicians (PCPs) also reported high satisfaction with it.

The first author of the paper is Jeanhee Chung, MS, MD, primary care physician at MGH. The senior author is Brian Skotko, MD, MPP, director of the Down Syndrome Program and Emma Campbell Endowed Chair on Down Syndrome at MGH.

The study was a national randomized controlled trial of 230 caregivers who had children or dependents with DS but no access to a specialist. Of these, 117 were randomized to receive DSC2U while 113 received usual care. A total of 213 participants completed a seven-month long follow-up evaluation. Those who received DSC2U had a 1.6-fold increase in the number of guideline-indicated evaluations their primary care provider recommended or completed compared with controls.

Clinicians at MGH's Down Syndrome Program launched DSCU2 in August of this year. The program aggregates the clinical experience of specialists and others who care for these patients. It then connects patients' families with customized information to augment the work of local care providers. Skotko and his colleagues see approximately 600 patients a year at their clinic. DSC2U now brings MGH's expertise in caring for individuals with Down syndrome to families around the globe.

To participate, users are asked to identify current symptoms in their loved one with Down syndrome along with any past medical or behavioral diagnoses and any recent blood work or diagnostic testing. They are additionally offered an optional set of questions about nutrition, education, therapies, life skills and community resources.

Responses are electronically analyzed by an evidence-based set of rules, and the output comprises personalized checklists that can be used during annual wellness visits with the patient's PCP.

"Rather than asking families around the world to come to Boston, we are instead bringing the most accurate and up-to-date information to families in their home settings," says Skotko.

"About 95 percent of patients with Downs syndrome do not have access to specialist care," he adds. Specialist care is particularly important for them as these patients have a wide range of different health, social, and developmental issues.

Charlottesville, VA (September 8, 2020). The University of Glasgow's Sir Graham Teasdale, co-creator of the Glasgow Coma Scale, once again has teamed with Paul M. Brennan and Gordon D. Murray of the University of Edinburgh. The object: to create a simple and practical tool for use in assessing impaired consciousness in the clinical setting when the verbal component of the Glasgow Coma Scale is missing. The resulting tool and evaluation of its functionality are described and evaluated in the paper, "A practical method for dealing with missing Glasgow Coma Scale verbal component scores," published today in the Journal of Neurosurgery.

Background

The Glasgow Coma Scale (GCS) was first introduced in 1974 by Bryan Jennett and Graham Teasdale to assess coma and impaired consciousness in patients who have suffered head injury or other acute brain damage. The scale is used to describe variations in three clinical features: the patient's eye, motor, and verbal responses. The authors assigned numerical scores to each feature depending on the quality of the response. GCS sum scores (including eye + motor + verbal responses) range from 3 (deep coma) to 15 (full consciousness).

The GCS is used in clinics worldwide by physicians, nurses, and emergency medical technicians; it is also applied widely as a component of many, more complex systems that are used in assessing acute brain damage, such as the Revised Trauma Score, Trauma and Injury Severity Score, and World Federation of Neurosurgical Societies Subarachnoid Hemorrhage Scale.

Unfortunately, there are times when all three clinical features of the GCS cannot be determined. Most commonly, it is the verbal response that cannot be tested. Patients with severe brain injury are often intubated, rendering it impossible to determine a verbal response.

Without data on a patient's verbal response, one cannot calculate an actual GCS sum score. This limits application of the sum score in the clinical setting and as a component in prediction modelling systems.

The Present Study

The authors of the present study first examined the frequency and pattern of missing GCS verbal components in a large cohort of patients (11,989) with traumatic brain injury, whose GCS data had been collected in the IMPACT1 database. Eye and motor component scores were available for all patients, but verbal scores were missing in 11% of the GCS assessments. Verbal scores were most often missing in patients with low eye and motor scores, that is, in patients with severe brain injury, who may have been intubated at the time of testing.

Using GCS data recorded in a larger database of 54,069 patients, the authors determined the distribution of verbal scores for each combination of eye score and motor score. Following this, the authors combined GCS eye and motor scores together into unified eye + motor (EM) scores, and then determined the distribution of verbal scores for each EM score. Based on this distribution, the authors identified a single verbal score that could be imputed for each EM score (see figure).

To determine how effective these imputed verbal scores could be, the authors examined the effect of substituting imputed verbal scores for actual verbal scores within the framework of GCS-PA CT prognostic charts, which the authors developed a couple of years ago.2 These charts take into account the GCS sum score, pupil response, age of the patient, and computed tomography findings of abnormalities. The charts, which provide predictions about patient outcomes, are designed to aid clinical decision-making and communication between clinical teams.

The authors found that the information gained using the simple method of imputing verbal scores according to each EM score was comparable to information based on more complex variations between precise eye and motor scores. The information gained using the simple method was also close to that obtained from full information on verbal, eye, and motor responses.

The authors note that the imputed verbal score does not add new information but does permit the use of prediction and prognostic models, by filling in verbal data to enable those systems to work. In particular, the authors believe that this simple method of adding verbal scores will help clinicians quickly determine the severity of acute brain injury and estimate patient outcomes.

When asked about the article, Dr. Brennan responded, "This paper extends our recent work (the GCS-Pupils score and GCS-PA Charts) refreshing the practical utility of the GCS in providing an index of severity and prognosis across the full spectrum of head injured victims. Our simple, new strategy for imputing missing GCS verbal score will benefit patients with altered consciousness, because clinicians can now easily and confidently determine the GCS sum score when the verbal component is missing, and then use this to calculate disease severity and to predict patient outcome."

Treatments for kidney cancer have improved considerably over the past few decades. In 1988, when Memorial Sloan Kettering oncologist Robert Motzer started researching the disease, the average survival was less than one year. There were no approved therapies at the time besides surgery. By 2005, with the development of targeted drugs such as sunitinib (Sutent®), survival nearly tripled. Today, with the addition of immunotherapy drugs to these regimens, people with kidney cancer are living even longer, and some even seem to be cured.

Despite this clear progress, it remains difficult to predict who will respond to these therapies, and what underlying biological factors influence these responses. To help answer these questions, an international team of investigators led by Dr. Motzer performed an in-depth study of kidney cancer tumors from nearly 900 people who were treated as part of a large, phase III clinical trial.

That trial compared two different treatments: a combination of avelumab (an anti-PD-L1 immunotherapy) and axitinib (a drug targeting tumor blood vessels), versus sunitinib (another blood vessel-targeting drug) given alone. People with advanced renal cell carcinoma who received the combination did better (in terms of the length of time their cancer shrunk or did not get worse) than people who received sunitinib alone. On the basis of these results, the US Food and Drug Administration approved the combination of avelumab (Bavencio®) and axitinib (Inlyta®) to treat kidney cancer in May 2019, establishing a new standard of care for this disease.

While that might seem like crossing the finish line, Dr. Motzer and his colleagues wanted to extract all the useful information they could out of the clinical trial data.

"Oftentimes, when a drug is approved, there's not really an effort on the part of pharmaceutical companies to understand the underlying biology of tumors collected from patients treated on the pivotal trial," Dr. Motzer says. "With this study, which we conducted in partnership with Pfizer, we wanted to take a deep dive into the biology so that we could generate new avenues of research to keep the field moving forward."

The results of this deep dive -- including identification of several novel biomarkers of response -- were reported on September 7 in the journal Nature Medicine.

Beyond PD-1 and TMB

Among the variables the team analyzed were levels of a biomarker called PD-L1 (a common immunotherapy target) and the number of mutations present in the tumor (dubbed tumor mutation burden or TMB). Both these measures have been associated with improved responsiveness and better survival in other cancer types. Somewhat surprisingly, neither measure correlated to a better response to the immunotherapy and targeted therapy combination in this trial.

In addition to these well-known biomarkers, the scientists also looked for patterns of gene activity and specific genetic mutations that correlated with treatment response. Here, they found clear contenders.

In particular, they identified a set of 26 genes whose activity correlated with progression-free survival (PFS) in the combination arm of the trial. They dubbed this the "Renal 101 Immuno signature." They also identified mutations in 11 other genes that were associated with differences in PFS in the combination arm.

Likewise, in the sunitinib-only arm, the investigators found a specific pattern of gene activity that correlated with longer progression-free survival. Because the genes are mostly involved in generating new blood vessels, a process called angiogenesis, they dubbed this the "Renal 101 Angio signature."

By testing for these specific markers in tumors, doctors could potentially personalize treatments for patients based on whether they are more or less likely to respond. The gene signatures and mutations also provide scientists with new avenues of biological research to understand how these genes are contributing to the response.

"My priority right now as a clinical investigator in kidney cancer is to help facilitate this kind of collaborative translational research between clinicians and laboratory scientists so that we can identify why these new combinations are working and maybe develop even better treatments as a result," he says.

If silence is golden, speech is silver - and singing the worst.

Singing doesn't need to be silenced, however, but at the moment the wisest thing is to sing with social distancing in place. The advice comes from aerosol researchers at Lund University in Sweden. They have studied the amount of particles we actually emit when we sing - and by extension - if we contribute to the increased spread of Covid-19 by singing.

"There are many reports about the spreading of Covid-19 in connection with choirs singing. Therefore, different restrictions have been introduced all over the world to make singing safer. So far, however, there has been no scientific investigation of the amount of aerosol particles and larger droplets that we actually exhale when we sing", says Jakob Löndahl, associate professor of Aerosol Technology at Lund University.

Aerosols are small airborne particles. To get a better understanding of the amount of aerosols and virus particles we actually emit when we sing, 12 healthy singers and two people with confirmed Covid-19 took part in a research project. Seven of the participants were professional opera singers.

The study shows that singing - particularly loud and consonant-rich singing - spreads a lot of aerosol particles and droplets into the surrounding air.

"Some droplets are so large that they only move a few decimetres from the mouth before they fall, whereas others are smaller and may continue to hover for minutes. In particular, the enunciation of consonants releases very large droplets and the letters B and P stand out as the biggest aerosol spreaders", says Malin Alsved, doctoral student of Aerosol Technology at Lund University.

During the research experiments at Lund University's Aerosol Laboratory, the singers had to wear clean air suits and enter a specially built chamber supplied with filtered, particle-free air. In the chamber, analysis was conducted of the number and mass of particles emitted by singers during breathing, talking, different types of singing and singing with a face mask.

What they sang was a short and plosive-rich Swedish song, "Bibbis pippi Petter", which was repeated 12 times in two minutes at constant pitch. The same song was also repeated with the consonants removed, leaving only the vowels. During the song tests, aerosols and larger droplets were measured using strong lamps, a high-speed camera and an instrument that can measure very small particles. The louder and more powerful the song, the greater the concentration of aerosols and droplets.

"We also carried out measurements of virus in the air close to two people who sang when they had Covid-19. Their air samples contained no detectable amount of virus, but the viral load can vary in different parts of the airways and between different people. Accordingly, aerosols from a person with Covid-19 may still entail a risk of infection when singing", says Malin Alsved.

Can we still have choral singing, singalongs during concerts, chanting at sporting events and loud talk in bars? The researchers consider that if we have a good understanding of the risks involved when a group of people sing together, we can also sing in a safer way. The song can be sung with social distancing, good hygiene and good ventilation, which reduces the concentration of aerosol particles in the air. Face masks can also make a difference.

"When the singers were wearing a simple face mask this caught most of the aerosols and droplets and the levels were comparable with ordinary speech", says Jakob Löndahl.

"Singing does not need to be silenced, but presently it should be done with appropriate measures to reduce the risk of spreading infection", says Jakob Löndahl.

Below please find summaries of new articles that will be published in the next issue of Annals of Internal Medicine. The summaries are not intended to substitute for the full articles as a source of information. This information is under strict embargo and by taking it into possession, media representatives are committing to the terms of the embargo not only on their own behalf, but also on behalf of the organization they represent.

1. Prophylactic antivirals prevent chronic hepatitis C in patients receiving kidneys from positive donors

Abstract: https://www.acpjournals.org/doi/10.7326/M20-1468

URL goes live when the embargo lifts

Prophylactic treatment with direct-acting antivirals (DAAs) prevented chronic hepatitis C virus (HCV) infection in 10 patients receiving kidneys from HCV positive deceased donors. This approach has potential to help shorten waiting times on the organ waitlist. A brief research report is published in Annals of Internal Medicine.

Kidneys from deceased donors with HCV are increasingly available, yet hundreds are discarded annually because of a limited number of HCV-viremic candidates. An innovative strategy of transplanting kidneys from HCV-positive donors to HCV-negative recipients (HCV D+/R-) by using DAAs has shown early success, but the optimal timing and duration of DAA therapy remain unclear.

In the REHANNA (Renal Transplants in Hepatitis C Negative Recipients With RNA Positive Donors) clinical trial, researchers from Johns Hopkins School of Medicine investigated outcomes with 4-week prophylaxis with the pan-genotypic combination of glecaprevir and pibrentasvir (G/P). Eligible candidates had HCV antibody and RNA negativity, were on the deceased-donor kidney transplant waitlist, and did not have HIV, active hepatitis B virus, or liver disease. Participants received 1 G/P dose before organ perfusion, then 1 dose daily for 4 weeks. HCV RNA was measured on postoperative days 1 and 4; prophylaxis weeks 1, 2, and 4; and post-prophylaxis follow-up weeks 1, 4, 8, and 12. The researchers found that in all 10 cases where a patient received a kidney from an HCV-positive donor, 4-week G/P prophylaxis prevented HCV without treatment-related adverse events or substantial liver enzyme abnormalities.

Media contacts: For an embargoed PDF, please contact Lauren Evans at laevans@acponline.org. To reach the corresponding author, Christine Durand, MD, please contact Michael Newman at mnewma25@jhmi.edu.

2. Rising cost may be a barrier to widespread use of HIV PrEP

Cost of PrEP increased an average of 5% each year between 2014 and 2018

Abstract: https://www.acpjournals.org/doi/10.7326/M20-0786

Editorial: https://www.acpjournals.org/doi/10.7326/M20-5643

URL goes live when the embargo lifts

A retrospective cohort study found that cost may be a key factor in preventing more widespread use of HIV preexposure prophylaxis (PrEP). National expenditures on tenofovir disoproxil fumarate with emtricitabine (TDF-FTC) for PrEP increased nearly 20-fold from $114 million in 2014 to $2.08 billion in 2018. In 2018, 204,270 patients used PrEP, representing only 18 percent of those with an indication for PrEP receiving it. The findings are published in Annals of Internal Medicine.

Although PrEP is highly effective, is recommended by the Centers for Disease Control and Prevention (CDC) and U.S. Preventive Services Task Force (USPSTF), and is a key component of the federal government's Ending the HIV Epidemic plan, only a fraction of persons who could benefit from PrEP receive it.

Researchers from the CDC used data from a large national pharmacy database to estimate out-of-pocket (OOP) and third-party payments for PrEP. They found that the cost increased an average of 5 percent each year between 2014 and 2018 from $1,350 to $1,638 for a month supply. At least $2 billion was spent on PrEP medication costs in the US in 2018, and this accounted for PrEP coverage of 18 percent of persons with an indication for PrEP. Expanding PrEP use is needed to reach the Ending the HIV Epidemic goal of 50 percent of persons with an indication for PrEP using it. According to the study authors, the overall health care cost of PrEP will likely increase as more persons gain access to and continue to use PrEP. Action to lower PrEP costs can prevent coverage denials, eliminate prior authorizations, and increase access.

Media contacts: For an embargoed PDF, please contact Lauren Evans at laevans@acponline.org. To reach the corresponding author, Nathan W. Furukawa, MD, MPH, please contact him directly at nmt6@cdc.gov.

3. New guidelines focus on the diagnosis and management of hereditary hemorrhagic telangiectasia

Abstract: https://www.acpjournals.org/doi/10.7326/M20-1443

URL goes live when the embargo lifts

Hereditary hemorrhagic telangiectasia (HHT) is a rare and underdiagnosed bleeding disorder that affects the blood vessels, and may result in chronic bleeding, acute hemorrhage, and complications from shunting through vascular malformations characteristic of the disease. A diagnosis of HHT allows appropriate screening and preventive treatment to be undertaken in a patient and their affected family members. The Second International Guidelines for the Diagnosis and Management of Hereditary Hemorrhagic Telangiectasia are published in Annals of Internal Medicine.

The goal of the Second International HHT Guidelines process was to develop evidence-informed consensus guidelines regarding the diagnosis of HHT, prevention of HHT-related complications, and treatment of symptomatic disease in areas not previously addressed by guidelines and those where significant new literature had been published. Several other recommendations from the first International HHT Guidelines were not reassessed during this process and remain currently recommended.

The new guidelines cover a broad range of symptoms and make multiple recommendations for addressing each, taking individual patient response into consideration. Symptom areas include epistaxis, gastrointestinal (GI) bleeding, anemia and anticoagulation, and liver vascular malformations. The guidelines also make recommendations regarding pediatric care and pregnancy and delivery. The Guidelines address the use of first-line therapies for chronic bleeding and anemia in HHT and for liver vascular malformations, but also, for the first time, address the role for novel anti-angiogenic therapies in HHT. These Guidelines bring continuity of care through pregnancy, delivery and the pediatric years, with comprehensive recommendations for HHT diagnosis and for screening for lung and brain arteriovenous malformations.

Media contacts: For an embargoed PDF, please contact Lauren Evans at laevans@acponline.org. To reach the corresponding author, Marie E. Faughnan, MD, MSc, please contact her directly at marie.faughnan@unityhealth.to.

4. Researchers identify a novel histiocytosis with synovial and skin involvement

Abstract: https://www.acpjournals.org/doi/10.7326/L20-0092

URL goes live when the embargo lifts

Researchers from San Raffaele Scientific Institute, Milan, Italy describe the case of a novel Langerhans-related histiocytosis whose clinical, histopathologic, and genetic features differ from those of any other histiocytic disorder. Their case is published in Annals of Internal Medicine.

Histiocytoses are rare disorders characterized by tissue infiltration by macrophages, dendritic cells, or monocytederived cells. Different subtypes have been described, which collectively encompass a wide range of clinical manifestations from mild to disseminated or life-threatening forms. Classifications of histiocytoisis include Langerhans-related, cutaneous or mucocutaneous, and malignant histiocytoses; Rosai-Dorfman disease; and hemophagocytic lymphohistiocytosis.

This novel Langerhans-related histiocytosis was identified in a 43-year-old patient with debilitating knee pain and inflammation (synovitis) that did not respond to treatment. Her other joints were involved, as well, and multiple nodular skin lesions were present on her face, trunk, and limbs. Laboratory tests showed elevated C-reactive protein levels and erythrocyte sedimentation rate, mild hypernatremia consistent with diabetes insipidus, and elevated serum levels of proinflammatory cytokines. While this clinical picture differed significantly from typical histiocytosis, the researchers studied the skin lesions and found gene representation suggesting histiocytosis, as well as a novel KRAS mutation in myeloid cells. As such, treatment with cobimetinib resolved her symptoms and she remained symptom-free one year later.

Media contacts: For an embargoed PDF, please contact Lauren Evans at laevans@acponline.org. To reach the corresponding author, Giulio Cavalli, MD, please contact Nicola Quadri at quadri.nicola@hsr.it or Gea Gardini at gardini.gea@hsr.it.

Selecting treatments according to genetic differences could help children and teenagers with asthma, according to research presented at the European Respiratory Society International Congress. [1]

The trial, which compares patients treated according to small genetic differences with patients treated according to existing guidelines, is the first of its kind in children and teenagers.

Researchers say that more work is needed, but their findings hint that children's asthma symptoms could be better controlled with personalised treatments.

The study was presented at the virtual conference by Dr Tom Ruffles, honorary consultant in paediatric respiratory medicine, who worked with the study team led by Professor Somnath Mukhopadhyay, Chair in Paediatrics. Both are at the Royal Alexandra Children's Hospital, Brighton and Sussex Medical School, UK. The trial was conducted and managed by the Tayside Clinical Trials Unit at the University of Dundee, UK.

Dr Ruffles told the conference: "Asthma is a common condition in children that causes coughing, wheezing and difficulty breathing. In the UK, for example, asthma affects one in 11 children and every 18 minutes a child is admitted to hospital because of their asthma.

"We have a number of medicines that are generally effective in treating children with asthma, but they don't work equally well for all children. We think that genetic differences could have an effect on whether these medicines work, and that's what we wanted to examine in this study."

The research involved 241 children aged between 12 and 18 years who were all being treated for asthma by their GPs. The children were randomly assigned either to receive treatment according to existing guidelines, or to receive treatment according to particular genetic differences (their genotype), an approach known as personalised medicine.

Treatment according to genotype meant the children were asked to give a sample of cells scraped from the inside of their cheeks. These samples were tested for different versions of a particular gene, using a test that costs less than €20.

The researchers were testing for a small difference in the gene that contains instructions for making the beta-2 receptor and they were looking for children who had either with one copy of the altered gene or with two copies of the altered gene. The beta-2 receptor is the molecule that is targeted by asthma treatments. Therefore, researchers believe that different versions of the gene for making this receptor can influence how well treatments work.

Previous research suggests that the majority of children with asthma will benefit from standard treatment with an asthma preventer called salmeterol in addition to their regular steroid inhaler. However, around one in seven children have a small genetic difference that means using this medication could actually result in these children having more asthma symptoms.

In this trial, children in the personalised medicine group who had this genetic difference were treated with an alternative asthma medicine called montelukast.

Researchers followed the children for a year to monitor their quality of life, with a score between one and seven according to how their symptoms were, whether their normal activities were limited by their asthma and how their asthma made them feel.

They compared the average score of the group of children who had their medication decided on the basis of their genetics with the average score of children who were treated according to current practice that does not involve any genetic testing, and found only a small improvement of 0.16 with those who received personalised care.

However, when the researchers looked specifically at the children who were found to have two copies of the altered beta-2 receptor gene, they found a greater benefit, with children experiencing an average 0.42 improvement in their quality of life score. The researchers say this would translate to a noticeably better quality of life for the children with two altered gene copies.

Professor Mukhopadhyay said: "These results are very promising because they show, for the first time, that it could be beneficial to test for certain genetic differences in children with asthma and select medication according to those differences.

"In this study, we saw only a modest effect, but this may be partly because the children's asthma was generally very well controlled and only a few children experienced any serious symptoms during the 12-month period. Larger trials, with a focus on those with poorer asthma control, may help us determine the true benefit for children of prescribing in this way."

Professor Chris Brightling, from the University of Leicester, UK, is European Respiratory Society Science Council Chair and was not involved in the research. He said: "This approach of 'personalised care' for both children and adults with asthma is an important goal for respiratory research.

"In this study, researchers used genetic information that we know is linked to how well patients respond to some inhaler treatments. They found that making use of this genetic information improved the outcome for children with asthma."

BOSTON - For many individuals with different types of cancer, immune checkpoint inhibitors can effectively boost their immune system to fight their disease, but not all patients benefit from these medications. Now a team led by investigators at Massachusetts General Hospital (MGH) and Harvard Medical School (HMS) has developed an approach to help identify potential clinical markers that may indicate which patients will respond to immune checkpoint inhibitors and which should be treated with other strategies. The findings are published in the Proceedings of the National Academy of Sciences.

For the study, the scientists developed an approach whereby they implanted breast cancer tumors into mice and then treated the animals with immune checkpoint inhibitors. "We first developed a resection and response bilateral tumor model in which we put one breast tumor in each side of the mouse breast. We then remove one tumor to evaluate the tumor microenvironment and we monitor the response of the other, non-resected, tumor to immune checkpoint blockade, identifying the mouse as a responder or a non-responder," explained lead author Ivy X. Chen, PhD, a former postdoctoral fellow at MGH's E.L. Steele Laboratories for Tumor Biology. Using this model system, the researchers found that the responding tumors contained higher numbers of cancer-killing "cytotoxic" T immune cells and fewer numbers of certain immune suppressor cells early after the start of treatment.

Gene expression analyses of the cytotoxic T cells within the tumors revealed distinct gene signatures distinguishing responders from non-responders--specifically, the presence of T cell activation signals in responding tumors and T cell exhaustion signals in non-responding tumors. "Importantly, we found that these gene signatures for responder and non-responder tumors significantly correlated with responder and non-responder gene signatures derived from patients with melanoma who were treated with immune checkpoint inhibitors, as well as with overall survival in a group of patients with breast cancer," said co-senior author Meromit Singer, PhD, an Assistant Professor in the Department of Data Science at the Dana-Farber Cancer Institute and the Department of Immunology at Harvard Medical School.

The impact of this study may go beyond the identification of novel markers to predict patient response to immune checkpoint inhibitors. "Our study highlights the importance of investigating the dynamic immune modulation of the tumor microenvironment to understand the potential benefit of immunotherapy," said co-senior author Rakesh Jain, PhD, director of the Steele Laboratories at MGH and the A.W. Cook Professor of Radiation Oncology at Harvard Medical School. "We hope to extend our approach to study and discover resistance mechanisms and biomarkers of response to immune checkpoint inhibitors in other tumor types."

Jasmin Teurlings is one of 176 million women worldwide who have endometriosis, a chronic, painful gynaecological condition that affects nearly three times as many women as breast cancer.

The 21-year-old University of South Australia (UniSA) journalism student has lived with the condition for five years after first experiencing symptoms at age 16, but it has taken invasive laparoscopic surgery for an official diagnosis.

Keyhole surgery is the standard option to reliably diagnose the three types of endometriosis (peritoneal, ovarian and deep infiltrating endometriosis), but comes with risks, delays, and sometimes a negative result.

"Undergoing an invasive procedure is stressful, even more so if it proves unnecessary" says University of South Australia researcher Alison Deslandes, who is exploring alternative diagnosis options for women with deep infiltrating endometriosis (DIE), the most severe and challenging type to manage.

"In recent years, transvaginal ultrasound (TVUS) has begun to play a role in the diagnosis of DIE and ovarian endometriosis, but it's typically only offered by specialised gynaecologists," Deslandes says.

The UniSA researcher is investigating the accuracy of TVUS and whether sonographers could perform the procedure in an outpatient facility, making it more accessible to women who are experiencing symptoms of endometriosis.

"In cases of DIE, extensive adhesions of the pelvic organs may not be discovered until the time of surgery, often requiring additional specialist surgeons. TVUS is a low cost and readily available imaging technique which could be used to identify more complex conditions, aiding surgery, as well as diagnosing the condition non-invasively."

In a review of 35 articles, exploring the accuracy of TVUS for deep infiltrating endometriosis, Deslandes says it rates highly as a valuable, accurate diagnosis tool, apart from DIE detection in the bladder, which requires more data.

"We now need to take this a step further to see if sonographers could perform the same procedure as gynaecologists to the same level of accuracy. This would reduce diagnostic delays and give women with DIE a non-invasive yet highly accurate diagnostic test," Deslandes says.

Endometriosis affects approximately 10 per cent of women worldwide and occurs when tissue like that which lines the uterus (endometrial tissue) grows outside of the uterus, forming legions on the ovaries, bowel and pelvis - sometimes spreading to other organs.

It causes severe pain, typically with periods but also with sex, passing urine and bowel movements. It can also cause heavy or dysfunctional menstrual bleeding, a symptom that was the first red flag for Jasmin Teurlings while still in secondary school.

"My mother had previously been diagnosed with endometriosis so recognised the signs and was very quick to act," Jasmin says. "Despite those symptoms and my family history, the first gynaecologist I saw said I was too young to have endometriosis."

It took five more years for Jasmin to agree to laparoscopic surgery, convinced by medical specialists and even her own conflicting doubts that it was "all in her head".

Diagnostic delays are common as the symptoms are often vague and medical professions are reluctant to subject women to surgery unless the signs persevere over a long period, Deslandes says.

"There is no cure for endometriosis so once a woman is diagnosed with it, she has it for life. If left untreated it can lead to fertility problems, and even renal failure in extreme cases.

"Surgery removes the deposits, although some hormone-based medications are prescribed to help stop the disease progressing and to reduce pain. For some women, one surgery will be all that is needed, and their pain will never return. Most women, however, require multiple surgeries and are never entirely free of pain," Deslandes says.

Jasmin falls into the latter group.

"While the laparoscopy hasn't cured my endometriosis, the diagnosis has gone a long way to reaffirming that the symptoms I have are real," she says. "If an alternative diagnostic method can be found that doesn't require invasive surgery, women will no longer have to wait years to be diagnosed and that would make a huge difference," she says.

A video explaining the research can be viewed at: https://youtu.be/d0df5lgwSJU

(Boston) -- Osteoarthritis is the most common form of arthritis worldwide, affecting more than 300 million people. It causes substantial pain, functional limitations, and disability in patients.

The pain experience in patients with knee osteoarthritis changes over time. People initially experience primarily weight-bearing related pain, such as with jogging and stair-climbing. Over time, the pain becomes more persistent and can flare unpredictably.

To better understand why this change in the pain experience occurs, researchers from the Boston University schools of Medicine (BUSM) and Public Health reviewed data from the Multicenter Osteoarthritis Study about the pain experience of 2,794 older adults with or at risk of knee osteoarthritis. They found that people with more pain sensitization were more likely to suffer from constant and unpredictable pain, rather than just intermittent pain. This study has identified for the first time a potential underlying mechanism in the nervous system responsible for why people experience varying pain patterns with knee osteoarthritis.

"Our findings support the clinical relevance of neurobiological mechanisms that affect the pain experience in knee osteoarthritis, including not only the severity of pain, but whether the pain is intermittent or constant, and whether the pain is unpredictable," said senior author Tuhina Neogi, MD, PhD, professor of medicine and epidemiology at Boston University School of Medicine.

By understanding the different mechanisms that contribute to the pain experience of knee osteoarthritis, healthcare providers can begin to personalize pain management to each patient. For example, if a patient has pain sensitization, therapies that can alter those nervous system signaling pathways may be helpful. This would improve the current 'one-size-fits-all' approach, in which each patient is started with the same treatment and then moved on to something else if the first approach did not work.

"By understanding these mechanisms, determining ways to identify those mechanisms in the clinic, and developing treatments to target those mechanisms, we can provide better management options to the millions of people worldwide with osteoarthritis," said Dr. Neogi.

The higher the severity of an infection is thought to be, the greater the motivation is to socially distance. That is one result of a study conducted by the psychologist Professor Kai Kaspar at the University of Cologne. Kaspar explored which factors constitute people's motivation to socially distance and to use different corona apps. The results have been published in the Journal of Medical Internet Research under the title 'Motivations for Social Distancing and App Use as Complementary Measures to Combat the COVID-19 Pandemic: Quantitative Survey Study'.

Current government measures to contain the corona pandemic include social distancing and the recommendation to use corona apps. However, these measures are not supported by all citizens equally. Professor Kaspar wanted to find out why that is so. His study showed that the higher people gauged the severity of their own potential infection to be, the greater their motivation to socially distance was.

Perceived rewards for non-compliance with the rules of social distancing also play a role, such as the perceived pleasure of close personal encounters: If such rewards are perceived, this endangers appropriate distancing behaviour. If people are convinced that they can maintain an appropriate distance to others and that this measure will actually help to prevent infections, people's motivation to follow social distancing rules is higher.

Social behaviour is also important: 'Participants in the study reported higher motivation to maintain physical distance when their trust in the motivation of their fellow human beings to maintain distance was high. Solidarity in the fight against the current pandemic therefore seems very important', Professor Kaspar explained.

The psychologist analysed not only social distancing, but also people's motivation to voluntarily use two corona apps: one app for contact tracing - in the sense of the corona warning app - and the corona data donation app of the Robert Koch Institute, the leading government institution in the field of infectious diseases, which safeguards public health in Germany. With the corona warning app, users can track contacts with possibly infected persons and inform others about their own infection status. With the corona data donation app, which analyses data from smartwatches and fitness bracelets, people can provide the Robert Koch Institute with their health and activity data.

Regarding the use of corona apps, the study found that people's motivation to use a corona warning app was higher than their motivation to use the corona data donation app. 'Although both apps do not actively protect against infection, an app with contact tracing at least allows you to check critical contacts you had with infected people. On the other hand, individual users do not benefit directly from the corona data donation app because this app aims to analyse the spread of the corona virus on a large scale', Kaspar said.

People's willingness to use corona apps is closely related to their motivation to socially distance. Motivation to use a corona warning app was higher, the more effective people regarded themselves in social distancing, the more they assessed social distancing as an effective measure, and the higher the perceived response costs associated with social distancing were. 'These factors are not directly related to the use of apps, but rather to social distancing. However, this shows that the acceptance of different measures to combat the pandemic is partly related to identical personal appraisal processes', Kaspar said.

The study also made clear that users' trust in the confidential handling of their personal data is very important. 'The greater the trust in official app providers and the lower the concern that the data provided could be misused, the higher was the reported motivation to use both a corona warning app and a corona data donation app. This relationship also applies to people's willingness to provide their infection status to a corona warning app', he emphasized.

The new paper reports the findings of two open-label, non-randomised phase 1/2 trials looking at a frozen formulation and a freeze-dried formulation of a two-part vaccine. The two-part vaccine included two adenovirus vectors - recombinant human adenovirus type 26 (rAd26-S) and recombinant human adenovirus type 5 (rAd5-S)

In the phase 1 part of each trial, the individual components of the two-part vaccine (rAd26-S and rAd5-S) were tested for safety. The phase 2 study then tested whether the vaccine elicited an immune response by giving the full two-part vaccine - rAd26-S was given first, then rAd5-S was given 21 days later

The two 42-day trials - including 38 healthy adults each - did not find any serious adverse effects among participants, and confirmed that the vaccine candidates elicit an antibody response

Large, long-term trials including a placebo comparison, and further monitoring are needed to establish the long-term safety and effectiveness of the vaccine for preventing COVID-19 infection

Results from two early-phase Russian non-randomised vaccine trials (Sputnik V) in a total of 76 people are published today in The Lancet, finding that two formulations of a two-part vaccine have a good safety profile with no serious adverse events detected over 42 days, and induce antibody responses in all participants within 21 days.

Secondary outcomes (planned outcome measures that are not as important as the primary outcome measure, but are still of interest in evaluating the effect of an intervention [1]) from the trial also suggest the vaccines also produce a T cell response within 28 days.

The new paper reports the findings from two small phase 1/2 trials lasting 42 days - one studying a frozen formulation of the vaccine, and another involving a lyophilised (freeze-dried) formulation of the vaccine. The frozen formulation is envisaged for large-scale use using existing global supply chains for vaccines, while the freeze-dried formulation was developed for hard-to-reach regions as it is more stable and can be stored at 2-8 degrees centigrade.

The two-part vaccine includes two adenovirus vectors - recombinant human adenovirus type 26 (rAd26-S) and recombinant human adenovirus type 5 (rAd5-S) - which have been modified to express the SARS-CoV-2 spike protein. The adenoviruses are also weakened so that they cannot replicate in human cells and cannot cause disease (adenovirus usually causes the common cold).

These types of recombinant adenovirus vectors have been used for a long time, with safety confirmed in many clinical studies. Currently, several candidate COVID-19 vaccines using these vectors and targeting the SARS-CoV-2 spike protein have been tested in clinical trials [2]. These vaccines aim to stimulate both arms of the immune system - antibody and T cell responses - so they attack the virus when it is circulating in the body, and attack cells infected by SARS-CoV-2 [3].

Explaining why they are using two different adenovirus vectors, lead author Dr Denis Logunov, N F Gamaleya National Research Centre for Epidemiology and Microbiology, Russia, says: "When adenovirus vaccines enter people's cells, they deliver the SARS-CoV-2 spike protein genetic code, which causes cells to produce the spike protein. This helps teach the immune system to recognise and attack the SARS-CoV-2 virus. To form a powerful immune response against SARS-CoV-2, it is important that a booster vaccination is provided. However, booster vaccinations that use the same adenovirus vector might not produce an effective response, because the immune system may recognise and attack the vector. This would block the vaccine from entering people's cells and teaching the body to recognise and attack SARS-CoV-2. For our vaccine, we use two different adenovirus vectors in a bid to avoid the immune system becoming immune to the vector." [4]

The trials took place in two hospitals in Russia. The trials were open-label and non-randomised, meaning that participants knew that they were receiving the vaccine and were not assigned by chance to different treatment groups.

The trials involved healthy adults aged 18-60 years, who self-isolated as soon as they were registered for the trial and remained in hospital for the first 28 days of the trial (from when they were first vaccinated).

The frozen vaccine (Gam-COVID-Vac) was trialled in a branch of Burdenko Hospital, an agency of the Ministry of Defence, and involved both civilian and military volunteers. The freeze-dried vaccine (Gam-COVID-Vac-Lyo) took place at Sechenov University and all volunteers were civilians. All participants provided written informed consent.

In the phase 1 of each trial, participants received one component of the two-part vaccine on day 0 (four groups of nine participants were given the frozen or freeze-dried rAd26-S or rAd5-S component - see Figure 1). In the phase 2, which began no earlier than five days after the phase 1 trial began, participants received the full two-part vaccine (they received a prime vaccination with the rAd26-S component on day 0, followed by a booster vaccination with rAd5-S component on day 21. There were 20 participants each in the frozen and freeze-dried vaccine groups).
The trial was designed to study the number of adverse events of the vaccines (safety), and the antibody response elicited by the vaccines (immunogenicity). Secondary outcome measures of the trials [1] included the neutralising antibody response and the T cell response elicited. To compare post-vaccination immunity with natural immunity formed by infection with SARS-CoV-2, the authors obtained convalescent plasma from 4,817 people who had recovered from mild or moderate COVID-19.

Both vaccine formulations were safe over the 42-day study period and well tolerated. The most common adverse events were pain at injection site (44/76 participants - 58%), hyperthermia (high temperature - 38/76 - 50%), headache (32/76 - 42%), asthenia (weakness or lack of energy - 21/76 - 28%), and muscle and joint pain (18/76 - 24%). Most adverse events were mild, and no serious adverse events were detected within 42 days of vaccination. The authors note that these adverse effects are characteristic of those seen with other vaccines, particularly those based on recombinant viral vectors.

All participants in the phase 2 trials (40 participants) produced antibodies against the SARS-CoV-2 spike protein - with levels of antibody against the SARS-CoV-2 spike protein (geometric mean titres of SARS-CoV-2 receptor binding domain-specific IgG) at 14,703 for the frozen formulation, and at 11,143 for the freeze-dried formulation on day 42 of the trial.

In addition, neutralising antibody responses occurred in all 40 participants in the phase 2 trials by day 42 (geometric mean titre levels of 49.25 with the frozen formulation and 45.95 with the freeze-dried formulation at day 42), whereas neutralising antibody responses were only found in 61% of participants in the phase 1 study who only received rAd26-S (combined data for both the lyophilised and frozen vaccine formulations).

Comparing the antibody responses from the vaccination and from infection (using the convalescent plasma samples), the authors say that the antibody responses from vaccination appear to be higher in people vaccinated. Vaccination also elicited the same level of SARS-CoV-2 neutralising antibodies as in people who had recovered from COVID-19.

T cell responses occurred in all participants in the phase 2 trials within 28 days of vaccination - including formation of T-helper (CD4) cells and T-killer (CD8) cells. The number of T-helper cells increased by 2.5% and the number of T-killer cells increased by 1.3% after vaccination with the frozen formulation, and by 1.3% and 1.1%, respectively, after vaccination with the freeze-dried formulation.

The authors say that despite there being neutralising antibody responses against the adenovirus vectors, the antibody response to the SARS-CoV-2 spike protein was not affected. In addition, the neutralising antibodies against rAd26 did not interfere with rAd5, or vice versa. They say that this suggests that using different adenovirus vectors is an effective approach to elicit a robust immune response and to overcome the immune reaction to the first viral vector, but note that more research will be needed to confirm this.

The authors note some limitations to their study, including that it had a short follow-up (42 days), it was a small study, some parts of the phase 1 trials included only male volunteers, and there was no placebo or control vaccine. In addition, they note that despite planning to recruit healthy volunteers aged 18-60 years, in general, their study included fairly young volunteers (in their 20s and 30s, on average).

They say that more research is needed to evaluate the vaccine in different populations, including older age groups, individuals with underlying medical conditions, and people in at-risk groups.

Explaining the next steps of their research, Professor Alexander Gintsburg, N F Gamaleya National Research Centre for Epidemiology and Microbiology, Russia, says: "Unprecedented measures have been taken to develop a COVID-19 vaccine in Russia. Preclinical and clinical studies have been done, which has made it possible to provisionally approve the vaccine under the current Decree of the Government of the Russian Federation of April 3, 2020 no 441. This provisional licensure requires a large-scale study, allows vaccination in a consented general population in the context of a phase 3 trial, allows the vaccine to be brought into use in a population under strict pharmacovigilance, and to provide vaccination of risk groups." [4]

"The phase 3 clinical trial of our vaccine was approved on 26 August 2020. It is planned to include 40,000 volunteers from different age and risk groups, and will be undertaken with constant monitoring of volunteers through an online application." [4]

Writing in a linked Comment, lead author Dr Naor Bar-Zeev, International Vaccine Access Center, Johns Hopkins Bloomberg School of Public Health, USA (who was not involved in the study), says: "Similar to these studies before it, Logunov and colleagues' studies are encouraging but small. The immunogenicity bodes well, although nothing can be inferred on immunogenicity in older age groups, and clinical efficacy for any COVID-19 vaccine has not yet been shown... Showing safety will be crucial with COVID-19 vaccines, not only for vaccine acceptance but also for trust in vaccination broadly. Safety outcomes up to now are reassuring, but studies to date are too small to address less common or rare serious adverse events. Unlike clinical trials of therapeutics, in which safety is balanced against benefit in patients, vaccine trials have to balance safety against infection risk, not against disease outcome. Since vaccines are given to healthy people and, during the COVID-19 pandemic, potentially to everyone after approval following phase 3 trials, safety is paramount..."

"Licensure in most settings should depend on proven short-term and long-term efficacy against disease (not just immunogenicity) and more complete safety data... Safety assurance will then require further large-scale surveillance after licensure. Such surveillance is not well established in many settings, and rapid efforts need to be made by governments, regulators, and global research funders to get those systems in place. Surveillance will also be vital for showing transmission reduction, which is to come from phase 3 trials since these are powered to detect COVID-19 disease outcomes and not asymptomatic SARS-CoV-2 infection..."

"To be sure, most past vaccines were designed to target disease and not infection as such, but with COVID-19, the general public could be expecting striking reductions in disease transmission after widespread vaccine introduction. Such effects would be very welcome if they occur, but they are far from certain. A vaccine that reduces disease but does not prevent infection might paradoxically make things worse. It could falsely reassure recipients of personal invulnerability, thus reducing transmission mitigating behaviours. In turn, this could lead to increased exposure among older adults in whom efficacy is likely to be lower, or among other higher-risk groups who might have lower vaccine acceptance and uptake..."

"In view of the ongoing painful toll of the COVID-19 pandemic and its magnitude, the more vaccine candidates that have successful early results the better. Ultimately, all vaccine candidates will need to show safety and prove durable clinical efficacy (including in groups at greater risk) in large randomised trials before they can be put into widespread use. Equitable access will require multiple vaccine producers and providers in a range of settings. Each of their successes will together lead us towards our collective, longed for, new day."

The new paper reports the findings of two open-label, non-randomised phase 1/2 trials looking at a frozen formulation and a freeze-dried formulation of a two-part vaccine. The two-part vaccine included two adenovirus vectors - recombinant human adenovirus type 26 (rAd26-S) and recombinant human adenovirus type 5 (rAd5-S)

In the phase 1 part of each trial, the individual components of the two-part vaccine (rAd26-S and rAd5-S) were tested for safety. The phase 2 study then tested whether the vaccine elicited an immune response by giving the full two-part vaccine - rAd26-S was given first, then rAd5-S was given 21 days later

The two 42-day trials - including 38 healthy adults each - did not find any serious adverse effects among participants, and confirmed that the vaccine candidates elicit an antibody response

Large, long-term trials including a placebo comparison, and further monitoring are needed to establish the long-term safety and effectiveness of the vaccine for preventing COVID-19 infection

Results from two early-phase Russian non-randomised vaccine trials (Sputnik V) in a total of 76 people are published today in The Lancet, finding that two formulations of a two-part vaccine have a good safety profile with no serious adverse events detected over 42 days, and induce antibody responses in all participants within 21 days.

Secondary outcomes (planned outcome measures that are not as important as the primary outcome measure, but are still of interest in evaluating the effect of an intervention [1]) from the trial also suggest the vaccines also produce a T cell response within 28 days.

The new paper reports the findings from two small phase 1/2 trials lasting 42 days - one studying a frozen formulation of the vaccine, and another involving a lyophilised (freeze-dried) formulation of the vaccine. The frozen formulation is envisaged for large-scale use using existing global supply chains for vaccines, while the freeze-dried formulation was developed for hard-to-reach regions as it is more stable and can be stored at 2-8 degrees centigrade.

The two-part vaccine includes two adenovirus vectors - recombinant human adenovirus type 26 (rAd26-S) and recombinant human adenovirus type 5 (rAd5-S) - which have been modified to express the SARS-CoV-2 spike protein. The adenoviruses are also weakened so that they cannot replicate in human cells and cannot cause disease (adenovirus usually causes the common cold).

These types of recombinant adenovirus vectors have been used for a long time, with safety confirmed in many clinical studies. Currently, several candidate COVID-19 vaccines using these vectors and targeting the SARS-CoV-2 spike protein have been tested in clinical trials [2]. These vaccines aim to stimulate both arms of the immune system - antibody and T cell responses - so they attack the virus when it is circulating in the body, and attack cells infected by SARS-CoV-2 [3].

Explaining why they are using two different adenovirus vectors, lead author Dr Denis Logunov, N F Gamaleya National Research Centre for Epidemiology and Microbiology, Russia, says: "When adenovirus vaccines enter people's cells, they deliver the SARS-CoV-2 spike protein genetic code, which causes cells to produce the spike protein. This helps teach the immune system to recognise and attack the SARS-CoV-2 virus. To form a powerful immune response against SARS-CoV-2, it is important that a booster vaccination is provided. However, booster vaccinations that use the same adenovirus vector might not produce an effective response, because the immune system may recognise and attack the vector. This would block the vaccine from entering people's cells and teaching the body to recognise and attack SARS-CoV-2. For our vaccine, we use two different adenovirus vectors in a bid to avoid the immune system becoming immune to the vector." [4]

The trials took place in two hospitals in Russia. The trials were open-label and non-randomised, meaning that participants knew that they were receiving the vaccine and were not assigned by chance to different treatment groups.

The trials involved healthy adults aged 18-60 years, who self-isolated as soon as they were registered for the trial and remained in hospital for the first 28 days of the trial (from when they were first vaccinated).

The frozen vaccine (Gam-COVID-Vac) was trialled in a branch of Burdenko Hospital, an agency of the Ministry of Defence, and involved both civilian and military volunteers. The freeze-dried vaccine (Gam-COVID-Vac-Lyo) took place at Sechenov University and all volunteers were civilians. All participants provided written informed consent.

In the phase 1 of each trial, participants received one component of the two-part vaccine on day 0 (four groups of nine participants were given the frozen or freeze-dried rAd26-S or rAd5-S component - see Figure 1). In the phase 2, which began no earlier than five days after the phase 1 trial began, participants received the full two-part vaccine (they received a prime vaccination with the rAd26-S component on day 0, followed by a booster vaccination with rAd5-S component on day 21. There were 20 participants each in the frozen and freeze-dried vaccine groups).

The trial was designed to study the number of adverse events of the vaccines (safety), and the antibody response elicited by the vaccines (immunogenicity). Secondary outcome measures of the trials [1] included the neutralising antibody response and the T cell response elicited. To compare post-vaccination immunity with natural immunity formed by infection with SARS-CoV-2, the authors obtained convalescent plasma from 4,817 people who had recovered from mild or moderate COVID-19.

Both vaccine formulations were safe over the 42-day study period and well tolerated. The most common adverse events were pain at injection site (44/76 participants - 58%), hyperthermia (high temperature - 38/76 - 50%), headache (32/76 - 42%), asthenia (weakness or lack of energy - 21/76 - 28%), and muscle and joint pain (18/76 - 24%). Most adverse events were mild, and no serious adverse events were detected within 42 days of vaccination. The authors note that these adverse effects are characteristic of those seen with other vaccines, particularly those based on recombinant viral vectors.

All participants in the phase 2 trials (40 participants) produced antibodies against the SARS-CoV-2 spike protein - with levels of antibody against the SARS-CoV-2 spike protein (geometric mean titres of SARS-CoV-2 receptor binding domain-specific IgG) at 14,703 for the frozen formulation, and at 11,143 for the freeze-dried formulation on day 42 of the trial.

In addition, neutralising antibody responses occurred in all 40 participants in the phase 2 trials by day 42 (geometric mean titre levels of 49.25 with the frozen formulation and 45.95 with the freeze-dried formulation at day 42), whereas neutralising antibody responses were only found in 61% of participants in the phase 1 study who only received rAd26-S (combined data for both the lyophilised and frozen vaccine formulations).

Comparing the antibody responses from the vaccination and from infection (using the convalescent plasma samples), the authors say that the antibody responses from vaccination appear to be higher in people vaccinated. Vaccination also elicited the same level of SARS-CoV-2 neutralising antibodies as in people who had recovered from COVID-19.

T cell responses occurred in all participants in the phase 2 trials within 28 days of vaccination - including formation of T-helper (CD4) cells and T-killer (CD8) cells. The number of T-helper cells increased by 2.5% and the number of T-killer cells increased by 1.3% after vaccination with the frozen formulation, and by 1.3% and 1.1%, respectively, after vaccination with the freeze-dried formulation.

The authors say that despite there being neutralising antibody responses against the adenovirus vectors, the antibody response to the SARS-CoV-2 spike protein was not affected. In addition, the neutralising antibodies against rAd26 did not interfere with rAd5, or vice versa. They say that this suggests that using different adenovirus vectors is an effective approach to elicit a robust immune response and to overcome the immune reaction to the first viral vector, but note that more research will be needed to confirm this.

The authors note some limitations to their study, including that it had a short follow-up (42 days), it was a small study, some parts of the phase 1 trials included only male volunteers, and there was no placebo or control vaccine. In addition, they note that despite planning to recruit healthy volunteers aged 18-60 years, in general, their study included fairly young volunteers (in their 20s and 30s, on average).

They say that more research is needed to evaluate the vaccine in different populations, including older age groups, individuals with underlying medical conditions, and people in at-risk groups.

Explaining the next steps of their research, Professor Alexander Gintsburg, N F Gamaleya National Research Centre for Epidemiology and Microbiology, Russia, says: "Unprecedented measures have been taken to develop a COVID-19 vaccine in Russia. Preclinical and clinical studies have been done, which has made it possible to provisionally approve the vaccine under the current Decree of the Government of the Russian Federation of April 3, 2020 no 441. This provisional licensure requires a large-scale study, allows vaccination in a consented general population in the context of a phase 3 trial, allows the vaccine to be brought into use in a population under strict pharmacovigilance, and to provide vaccination of risk groups." [4]

"The phase 3 clinical trial of our vaccine was approved on 26 August 2020. It is planned to include 40,000 volunteers from different age and risk groups, and will be undertaken with constant monitoring of volunteers through an online application." [4]

Writing in a linked Comment, lead author Dr Naor Bar-Zeev, International Vaccine Access Center, Johns Hopkins Bloomberg School of Public Health, USA (who was not involved in the study), says: "Similar to these studies before it, Logunov and colleagues' studies are encouraging but small. The immunogenicity bodes well, although nothing can be inferred on immunogenicity in older age groups, and clinical efficacy for any COVID-19 vaccine has not yet been shown... Showing safety will be crucial with COVID-19 vaccines, not only for vaccine acceptance but also for trust in vaccination broadly. Safety outcomes up to now are reassuring, but studies to date are too small to address less common or rare serious adverse events. Unlike clinical trials of therapeutics, in which safety is balanced against benefit in patients, vaccine trials have to balance safety against infection risk, not against disease outcome. Since vaccines are given to healthy people and, during the COVID-19 pandemic, potentially to everyone after approval following phase 3 trials, safety is paramount..."

"Licensure in most settings should depend on proven short-term and long-term efficacy against disease (not just immunogenicity) and more complete safety data... Safety assurance will then require further large-scale surveillance after licensure. Such surveillance is not well established in many settings, and rapid efforts need to be made by governments, regulators, and global research funders to get those systems in place. Surveillance will also be vital for showing transmission reduction, which is to come from phase 3 trials since these are powered to detect COVID-19 disease outcomes and not asymptomatic SARS-CoV-2 infection..."

"To be sure, most past vaccines were designed to target disease and not infection as such, but with COVID-19, the general public could be expecting striking reductions in disease transmission after widespread vaccine introduction. Such effects would be very welcome if they occur, but they are far from certain. A vaccine that reduces disease but does not prevent infection might paradoxically make things worse. It could falsely reassure recipients of personal invulnerability, thus reducing transmission mitigating behaviours. In turn, this could lead to increased exposure among older adults in whom efficacy is likely to be lower, or among other higher-risk groups who might have lower vaccine acceptance and uptake..."

"In view of the ongoing painful toll of the COVID-19 pandemic and its magnitude, the more vaccine candidates that have successful early results the better. Ultimately, all vaccine candidates will need to show safety and prove durable clinical efficacy (including in groups at greater risk) in large randomised trials before they can be put into widespread use. Equitable access will require multiple vaccine producers and providers in a range of settings. Each of their successes will together lead us towards our collective, longed for, new day."