Hepatitis A
Vaccination Required for Herd Immunity in People Experiencing Homelessness or
Who Use Drugs
In the U.S., hepatitis A outbreaks are repeatedly affecting people
experiencing homelessness or who use drugs. A 2017-19 Kentucky outbreak
primarily among these groups resulted in 501 cases, six deaths. Vaccination
efforts likely averted 30 hospitalizations and $490K in costs, but UC San Diego
and Oxford researchers say more could have been saved if initiated earlier and
faster. They determined herd immunity in these populations requires 77 percent
vaccinated, underscoring need for outreach.
The study,
published
October 18, 2021 in Vaccine, was led
by Natasha Martin, DPhil, professor at UC San Diego School of Medicine, and
Emmanuelle Dankwa and Christl Donnelly, CBE FMedSci FRS, at University of
Oxford.
Pictured: A UC San Diego Health
employee is vaccinated against hepatitis A during an outbreak in San Diego,
Calif. in 2017. Credit: Erik Jepson/UC San Diego Publications
Study of highly vaccinated health workers found more contagious delta variant, combined with masking mandate end, was associated with increased breakthrough cases, paralleling exponential rise of COVID-19 infections in San Diego community
In a letter to The New England Journal of Medicine, publishing online September 1, 2021, an interdisciplinary team of physicians and public health experts at University of California San Diego measured the effectiveness of COVID-19 mRNA vaccines among health workers at UC San Diego Health, most notably during the emergence of the highly transmissible delta virus variant and coincident with the end of the state’s mask mandate, allowing fully vaccinated persons to forgo face coverings in most places.
The letter’s authors report that the effectiveness of both the Pfizer and Moderna mRNA COVID-19 vaccines significantly waned over time. Both vaccines were granted emergency use authorization by the Food and Drug Administration in December 2020, with vaccinations of the UC San Diego Health work force beginning the same month for health care workers with direct, patient-facing duties.
In the letter, the authors note that from March through June 2021 vaccine effectiveness against symptomatic infection was estimated to exceed 90 percent; by July, however, it had fallen to approximately 65 percent.
“The decline in effectiveness is not entirely surprising,” said co-senior author Francesca Torriani, MD, professor of clinical medicine in the Division of Infectious Diseases and Global Public Health in the UC San Diego School of Medicine and program director of Infection Prevention and Clinical Epidemiology at UC San Diego Health.
“Clinical trial data suggested decreased effectiveness would occur several months after full vaccination, but our findings indicate that confronted by the delta variant, vaccine effectiveness for mildly symptomatic disease was considerably lower and waned six to eight months after completing vaccination.”
UC San Diego Health, with a work force of approximately 19,000, operates a robust SARS-CoV-2 testing program. If an employee reports even one mild symptom of COVID-19 during daily screening or an identified exposure, a test is triggered.
Then and now, UC San Diego Health has maintained rigorous, mandatory masking and transmission mitigation measures throughout its hospitals and clinical facilities. Diagnosed positive cases among health workers have universally been identified as community acquired.
In December 2020, workers at UC San Diego Health, like the population overall, began experiencing a surge of SARS-CoV-2 infections, the virus that causes COVID-19.
The situation improved significantly after UC San Diego Health began to inoculate employees using the Pfizer and Moderna vaccines. By March 2021, 76 percent of workers were fully vaccinated, rising to 83 percent by July 2021.
Concomitant with increased vaccination coverage was a decline between March and June in the number of workers reporting at least one symptom of COVID-19 and a positive PCR test. That number declined to fewer than 30 employees per month.
In July 2021, however, cases among this highly vaccinated population began to rise again, coincident with the emerging dominance of the delta variant in San Diego and the ending of California’s masking mandate on June 15. By July, 125 workers had been diagnosed with SARS-CoV-2 and unlike in previous months when approximately 20 percent of these cases involved vaccinated workers, the percentage had risen to 75 percent.
Notably, the vaccines still provide significant protection from severe infection outcomes, such as hospitalization and death. Among the UC San Diego Health employee cases documented, no hospitalizations were reported in vaccinated individuals and only one among unvaccinated persons.
“Unlike what was experienced with other variants, with the delta variant parents are frequently getting infected by their young children, ages 5 to 11,” said co-first author Lucy Horton, MD, MPH, an assistant professor of medicine in the Division of Infectious Diseases and director of the UC San Diego Health COVID-19 case investigation and contact tracing team. “Unvaccinated people are seven times more likely to test positive for COVID-19 than those who are fully vaccinated. More importantly, while children rarely need medical attention, unvaccinated adults are 32 times more likely to require hospitalization compared to those who are fully vaccinated.”
Vaccine effectiveness was linked to the passage of time. For workers diagnosed in July, those who became fully vaccinated in January and February had higher infection rates than those vaccinated later in March through May. The infection rate among unvaccinated persons has remained consistently higher than for any vaccinated group, although the difference in rates between the two groups has decreased over time.
“The dramatic change in vaccine effectiveness from June to July is likely due to a combination of factors,” said co-author Nancy Binkin, MD, MPH, professor of epidemiology in the UC San Diego School of Medicine and Herbert Wertheim School of Public Health and Human Longevity Science. “It’s the emergence of the delta variant and waning immunity over time, compounded by the end of broad masking requirements and the resulting greater exposure risk throughout the community.”
Co-senior author Shira Abeles, MD, an assistant professor of medicine in the Division of Infectious Diseases who has led the COVID-19 vaccination effort at UC San Diego Health, said the findings underscore the importance of rapidly reinstating key interventions, such as indoor masking and intensive testing strategies, plus continuing efforts to boost vaccination rates.
“Similar findings are being reported in other settings in the U.S. and internationally, and it is likely that booster doses will be necessary.”
Lab studies reveal protein HSP27’s role in blood vessel leakage, opening the possibility that therapeutically dialing its activity up or down might stabilize patients with sepsis
Sepsis occurs when the body works so hard to fight an infection that the over-activated immune system harms a patient’s own tissues as collateral damage. As a result, blood vessels can become leaky and major organs can’t get the oxygen and nutrients they require to sustain life. Sepsis is a major reason that patients, including many with COVID-19, end up in the intensive care unit. The condition is notoriously difficult to treat, and there are no drugs that help stabilize the cell barrier that lines blood vessels.
University of California San Diego School of Medicine researchers are working to better understand how the body controls blood vessel permeability, and how they might intervene to restore blood vessel integrity during sepsis, trauma or other conditions.
The team recently discovered that a protein called HSP27 plays a role in regulating blood vessel leakage. To help breakdown or buildup blood vessel barrier, cells add and remove chemical tags on HSP27.
The study, publishing August 31, 2021 in Science Signaling, provides new potential targets for the development of drugs that shore up blood vessel barriers, preventing fluid loss.
“This new information will help us home in on the root cause of leaky blood vessels, rather than taking a broad strokes approach that may have many off-target effects,” said senior author JoAnn Trejo, PhD, professor of pharmacology and assistant vice chancellor of the Office of Health Sciences Faculty Affairs at UC San Diego School of Medicine.
Pictured above: This image, taken by confocal microscopy, shows a blood vessel. The protein actin, which helps make up the skeleton of a cell, is labeled in green. Thrombin, a pro-inflammatory mediator, causes gaps between blood vessel barrier cells. When the immune system is over-activated, as occurs in sepsis, blood vessels can become leaky and major organs can’t get the oxygen and nutrients they require to sustain life.
Blood vessel barriers need to be dynamic — permeable enough to allow immune cells to squeeze out to reach the site of an infection, for example, but not so leaky that the situation becomes life-threatening. According to Trejo, HSP27 binds to proteins that help form the cell’s “skeleton.” She and colleagues suspect that’s why HSP27 can affect blood vessel permeability — by fortifying the skeleton of cells that maintain the barrier.
Trejo has long studied G-protein-coupled receptors (GPCRs), proteins that are embedded in cell membranes throughout the body, where they act as signal transducers, allowing cells to respond to their external environments. GPCRs play a crucial role in most biological functions. Approximately one-third of all therapeutic drugs on the market work because they influence GPCR signals.
In their latest study, the team found that during inflammation, GPCRs tell enzymes called kinases to add chemical (phosphate) tags to HSP27. The tags perturb HSP27’s structure in a way that disrupts blood vessel barriers. When HSP27 reassembles, the barriers recover. The researchers validated their lab studies in mice, where they found that inhibiting HSP27 increases blood vessel leakage.
Cancer immunotherapy doesn’t directly target tumors. Instead, these treatments activate or train the immune system to recognize and attack cancer cells. Checkpoint inhibitors are a type of immunotherapy in which antibodies interfere with cancer cells’ ability to evade immune system attack. These therapeutics are now used to treat many tumors, including melanoma and head and neck cancers.
However, like many medications, checkpoint inhibitors can cause some rare but dangerous side effects. To better understand these effects, University of California San Diego researchers looked at the FDA’s Adverse Effect Reporting System (FAERS) — a database of more than 16 million reports of adverse effects while taking a medication — to compare outcomes of patients receiving different checkpoint inhibitors, and some combinations, and their instances of serious heart-related side effects.
In the study, published August 30, 2021 in Scientific Reports, the team confirmed a link between checkpoint inhibitor medications and myocarditis, inflammation of the heart muscle, a potential life-threatening complication. Myocarditis occurred in 0.25 to 2.48 percent of patients receiving checkpoint inhibitors alone or in combination.
The study was led by Ruben Abagyan, PhD, professor in the Skaggs School of Pharmacy and Pharmaceutical Sciences at UC San Diego and team, including Tigran Makunts, PharmD, Ila M. Saunders, PharmD, and Sandip Patel, MD. The concept and question stemmed from Makunts’ rotation as a pharmacy student in Saunders’ clinical practice at Moores Cancer Center at UC San Diego Health.
What might this mean for patients and their health care providers? Abagyan says the risk of myocarditis associated with checkpoint inhibitors is real, but it is not uniform — some combination therapies are more likely to result in life-threatening complications than others. In addition, the cardiac complications associated with checkpoint inhibitors may develop many months after the patient has stopped receiving the treatment, and doesn’t necessarily depend on how long they underwent the treatment.
The study does not reveal the absolute frequency of myocarditis for all people receiving checkpoint inhibitor therapy, since reporting in the FAERS is voluntary, “but the optimal treatment regimen for cancer patients with heart disease should at least take our observations into account,” Abagyan said.
According to Patel, checkpoint inhibitors have transformed cancer immunotherapy, often providing durable remission, even for patients with metastatic disease.
“Immune myocarditis often presents with chest pain, shortness of breath and fatigue — timely intervention and consultation with cardiology colleagues can be life-saving and ensure patients receive the full benefit of cancer immunotherapy,” said Patel, associate professor and medical oncologist at UC San Diego Health.
— Heather Buschman, PhD
Pictured above: Myocarditis, inflammation of heart muscle, as viewed under a microscope. The purple circles are immune cells that have infiltrated the tissue. Image credit: Mikael Häggström, MD
Immune checkpoints are signaling molecules designed to prevent an overly strong immune response to health threats, one that would destroy healthy cells too. Immune checkpoint inhibitors (ICIs) are a class of immunotherapy drugs designed to block the checkpoint proteins from binding to target proteins, preventing the “off” signal so that the immune response can continue unabated.
ICI-based immunotherapy has been approved for a variety of cancers, including breast, bladder, liver, lung, stomach, skin and head and neck. One type of malignancy, however, has proved resistant to the approach: pancreatic cancer.
In a paper published August 10, 2021 in the journal JCI Insight, a research team at UC San Diego Moores Cancer Center, led by first author Gregory Botta, MD, PhD, a medical oncologist, and senior author Razelle Kurzrock, MD, professor of medicine, did a deep dive into the genomics of 6,831 pancreatic cancer patients, identifying a small subset of patients with specific genomic alterations that indicate potential responsiveness to ICI treatment.
The findings, they said, suggest the need for prospective clinical trials. Roughly 60,430 persons in the U.S. are diagnosed with pancreatic cancer each year; 48,220 die annually from the disease, according to the American Cancer Society. Pancreatic cancer accounts for 3 percent of all cancers in the U.S., but 7 percent of all deaths.
In a Brief Communication, published July 29, 2021 in the journal Transplant Infectious Disease, a team of physician-scientists at University of California San Diego School of Medicine found that solid organ transplant recipients who were vaccinated experienced an almost 80 percent reduction in the incidence of symptomatic COVID-19 compared to unvaccinated counterparts during the same time.
“Persons who have received an organ transplant are considered to be at increased risk for COVID-19 and for a severe outcome because their immune systems are necessarily suppressed to ensure their transplants are successful and lasting,” said Saima Aslam, MD, professor of medicine at UC San Diego School of Medicine and medical director of the Solid Organ Transplant Infectious Disease Service at UC San Diego Health. “These findings offer strong evidence that getting vaccinated provides significant protection.”
The researchers examined clinical data from the UC San Diego Health transplant registry from January 1, 2021 through June 2, 2021, encompassing 2,151 solid organ transplant recipients, including kidney, liver, lung and heart. Of this total number, 912 patients were fully vaccinated and 1,239 were controls (1,151 were unvaccinated and 88 partially vaccinated). Nearly 70 percent of the vaccinated patients received the mRNA-1273 vaccine (Moderna).
During the study period, there were 65 diagnosed cases of COVID-19 among the organ recipients: four among fully vaccinated individuals and 61 among the controls (two involving partially vaccinated individuals). There were no deaths among the breakthrough COVID-19 cases, but two among the 61 control cases.
“These findings are encouraging for a couple of reasons,” said co-author Kristin Mekeel, MD, chief of Transplant and Hepatobiliary Surgery at UC San Diego Health. “First, it demonstrates real world clinical effectiveness of COVID-19 vaccination in a vulnerable population. Second, the effectiveness is better than expected, given that studies have found that only about half of solid organ transplant recipients develop detectable anti-spike antibodies after vaccination.“
“We started, six to eight months ago, talking to the private sector on how to help our people with their health and the economy of our state. We have to accelerate the pace of recovery from this pandemic because our health and our economy are hurting,” said Luis Lutteroth, president of Consejo de Desarrollo de Tijuana, speaking on behalf of Cámara Nacional de la Industria de la Transformación Tijuana and the participating companies: Poly, Compañía Embotelladora Del Fuerte-Coca Cola, Jacuzzi, Flex, Call Center Services International-CCSI and Sempra-IEnova.
Approximately 1,500 workers, recruited by their employers, will be vaccinated daily over seven non-consecutive days at a temporary UC San Diego Health mobile clinic in San Ysidro, California. The companies are covering operating and vaccine costs.
“No virus, especially one as infectious as COVID-19, recognizes borders. As a leading advocate and provider for health care across our region, UC San Diego Health recognizes the public health benefit in joining our binational community in expanding outreach and supporting the widespread deployment of COVID-19 vaccines to help end this pandemic,” said Shira Abeles, MD, infectious disease specialist at UC San Diego Health.
Because of the complex logistics required to vaccinate 10,000 people, the single-dose Johnson & Johnson vaccine was selected for this clinic.
The vaccination clinic was made possible through the efforts of the Consulate General of Mexico and County of San Diego, which secured approval from the State of California. The vaccine was provided by the State of California at the request of the County. If this pilot program proves successful, it may be expanded using state, county or other vaccine sources.
“This example of trans-border collaboration truly symbolizes the notion that although we are two countries, we are in fact only one region,” said Carlos Gonzalez Gutierrez, Consul General of Mexico in San Diego. “Local partners in the border area are best suited to reach innovative regional solutions to binational challenges, such as COVID.“
As of May 25, 2021, 68 percent of San Diegans have received at least one vaccine dose against the SARS-CoV-2 virus that causes COVID-19. The region is 90 percent toward its herd immunity goal of fully vaccinating 75 percent of the population 12 years and older.
“We continue to have different interventions so that everyone in San Diego has access to vaccines. We no longer have a vaccine problem in San Diego County,” said Nora Vargas, vice chair, County of San Diego Board of Supervisors. “It is really important that in a binational community like ours, we do everything we can do to ensure that both sides of the border are taken care of. This historic initiative allows us to provide vaccines to our communities and neighbors to the south.”
Across the globe there has been rise in the demand for goods, but supply chains have slowed because of COVID-19. This new partnership helps to strengthen binational relations and the economy.
“Mexico is our largest trading partner and we need the border workforce to be healthy,” said San Diego County Board of Supervisors Chair Nathan Fletcher. “This vaccine pilot project will protect the working population, slow disease transmission and speed-up the production and shipping of goods between the U.S. and Mexico.”
COVID-19 vaccines offered in the U.S. have been shown to be safe and effective in reducing the risk for serious illness, even if a vaccinated person subsequently becomes infected by SARS-CoV-2. As more people are vaccinated, the presence of the virus will be reduced and community members will be better protected through herd immunity.
Vaccines are readily available for San Diego residents age 12 and older at numerous locations throughout the county. Don’t delay, visit health.ucsd.edu or sandiegocounty.gov to find the nearest vaccine clinic.
The human body is constantly exposed to various environmental actors, from viruses to bacteria to fungi, but most of these microbial organisms provoke little or no response from our skin, which is charged with monitoring and protecting from external dangers.
Until now, researchers weren’t quite sure how that happened — and why our skin wasn’t constantly alarmed and inflamed.
In a study published May 21, 2021 in Science Immunology, scientists at University of California San Diego School of Medicine identify and describe two enzymes responsible for protecting our skin and body’s overall health from countless potential microbial intruders. These enzymes, called histone deacetylases (HDACs), inhibit the body’s inflammatory response in the skin.
“We have figured out why we tolerate certain microbes living on our skin, while the same bacteria would make us very sick if exposed elsewhere in the body,” said Richard Gallo, MD, PhD, Ima Gigli Distinguished Professor of Dermatology and chair of the Department of Dermatology at UC San Diego School of Medicine. “In our research, we identified enzymes that act on the chromosome of specific skin cells that provide immune tolerance by the skin.
“Without these enzymes telling our cells to ignore certain bacteria, we’d have a constant rash on our skin.”
Researchers at University of California San Diego School of Medicine have discovered one way in which SARS-CoV-2, the coronavirus that causes COVID-19, hijacks human cell machinery to blunt the immune response, allowing it to establish infection, replicate and cause disease.
In short, the virus’ genome gets tagged with a special marker by a human enzyme that tells the immune system to stand down, while at the same time ramping up production of the surface proteins that SARS-CoV-2 uses as a “doorknob” to enter cells.
The study, published April 22, 2021 in Cell Reports, helps lay the groundwork for new anti-viral immunotherapies — treatments that work by boosting a patient’s immune system, rather than directly killing the virus.
“It’s very smart of this virus to use host machinery to simultaneously go into stealth mode and get inside more cells,” said Tariq Rana, PhD, professor and chief of the Division of Genetics in the Department of Pediatrics at UC San Diego School of Medicine and Moores Cancer Center. “The more we know about how the virus establishes itself in the body, the better equipped we are to disrupt it.”
In human cells, genes (DNA) are transcribed into RNA, which is then translated into proteins, the molecules that make up the majority of cells. But it’s not always so straightforward. Cells can chemically modify RNA to influence protein production. One of these modifications is the addition of methyl groups to adenosine, one of the building blocks that make up RNA. Known as N6-methyladenosine (m6A), this modification is common in humans and other organisms, including viruses.
In contrast to humans, the entire genomes of some viruses, including SARS-CoV-2, are made up of RNA instead of DNA. And rather than carry around the machinery to translate that into proteins, the coronavirus gets human cells to do the work.
Rana and his team previously discovered that m6A plays an important role in HIV and Zika virus infections. In their latest study, the researchers discovered that the human enzyme METTL3 adds methyl groups to introduce m6A in SARS-CoV-2’s RNA. That modification prevents the virus’ RNA from triggering inflammatory molecules known as cytokines. To the team’s surprise, METTL3’s activity also led to increased expression of pro-viral genes — those that encode proteins needed for SARS-CoV-2 replication and survival, such as ACE2, the cell surface receptor that the virus uses to enter human cells.
“It remains to be seen why our cells help the virus out like this,” Rana said.
A clinical trial of college students, including those at UC San Diego, will try to answer that question, and whether vaccinated persons might still pose an infection risk to others
COVID-19 vaccines were designed to reduce the likelihood that infection by the SARS-CoV-2 virus would lead to severe outcomes, such as hospitalization and death. In that sense, all of the currently approved vaccines — Moderna, Pfizer and Johnson & Johnson — have proven comparably effective.
But much less is known about the actual ability of these vaccines to prevent infection, most notably asymptomatic cases in which vaccinated persons might not become ill or display symptoms, but could still carry sufficient levels of the virus to pose a potential transmission threat to others.
New research is beginning to fill this knowledge gap. A recent UC San Diego School of Medicine study, published in The New England Journal of Medicine of vaccinated health care workers found the risk of infection to be small, but possible. A subsequent study by the Centers for Disease Control and Prevention reported both the Moderna and Pfizer vaccines were highly effective at preventing symptomatic and asymptomatic infections among a larger cohort of vaccinated health care workers and first responders.
Researchers at University of California San Diego, with participating academic institutions across the country, will now look a different demographic group: students.