UCSF Grand Rounds: Worldwide updates and questions regarding patients with weaker immune systems

Dr. George Rutherford, UCSF professor of epidemiology and biostatistics, kicked off Grand Rounds with a look at the global Covid-19 numbers, which continue to surge in many parts of the world. 

“Things are not going well,” he said. 

Though cases have “leveled out here a tiny bit in the last two weeks,” Rutherford said, mortality rates are climbing worldwide and “India is leading the surge.” Globally, there have been more than 150 million covid cases and more than 3 million deaths.

Though the United States and Canada are faring better, South America is also struggling with major outbreaks in Peru and Colombia. Brazil continues to be a major source of cases, Rutherford said. 

In India, there have been over 21 million cases and 230,000 deaths. The country “is in dire straits. They’ve run out of oxygen. They’ve taken all the industrial oxygen and moved it for health care,” he said. 

Although India has produced vaccines for the rest of the world, only five percent of its adult population is vaccinated. In late March, the country stopped exporting vaccines to vaccinate its own population as quickly as possible. That move, said Rutherford, “ is throwing a huge wrench into vaccination programs in other parts of the world, predominantly in Africa.” 

The Biden administration announced last week it will donate up to 60 million AstraZeneca vaccines to India, pending approval from the Food and Drug Administration, and yesterday the United States said it would support compulsory licensing of covid vaccines, what Rutherford described as “basically a waiver of intellectual property for public health emergencies.” As a result, countries who apply for a waiver will be able to manufacture vaccines without intellectual property infringement, including countries with robust vaccine industries, such as India, Brazil and Thailand. 

“Here in the US, things are going well, and in California, they’re going very well,” Rutherford said, noting that California has the fewest cases per capita in the United States, with fewer than 2,000 cases per day. 

California is currently vaccinating anyone 16 years and older, though Rutherford predicted this may open up to those 12 and older next week, when the FDA will likely extend Pfizer’s Emergency Use Authorization to include that age group. Rutherford, a pediatrician, said he would “absolutely” vaccinate twelve-year-olds because of the surges across the country that have been driven by outbreaks among middle- and high-school sports teams.

Some 300 million doses have been administered in the United States so far, but vaccinations have dropped off nationally and in California. The J&J vaccine’s use is “really down to a trickle,” Rutherford said. Though the number of individuals who were hesitant to get vaccinated in a survey Rutherford cited has remained consistent from December through March, and many of those who indicated they were willing to get vaccinated have been doing so. Currently, 48.2 percent of Californians and 44.6 percent of San Franciscans are fully vaccinated, and Rutherford said that the Bay Area will likely reach regional herd immunity in the “next couple months” as more counties enter the yellow tier.

Patients with weakened immune systems, also known as immunocompromised

Next, the moderator Dr. Bob Wachter welcomed a panel of three experts to talk about issues related to the pandemic, vaccines, and those with weakened immune systems, a “hot issue” at UCSF, where there are many immunocompromised patients. What that means is that they are taking medications for other conditions, such as cancer, organ transplants or autoimmune diseases, that suppress one or both arms of the immune system, making Covid more deadly, but also making vaccines less effective.

Dr. Lianne Gensler, professor of medicine in the division of rheumatology at the VA, broke down the basics of the immune system in her presentation. It has, she said, two major branches: the innate immune system, which works quickly but is not “specific,” and the adaptive immune system, which takes longer to work but is “much smarter” and “more specific.” Initial vaccine inoculation is important to the innate immune system, while the adaptive immune system creates long lived responses to covid exposures. 

The adaptive immune response comprises several key cells, including B lymphocytes (B cells), which recognize infections and proliferate and differentiate into plasma and memory B cells; and T cells, which are important in recognizing foreign invaders such as the Covid virus. These multiply and develop into more specialized cells that aid in the creation of antibodies to fight invaders. 

When vaccinated with an mRNA vaccine, many cells travel to the site of the inoculation as part of the innate immune response. Once these cells uptake the mRNA from the vaccine, they are instructed to express a spike protein that is taken to a lymph node. Once it gets there, it presents the protein to B cells. 

In lymph nodes, T and B cells communicate to produce more cells and initiate differentiation into other immune-fighting cells. Antibodies formed in response to these spike proteins then migrate from the lymph node to the bone marrow, where they continue to produce antibodies and circulate to prevent infection.

Vaccines, Gensler said, should prevent infection (mainly through antibodies) and reduce the severity of infection (which is reliant on T cells to kill infected cells). She cited a UCSF preprint study that suggests good T cell response correlates “really well” with a good B cell response, which is important for the success of vaccines. 

“What’s important, I think, to this conversation today is that many of the medications we use suppress one or both of these arms of the immune system, and so may alter that response to vaccines,” Gensler said. 

The study found that medications that deplete B cells, such as rituximab, and antimetabolites like methotrexate, which are used to treat autoimmune disorders such as rheumatoid arthritis, as well as cancer patients, “had an enormous effect on being able to make antibodies.” One surprise was that medications like prednisone, “which many of us use, had an impressive effect as well,” Gensler said.

Next, Dr. Brian Schwartz, UCSF professor of medicine, discussed several other studies of immunocompromised patients and Covid. Immunocompromised patients are a heterogenous group, meaning they take different medications that affect different pathways of the immune system.  

Last week, Schwartz said, was the largest case series of covid he had seen among vaccinated immunocompromised patients. Seven organ transplant recipients in Florida who had been vaccinated presented with covid. Five out of the seven had received both doses of an mRNA vaccine.  Four to five of the seven were sick enough to require hospitalization, and four did not present spike antibodies when tested. It is likely that patients who have negative antibody tests “are less well protected” than those who have positive tests, Schwartz said. 

Though the strategies to enhance immune responses of immunocompromised patients need more study, Schwartz suggested that increasing the antigen (foreign agent) dose, delaying administration of immunosuppressive medication, or getting a booster are potential methods that need further study. 

He suggested that immunocompromised patients “build a wall of immunity at home,” making sure that close friends and family are vaccinated and, if possible, complete their vaccine series before getting on medications that will weaken their immune systems.

To conclude, Dr. Shagun Arora, assistant professor of medicine at UCSF, came on screen to ask Gensler and Schwartz how they would respond to specific immunocompromised patient cases, including an unvaccinated 65-year-old woman on long term immunosuppression, and another unvaccinated 65-year-old patient with lymphoma who may need to start more treatment. 

Though the speakers clarified that questions should be answered on a case-by-case basis, they made a few generalizations.

“When a patient gets covid who is immunosuppressed, there are certain medications they’re on that probably increase the risk of them having a worse outcome,” said Gensler, listing several of the drugs she previously spoke about. She encouraged vaccinations. 

For patients who may be put on an immunosuppressant, it should be a shared decision between the doctor and patient to figure out the balance between the risk of not treating the patient immediately versus not having immunity against Covid, she said. Wachter noted that the prevalence of the pandemic in one’s location should also play a factor in this decision. 

Though there are several ongoing studies related to covid and vaccines among immunocompromised patients, there is “still a little bit of an information vacuum” for this group today, Wachter said. 

In an earlier version of UCSF’s Grand Rounds we reported that some 30 million doses have been administered in the United States so far. This is incorrect, as there have been over 30 million doses administered in California and over 300 million in the United States.  Additionally, Dr. George Rutherford was misquoted saying that there were fewer than 20 cases per day in California. That number should have read 2,000. We apologize for these errors to our readers and Dr. Rutherford. All have been corrected.

See our previous Grand Rounds coverage here.