Understanding Poor Vaccine Responses in Individuals With Weakened Immune Systems

When the COVID-19 vaccine first became available, people eagerly signed up for coveted slots to boost their antibodies against the virus that shut down much of the world. But not everyone who rolled up their sleeve received equal protection from illness.

A significant proportion of the population has weakened immune systems, including cancer patients, those with autoimmune disease, and organ transplant recipients. The immune systems of these individuals are unable to ward off disease as effectively, and their responses to vaccines are not as robust. Now, Yale researchers have received a $12 million award from the NIH as part of the Human Immune Project Consortium (HIPC) to study vaccine responses in vulnerable groups, including patients with multiple sclerosis (MS) undergoing B cell depletion therapy, older adults including particularly vulnerable older residents of long-term care facilities, and individuals with sickle cell disease who have substantial and potentially disabling morbidity and early mortality for whom fundamental challenges to improve clinical outcomes remain.

“We would love to have the ability to improve vaccine responsiveness in vulnerable populations,” says Ruth Montgomery, PhD, professor of medicine and of epidemiology (microbial diseases), associate dean for scientific affairs, and co-principal investigator.

HIPC is a national consortium led by the National Institute for Allergy and Infectious Diseases (NIAID) focused on the high-dimensional profiling of immune cells and developing a shared data resource and in-depth computational models of infection and vaccine responses in humans. This is the third consecutive five-year cycle Yale has received funding from this network, and Yale joins seven other HIPC centers in the nation (at Benaroya Research Institute, Columbia, La Jolla Institute, MIT, Mount Sinai, Seattle Children’s Hospital, and Stanford).

Patients with autoimmune diseases such as multiple sclerosis and rheumatoid arthritis often require depletion of B cells, the arm of the immune system responsible for antibody production, to manage their conditions. While this therapy can profoundly improve the quality of life for recipients, these individuals are uniquely at risk to poor outcomes from COVID-19. “Understanding why they’re not responding to the vaccine and how we can get them to respond is a critical question,” says David Hafler, MD, chair and William S. and Louis Stiles Edgerly Professor of Neurology, professor of immunobiology, and co-principal investigator.

Hafler’s group with co-investigator Mary Tomayko, MD, PhD, associate professor of dermatology, and collaborator Erin Longbrake, MD, PhD, assistant professor of neurology, has been banking blood from immunocompromised patients with multiple sclerosis before and after they receive mRNA vaccinations. Furthermore, in a subgroup of patients, the researchers are taking skin and axillary lymph node biopsies (in collaboration with David Madoff, MD, professor of radiology and biomedical imaging) after vaccination. They are performing an array of analyses of blood and tissue using single cell expression approaches as well as novel spatial expression and antibody and cytokine arrays developed by Rong Fan, PhD, professor of biomedical engineering, and colleagues. Together these analyses will enable this group to better understand how the immune system changes in response to vaccination in immunocompromised individuals compared with those who are not immunocompromised.

Hafler hopes that this project will help scientists develop ways of administering vaccines so that the immune systems of patients with autoimmune disease generate a greater response. He also hopes to better understand how the mechanisms of the immune system respond after the system’s B cells are depleted. “One of the big surprises to date in our preliminary look at the data is that while patients who are B cell depleted are not making antibodies, they are mounting a very robust T cell response,” says Hafler. “This other arm of the immune system seems to be responding more robustly than we thought.”

Along with wrinkles and gray hairs, many changes occur within our bodies as we age. Research has shown that older adults often experience a state of chronic inflammation, which scientists believe may be a result of a misdirected immune response to cellular damage. Furthermore, many cellular changes occur within immune cells as people age. The production of fundamental cells like T cells, for example, shrinks to almost nothing in many older adults. “We saw in the earliest phase of the COVID pandemic that older individuals were at a higher risk of severe outcomes,” says Albert Shaw, MD, PhD, professor of medicine (infectious diseases), who is the project leader. “All of these [aging-related] factors conspire to impair immune responses.”

For this project, Shaw’s team is studying the immune responses to the two influenza vaccines currently approved for use in adults over age 65 and recommended to be given annually. Participants in the study will either receive a high-dose influenza vaccine or a standard dose vaccine containing an adjuvant (MF59)—a chemical compound that boosts immune response. The researchers will focus on older adults who are residents of long-term care facilities—individuals with multiple pre-existing medical conditions and disability who are particularly vulnerable to adverse outcomes from infections and poor responses to vaccination.

A group led by James Lai, MD, associate clinical professor of medicine (geriatrics) and including Alessandra Capobianco, MD, Ann Datunashvili, MD, and Gerald Kerins, MD, from the section of geriatrics—the medical directors of three long-term care facilities in Greater New Haven—will be integral collaborators in these studies. The immunologic, gene expression, and proteomic signatures of response to these two vaccines will be compared in both the older long-term care facility residents and in young adults, to understand mechanisms of how these two vaccines work at a highly defined level. Other collaborators in this project at Yale are Akiko Iwasaki, PhD, Sterling Professor of Immunobiology, and Insoo Kang, MD, professor of medicine (Rheumatology).

“We’re trying to arrive at a better understanding of how these vaccines work and whether there are particular differences in the mechanism of action of the two vaccines that can shed insight on designing even better vaccines for older adults,” says Shaw.

Even before the onset of COVID-19, influenza was a significant cause of morbidity and mortality in older adults. Influenza takes the lives of around 30,000 to 80,000 individuals each year, says Shaw, and about 90% of these deaths occur in adults aged 65 and older. Furthermore, older adults are much more vulnerable to future outbreaks of new respiratory viruses. Shaw hopes his team’s work will provide the clues to help protect aging adults from these outbreaks, and also provide new insights into vaccination against COVID-19 and other infectious diseases.0

Sickle cell disease is the most common genetic blood disorder in the United States and is vastly understudied. The disease is caused by a single mutation in the gene encoding beta-globin, a critical protein in the hemoglobin oxygen carrying protein in red blood cells. The abnormal hemoglobin protein results in damage to and destruction of red blood cells, painful crises, and serious outcomes such as strokes. When the sickle-shaped red blood cells cause blood vessel damage and impaired blood flow, sickle cell disease also creates a chronic inflammatory state, and causes damage to the spleen, an important immune system organ. Patients with sickle cell disease have substantial morbidity and mortality from infections as a result. The health implications are significant: studies show that individuals with sickle cell disease live approximately two decades shorter. The disease is mostly seen in Black individuals, who also are more likely to have disadvantaged access to healthcare.

“The overall goal of our project is to create data to learn more about the immunobiology of sickle cell disease and increase the protection provided to individuals by vaccines against infectious diseases,” says Inci Yildirim, MD, PhD, associate professor of pediatrics (infectious diseases) and of public health (epidemiology of microbial diseases).

Montgomery and Yildirim will work together to profile the baseline immune status of patients with sickle cell disease and changes following from treatment and long-term transfusions. Working with Farzana Pashankar, MD, director of the Pediatric Sickle Cell Program, Cece Calhoun, MD, assistant professor of medicine (hematology), and Lakshmanan Krishnamurti, MD, chief of pediatric hematology, oncology, and bone marrow transplant, the team will investigate immune responses to pneumococcal vaccines and compare the participants to a control group that includes family members without the disease. The investigators also plan to study whether individuals respond differently to the influenza vaccine that contains the adjuvant given to older adults. These vaccines are currently not authorized for pediatric or young adult patients, even if they have sickle cell disease.

Montgomery and Yildirim hope their team’s project will allow them to develop a signature of a patient’s inflammatory state and perhaps predict disease outcome. In particular, they hope this research will help develop better vaccines for those with the disease. “I’m excited about creating data for a disease that has not been well studied, but is very common and has significant implications,” says Yildirim. “We’re talking about two decades of shorter life as a result of this disease even in developed countries with state of the art care. Anything that can be done to improve outcomes—better treatments, more effective vaccines—would be quite impactful.”

The systems-level profiling data generated as part of these three projects will be analyzed and integrated by a data management and analysis core led by Steven Kleinstein, PhD, professor of pathology and of immunobiology, and co-director of the Program in Computational Biology and Bioinformatics. Additional Yale faculty collaborating in Core resources include Heather Allore, PhD, professor of medicine (geriatrics), Leying Guan, PhD, assistant professor of biostatistics, and Rong Fan, PhD, professor of biomedical engineering and pathology. According to Kleinstein, “Comparative analysis across these three projects will inform definitions of a broad signature of effective vaccine responses and reveal molecular mechanisms that account for the differential dynamics in these vulnerable populations.” Kleinstein also leads the national coordinating center for HIPC (awarded jointly to Yale and La Jolla Institute) that will facilitate analysis, visualization and integration of data across HIPC centers nationally.