“Vaccines must be completely safe and effective in all children. We need to identify key signatures of optimal immune responses upon vaccination, and apply these knowledges to improve the responses in the so called “poor responders”, especially the ones with high-risk of infections or immunocompromised.”
Safety and efficacy of vaccinations in immunocompromised children
FUNDED: JANUARY 2020
FUNDED BY: the generosity of 2019-20 Various Donors and David & Lila Webb
Childhood vaccines are important to prevent life-threatening infections and establish protective memory immune responses. Active immunity is acquired after the exposure to a pathogen or upon vaccination; in these contexts, the immune system is stimulated to produce secreted molecules called antibodies, which can fight the pathogen. Vaccines are designed to interact with and stimulate the immune system and they can often induce an immune response similar to that produced by the natural infection. In general, there are two type of vaccine formulations: live attenuated and inactivated. Generally, live attenuated vaccines can induce better immune responses, but they might be dangerous in immunocompromised patients, since they can cause mild to fatal adverse reactions.
Immunocompromised individuals can be affected by several pathological conditions. Among primary immunodeficiencies, common variable immunodeficiency (CVID) is one of the most frequently diagnosed diseases. It affects about 1 in 2000 children, 20-30% of them presenting with associated autoimmunity. Children affected by CVID often suffer from recurrent infections and poor responses to certain type of vaccines, such as pneumococcal conjugates or flu vaccines. Severe immune dysregulation and poor protection occur also in children affected by systemic lupus erythematous (SLE), a debilitating and life-threatening autoimmune disease in which the immune system attacks and destroys its own organs and tissues. In the U.S., the disease affects 5,000 to 10,000 youngsters. Lupus children are often treated with immunosuppressive drugs. As for CVID, children with lupus can show lower protection after vaccination and recurrent infections, often accompanied by concerns about the potential adverse reactions to vaccines, which may occur in some subjects.
Both diseases are characterized by a perturbation of T and B lymphocytes. Antigen-specific, long-lasting antibody responses are commonly generated during immune processes occurring in the germinal centers (GCs) of lymphoid tissues, in which T follicular helper (TFH) cells aid B cells to produce protective antibodies. Several reports described impaired antibody responses and defective memory generation in both children with CVID and SLE following vaccination, hence supporting the idea that failure to mount good immune response might derive from dysregulated GC-dependent mechanisms.
The primary goal of this study is to evaluate the safety and efficacy of vaccines in these patients. The aim of this proposal is to integrate interdisciplinary system biology approaches to evaluate the gene profile and repertoire of antigen specific T and B cells, following common vaccination protocols in normal and immunocompromised children, in order to identify key signatures of optimal protective immune responses, and apply these knowledges to improve vaccinations in so called “poor responders”.
Six-Month Project Update
My project faced challenges due to the COVID-19 restrictions and closures of medical centers where children are normally recruited and receive vaccinations, but we’ve made progress this summer. We received samples from Rady Children’s Hospital from patients with confirmed or suspected cases of Common Variable Immune Deficiency (CVID) that received their pneumococcal or Tdap vaccines. From these samples we saw that in some patients the level of pertussis antibodies and B cells are reduced, which supports our hypothesis that immunodeficient children have less effective immune responses to vaccines. We also analyzed these samples for immune cell phenotype and are planning additional studies once more donor samples are collected to help determine if a particular type of cell is causing the deficient response. The second cohort for this project, composed of children affected by pediatric lupus, will be recruited soon and similar analyses will be performed. Also my lab recently purchased a powerful machine, called the Cytek Aurora, which analyzes up to 40 immunological related molecules and performs sophisticated immune cells phenotyping. This will greatly benefit my efforts to define the quality and quantity of the immune cells of these children, as this machine is incredibly precise even with our limited access to patient samples.