Study Reveals Mechanism of Antileukemic Effects of Early Childhood Vaccination

A new study by an international team led by researchers at the University of California, San Francisco (UCSF), has shed light on the mechanism of action for the anticancer effects of the Haemophilus influenzae Type b (Hib) vaccine, specifically against acute lymphoblastic leukemia (ALL).¹

The Hib vaccine is part of the standard vaccination schedule recommended by the Centers for Disease Control and Prevention (CDC), and is routinely administered in four doses during the first 15 months of age. Although epidemiological studies have previously established the antileukemic effect of the vaccine, the mechanism underlying this effect has been unclear.

Based on the observations that childhood ALL “can often be traced to a preleukemic clone carrying a prenatal genetic lesion” and that “acquired mutations then drive clonal evolution toward overt leukemia,” the research team, led by Srividya Swaminathan, PhD, currently at Stanford University School of Medicine, and Lars Klemm, assistant research specialist at UCSF, focused on the enzymes RAG1-RAG2 (recombination-activating genes) and AID (activation-induced cytidine deaminase). These enzymes, which diversify immunoglobulin-encoding genes “are strictly segregated in developing cells during B lymphopoiesis and in peripheral mature B cells, respectively,” they noted in an article published May 18, 2015 in Nature Immunology.²

The researchers used a murine model to determine whether chronic inflammation caused by recurrent infections might cause “collateral damage” – additional genetic lesions – in blood cells already carrying an oncogene, promoting their transformation to overt disease. AID and RAG introduce mutations in DNA that allow immune cells to adapt to infectious challenges, and these enzymes are necessary for a normal and efficient immune response. In the presence of chronic infection, however, the investigators found that AID and RAG are strongly hyperactivated, and they cut and mutate genes randomly, including important gatekeepers against cancer.

By studying genetically engineered preleukemia cells lacking either AID or RAG, as well as cells lacking both enzymes, the team found that AID and RAG working together is critical to introduce the additional lesions that result in life-threatening disease. Repeated exposure to the enzymes RAG1-RAG2 and AID, which diversify immunoglobulin-encoding genes, “drove leukemic clonal evolution with repeated exposure to inflammatory stimuli, paralleling chronic infections in childhood,” the researchers concluded.

“These experiments help explain why the incidence of leukemia has been dramatically reduced since the advent of regular vaccinations during infancy,” said Markus Müschen, MD, PhD, professor of laboratory medicine at UCSF and senior author of the study. “Hib and other childhood infections can cause recurrent and vehement immune responses, which we have found could lead to leukemia, but infants that have received vaccines are largely protected and acquire long-term immunity through very mild immune reactions.”

“The study provides mechanistic support for the hypothesis that infection or inflammation promotes the evolution of childhood leukemia and that the timing of common infections in early life is critical,” added coauthor Mel F. Greaves, MD, PhD, professor of cell biology at the Institute of Cancer Research in London. Other coauthors include researchers from the University of Freiburg; Cambridge University; the Wellcome Trust Sanger Institute; the University of Southern California; Heinrich-Heine-Universität Düsseldorf; the University of Ulm; the National Institute of Arthritis and Musculoskeletal and Skin Diseases; and Yale School of Medicine.

The study was funded by the National Institutes of Health; the National Cancer Institute; the Leukemia and Lymphoma Society; the William Lawrence and Blanche Hughes Foundation; the California Institute for Regenerative Medicine; the Wellcome Trust; and Cancer Research UK.

The research team believes that the same mechanisms may be at work in viral infections, and is currently conducting experiments to determine if protection against leukemia is also provided by antiviral vaccines, such as the MMR vaccine.

References:

• Bunim J. (2015). UCSF-Led Study Explains How Early Childhood Vaccination Reduces Leukemia Risk. University of California, San Francisco.
• Swaminathan S, Klemm L, Park E, et al. (2015). Mechanisms of clonal evolution in childhood acute lymphoblastic leukemia. Nature Immunology.