Scientists discovered years ago that newborns depend on the immune components transferred from their mothers to survive the onslaught of pathogens that begin invading their bodies as soon as they are born. Eventually, children develop their own immune systems, built by surviving natural exposure to viruses and bacteria and boosted by a phalanx of well-established childhood vaccines. But in the meantime, it’s one of the most important gifts a mother keeps her babies safe: antibodies.
Now, a large-scale study published June 8, 2022 in Nature, provides a surprising explanation of how those early days of mother-provided immunity actually work and what this information might mean to prevent death and disability from a wide range of infectious diseases. The findings suggest that researchers may be able to mimic the amplified antibodies that expectant mothers produce to create new drugs to treat diseases and improved vaccines to prevent them.
“For many years, scientists believed that antibodies could not enter cells. They do not have the necessary machinery. And so, it was thought that infections caused by pathogens that live exclusively inside cells were invisible to the eyes. antibody-based therapies, “says Sing Sing Way, MD, PhD, Division of Infectious Diseases at Cincinnati Children’s. “Our results show that pregnancy changes the structure of some sugars attached to antibodies, which allows them to protect babies from infection by a much wider range of pathogens.”
“The maternal-infant dyad is so special. It’s the intimate connection between a mother and her baby,” says John Erickson, MD, PhD, Division of Neonatology and first author of the study.
Both Way and Erickson are part of the Cincinnati Children’s Center for Inflammation and Tolerance and the Perinatal Institute, which is committed to improving outcomes for all pregnant women and their newborns.
Erickson continues: “This special connection begins when babies are in the womb and continues after birth. I love to see the closeness between mothers and their babies in our infant care units. This discovery paves the way for pioneering new therapies that they can specifically target infections in pregnant mothers and newborns. I believe these findings will have far-reaching implications for antibody-based therapies in other fields as well. “
How mothers produce super antibodies
The new study identifies which specific sugar is changed during pregnancy, as well as how and when the change occurs. During pregnancy, the “acetylated” form of sialic acid (one of the sugars attached to antibodies) changes to the “deacetylated” form. This very subtle molecular shift allows immunoglobulin G (IgG) – the most common type of antibody in the body – to take on an expanded protective role by stimulating immunity through receptors that respond specifically to deacetylated sugars.
“This change is the light switch that allows maternal antibodies to protect babies from infections within the cells,” Way says.
“Mothers always seem to know best,” adds Erickson.
Revved-up antibodies can be produced in the laboratory
Using advanced mass spectrometry techniques and other methods, the research team identified the main biochemical differences between antibodies in virgin versus pregnant mice. They also identified the enzyme naturally expressed during pregnancy responsible for driving this transformation.
In addition, the team successfully restored lost immune protection by providing stocks of laboratory-grown antibodies from healthy pregnant mice to pups born to mothers that had been genetically engineered to lack the ability to remove acetylation from antibodies to improve protection.
Hundreds of monoclonal antibodies have been produced as potential treatments for various ailments including cancer, asthma, multiple sclerosis, as well as hard-to-shake viral and bacterial infections, including rapidly developed new treatments for COVID-19. Some are already approved by the FDA, many others are in clinical trials, and some have not shown obvious results.
Way says the molecular alteration of antibodies that occurs naturally during pregnancy can be replicated to change the way antibodies stimulate the immune system to refine their effects. This could potentially lead to better treatments for infections caused by other intracellular pathogens including HIV and respiratory syncytial virus (RSV), a common virus that poses serious risks to children.
Another reason to accelerate vaccine development
“We have known for years the many far-reaching benefits of breastfeeding,” says Erickson. “An important factor is the transfer of antibodies into breast milk.”
The study shows that the molecular switch persists in nursing mothers so that antibodies with greater protective capacity are also transferred to babies through breast milk.
Additionally, Way says, the findings underscore the importance of receiving all vaccines available to women of reproductive age, as well as the need for researchers to develop even more vaccines against infections that are especially important in pregnant women or infants. .
“Immunity must exist within the mother in order to be passed on to her child,” Way says. “With no natural exposure or vaccination-triggered immunity, when the light switch goes on during pregnancy, there is no electricity behind it.”
About the study
A patent on the sialic acid modification of antibodies has been filed by Cincinnati Children’s Hospital with first author Erickson and senior author Way as inventors (PCT / US2022 / 018847).
In addition to Erickson and Way, the studio in Nature co-authored 9 researchers at Cincinnati Children’s and the University of Cincinnati: Alexander Yarawsky, BS, Jeanette LC Miller, PhD, Tzu-Yu Shao, BS, Ashley Severance, PhD, Hilary Miller-Handley, MD, Yuehong Wu , MS, Giang Pham, PhD, Yueh-Chiang Hu, PhD, and Andrew Herr, PhD.
Experts from the University of Georgia, Ohio State University, Cornell University, and Buffalo’s Roswell Park Comprehensive Cancer Center also collaborated.
Funding sources included grants from the National Institutes of Health (F32AI145184x, K12HD028827, DP1AI131080, R01AI145840, R01AI124657, U01AI144673, T32DK007727, R24GM137782, R01GM09416293 and R01AI64); the scholars program of the HHMI faculty; the Burroughs Wellcome Fund; the collaboration of the March of Dimes Foundation Ohio; and GlycoMIP, a National Science Foundation materials innovation platform funded through the DMR-1933525 cooperation agreement.