This very subtle molecular change allows immunoglobulin G (IgG)–the body’s most common type of antibody—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 against infection inside cells,” Way says.
“Mothers always seem to know best,” Erickson adds.
The findings impressed Louis Muglia, MD, PhD, former director of Human Genetics at Cincinnati Children’s, now president and CEO of the Burroughs Wellcome Fund, which provided support for this study.
“The Burroughs Wellcome Fund prioritizes research funding in reproductive sciences that has the potential to transform our understanding of pregnancy health. Drs. Way and Erickson reveal novel immunological changes that occur during pregnancy that optimizes antimicrobial host defense during these developmental windows of vulnerability,” Muglia says.
Revved-up antibodies can be produced in the lab
Using advanced mass spectrometry techniques and other methods, the research team pinned down the key biochemical differences between antibodies in virgin mice compared to pregnant ones. They also identified the enzyme naturally expressed during pregnancy responsible for driving this transformation.
Further, the team successfully restored lost immune protection by supplying lab-grown supplies of the antibodies from healthy pregnant mice to pups born to mothers that were gene-edited to lack the ability to remove acetylation from antibodies to enhance protection.
Hundreds of monoclonal antibodies have been produced as potential treatments for various disorders including cancer, asthma, multiple sclerosis, as well as hard-to-shake viral and bacterial infections—including new treatments rapidly developed for COVID-19. Some are already FDA approved, many more are in clinical trials, and some have failed to show strong results.
Way says the molecular alteration of antibodies that naturally occurs during pregnancy can be replicated to change how antibodies stimulate the immune system to fine-tune their effects. This potentially could lead to improved treatments for infections caused by other intracellular pathogens including HIV, herpes, and respiratory syncytial virus (RSV), a common virus that poses serious risks to infants.
Another reason to accelerate vaccine development
It may take 20 years of further research to follow the multiple trails opened by this discovery, Erickson says. But some potential impacts could be realized much sooner.
“We’ve known for years the many far-reaching benefits of breastfeeding,” Erickson says. “One major factor is the transfer of antibodies in breastmilk.”
The study shows that the molecular switch persists in nursing mothers so that antibodies with enhanced protective scope are also transferred to babies through breastmilk.
Additionally, Way says the findings underscore the importance of receiving all available vaccines for women of reproductive age—as well as the need for researchers to develop even more vaccines against infections that which are especially prominent in women during pregnancy or in newborn babies.
“The immunity needs to exist within the mother for it to be transferred to her child,” Way says. “Without natural exposures or immunity primed by vaccination, when that light switch flips during pregnancy, there’s no electricity behind it.”
About the study
A patent on antibody sialic acid modification 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 study in Nature was co-authored by 9 researchers at Cincinnati Children’s and the University of Cincinnati: Alexander Yarawsky, BS, Jeanette L.C. 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.
Contributors also included experts from the University of Georgia, the Ohio State University, Cornell University, and Roswell Park Comprehensive Cancer Center in Buffalo.
Funding sources included grants from the National Institutes of Health (F32AI145184x, K12HD028827, DP1AI131080, R01AI145840, R01AI124657, U01AI144673, T32DK007727, R24GM137782, R01GM094363, and R01AI162964); the HHMI Faculty Scholar’s Program; the Burroughs Wellcome Fund; the March of Dimes Foundation Ohio Collaborative; and GlycoMIP, a National Science Foundation Materials Innovation Platform funded through Cooperative Agreement DMR-1933525.