Could IgA from Human Breast Milk Offer Insights into Potential Treatments for COVID-19?

As of the date of this writing, there have been more than 8 million confirmed cases of COVID-19 worldwide, and close to half a million deaths. The pandemic’s initial, exponential growth trajectory has been contained through massive voluntary and mandatory isolation efforts; however, these have had their own disastrous consequences for the economy and for the social and emotional wellbeing of people everywhere. With human stamina for isolation wearing thin, COVID-19 cases are once again surging.

The need to find post-COVID normalcy is urgent, and is dependent on the development of preventive vaccines, as well as therapeutic strategies to reduce the severity of active infection and lessen disease mortality.

Against this backdrop, we read with interest a manuscript preprint from the research group of Rebecca Powell, an assistant professor at the Icahn School of Medicine at Mount Sinai in New York, NY. Titled, “Evidence of a significant secretory-IgA-dominant SARS-CoV-2 immune response in human milk following recovery from COVID-19,” This paper reports preliminary analysis of a subset of samples from an ongoing study of the human-milk immune response in lactating mothers who have recovered from infection with the SARS-CoV-2 virus.

While the findings are preliminary and the paper has yet to go through the peer review process, it highlights an interesting question whose answers might be critical to the global effort to manage the COVID-19 pandemic:

Is there a role for maternal secretory IgA in conferring protection against COVID-19, what is the mechanism, and can it be harnessed as a therapeutic strategy?

IgA (immunoglobulin A) is the predominant antibody isotype found in the tissues and secretions of the mucosal immune system, which includes the tissues of the gastrointestinal tract, respiratory tract, and vaginal tract, as well as mucous, tears, and saliva. A major function of the mucosal tissues, mediated in part by IgA, is to stop, trap, neutralize, and dispose of microbial and viral pathogens before they can enter the body.

Secretory IgA also makes up about 90% of the immunoglobulin protein in human milk colostrum and is largely responsible for the passive immunity that protects immunologically naïve infants from environmental pathogens until they develop independent immune defenses.

Dr. Powell’s research interests have previously focused on the protective effect of breastmilk against mother-to-child transmission of HIV, so she was well-positioned to pivot to COVID-19 research. In May of this year, she began collecting donated breastmilk from lactating women who had either recovered from a confirmed case of COVID-19 (N=600) or who had recovered from COVID-19 like symptoms but had not been tested (N=1000). The results shared so far are from a pilot analysis of 15 of those samples, compared to 10 COVID-naïve samples collected and banked prior to December 2019.

What the pilot study found is that, compared to baseline, 80% of milk samples from COVID-recovered donors showed elevated secretory IgA-mediated reactivity against the Receptor Binding Domain (RBD) of the SARS-CoV-2 Spike protein. Furthermore, analysis of IgM and IgG responses showed that the secretory IgA response was the predominant antibody response in milk after infection.

These initial results generated the preliminary data necessary to justify moving forward with the large-scale study and with additional research to define the potential protective or therapeutic properties of IgA.

In commentary about the project, Dr. Powell speculated that breastmilk-derived IgA from recovered COVID-19 patients could be similar to “convalescent plasma” in its ability to save lives. However, sourcing of specific IgA from donated breastmilk, at sufficient scale for therapeutic use, is likely to face enormous logistical, economic, and ethical challenges. The key to utilizing it as a therapeutic will be to develop simple methods for high-yield recombinant and/or biosynthetic expression, analogous to IgG monoclonal antibody production using mammalian cell culture.

So far this has proved technically challenging. IgA is structurally related to but distinct from IgG and other antibody isotypes. It also exists in two distinct structural forms; the IgA that originates in blood plasma is monomeric in structure like IgG, whereas IgA secreted into the mucosa takes on a dimeric form and is wrapped in a secretory component. This makes secretory IgA a very large protein and it is less susceptible to enzymatic degradation and better suited to the potentially withstand the harsh environments of the respiratory and digestive tracts.

Unfortunately, secretory IgA’s unusual structure also makes it more challenging to produce biosynthetically compared to IgG.

We believe that research like Dr. Powell’s will answer intriguing questions about passive immunity in nursing mother-infant pairs, as well as about how the composition of milk IgA changes in response to new pathogenic challenges. In the meantime, the global circumstances precipitated by the current pandemic highlight the need for reliable, scalable methods to produce fully functional secretory IgA molecules and other complex proteins that may represent the next frontier in biologics for the treatment of disease.