Passive Immunity to <em>Vibrio cholerae</em> O1 Afforded by a Human Monoclonal IgA1 Antibody Expressed in Milk

Abstract

Background: In cholera epidemics, the spread of disease can easily outpace vaccine control measures. The advent of technologies enabling the expression of recombinant proteins, including antibodies, in the milk of transgenic animals raises the prospect of developing a self-administered and cost-effective monoclonal antibody (MAb)-based prophylactic to reduce the incidence of Vibrio cholerae infection.Methods: We generated a transgenic mouse line in which the heavy and light chain variable regions (Fv) specific for a conserved epitope in the core/lipid A of V. cholerae O1 lipopolysaccharide were expressed as a full-length human dimeric IgA1 (ZAC-3) and secreted into the milk of lactating dams. Milk containing ZAC-3 IgA1 was assessed for the ability to passively protect against experimental cholera infection in a newborn mouse model and to impact bacterial swimming behavior.Results: Newborn mice that were passively administered ZAC-3 IgA1 containing milk, or that suckled on dams expressing ZAC-3 IgA1, were immune to experimental cholera infection, as measured by a reduction of V. cholerae O1 colony forming units recovered from intestinal lysates 12 hours after oral challenge. In vitro analysis revealed that ZAC-3 hIgA1-containing milk arrested V. cholerae motility in soft agar and liquid media and was effective at promoting bacterial agglutination, possibly accounting for the observed reduction in bacterial colonization in vivo.Conclusions: These results demonstrate that consumption of milk-derived antibodies may serve as a strategy to passively protect against cholera and possibly other enteric pathogens.

Recombinant Human Secretory IgA Induces Salmonella Typhimurium Agglutination and Limits Bacterial Invasion into Gut-Associated Lymphoid Tissues

“… 29 − 31 While there are examples in which passively administered mouse IgA or SIgA has been shown to afford immunity against experimental shigellosis and cholera, the use of human SIgA is only beginning to be explored. 32 − 35 For example, we recently showed in a mouse model of invasive Salmonella infection that Sal4 IgA, an anti-lipopolysaccharide mouse mAb, was sufficient at reducing the invasion of Salmonella enterica serovar Typhimurium (STm) into Peyer’s patch tissues. 36 Sal4 SIgA was superior to Sal4 IgG.…”

“…These unique attributes have garnered interest in SIgA as an alternative or supplement to antibiotic-based therapeutics for enteric diseases. Recent advancements in the generation of recombinant antibodies via multivector mammalian expression systems have enabled the production of SIgA monoclonal antibodies (mAbs). − While there are examples in which passively administered mouse IgA or SIgA has been shown to afford immunity against experimental shigellosis and cholera, the use of human SIgA is only beginning to be explored. − For example, we recently showed in a mouse model of invasive Salmonella infection that Sal4 IgA, an anti-lipopolysaccharide mouse mAb, was sufficient at reducing the invasion of Salmonella enterica serovar Typhimurium (STm) into Peyer’s patch tissues . Sal4 SIgA was superior to Sal4 IgG .…”

A dysbiotic gut microbiome suppresses antibody mediated-protection against Vibrio cholerae

“…During the course of infection, class-switching to IgA and the secretion of antigen-specific secretory IgA (S-IgA) serves as the main means of protection by binding to V. cholerae and preventing pathogen access to epithelium, and neutralizing cholera toxin ( Apter et al., 1993 ). Recent studies have also indicated that anti-O-specific polysaccharide antibodies in sera from humans surviving cholera can agglutinate Vibrio and prevent motility ( Charles et al., 2020 ), and that expression of a monoclonal human anti-LPS IgA1 in mice can provide passive protection to infants from milk ( Baranova et al., 2020 ). For an up-to-date article of cholera immunity, please read Holmgren J, Trop.…”

The prospect of orally administered monoclonal secretory IgA (SIgA) antibodies to prevent enteric bacterial infections

“…76 Alternative strategies such as transgenic animals that express human MAbs including human IgA in colostrum and breast milk are also worthy of investigation, especially considering their track record with other biologics. 77,78 While oral administration of MAbs and MAb cocktails has obvious benefits over intravenous and subcutaneous routes of delivery, the pharmacokinetics and stability of SIgA in the human gastric and intestinal environments remain unknown and need to be taken in consideration. 55,57 Within the context of the gut, the benefit of SIgA over IgG is obvious and is likely due to SIgA glycosylation and resistance to intestinal proteases.…”