The Shigella outbreak that began in December 2022 at the Wisconsin National Primate Research Center provided researchers with valuable immune data for vaccine development. In the study published in Science Translational Medicine, scientists examined data obtained from infected nonhuman primates to identify effective immune responses against the bacterium and potential vaccine targets.
The outbreak involved 169 microbiologically confirmed cases of shigellosis among nonhuman primates. The researchers collected 151 Shigella isolates for serotyping and performed whole-genome sequencing of 95 representative isolates. The outbreak was caused by two related clusters of Shigella flexneri, which is common among captive primates. Although Shigella sonnei is more commonly responsible for human outbreaks, both species can infect both primate groups. Of the 90 isolates tested for antimicrobial resistance, 63% were multidrug-resistant. While most cases caused mild diarrhea, some animals showed no symptoms, and severe disease developed in some cases; infants were the most affected group.
The scientists collected serum, plasma and immune cells from 41 infected animals during the course of infection. The samples were collected 1, 2 and 4 to 6 weeks after the infection was identified. The analyses found antibodies targeting the O-antigen, the outer component of the LPS molecule on the bacterium’s outer surface. Some antibodies were found to develop through repeated exposure and to be capable of attacking the O-antigens of different Shigella serotypes. Antibodies that bound strongly to the O-antigen could also trigger chains of plasma proteins that break down bacteria.
The researchers also examined antibodies targeting the IpaB and IpaD proteins at the tip of the needle-like type 3 secretion system (T3SS) that the bacterium uses to attack cells. These antibodies were able to stimulate protective immune responses, including T cells. While some antibodies facilitated the breakdown of blood cells, the beneficial ones prevented it. It was reported that the two types of antibodies bind to different regions of the proteins and that the exact binding site of the protective antibodies was identified. The findings offer new targets for designing a vaccine effective against different Shigella species.
Why it matters
The study’s main contribution is showing that immunity against Shigella is not merely a general response resulting from having an infection, but can be studied through antibodies that target different parts of the bacterium and have distinct functions. The ability of antibodies that recognize the O-antigen to be effective against different serotypes offers a framework for understanding how the diversity among species could be overcome in vaccine design. Identifying the specific regions targeted by protective antibodies binding to T3SS proteins narrows down the question of which immune responses candidate vaccines should stimulate. However, the outbreak, in which multidrug resistance is widespread and severe disease can occur particularly in infants, also highlights the limited treatment options beyond vaccination. How the findings will translate into a vaccine that provides protection in humans remains unclear.