NIAID-Funded Adjuvant Improves Typhoid Vaccine Candidate in Animal Studies

NIAID Now | August 17, 2022

S. Typhi shown under a microscope

Salmonella enterica serovar Typhi shown under a microscope with flagellar stain.

Credit: Microbewriter, CC BY-SA 4.0

An investigational typhoid vaccine containing a component developed with NIAID funding may overcome some of the shortcomings of available typhoid vaccines, according to a paper published in the journal Vaccine in June.

Typhoid fever sickens 11 million to 21 million people worldwide every year and causes an estimated 200,000 deaths, according to the World Health Organization. The bacterium Salmonella enterica serovar Typhi causes the disease, transmitted primarily through contaminated food and water. Vaccination is the most effective way to reduce illness and death from typhoid fever in many developing countries because S. Typhi has become resistant to widely available oral antibiotics. Although several kinds of typhoid vaccines are available, one that is inexpensive and easy to manufacture and that provides robust and durable protection for people of all ages—especially very young children—remains elusive.

Many bacteria, including S. Typhi, have a protective outer layer made of carbohydrates that presents challenges for vaccine development. Antibodies against the carbohydrates that compose this layer—called the bacterial capsular polysaccharide, or CPS—protect people from disease. But vaccines that present purified bacterial carbohydrates to the immune system don’t induce an effective antibody response in infants and children because they don’t activate a type of immune cell called T-helper cells. If the bacterial carbohydrate is covalently linked to a protein in the vaccine, however, this combination engages both B cells and T-helper cells in young children, producing carbohydrate-specific antibodies that are more plentiful and durable. Such vaccines for typhoid fever are available and highly effective, but the chemical processes of attaching the carbohydrate to a protein make these vaccines difficult and expensive to manufacture, impeding their widespread use.

Matrivax Corporation in Boston found a way around this problem by developing a vaccine called Typhax that entraps S. Typhi carbohydrate inside a protein cage instead of covalently attaching the carbohydrate to a protein. Manufacturing this encaged carbohydrate is easier, and thus potentially less expensive, than manufacturing a protein-bonded carbohydrate.

With the cost issue potentially addressed, a new challenge arose when Typhax was tested in people. In a small, early-stage trial of Typhax formulated with alum, a commonly used adjuvant (a substance designed to boost immune responses), the first shot participants received generated a strong antibody response to S. Typhi, but a booster shot failed to further elevate antibody levels. The researchers determined that this was the result of a phenomenon called polysaccharide-induced immune inhibition. (Polysaccharide is another term for carbohydrate.)

When a vaccine uses a protein to generate an immune response, the response usually gets stronger after a booster shot. When a vaccine uses a carbohydrate, however, the response after a booster may diminish instead. This polysaccharide-induced immune inhibition happens because antibody-producing B cells can get overwhelmed when processing too much carbohydrate and consequently hit the brakes.

To try to overcome this problem, researchers reformulated Typhax with an adjuvant called Advax-CpG, which was created through NIAID’s Adjuvant Discovery Program by a company called Vaxine Pty Ltd. of Adelaide, Australia. When tested in mice, rabbits and monkeys, this version of the vaccine triggered a sequence of events that ultimately helped B cells generate a better antibody response to S. Typhi than the alum-adjuvanted version did. In addition, even though the carbohydrate in the vaccine was not physically attached to a protein, it still activated T-helper cells. Consequently, Advax-CpG adjuvanted Typhax elicited high and sustained levels of anti-S. Typhi antibodies in animals that rose higher after a booster shot. Importantly, the vaccine also induced high levels of S. Typhi-killing activity in the blood.

Plans for a an early-stage clinical trial of Advax-CpG adjuvanted Typhax in Australia are underway.

Reference: Y Honda-Okubo, et al. A typhoid fever protein capsular matrix vaccine candidate formulated with Advax-CpG adjuvant induces a robust and durable anti-typhoid Vi polysaccharide antibody response in mice, rabbits and nonhuman primates. Vaccine DOI: 10.1016/j.vaccine.2022.06.043 (2022).

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