Researchers from the University of Texas at Austin and Synthetic Biologics Inc. have produced humanized monoclonal antibodies that bound pertussis toxin and prevented or mitigated whooping cough in mice and baboons by binding to its major toxin.

The findings, which the team published in the Dec. 2, 2015, issue of Science Translational Medicine, provide the rationale for further preclinical studies of the antibody mix, in particular for a direct comparison of the two methods that hold the most promise in reducing infant deaths – maternal immunization and administering antibodies to the neonates themselves.

In the developing world, pertussis is a serious problem for newborns. The World Health Organization lists it, along with measles, polio, diphtheria and tetanus, among the most deadly childhood diseases in its fact sheet on reducing child mortality. Between 150,000 and 200,000 children die from pertussis every year.

Whooping cough, or pertussis, is on the rise in the U.S. as well. Vaccine skepticism is part of the problem, but not the bigger part.

There are "definitely pockets in California, Oregon and Washington where that does become an issue," corresponding author Jennifer Maynard, who is an associate professor of chemical engineering at the University of Texas at Austin, told BioWorld Today.

But the larger issue is that the current form of the vaccine confers protection for only a few years.

The other issue is that infants do not get their first regular pertussis vaccination until they are 2 months old – at which point a good part of the six-month high-risk period in which the vast majority of deaths occur.

Pertussis can be a serious problem, and quite painful, beyond those six months. But it is very unlikely to kill those who become infected.

That also means, however, that even protection that is effective for only a short time period can make a big difference, if it is present during the right short time period.

One of the options being explored is the vaccination of pregnant mothers. Another possibility would be to administer antibodies at birth – in the developing world, "the only time in their life that many of these kids will see a doctor," co-corresponding author and Synthetic Biologics' senior vice president of research and development, Michael Kaleko, told BioWorld Today.

In the experiments, the team tested two humanized mouse monoclonal antibodies, murine 1B7 (m1B7) and 11E6 (m11E6), that have been highly validated in vitro and in animal models as being protective in pertussis infection. Both bind to pertussis toxin, which is thought to be the most important of the multiple virulence factors produced by Bordella pertussis.

The team first tested the antibodies prophylactically in mice, both separately and together.

Kaleko said that even when either antibody was given alone, "the mice did much better," and when both were given together, the animals showed neither weight loss nor the rise in white blood cell counts that is a key symptom of pertussis.

The team next tested whether the antibodies could be useful for treatment as well as prevention of infection. Such treatment might be possible either on its own or in conjunction with antibiotics, since "sometimes children continue to go downhill" even after antibiotics have killed the bacteria – a phenomenon that is likely due to the presence of residual toxin.

The team first infected baboons, which serve as the best model system for pertussis with protocols developed in recent years. After three days, when white blood cell counts are half to two-thirds of the way to their maximal value, the team intravenously treated the animals with a combination of both antibodies.

With such treatment, Kaleko said, the white blood cell elevation was "virtually immediately blunted."

Treatment also accelerated bacterial clearance, though the antibodies do not directly target the bacteria. Kaleko said pertussis toxin impairs the innate immune system, and by neutralizing the toxin, "we believe we re-establish good immune function."

The team next hopes to test their antibodies on neonatal baboons, and to directly compare the protection that can be achieved through prophylactic administration of antibodies to that achieved by maternal immunization. The results of those studies, Maynard said, "will give us our go-no go decision."

The team also plans to look at whether prophylactic administration of antibodies has any effect on the efficacy of vaccination at a later time.

Synthetic Biologics has undergone several transformations. Founded in 2001 as Adeona Therapeutics Inc., the company changed its name and its focus in 2011. Currently, its "primary focus is on therapies that protect the gut microbiome," Chief Financial Officer Steven Shallcross told BioWorld Today.

The company also presented top-line results from its phase IIa trial of SYN-004, which aims to prevent Clostridium difficile infection by selectively deactivating beta-lactam antibiotics in the gut while leaving blood levels and activity unaffected. In the randomized, open-label trial of 10 healthy ileostomized patients, treatment with either 75 mg or 150 mg of SYN-004 after intravenous treatment with the beta-lactam antibiotic ceftriaxone degraded that antibiotic in the digestive fluid of the small intestine, or chyme, without affecting the intended level of ceftriaxone in the bloodstream.