Arming against MRSA

National report - A potential vaccine against Staphylococcus aureus has shown promise in a murine model, and researchers believe there is reason for optimism that the concept will translate to human trials.

The quadrivalent vaccine construct afforded broad protection against five challenge strains of Staphylococcus aureus, which has an uncanny ability to develop resistance to drugs used against it, either through mutation or through acquisition of genetic elements from other bacteria. Methicillin-resistant S. aureus (MRSA) is a growing community health problem in the United States.

Researchers believe vaccination may be a useful strategy to rein in the deadly pathogen.

Previous attempts to develop a vaccine against MRSA used killed, live attenuated or subunits of the bacterium to generate an immune response. But they failed to provide much protection. Dr. Schneewind believes it is because they did not recognize the specific cell surface proteins that are responsible for MRSA's virulence.

Dr. Schneewind and his colleagues turned to reverse vaccinology. They combed through the genome of eight deadly variants of S. aureus to identify a list of 19 cell surface proteins that are conserved across all of the strains. They evaluated each protein individually in a murine model and selected four that generated the strongest immune response for further evaluation.

Two of the proteins, IsdA and IsdB, are involved with the bacteria's acquisition of needed iron form host blood cells, while the other two, SdrD and SdrE, are associated with bacterial adhesion to host tissue.

Antibodies to the four proteins were generated in rabbits and analyzed in vitro in the presence of human polymorphonuclear leukocytes and staphylococci. Each induced significant levels of opsonophagocytosis.

Next the four antigens were individually injected into mice to generate antibodies and the animals were later challenged with a dose of S. aureus sufficient to kill half of them. Individually the antigens offered little or no protection, but when the four were combined in a single inoculation, all of the animals survived.

Unvaccinated mice had clear evidence of kidney infection, but the bacterial load of vaccinated mice was below the level of detection, Dr. Schneewind tells Dermatology Times.

Mice inoculated with the quadrivalent vaccine construct were then challenged with five different strains of MRSA, including the now ubiquitous and virulent USA400 strain of CA-MRSA. The vaccine completely protected against two strains and offered 60 percent to 90 percent survival against the other three strains.

For example, all of the unvaccinated mice challenged with the common hospital-acquired USA100 strain of MRSA died within 36 hours, but 60 percent of the vaccinated mice survived.

Immune responses similar

Dr. Schneewind says, "The mechanisms and the molecules of the murine innate immune response closely resemble those of humans. And murine MRSA recapitulates all of the elements of the disease that are seen in humans."

Furthermore, three of the four antigens used in the vaccine are known to be immunogenic in humans. So he is optimistic that the principle of vaccination that was demonstrated in mice will translate to humans.

However, there are some reports that S. aureus, which is essentially a human pathogen and is not commonly found in other hosts, has acquired some means of escape from human immune responses. That will have to be carefully evaluated in humans.

Dr. Schneewind foresees many potential uses for a vaccine against MRSA, ranging from prophylactic use in advance of surgery to the vaccine becoming part of the standard repertoire of childhood immunizations for protection against CA-MRSA. Contemplating such use will depend upon first demonstrating a proof of principle in humans, then gaining a better understanding of the mechanisms of protection, and the level and durability of antibody titers required for protection.

Dr. Schneewind has had discussions with companies about moving the research into human trials, and those companies are evaluating how that might fit into their overall research portfolios.