Reply to Kernodle

TO THE EDITOR—We appreciate the thoughtful commentary Dr Kernodle has provided on past and present immunization strategies directed to target the α-hemolysin (α-toxin or Hla) of Staphylococcus aureus. Most important, his commentary highlights the principal challenge that faces the S. aureus vaccine field today—namely, how to translate success with preclinical vaccine candidates into a product that prevents or moderates human disease. This challenge applies not only to antitoxin vaccine efforts but also to other candidate S. aureus immunogens for which substantial preclinical evidence suggests efficacy. Such a challenge must also drive the field to carefully consider experiments of the past in order to best design strategies of the future. It is indeed true that a limited measure of success was achieved with anti-α-toxin therapies in the early to mid-20th century, leading to an abandonment of these strategies. Although these early clinical trials provide a glimpse of the potential for anti–α-toxin immunotherapy, it is essential to evaluate these trials in light of our current understanding of S. aureus disease. These studies were conducted on relatively small numbers of patients with furuncles, and even smaller numbers of patients with other types of S. aureus infection, including bacteremia, osteomyelitis, meningitis, and empyema. To date, the biological significance of S. aureus α-toxin in the manifestations of these syndromes is not clearly defined. Indeed, antitoxin-based therapy was initially pursued for treatment of furunculosis after “treatment by dead bacteria” was unsuccessful, thus prompting investigators to consider the successes of antitoxin strategies against diphtheria and tetanus [1]. It is important to recall that antitoxin antibodies primarily function to mitigate host tissue damage in the context of S. aureus infection. As such, they do not necessarily reduce the bacterial burden in the host. Parish and Cannon, in their 1960 commentary on antitoxin therapy, stated that antitoxin afforded protection “without disposing of all of the invaders” [2]. In our investigation of S. aureus pneumonia, live staphylococci were recovered in significant numbers from the lungs of immunized, infected animals, albeit in reduced numbers relative to sham-immunized controls [3]. Similarly, immunization in the skin-abscess model does not preclude abscess formation; however, it most potently prevents dermonecrotic skin injury [4]. These examples illustrate that antitoxin vaccines and immunotherapies target very specific facets of the disease process. In the lung and superficial epidermis, α-toxin–mediated injury may constitute the primary pathophysiology of disease, thus rendering a greater measure of success from this strategy than would be apparent for other S. aureus infections. Antitoxin based strategies necessitate a concomitant strategy (eg, antibiotic therapy) to eradicate the pathogen to achieve sterilizing immunity. By reducing tissue injury, anti–α-toxin antibodies may tip the scale in favor of native host immunologic clearance; alternatively, these antibodies may be most successful in the context of a multicomponent vaccine formulation that simultaneously combat other aspects of pathogen survival. Although our understanding of S. aureus disease pathogenesis has advanced to an appreciation of molecular details relative to that of the early to mid-20th century, we, as our predecessors, remain impaired by a lack of understanding of the host immunologic response to staphylococcal infection. In particular, it is not known what constitutes protective immunity against S. aureus infection. It is also not clear whether immunity to one manifestation of S. aureus infection predicts immunity against others. A number of studies have documented antibody responses to α-toxin and other S. aureus virulence factors in humans [5–11]. However, large prospective clinical trials will need to be conducted to understand the relevance of these responses to protection against staphylococcal infection. Until we are armed with this knowledge, the development of vaccines and immunotherapies targeting S. aureus will be predicated on the success of preclinical studies in animal models of disease and the presumption that these observations will translate to humans. The demands placed on an S. aureus vaccine are high—it must afford protection against a wide spectrum of disease, both for organ-system involvement and severity of disease. Protection must be achieved on the backdrop of a human population for which we do not currently know the correlates of protective immunity and, furthermore, who already have preformed immunologic responses to S. aureus. It is, thus, incumbent on the current generation of physicians and scientists to learn from the historic trials of S. aureus vaccination and immunotherapy, provide greater mechanistic detail of the pathogenesis of S. aureus infection, and conduct rigorous clinical studies to better understand the human response to S. aureus infection. The knowledge gained from these pursuits will enable the most critical appraisal of current preclinical investigations and lay a foundation to design a vaccine that will “provide clearer benefit in reducing the morbidity and mortality of S. aureus infection” [12].