There are effective vaccines against multiple extracellular bacterial pathogens, many of which contain surface antigens or toxoids of potent secreted exotoxins. But despite successful preclinical studies and multiple human trials using Staphylococcus aureus surface antigens as vaccine candidates, none have protected humans against S. aureus infections. In 2007, the CDC published that S. aureus is the most significant cause of serious infections in the US, causing skin/soft tissue infections, pneumonia, infective endocarditis, septicemia, osteomyelitis, and toxic shock syndrome (TSS). Thus having an effective vaccine is highly desirable.

In this issue, Pauli et al. provide a potential explanation for why it has been difficult to develop effective immunity against S. aureus. The organism encodes a myriad of virulence factors, one of the best characterized of which is Protein A (SpA). SpA inhibits phagocytosis by binding the Fc of human IgGs and also acts as a B cell superantigen that expands and then ablates variable heavy 3 (VH3) idiotype B cells in mice. Pauli et al. now show that the same SpA-induced expansion of VH3 B cells occurs in humans but without ablation, reminiscent of the differential response of mice versus humans to staphylococcal T cell superantigens.

Humans naturally infected with S. aureus were found to develop skewed antibody responses due to SpA B cell superantigenicity. The active B cell response in these individuals was focused exclusively on SpA, despite the presence of circulating B cells reactive to many other S. aureus surface antigens. The data presented are superb and provide strong evidence for the misdirection of humoral immune responses in many natural S. aureus infections. However, Pauli et al. do not address cases in which S. aureus–specific antibody responses successfully protect against subsequent infection. For example, by age 13, a majority (80%) of females develop high titers of antibodies to exotoxins, such as toxic shock syndrome toxin-1 (TSST-1), and are thus protected from menstrual TSS (mTSS). The remaining 20% who are susceptible do not develop antibodies in response to initial infection. Additionally, intravenous human immunoglobulins (IVIGs), which are pools of antibodies from thousands of healthy human volunteers, contain antibodies against all S. aureus superantigens, such that IVIG is often used as an adjunct therapy for serious S. aureus diseases. These data suggest that the type of S. aureus infection studied in the Pauli et al. manuscript may have influenced the skewing of the immune response to SpA. This could easily be the case if the causative strains were predominantly USA300 S. aureus, which are skin and soft tissue pathogens that do not produce the major recognized T cells superantigens.

The data provided by Pauli et al. may help explain the failure of vaccine efforts, although it remains unclear why this large immune response to SpA is not sufficient for protection. What is less clear is how these data might inform future vaccine design. The authors suggest that neutralizing SpA function through vaccination with a nonsuperantigenic SpA may be required for the generation of a successful vaccine against S. aureus. However, it was recently shown that a vaccine that included a nonsuperantigenic SpA linked with two other surface antigens substantially prolonged survival in mice, but ultimately did not provide protection. One must also consider that in all S. aureus vaccine trials to date, humans were vaccinated against surface antigens. In the absence of SpA, vaccinees developed strong humoral responses to the vaccine antigens, yet none of these trials resulted in protection against subsequent infection, and in at least one trial, vaccinees appeared to be even more susceptible. The latter finding might be explained by the observation that S. aureus aggregates contribute to disease, and aggregation may be facilitated by IgG against surface antigens.

To date, no human trials have used S. aureus toxoids as vaccine antigens, but animal studies suggest that this may be a promising approach. Alternatively, it is possible to produce Fabs of IgG against S. aureus surface antigens, including SpA, coagulases, and clumping factors, and use these to passively prevent potential aggregation-associated diseases.

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J. Exp. Med.