Vaccines targeting Staphylococcus aureus skin and bloodstream infections require different composition

Abstract

Staphylococcus aureus infections represent a major public health threat, but previous attempts at developing a universal vaccine have been unsuccessful. We attempted to identify a vaccine that would be protective against both skin/soft tissue and bloodstream infections. We first tested a panel of staphylococcal antigens that are conserved across strains, combined with aluminum hydroxide as an adjuvant, for their ability to induce protective immunity in both skin and bacteremia infection models. Antigens were identified that reduced dermonecrosis during skin infection, and other non-overlapping antigens were identified that showed trends to protection in the bacteremia model. However, individual antigens were not identified that mediated substantial protection in both the skin and bacteremia infection models. We therefore tested a variety of combinations of proteins to seek a single combination that could mediate protection in both models. After iterative testing, a vaccine consisting of 3 antigens, ABC transporter protein (SACOL2451), ABC2 transporter protein (SACOL0695), and α-hemolysin (SACOL1173), was identified as the most effective combination. This combination vaccine provided protection in a skin infection model. However, these antigens were only partially protective in the bacteremia infection model. Even by testing multiple different adjuvants, optimized efficacy in the skin infection model did not translate into efficacy in the bacteremia model. Thus protective vaccines against skin/soft tissue infections may not enable effective protection against bloodstream infections.

Protective efficacy of Alum adjuvanted Amidase protein vaccine against Staphylococcus aureus infection in multiple mouse models

“…Our results demonstrated the high efficacy of AM–hkSA–Al vaccine in peritonitis and kidney abscess models of infection. However, a careful observation by Luna et al noted that the protective efficacy displayed by an antigenic protein that is immunogenic in an infection model had little or no effect in other models of infection (Luna et al, 2019). Hence, we conclude that further studies in different models of infections are required to substantiate the efficacy of AM–hkSA–Al combination vaccine against staphylococcal infections.…”

Convergent Evolution of Neutralizing Antibodies to Staphylococcus aureus γ-Hemolysin C That Recognize an Immunodominant Primary Sequence-Dependent B-Cell Epitope

“…All efforts to develop a protective vaccine have failed to date, and it can also be argued that single-component vaccines may be inadequate to overcome the multitiered assault associated with S. aureus invasive infection. Indeed, the prevention of different staphylococcal clinical infections may require vaccines incorporating different antigens, such as for bacteremia or SSTIs (30,31), and pairing with an adjuvant that induces a Th1-biased or Th17-biased response may further enhance host protection (32,33). Our studies provide further validation of newly developed tools that should be widely applicable for the evaluation of the "fitness" of potential vaccine components of an antistaphylococcal antibody response for recognition of neutralization-associated epitopes.…”

Targeting Skin-Resident Memory T Cells via Vaccination to Combat Staphylococcus aureus Infections

“…Nevertheless, indirect evidence for resident immunity is apparent in previously published studies. First, numerous reports in both in vivo mouse and ex vivo human models have revealed that the immune response during S. aureus SSTIs and bloodstream infections is distinct, suggestive of tissue-specific mediators acting during such infections [36][37][38]. Second, enhanced protection during secondary murine skin infection is most pronounced at the exact site of primary infection, confirming that mediators of immunity to S. aureus are not solely circulatory [10,39].…”