Multivalent Toxoid Vaccine for recurrent Staphylococccus aureus disease

Project Summary
Staphylococcus aureus (S. aureus; SA) is a major public health threat causing a variety of diseases from the
skin and soft tissue infections (SSTI), comprising over 90% of infections, to invasive and life-threatening
infections, the major cause of SA mortality. The problem is further exacerbated by growing antibiotic resistance
and a lack of a vaccine. SA has a remarkable ability to evade and manipulate immune responses through a
range of virulence factors, including a plethora of toxins, mainly the pore-forming toxins (PFTs) and
superantigens (SAgs). Several SA surface antigen vaccines were tested in human efficacy trials and all have
failed. There is a profound knowledge gap about the nature of a protective immune response to SA infection. In
the past 10-15 years, we have learned that using staphylococcal surface antigens to enhance opsonophagocytic
clearance is not a viable strategy against SA, and response to cell-associated antigens can trigger deleterious
immune responses. Antitoxin antibodies and an effective T cell response are critical for protection against SA
infection. Neutralizing antibodies against key SA toxins, primarily PFTs, and SAgs, correlate with better clinical
outcomes. Under the prior R01 preceding this renewal application, we developed a multi-component vaccine,
IBT-V02, and demonstrated its efficacy in multiple models including primary and recurrent SSTI. IBT-V02
received further funding from CARB-X and a VC firm for advanced development and is now scheduled to enter
Phase 1 clinical trial in 2022. We intend to evaluate the efficacy of the vaccine against recurrent SSTI in a follow-
on Phase 2/3 trial in patients presenting with a primary SA-SSTI. In the current renewal application, we will test
the hypothesis, in humans, that neutralizing PFTs and SAgs reduce the rate of recurrent SA-SSTI by protecting
tissues, innate immune cells, and T cells from the cytolytic and immune-modulatory effects of these toxins. In
Aim 1, we will conduct a clinical study at Olive View-UCLA emergency Department with longitudinal sampling of
patients presenting with SA-SSTI over a one-year period with monitoring for possible recurrence. This study will
provide an accurate estimate of the rate of recurrence with a tightly defined case definition and, for the first time,
provide longitudinal microbiological and immunological samples during and after a primary infection through the
time of recurrence. In Aim 2, the bacterial isolates and longitudinal immunological samples will be characterized,
and the relationship between immunological markers and probability of recurrence will be analyzed by state-of-
the-art statistical methodologies. In Aim 3, using humanized mouse models and cytokine reporter mice, we will
test the hypothesis that neutralization of PFTs and SAgs will enable the host to mount effective Th17 and γδ T
cell responses. A highly experienced team of vaccine development experts, clinicians, and immunologists with
decades of experience with SA and biostatistics experts with an extensive track record has been assembled to
address these questions. The result of this study will elevate our understanding of basic immunology of
staphylococcal infections and also inform clinical development of urgently needed vaccines for this pathogen.

Grant Number: 5R01AI111205-10
NIH Institute/Center: NIH
Principal Investigator: M Aman